FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hadler, NM AF Hadler, Nortin M. BA Hadler, NM BF Hadler, NM TI THE AGED WORKER SO RETHINKING AGING: GROWING OLD AND LIVING WELL IN AN OVERTREATED SOCIETY LA English DT Article; Book Chapter C1 [Hadler, Nortin M.] Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. [Hadler, Nortin M.] Clin Res Ctr London, London, England. [Hadler, Nortin M.] Univ N Carolina, Chapel Hill, NC 27515 USA. RP Hadler, NM (reprint author), Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV NORTH CAROLINA PRESS PI CHAPEL HILL PA BOX 2288, CHAPEL HILL, NC 27514 USA BN 978-0-80786-923-9 PY 2011 BP 89 EP 108 PG 20 WC Gerontology SC Geriatrics & Gerontology GA BWK03 UT WOS:000294057200005 ER PT J AU Hadler, NM AF Hadler, Nortin M. BA Hadler, NM BF Hadler, NM TI DECREPITUDE SO RETHINKING AGING: GROWING OLD AND LIVING WELL IN AN OVERTREATED SOCIETY LA English DT Article; Book Chapter C1 [Hadler, Nortin M.] Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. [Hadler, Nortin M.] Clin Res Ctr London, London, England. [Hadler, Nortin M.] Univ N Carolina, Chapel Hill, NC 27515 USA. RP Hadler, NM (reprint author), Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV NORTH CAROLINA PRESS PI CHAPEL HILL PA BOX 2288, CHAPEL HILL, NC 27514 USA BN 978-0-80786-923-9 PY 2011 BP 109 EP 157 PG 49 WC Gerontology SC Geriatrics & Gerontology GA BWK03 UT WOS:000294057200006 ER PT J AU Hadler, NM AF Hadler, Nortin M. BA Hadler, NM BF Hadler, NM TI FRAILTY SO RETHINKING AGING: GROWING OLD AND LIVING WELL IN AN OVERTREATED SOCIETY LA English DT Article; Book Chapter C1 [Hadler, Nortin M.] Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. [Hadler, Nortin M.] Clin Res Ctr London, London, England. [Hadler, Nortin M.] Univ N Carolina, Chapel Hill, NC 27515 USA. RP Hadler, NM (reprint author), Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV NORTH CAROLINA PRESS PI CHAPEL HILL PA BOX 2288, CHAPEL HILL, NC 27514 USA BN 978-0-80786-923-9 PY 2011 BP 159 EP 174 PG 16 WC Gerontology SC Geriatrics & Gerontology GA BWK03 UT WOS:000294057200007 ER PT J AU Hadler, NM AF Hadler, Nortin M. BA Hadler, NM BF Hadler, NM TI THE REAPER SO RETHINKING AGING: GROWING OLD AND LIVING WELL IN AN OVERTREATED SOCIETY LA English DT Article; Book Chapter C1 [Hadler, Nortin M.] Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. [Hadler, Nortin M.] Clin Res Ctr London, London, England. [Hadler, Nortin M.] Univ N Carolina, Chapel Hill, NC 27515 USA. RP Hadler, NM (reprint author), Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV NORTH CAROLINA PRESS PI CHAPEL HILL PA BOX 2288, CHAPEL HILL, NC 27514 USA BN 978-0-80786-923-9 PY 2011 BP 175 EP 194 PG 20 WC Gerontology SC Geriatrics & Gerontology GA BWK03 UT WOS:000294057200008 ER PT J AU Hadler, NM AF Hadler, Nortin M. BA Hadler, NM BF Hadler, NM TI AUTUMN SO RETHINKING AGING: GROWING OLD AND LIVING WELL IN AN OVERTREATED SOCIETY LA English DT Article; Book Chapter C1 [Hadler, Nortin M.] Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. [Hadler, Nortin M.] Clin Res Ctr London, London, England. [Hadler, Nortin M.] Univ N Carolina, Chapel Hill, NC 27515 USA. RP Hadler, NM (reprint author), Massachusetts Gen Hosp, NIH, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV NORTH CAROLINA PRESS PI CHAPEL HILL PA BOX 2288, CHAPEL HILL, NC 27514 USA BN 978-0-80786-923-9 PY 2011 BP 195 EP 200 PG 6 WC Gerontology SC Geriatrics & Gerontology GA BWK03 UT WOS:000294057200009 ER PT J AU Rasmussen, A Sevier, S Kelly, JA Glenn, SB Aberle, T Cooney, CM Grether, A James, E Ning, J Tesiram, J Morrisey, J Powe, T Drexel, M Daniel, W Namjou, B Ojwang, JO Nguyen, KL Cavett, JW Te, JL James, JA Scofield, RH Moser, K Gilkeson, GS Kamen, DL Carson, CW Quintero-del-Rio, AI Ballesteros, MD Punaro, MG Karp, DR Wallace, DJ Weisman, M Merrill, JT Rivera, R Petri, MA Albert, DA Espinoza, LR Utset, TO Shaver, TS Arthur, E Anaya, JM Bruner, GR Harley, JB AF Rasmussen, Astrid Sevier, Sydney Kelly, Jennifer A. Glenn, Stuart B. Aberle, Teresa Cooney, Carisa M. Grether, Anya James, Ellen Ning, Jared Tesiram, Joanne Morrisey, Jean Powe, Tiny Drexel, Mark Daniel, Wes Namjou, Bahram Ojwang, Joshua O. Nguyen, Kim L. Cavett, Joshua W. Te, Jeannie L. James, Judith A. Scofield, R. Hal Moser, Kathy Gilkeson, Gary S. Kamen, Diane L. Carson, Craig W. Quintero-del-Rio, Ana I. Ballesteros, Maria del Carmen Punaro, Marilynn G. Karp, David R. Wallace, Daniel J. Weisman, Michael Merrill, Joan T. Rivera, Roberto Petri, Michelle A. Albert, Daniel A. Espinoza, Luis R. Utset, Tammy O. Shaver, Timothy S. Arthur, Eugene Anaya, Juan-Manuel Bruner, Gail R. Harley, John B. TI The Lupus Family Registry and Repository SO RHEUMATOLOGY LA English DT Review DE Systemic lupus erythematosus; Registry; Repository; Autoimmune diseases; Genetics; Heritability; Genome-wide association studies; Linkage analysis; Minorities; Women ID HONG-KONG CHINESE; GENOME-WIDE ASSOCIATION; COPY-NUMBER VARIATION; DISEASE SUSCEPTIBILITY; RHEUMATOID-ARTHRITIS; ERYTHEMATOSUS SLE; FUNCTIONAL VARIANTS; AMERICAN FAMILIES; REVISED CRITERIA; GENETIC-VARIANTS AB The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR's effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE. C1 [Rasmussen, Astrid; Sevier, Sydney; Kelly, Jennifer A.; Glenn, Stuart B.; Aberle, Teresa; Grether, Anya; James, Ellen; Ning, Jared; Tesiram, Joanne; Morrisey, Jean; Powe, Tiny; Drexel, Mark; Daniel, Wes; Namjou, Bahram; Ojwang, Joshua O.; Nguyen, Kim L.; Cavett, Joshua W.; Te, Jeannie L.; Scofield, R. Hal; Moser, Kathy; Bruner, Gail R.; Harley, John B.] Oklahoma Med Res Fdn, Arthrit & Immunol Res Program, Oklahoma City, OK 73104 USA. [Sevier, Sydney; James, Judith A.; Scofield, R. Hal; Harley, John B.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Cooney, Carisa M.] So Illinois Univ, Sch Med, Div Plast & Reconstruct Surg, Springfield, IL USA. [James, Judith A.] Oklahoma Med Res Fdn, Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Scofield, R. Hal; Harley, John B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Gilkeson, Gary S.; Kamen, Diane L.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Carson, Craig W.] Oklahoma Arthrit Ctr, Edmond, OK USA. [Quintero-del-Rio, Ana I.; Ballesteros, Maria del Carmen] Ponce Sch Med, Div Genet, Dept Biochem, Ponce, PR USA. [Quintero-del-Rio, Ana I.; Ballesteros, Maria del Carmen] Univ Cent Caribe, Dept Pediat, Bayamon, PR USA. [Punaro, Marilynn G.] Texas Scottish Rite Hosp Children, Pediat Rheumatol Serv, Dallas, TX 75219 USA. [Punaro, Marilynn G.; Karp, David R.] Univ Texas SW Med Ctr Dallas, Div Rheumat Dis, Dallas, TX 75390 USA. [Weisman, Michael] Cedars Sinai Med Ctr, Div Rheumatol, W Hollywood, CA USA. [Merrill, Joan T.] Oklahoma Med Res Fdn, Clin Pharmacol Res Program, Oklahoma City, OK 73104 USA. [Rivera, Roberto] Hosp Dr Susoni, Arecibo, PR USA. [Petri, Michelle A.] Johns Hopkins Univ, Dept Med, Div Rheumatol, Baltimore, MD USA. [Albert, Daniel A.] Dartmouth Hitchcock Med Ctr, Div Rheumatol, Lebanon, NH 03766 USA. [Espinoza, Luis R.] Louisiana State Univ, Hlth Sci Ctr, Sch Med, Rheumatol Sect, New Orleans, LA USA. [Utset, Tammy O.] Univ Chicago, Pritzker Sch Med, Rheumatol Sect, Chicago, IL 60637 USA. [Shaver, Timothy S.] Arthrit & Rheumatol Clin Kansas, Wichita, KS USA. [Arthur, Eugene] McBride Clin, Oklahoma City, OK USA. [Anaya, Juan-Manuel] Univ Rosario, Sch Med & Hlth Sci, Ctr Autoimmune Dis Res, Bogota, Colombia. RP Harley, JB (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Rheumatol, MLC 4010,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM john.harley@cchmc.org RI Anaya, Juan-Manuel/J-1960-2016 OI Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Anaya, Juan-Manuel/0000-0002-6444-1249 FU National Institutes of Health [R37AI24717, R01AR42460, P20RR020743, R01AR053734, P01AR049084, P20AR04 6669, RC1AR058554, R01AR043274]; National Institute of Arthritis, Musculoskeletal and Skin Diseases [N01AR62277]; South Carolina Clinical & Translational Research Institute; Medical University of South Carolina's Clinical and Translational Science Award (CTSA); National Institutes of Health/National Center for Research Resources [UL1RR029882]; Board of Regents of the State of Louisiana FX This work was supported by the National Institutes of Health, mainly from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (N01AR62277) with important contributions from additional grants from the National Institutes of Health (R37AI24717, R01AR42460, P20RR020743, R01AR053734, P01AR049084, P20AR04 6669, RC1AR058554 and R01AR043274). G. S. G. and D. L. K. were supported by the South Carolina Clinical & Translational Research Institute, Medical University of South Carolina's Clinical and Translational Science Award (CTSA) and National Institutes of Health/National Center for Research Resources (UL1RR029882). L. R. E. was funded by the Board of Regents of the State of Louisiana. NR 65 TC 30 Z9 31 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JAN PY 2011 VL 50 IS 1 BP 47 EP 59 DI 10.1093/rheumatology/keq302 PG 13 WC Rheumatology SC Rheumatology GA 692ZD UT WOS:000285193500008 PM 20864496 ER PT J AU Mikuls, TR Fay, BT Michaud, K Sayles, H Thiele, GM Caplan, L Johnson, D Richards, JS Kerr, GS Cannon, GW Reimold, A AF Mikuls, Ted R. Fay, Brian T. Michaud, Kaleb Sayles, Harlan Thiele, Geoffrey M. Caplan, Liron Johnson, Dannette Richards, John S. Kerr, Gail S. Cannon, Grant W. Reimold, Andreas TI Associations of disease activity and treatments with mortality in men with rheumatoid arthritis: results from the VARA registry SO RHEUMATOLOGY LA English DT Article DE Rheumatoid arthritis; Mortality; US veterans; Men; MTX; Glucocorticoids ID CARDIOVASCULAR-DISEASE; VIETNAM VETERANS; EXCESS MORTALITY; COHORT; METHOTREXATE; OUTCOMES; MANIFESTATIONS; POPULATION; PREDICTORS; MORBIDITY AB Methods. Men with RA were enrolled and followed until death or censoring. Vital status was ascertained through systematic record review and standardized mortality ratios (SMRs) were calculated using US life tables for men. Multivariate Cox proportional hazards regression was used to examine the independent associations of patient factors including socio-demographics, comorbidity, measures of RA disease activity/severity and medication use with mortality. Measures of RA disease activity and medications were examined as time-varying factors. Results. A total of 138 deaths were observed during 2314 patient-years of follow-up (n = 1015 patients), corresponding to a crude morality rate of 5.9 deaths per 100 patient-years (95% CI 5.0, 7.0) and an SMR of 2.1 (95% CI 1.8, 2.5). After multivariate adjustment, factors independently associated with higher mortality risk in men with RA included older age, Caucasian race, low body weight, an increased frequency of rheumatology visits, higher ESR and RF concentrations, increased DAS28, subcutaneous nodules and prednisone use. In contrast, MTX use [hazard ratio (HR) 0.63; 95% CI 0.42, 0.96] was associated with similar to 40% lower mortality risk. Conclusion. Mortality rates among US male veterans with RA are more than twice those of age-matched men in the general population. These results suggest that optimizing disease control, particularly with regimens that include MTX and minimize glucocorticoid exposure, could improve long-term survival in this population. C1 [Mikuls, Ted R.; Fay, Brian T.; Michaud, Kaleb; Sayles, Harlan; Thiele, Geoffrey M.] Univ Nebraska, Med Ctr, Omaha Vet Affairs Med Ctr, Dept Med, Omaha, NE 68198 USA. [Mikuls, Ted R.; Fay, Brian T.; Michaud, Kaleb; Sayles, Harlan; Thiele, Geoffrey M.] Univ Nebraska, Med Ctr, Nebraska Arthrit Outcomes Res Ctr, Omaha, NE 68198 USA. [Caplan, Liron] Univ Colorado, Denver, CO 80202 USA. [Caplan, Liron] Denver VAMC, Dept Res, Denver, CO USA. [Johnson, Dannette] Jackson VAMC, Dept Med, Jackson, MS USA. [Johnson, Dannette] Univ Mississippi, Jackson, MS 39216 USA. [Richards, John S.; Kerr, Gail S.] DC VAMC, Dept Med, Washington, DC USA. [Richards, John S.; Kerr, Gail S.] Georgetown Univ, Washington, DC USA. [Cannon, Grant W.] George E Wahlin VAMC, Dept Med, Salt Lake City, UT USA. [Cannon, Grant W.] Univ Utah, Salt Lake City, UT USA. [Reimold, Andreas] Dallas VAMC, Dept Med, Dallas, TX USA. [Reimold, Andreas] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Mikuls, TR (reprint author), Univ Nebraska, Med Ctr, Omaha Vet Affairs Med Ctr, Dept Med, 986270 Nebraska Med Ctr, Omaha, NE 68198 USA. EM tmikuls@unmc.edu OI Thiele, Geoffrey/0000-0001-5688-8596 FU Veterans Health Administration (VHA); Abbott Laboratories; Bristol-Myers Squibb; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K23 AR050004, R03 AR054539]; VHA (VA Merit); VA HSR&D Career Development Award [CDP 09-388] FX The VARA Registry has received research support from the Health Services Research & Development (HSR&D) Program of the Veterans Health Administration (VHA) in addition to unrestricted research funds from Abbott Laboratories and Bristol-Myers Squibb. T. R. M. receives research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR050004, R03 AR054539) and the VHA (VA Merit). L. C. is supported by a VA HSR&D Career Development Award.; L.C. is supported by VA HSR&D Career Development Award (CDP 09-388). All other authors have declared no conflicts of interest. NR 41 TC 37 Z9 39 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JAN PY 2011 VL 50 IS 1 BP 101 EP 109 DI 10.1093/rheumatology/keq232 PG 9 WC Rheumatology SC Rheumatology GA 692ZD UT WOS:000285193500014 PM 20659916 ER PT B AU Jones, OAH Roberts, LD Maguire, ML AF Jones, Oliver A. H. Roberts, Lee D. Maguire, Mahon L. BE Ivanov, AR Lazarev, AV TI Mass Spectrometry-Based Metabolomics. Sample Preparation, Data Analysis, and Related Analytical Approaches SO SAMPLE PREPARATION IN BIOLOGICAL MASS SPECTROMETRY LA English DT Article; Book Chapter DE Chromatography; metabolomics/metabonomics; Mass spectrometry; Multivariate statistics ID PERFORMANCE LIQUID-CHROMATOGRAPHY; METABOLITE EXTRACTION STRATEGIES; NMR-BASED METABOLOMICS; H-1-NMR SPECTROSCOPY; ARABIDOPSIS-THALIANA; FUNCTIONAL GENOMICS; PLANT METABOLOMICS; METABONOMICS; TISSUE; MOUSE AB Metabolomics refers to the study of small-molecule metabolites (e.g. fats, sugars, nuclear acids) within biological samples such as cells, tissues, biofluids or even whole organisms. It has been found to be applicable to a wide range of fields, including the study of gene function, toxicology, plant sciences, environmental analysis, cancer, clinical diagnostics, nutrition and the discrimination of organism genotypes to name but a few. The approach combines high-throughput sample analysis with computer-assisted multivariate pattern-recognition techniques. A major challenge in metabolomics is to address the extremely diverse and complex nature of the subject matter and both past and future progress in the field depends in large part on the use and evolution of analytical techniques and instrumentation, especially mass spectrometry. This chapter therefore focuses on outlining and discussing current thinking behind the most commonly used analytical methodologies as well as associated multivariate data processing techniques. C1 [Jones, Oliver A. H.] Univ Durham, Sch Engn & Comp Sci, Durham DH1 3LE, England. [Roberts, Lee D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Maguire, Mahon L.] Univ Oxford, BHF Magnet Resonance Unit, Dept Cardiovasc Med, Wellcome Trust Ctr Human Genet, Oxford, England. RP Jones, OAH (reprint author), Univ Durham, Sch Engn & Comp Sci, Christopherson Bldg, Durham DH1 3LE, England. EM ojones@gmail.com; ldroberts@partners.org; mahon.maguire@gmail.com RI Jones, Oliver/B-9778-2008 OI Jones, Oliver/0000-0002-4541-662X NR 52 TC 3 Z9 3 U1 2 U2 5 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 978-94-007-0758-0 PY 2011 BP 853 EP 868 DI 10.1007/978-94-007-0828-0_40 D2 10.1007/978-94-007-0828-0 PG 16 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA BVY63 UT WOS:000293148700041 ER PT J AU Kuperberg, GR Kreher, DA Swain, A Goff, DC Holt, DJ AF Kuperberg, Gina R. Kreher, Donna A. Swain, Abigail Goff, Donald C. Holt, Daphne J. TI Selective Emotional Processing Deficits to Social Vignettes in Schizophrenia: An ERP Study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; emotion; affect; negative symptoms; semantic; language; P300; late positivity; event-related potentials ID FACIAL-AFFECT RECOGNITION; EVENT-RELATED POTENTIALS; GENERALIZED POOR PERFORMANCE; DIFFERENTIAL NEURAL RESPONSE; LANGUAGE COMPREHENSION; FEARFUL FACES; AFFECTIVE PICTURES; BRAIN POTENTIALS; PERCEPTION; EXPRESSIONS AB Schizophrenia is associated with abnormalities in emotional processing and social cognition. However, it remains unclear whether patients show abnormal neurophysiological responses during fast, online appraisals of the emotional meaning of social information. To examine this question, event-related potentials (ERPs) were collected while 18 schizophrenia patients and 18 demographically matched controls evaluated 2-sentence vignettes describing negative, positive, or neutral social situations. ERPs were time locked to a critical word (CW) in the second sentence that conferred emotional valence. A late positivity effect to emotional (vs neutral) CWs was seen in both groups (in controls, to negative and positive CWs; in patients, to negative CWs only). However, the controls showed a greater late positivity effect to the negative and positive (vs neutral) CWs than the schizophrenia patients at mid-posterior (negative vs neutral) and at right posterior peripheral (positive vs neutral) sites. These between-group differences arose from reduced amplitudes of the late positivity to the negative and positive CWs in the patients relative to the controls; there was no difference between the 2 groups in the amplitude of the late positivity to the neutral CWs. These findings suggest that schizophrenia is associated with a specific neural deficit during the online evaluation of emotionally valent, socially relevant information. C1 [Kuperberg, Gina R.; Kreher, Donna A.; Swain, Abigail] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Kuperberg, Gina R.; Goff, Donald C.; Holt, Daphne J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kuperberg, Gina R.; Goff, Donald C.; Holt, Daphne J.] Harvard Univ, Sch Med, Boston, MA USA. [Kuperberg, Gina R.; Holt, Daphne J.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Kreher, Donna A.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. RP Kuperberg, GR (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM kuperber@nmr.mgh.harvard.edu FU National Institute of Mental Health [RO1 MH02034, K23 MH076054]; National Alliance for Research in Schizophrenia and Depression; Sidney J. Baer Trust; Judge Baker Center Clinical Research Training Program; GlaxoSmithKline; Jerome Lyle Rappaport Charitable Foundation FX National Institute of Mental Health (RO1 MH02034 to G.R.K., K23 MH076054 to D.J.H.); National Alliance for Research in Schizophrenia and Depression with the Sidney J. Baer Trust (to G.R.K., D.J.H.); Judge Baker Center Clinical Research Training Program (to D.J.H.); GlaxoSmithKline Severe Mental Illness Award (to D.J.H.); Jerome Lyle Rappaport Charitable Foundation (to D.J.H.). NR 112 TC 7 Z9 7 U1 6 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JAN PY 2011 VL 37 IS 1 BP 148 EP 163 DI 10.1093/schbul/sbp018 PG 16 WC Psychiatry SC Psychiatry GA 701TC UT WOS:000285845300020 PM 19564165 ER PT J AU Holt, DJ Lakshmanan, B Freudenreich, O Goff, DC Rauch, SL Kuperberg, GR AF Holt, Daphne. J. Lakshmanan, Balaji Freudenreich, Oliver Goff, Donald C. Rauch, Scott L. Kuperberg, Gina R. TI Dysfunction of a Cortical Midline Network During Emotional Appraisals in Schizophrenia SO SCHIZOPHRENIA BULLETIN LA English DT Article DE cingulate cortex; default mode network; delusions; emotion; fMRI; medial prefrontal cortex ID MEDIAL PREFRONTAL CORTEX; POSTERIOR CINGULATE CORTEX; SURFACE-BASED ANALYSIS; DEFAULT NETWORK; SOCIAL COGNITION; PREDICTION-ERROR; REALITY DISTORTION; AFFECT RECOGNITION; NEURAL RESPONSE; BRAIN-FUNCTION AB A cardinal feature of schizophrenia is the poor comprehension, or misinterpretation, of the emotional meaning of social interactions and events, which can sometimes take the form of a persecutory delusion. It has been shown that the comprehension of the emotional meaning of the social world involves a midline paralimbic cortical network. However, the function of this network during emotional appraisals in patients with schizophrenia is not well understood. In this study, hemodynamic responses were measured in 14 patients with schizophrenia and 18 healthy subjects during the evaluation of descriptions of social situations with negative, positive, and neutral affective valence. The healthy and schizophrenia groups displayed opposite patterns of responses to emotional and neutral social situations within the medial prefrontal and posterior cingulate cortices-healthy participants showed greater activity to the emotional compared to the neutral situations, while patients exhibited greater responses to the neutral compared to the emotional situations. Moreover, the magnitude of the response within bilateral cingulate gyri to the neutral social stimuli predicted delusion severity in the patients with schizophrenia. These findings suggest that impaired functioning of cortical midline structures in schizophrenia may underlie faulty interpretations of social events, contributing to delusion formation. C1 [Holt, Daphne. J.; Freudenreich, Oliver; Goff, Donald C.; Kuperberg, Gina R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Holt, Daphne. J.; Freudenreich, Oliver; Goff, Donald C.; Rauch, Scott L.; Kuperberg, Gina R.] Harvard Univ, Sch Med, Boston, MA USA. [Holt, Daphne. J.; Kuperberg, Gina R.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Lakshmanan, Balaji] Kennedy Krieger Inst, Baltimore, MD USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Kuperberg, Gina R.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. RP Holt, DJ (reprint author), Massachusetts Gen Hosp East, Psychiat Neuroimaging Res Program, Room 2662,149,13th St, Charlestown, MA 02129 USA. EM dholt@partners.org FU National Institutes of Mental Health [K23 MH076054, RO1 MH02034]; Institute for Mental Illness and Neuroscience Discovery; National Alliance for Research in Schizophrenia and Depression; Sidney J. Baer Trust; Judge Baker Center Clinical Research Training Program; GlaxoSmithKline; Jerome Lyle Rappaport Charitable Foundation FX National Institutes of Mental Health (K23 MH076054 to D.J.H., RO1 MH02034 to G.R.K.); Institute for Mental Illness and Neuroscience Discovery; National Alliance for Research in Schizophrenia and Depression with the Sidney J. Baer Trust (to D.J.H., G.R.K.); Judge Baker Center Clinical Research Training Program (to D.J.H.); GlaxoSmithKline Severe Mental Illness Award (to D.J.H.); Jerome Lyle Rappaport Charitable Foundation (to D.J.H.). NR 85 TC 20 Z9 21 U1 5 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JAN PY 2011 VL 37 IS 1 BP 164 EP 176 DI 10.1093/schbul/sbp067 PG 13 WC Psychiatry SC Psychiatry GA 701TC UT WOS:000285845300021 PM 19605517 ER PT J AU White, T Magnotta, VA Bockholt, HJ Williams, S Wallace, S Ehrlich, S Mueller, BA Ho, BC Jung, RE Clark, VP Lauriello, J Bustillo, JR Schulz, SC Gollub, RL Andreasen, NC Calhoun, VD Lim, KO AF White, Tonya Magnotta, Vincent A. Bockholt, H. Jeremy Williams, Sumner Wallace, Stuart Ehrlich, Stefan Mueller, Bryon A. Ho, Beng-Choon Jung, Rex E. Clark, Vincent P. Lauriello, John Bustillo, Juan R. Schulz, S. Charles Gollub, Randy L. Andreasen, Nancy C. Calhoun, Vince D. Lim, Kelvin O. TI Global White Matter Abnormalities in Schizophrenia: A Multisite Diffusion Tensor Imaging Study SO SCHIZOPHRENIA BULLETIN LA English DT Article DE first-episode schizophrenia; fractional anisotropy; neuroimaging; DTI; microstructure ID CHILDHOOD-ONSET SCHIZOPHRENIA; PROGRESSIVE BRAIN CHANGES; DYSFUNCTION; ADOLESCENCE; EPISODE; DENSITY; CORTEX; MRI AB Background: Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. Methods: Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. Results: FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. Conclusions: We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure. C1 [White, Tonya; Mueller, Bryon A.; Lim, Kelvin O.] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55454 USA. [White, Tonya; Lim, Kelvin O.] Ctr Magnet Resonance Res, Minneapolis, MN 55454 USA. [White, Tonya] Erasmus Univ, Dept Child & Adolescent Psychiat, NL-3000 CB Rotterdam, Netherlands. [Magnotta, Vincent A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Bockholt, H. Jeremy; Williams, Sumner; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87106 USA. [Wallace, Stuart; Ehrlich, Stefan; Gollub, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Ehrlich, Stefan; Gollub, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Ho, Beng-Choon; Andreasen, Nancy C.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Jung, Rex E.; Clark, Vincent P.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87106 USA. [Bustillo, Juan R.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87106 USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87106 USA. [Lauriello, John] Univ Missouri, Dept Psychiat, Columbia, MO 65212 USA. [Lim, Kelvin O.] Minneapolis Vet Adm Med Ctr, Minneapolis, MN 55417 USA. RP White, T (reprint author), Erasmus MC, Dept Child & Adolescent Psychiat, Sophia Kamer WK219,Dr Molewaterpl 60,Postbus 2060, NL-3000 CB Rotterdam, Netherlands. EM t.white@erasmusmc.nl RI Lim, Kelvin/C-2201-2012; Ho, Beng-Choon/D-6959-2011; Calhoun, Vince/H-7146-2013; bustillo, juan/J-7067-2013; Clark, Vincent/B-3343-2010; OI Ho, Beng-Choon/0000-0003-3976-1555; Calhoun, Vince/0000-0001-9058-0747; Gollub, Randy L./0000-0002-9434-4044; Clark, Vincent/0000-0002-9151-2102; Ehrlich, Stefan/0000-0003-2132-4445 FU U.S. Department of Energy [DE-F02-99ER62764-A012]; Morphometry Biomedical Informatics Research Network [U24 RR021382]; National Institutes of Mental Health [K08 MH068540]; National Institutes of Health [NS050568, P30NS057091, P41 RR00807] FX U.S. Department of Energy (DE-F02-99ER62764-A012) to the Mind Research Network; the Morphometry Biomedical Informatics Research Network (U24 RR021382); National Institutes of Mental Health (K08 MH068540); National Institutes of Health (NS050568, P30NS057091, and P41 RR00807). NR 36 TC 58 Z9 63 U1 10 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD JAN PY 2011 VL 37 IS 1 BP 222 EP 232 DI 10.1093/schbul/sbp088 PG 11 WC Psychiatry SC Psychiatry GA 701TC UT WOS:000285845300026 PM 19770491 ER PT J AU Calvo, KR Landgren, O Roccaro, AM Ghobrial, IM AF Calvo, Katherine R. Landgren, Ola Roccaro, Aldo M. Ghobrial, Irene M. TI Role of MicroRNAs From Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma SO SEMINARS IN HEMATOLOGY LA English DT Article ID B-CELL LYMPHOMAS; INDUCE APOPTOSIS; EXPRESSION; CANCER; REPRESSION; CLUSTER; MIRNAS; GENES; RNA; DIFFERENTIATION AB microRNAs (miRNAs) are increasingly recognized as significant players in oncogenesis and tumor biology through post-transcriptional gene regulation impacting broad pathways of proliferation, differentiation, apoptosis, metastasis, and cell survival. Recent studies have found abnormal expression of miRNAs in multiple myeloma (MM). Currently, the precise role of these miRNAs in the biology of MM remains to be elucidated, although they are predicted to be involved in plasma cell proliferation, survival, homing, or in MM cell interactions with the bone marrow microenvironment. Furthermore, a limited number of studies focusing on MM precursor disease (monoclonal gammopathy of undetermined significance [MGUS]) reveal significant differences in miRNA profiles between MGUS and normal plasma cells. Interestingly, several of the microRNAs differentially expressed in MGUS also show aberrant expression in MM, suggesting a role in early myelomagenesis. miRNA profiles can discriminate molecular subtypes of MM that are defined based on gene expression profiling (GEP) and cytogenetic abnormalities, demonstrating the potential diagnostic/prognostic utility of miRNA profiling for subclassification of MM. Given the relative stability of miRNA and ability to isolate miRNA from routine clinical specimens, miRNA analysis promises to facilitate personalized diagnostics and therapies, and to provide insights into the biology of early myelomagenesis. Semin Hematol 48:39-45. (C) 2011 Published by Elsevier Inc. C1 [Calvo, Katherine R.] NIH, Hematol Sect, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Roccaro, Aldo M.; Ghobrial, Irene M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Boston, MA USA. [Landgren, Ola] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Calvo, KR (reprint author), NIH, Hematol Sect, Dept Lab Med, Ctr Clin, 10 Ctr Dr,Bldg 10-2C306, Bethesda, MD 20892 USA. EM calvok@mail.nih.gov RI Calvo, Katherine/A-8109-2009; OI Roccaro, Aldo/0000-0002-1872-5128; Calvo, Katherine/0000-0002-0771-4191 FU NIH Clinical Center; National Cancer Institute FX Support for this work was provided by the Intramural Research Program of the NIH Clinical Center and the National Cancer Institute. NR 55 TC 6 Z9 9 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 2011 VL 48 IS 1 BP 39 EP 45 DI 10.1053/j.seminhematol.2010.11.007 PG 7 WC Hematology SC Hematology GA 709AA UT WOS:000286406100006 PM 21232657 ER PT J AU Powe, CE Thadhani, R AF Powe, Camille E. Thadhani, Ravi TI Diabetes and the Kidney in Pregnancy SO SEMINARS IN NEPHROLOGY LA English DT Review DE Diabetes; pregnancy; renal disease; preeclampsia ID CONVERTING ENZYME-INHIBITION; URINARY ALBUMIN EXCRETION; BLOOD-PRESSURE CONTROL; STAGE RENAL-DISEASE; ANTIHYPERTENSIVE THERAPY; CARDIOVASCULAR-DISEASE; INDUCED HYPERTENSION; ACE-INHIBITORS; NEPHROPATHY; WOMEN AB The prevalence of diabetes in pregnant women is increasing, with 4% of deliveries in the United States occurring in women with pregestational or gestational diabetes. The proteinuria of late pregnancy is exaggerated in women with diabetes. However, diabetic women with preserved renal function before pregnancy appear to have little risk of deterioration of kidney function during pregnancy. Women with impaired renal function before pregnancy may be at risk for permanent decline of renal function during pregnancy, although it is unclear whether this represents the effect of pregnancy or the natural history of their diabetic renal disease. Preeclampsia, which is more common in women with diabetes, may be difficult to diagnose in this group of women. From the currently available literature, there appears to be no negative effect of pregnancy on the long-term progression of diabetic renal disease if renal function is normal and marked proteinuria is absent, but in light of recent findings in which preeclampsia appears to be associated with an increased risk of end-stage renal disease, large cohort studies will be necessary before this question can be definitively answered. Semin Nephrol 31:59-69 (C) 2011 Published by Elsevier Inc. C1 [Thadhani, Ravi] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Thadhani, R (reprint author), Massachusetts Gen Hosp, Div Nephrol, 55 Fruit St,Bullfinch 127, Boston, MA 02114 USA. EM rthadhani@partners.org FU Howard Hughes Medical Institute; NIEHS NIH HHS [P30 ES002109] NR 75 TC 8 Z9 9 U1 2 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JAN PY 2011 VL 31 IS 1 BP 59 EP 69 DI 10.1016/j.semnephrol.2010.10.006 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 716SW UT WOS:000286994800006 PM 21266265 ER PT J AU Miyamoto, DT Harris, JR AF Miyamoto, David T. Harris, Jay R. TI Molecular Predictors of Local Tumor Control in Early-Stage Breast Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID GENE-EXPRESSION SIGNATURE; ADJUVANT CHEMOTHERAPY; CONSERVING THERAPY; RANDOMIZED-TRIALS; ESTROGEN-RECEPTOR; PROGESTERONE-RECEPTOR; PROGNOSTIC SIGNATURE; DISTANT METASTASIS; AMERICAN-SOCIETY; REGIONAL RELAPSE AB Advances in surgery, radiation therapy, and systemic therapy have resulted in substantial improvements in local and distant tumor control in early-stage breast cancer, which in turn have improved breast cancer-specific and overall mortality. Although outcomes after breast-conserving therapy may be estimated using clinical and pathologic risk factors, more robust predictors of local tumor recurrence are necessary. Recent molecular profiling studies have shown that the risk of local and distant recurrence varies across different molecular subtypes of breast cancer. In addition, several molecular assays have emerged as promising prognostic and predictive markers of local and distant recurrence. The ability to use such molecular markers may allow for better tailoring of therapy and further reduction of recurrence rates and mortality in breast cancer. This is a rapidly evolving field, and prospective validation studies as well as the identification of new markers are needed. Semin Radiat Oncol 21:35-42 (C) 2011 Elsevier Inc. All rights reserved. C1 [Harris, Jay R.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Brigham & Womens Hosp,Dept Radiat Oncol, Boston, MA 02115 USA. [Miyamoto, David T.] Harvard Univ, Harvard Radiat Oncol Program, Sch Med, Boston, MA 02115 USA. RP Harris, JR (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Brigham & Womens Hosp,Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM jharris@lroc.harvard.edu NR 58 TC 8 Z9 9 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JAN PY 2011 VL 21 IS 1 BP 35 EP 42 DI 10.1016/j.semradonc.2010.08.005 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 700WS UT WOS:000285775600006 PM 21134652 ER PT J AU Hendriksen, ES Krishnan, AKS Vallabhaneni, S Johnson, S Raminani, S Kumarasamy, N Solomon, S Mayer, KKH Safren, SS AF Hendriksen, Ellen Setsuko Krishnan, A. K. Sri Vallabhaneni, Snigda Johnson, Sethu Raminani, Sudha Kumarasamy, N. Solomon, Suniti Mayer, Kenneth K. H. Safren, Steven S. TI Primary prevention lessons learned from those with HIV in Chennai, India SO SEXUAL HEALTH LA English DT Article DE AIDS; education; MSM; sex workers; sexual behaviour ID RANDOMIZED CONTROLLED-TRIAL; SOUTH-INDIA; SEXUAL PARTNERS; RISK BEHAVIORS; INFECTION; PROGRAM; STIGMA; WOMEN; MEN; INDIVIDUALS AB Background: As each HIV-infected individual represents a breakdown of HIV primary prevention measures, formative data from representative individuals living with HIV can help shape future primary prevention interventions. Little is known about sexual behaviours and other transmission risk factors of high-risk group members who are already HIV-infected in Chennai, India. Methods: Semi-structured qualitative interviews were conducted with 27 HIV-infected individuals representing each high-risk group in Chennai (five men who have sex with men (MSM), five female commercial sex workers (CSW), four truckers and other men who travel for business, four injecting drug users (IDU), five married male clients of CSW, and four wives of CSW clients, MSM, truckers, and IDU). Results: Themes relevant to HIV primary prevention included: (1) HIV diagnosis as the entry into HIV education and risk reduction, (2) reluctance to undergo voluntary counselling and testing, (3) gender and sexual roles as determinants of condom use, (4) misconceptions about HIV transmission, and (5) framing and accessibility of HIV education messages. Conclusions: These qualitative data can be used to develop hypotheses about sexual risk taking in HIV-infected individuals in South India, inform primary prevention intervention programs, and improve primary prevention efforts overall. C1 [Hendriksen, Ellen Setsuko] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Hendriksen, Ellen Setsuko; Raminani, Sudha; Mayer, Kenneth K. H.; Safren, Steven S.] Fenway Inst, Boston, MA 02215 USA. [Krishnan, A. K. Sri; Johnson, Sethu; Kumarasamy, N.; Solomon, Suniti] YRG Ctr AIDS Res & Educ, Madras 600113, Tamil Nadu, India. [Vallabhaneni, Snigda; Mayer, Kenneth K. H.] Brown Univ, Providence, RI 02912 USA. [Safren, Steven S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hendriksen, ES (reprint author), Univ Calif Los Angeles, Los Angeles, CA 90024 USA. EM ehendriksen@partners.org FU National Institute of Allergy and Infectious Diseases [5P30AI042853] FX Funding from this project came from a supplement to Grant 5P30AI042853 (Dr. Charles Carpenter, Principal Investigator) to Dr. Kenneth H. Mayer from the National Institute of Allergy and Infectious Diseases. NR 33 TC 0 Z9 0 U1 2 U2 4 PU CSIRO PUBLISHING PI COLLINGWOOD PA 150 OXFORD ST, PO BOX 1139, COLLINGWOOD, VICTORIA 3066, AUSTRALIA SN 1448-5028 J9 SEX HEALTH JI Sex Health PY 2011 VL 8 IS 2 BP 199 EP 206 DI 10.1071/SH10015 PG 8 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 766HL UT WOS:000290771500010 PM 21592434 ER PT B AU Willen, SS Yaroshenko, M Hannah, SD Vickery, K Good, MJD AF Willen, Sarah S. Yaroshenko, Marina Hannah, Seth Donal Vickery, Ken Good, Mary-Jo DelVecchio BE Good, MJD Willen, SS Hannah, SD Vickery, K Park, LT TI Portrait of a Psychiatrist SO SHATTERING CULTURE: AMERICAN MEDICINE RESPONDS TO CULTURAL DIVERSITY LA English DT Article; Book Chapter C1 [Willen, Sarah S.] Univ Connecticut, Anthropol, Storrs, CT 06269 USA. [Yaroshenko, Marina] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hannah, Seth Donal] Harvard Univ, Sociol, Cambridge, MA 02138 USA. [Vickery, Ken] Univ Illinois, External Fellowships, Urbana, IL 61801 USA. [Good, Mary-Jo DelVecchio] Harvard Univ, Sch Med, Social Med, Cambridge, MA 02138 USA. [Good, Mary-Jo DelVecchio] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. [Good, Mary-Jo DelVecchio] Asia Ctr, London, England. [Good, Mary-Jo DelVecchio] Ctr Middle Eastern Studies, New York, NY USA. [Good, Mary-Jo DelVecchio] Weatherhead Ctr Int Affairs, Cambridge, MA USA. RP Willen, SS (reprint author), Univ Connecticut, Anthropol, Storrs, CT 06269 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU RUSSELL SAGE FOUNDATION PI NEW YORK PA 112 EAST 64TH STREET, NEW YORK, NY 10021 USA BN 978-0-87154-060-7; 978-1-61044-752-2 PY 2011 BP 137 EP 151 PG 15 WC Ethnic Studies; Health Policy & Services SC Ethnic Studies; Health Care Sciences & Services GA BD5LC UT WOS:000361551800008 ER PT B AU Hannah, SD Park, LT Good, MJD AF Hannah, Seth Donal Park, Lawrence Taeseng Good, Mary-Jo DelVecchio BE Good, MJD Willen, SS Hannah, SD Vickery, K Park, LT TI Physicians' Perspectives on Financial Barriers to Equitable Care SO SHATTERING CULTURE: AMERICAN MEDICINE RESPONDS TO CULTURAL DIVERSITY LA English DT Article; Book Chapter ID MEDICAID MANAGED CARE; SAFETY-NET PROVIDERS; REFORM; MASSACHUSETTS C1 [Hannah, Seth Donal] Harvard Univ, Sociol, Cambridge, MA 02138 USA. [Park, Lawrence Taeseng] Massachusetts Gen Hosp, Psychiat, Boston, MA 02114 USA. [Good, Mary-Jo DelVecchio] Harvard Univ, Sch Med, Social Med, Cambridge, MA 02138 USA. [Good, Mary-Jo DelVecchio] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. [Good, Mary-Jo DelVecchio] Asia Ctr, New York, NY USA. [Good, Mary-Jo DelVecchio] Ctr Middle Eastern Studies, New York, NY USA. [Good, Mary-Jo DelVecchio] Weatherhead Ctr Int Affairs, New York, NY USA. RP Hannah, SD (reprint author), Harvard Univ, Sociol, Cambridge, MA 02138 USA. NR 12 TC 2 Z9 2 U1 1 U2 1 PU RUSSELL SAGE FOUNDATION PI NEW YORK PA 112 EAST 64TH STREET, NEW YORK, NY 10021 USA BN 978-0-87154-060-7; 978-1-61044-752-2 PY 2011 BP 217 EP 233 PG 17 WC Ethnic Studies; Health Policy & Services SC Ethnic Studies; Health Care Sciences & Services GA BD5LC UT WOS:000361551800013 ER PT J AU Huang, AJ Rosenthal, DI Palmer, WE AF Huang, Ambrose J. Rosenthal, Daniel I. Palmer, William E. TI Inadvertent intra-articular lumbar facet joint injection during fluoroscopically guided interlaminar epidural steroid injection SO SKELETAL RADIOLOGY LA English DT Article DE Radiology; Spine; Interventional; Epidural injections; Facet joint; Zygapophyseal joint ID ARTHROGRAPHY; SPREAD; SPONDYLOLYSIS; DISABILITY AB Inadvertent lumbar facet joint injection during an interlaminar epidural steroid injection (ESI) is rare when using the loss-of-resistance technique. The pattern of contrast material on the lateral view can mimic that of a successful ESI. The purpose of this study is to illustrate the imaging features of this event. From 2001 to 2009, 6,631 interlaminar lumbar ESIs were performed. Cases in which facet joint injection was recognized by the radiologist were identified by a text search of the report for the term "facet" and corroborated by review of the case images and the patients' medical records. Forty-two positive events were identified. Imaging features are characteristic and include sigmoid-shaped area of contrast material projecting over the posterior elements on the lateral view and an ovoid area of contrast material projecting over the facet joints on the anteroposterior (AP) view. Thirty-one out of 42 events were recognized by the operator during the procedure. In 17 cases, the final images documented the appropriate location of the needle tip within the epidural space. In 9 cases, simultaneous epidural and facet joint injection occurred. In 16 cases, epidural contrast material was not documented. Lumbar facet joint injection has a characteristic appearance and can be distinguished from epidural injection. However, since this event can simulate the appearance of a successful ESI, it may be unrecognized during the procedure. Therefore, the true incidence is likely higher than that suggested by this study. Recognizing the imaging features of this event permits the operator to further manipulate the needle tip and increase the success rate of ESIs. C1 [Huang, Ambrose J.; Rosenthal, Daniel I.; Palmer, William E.] Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. RP Huang, AJ (reprint author), Massachusetts Gen Hosp, Div Musculoskeletal Imaging & Intervent, Dept Radiol, 55 Fruit St,Yawkey 6E, Boston, MA 02114 USA. EM ajhuang@partners.org NR 19 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD JAN PY 2011 VL 40 IS 1 BP 33 EP 45 DI 10.1007/s00256-010-1025-y PG 13 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 682SD UT WOS:000284422400005 PM 20820772 ER PT J AU Avidan, AY Hays, RD Diaz, N Bordelon, Y Vassar, S Vickrey, B AF Avidan, A. Y. Hays, R. D. Diaz, N. Bordelon, Y. Vassar, S. Vickrey, B. TI HEALTH-RELATED QUALITY OF LIFE ASSOCIATIONS VARY BY TYPE OF SLEEP DISTURBANCES IN PARKINSON'S DISEASE SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Hays, R. D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hays, R. D.] Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA USA. [Diaz, N.] Harbor UCLA, Dept Neurol, Los Angeles, CA USA. [Vassar, S.; Vickrey, B.] VA Greater Los Angeles Healthcare Syst, Parkinsons Dis Res Educ & Clin Ctr, Los Angeles, CA USA. RI Hays, Ronald/D-5629-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0624 BP A216 EP A216 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400625 ER PT J AU Bianchi, MT Williams, KL McKinney, S Ellenbogen, JM AF Bianchi, M. T. Williams, K. L. McKinney, S. Ellenbogen, J. M. TI SLEEP ARCHITECTURE PREDICTS THE MISMATCH BETWEEN SUBJECTIVE AND OBJECTIVE SLEEP DURATION SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Bianchi, M. T.; Williams, K. L.; McKinney, S.; Ellenbogen, J. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0547 BP A187 EP A187 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400548 ER PT J AU Bonjean, M Baker, T Cash, S Bazhenov, M Halgren, E Sejnowski, T AF Bonjean, M. Baker, T. Cash, S. Bazhenov, M. Halgren, E. Sejnowski, T. TI INTERACTIONS BETWEEN CORE AND MATRIX THALAMOCORTICAL PROJECTIONS IN HUMAN SLEEP SPINDLE SYNCHRONIZATION SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Bonjean, M.; Baker, T.; Sejnowski, T.] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Bonjean, M.; Sejnowski, T.] Univ Calif San Diego, Dept Biomed Sci, La Jolla, CA 92093 USA. [Cash, S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Bazhenov, M.] Univ Calif Riverside, Dept Cellular Biol & Neurosci, Riverside, CA 92521 USA. [Halgren, E.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0104 BP A39 EP A39 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400106 ER PT J AU Buxton, O Hopcia, K Sembajwe, G Porter, J Dennerlein, J Kenwood, C Stoddard, A Hashimoto, D Sorensen, G AF Buxton, O. Hopcia, K. Sembajwe, G. Porter, J. Dennerlein, J. Kenwood, C. Stoddard, A. Hashimoto, D. Sorensen, G. TI RELATIONSHIP OF SLEEP DEFICIENCY TO PERCEIVED PAIN AND PHYSICAL DISABILITY IN HOSPITAL PATIENT CARE WORKERS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Buxton, O.; Porter, J.; Hashimoto, D.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Buxton, O.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Hopcia, K.; Sembajwe, G.; Hashimoto, D.] Partners Hlth Care Syst, Partners Occupat Hlth Serv, Boston, MA USA. [Hopcia, K.; Sorensen, G.] Harvard Univ, Sch Publ Hlth, Ctr Work Hlth & Wellbeing, Boston, MA 02115 USA. [Sembajwe, G.; Dennerlein, J.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Kenwood, C.; Stoddard, A.] New England Res Inst, Watertown, MA 02172 USA. [Hashimoto, D.; Sorensen, G.] Harvard Univ, Sch Publ Hlth, Dept Soc Hlth & Human Dev, Boston, MA 02115 USA. [Sorensen, G.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0643 BP A222 EP A223 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400644 ER PT J AU Casement, MD Marx, BP Bovin, MJ Sloan, DM AF Casement, M. D. Marx, B. P. Bovin, M. J. Sloan, D. M. TI NARRATIVE EXPOSURE TREATMENT FOR POSTTRAUMATIC STRESS DISORDER DECREASES INSOMNIA SYMPTOMS AND NIGHTMARES SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Casement, M. D.; Marx, B. P.; Bovin, M. J.; Sloan, D. M.] Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 PY 2011 VL 34 SU S MA 0735 BP A253 EP A253 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400736 ER PT J AU Chase, MH Zhang, J Fung, SJ Xi, M Sampogna, S AF Chase, M. H. Zhang, J. Fung, S. J. Xi, M. Sampogna, S. TI ASHWAGANDHA PROVIDES NEUROPROTECTION AGAINST APNEA-INDUCED NEURONAL DEGENERATION IN THE HIPPOCAMPUS OF ADULT GUINEA PIGS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Chase, M. H.; Zhang, J.; Fung, S. J.; Xi, M.; Sampogna, S.] Websci Int, Los Angeles, CA USA. [Chase, M. H.; Zhang, J.; Fung, S. J.; Xi, M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Chase, M. H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0148 BP A54 EP A54 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400149 ER PT J AU Chen, T Hek, K Eiriksdottir, G Gharib, SA Grabe, H Gudnason, V Punjabi, NM Tiemeier, H Watson, N Gottlieb, DJ AF Chen, T. Hek, K. Eiriksdottir, G. Gharib, S. A. Grabe, H. Gudnason, V Punjabi, N. M. Tiemeier, H. Watson, N. Gottlieb, D. J. TI A GENOME-WIDE ASSOCIATION ANALYSIS OF INSOMNIA: THE CHARGE CONSORTIUM SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Chen, T.; Gottlieb, D. J.] Boston Univ, Boston, MA 02215 USA. [Chen, T.; Gottlieb, D. J.] VA Boston Healthcare Syst, Boston, MA USA. [Hek, K.; Tiemeier, H.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Eiriksdottir, G.; Gudnason, V] Iceland Heart Assoc, Kopavogur, Iceland. [Gharib, S. A.; Watson, N.] Univ Washington, Seattle, WA 98195 USA. [Grabe, H.] Ernst Moritz Arndt Univ Greifswald, HANSE Klinikum, D-17487 Greifswald, Germany. [Punjabi, N. M.] Johns Hopkins Univ, Baltimore, MD USA. RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 1 Z9 1 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0493 BP A169 EP A170 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400494 ER PT J AU Dworak, M Kim, T McCarley, RW Basheer, R AF Dworak, M. Kim, T. McCarley, R. W. Basheer, R. TI SLEEP DEPRIVATION-DEPENDENT DIFFERENTIAL REGULATION OF ATP LEVELS IN RAT HYPOTHALAMUS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 VA Boston Healthcare Syst, Psychiat, W Roxbury, MA USA. Harvard Univ, Sch Med, W Roxbury, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0118 BP A44 EP A45 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400120 ER PT J AU Fenik, VB Lim, V Fung, SJ Chase, MH AF Fenik, V. B. Lim, V Fung, S. J. Chase, M. H. TI EXCITATORY INPUTS TO HYPOGLOSSAL MOTONEURONS ARE DIFFERENTIALLY DEPRESSED DURING REM SLEEP IN RATS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Fenik, V. B.; Lim, V; Fung, S. J.; Chase, M. H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Fenik, V. B.; Lim, V; Fung, S. J.; Chase, M. H.] WebSci Int, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0081 BP A31 EP A31 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400083 ER PT J AU Fung, CH Martin, JL Josephson, KR Jouldjian, S Alessi, CA AF Fung, C. H. Martin, J. L. Josephson, K. R. Jouldjian, S. Alessi, C. A. TI PREDICTORS OF BRIGHT LIGHT EXPOSURE IN OLDER POST-ACUTE REHABILITATION PATIENTS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Fung, C. H.] Cedars Sinai Med Ctr, Cedars Sinai Sleep Med Fellowship Program, Los Angeles, CA 90048 USA. [Martin, J. L.; Josephson, K. R.; Jouldjian, S.; Alessi, C. A.] VA Greater Los Angeles Healthcare, GRECC, North Hills, CA USA. [Martin, J. L.; Alessi, C. A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0891 BP A304 EP A305 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834401139 ER PT J AU Fung, SJ Xi, M Chase, MH AF Fung, S. J. Xi, M. Chase, M. H. TI ASHWAGANDHA ANTAGONIZES APNEA-INDUCED EXCITOTOXIC PROCESSES IN THE HIPPOCAMPAL CA3-CA1 PATHWAY SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Fung, S. J.; Xi, M.; Chase, M. H.] VA Greater LA Healthcare Syst, Los Angeles, CA USA. [Fung, S. J.; Xi, M.; Chase, M. H.] Websci Int, Los Angeles, CA USA. [Chase, M. H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0145 BP A53 EP A53 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400146 ER PT J AU Gajewski, ND Laitman, BM Mann, GL Kubin, L Ross, RJ Morrison, AR AF Gajewski, N. D. Laitman, B. M. Mann, G. L. Kubin, L. Ross, R. J. Morrison, A. R. TI alpha-1 ADRENOCEPTOR ANTAGONIST PRAZOSIN REDUCES NON-REM SLEEP (NREMS) AROUSALS IN FEAR-CONDITIONED WISTAR-KYOTO RATS (WKY) SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Gajewski, N. D.; Laitman, B. M.; Mann, G. L.; Kubin, L.; Ross, R. J.; Morrison, A. R.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Ross, R. J.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Ross, R. J.] Philadelphia VA Med Ctr, Behav Hlth Serv, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0209 BP A74 EP A75 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400210 ER PT J AU Kalinchuk, A Porkka-Heiskanen, T McCarley, RW Basheer, R AF Kalinchuk, A. Porkka-Heiskanen, T. McCarley, R. W. Basheer, R. TI ROLE OF THE BASAL FOREBRAIN CHOLINERGIC NEURONS IN THE NITRIC OXIDE-MEDIATED REGULATION OF SLEEP HOMEOSTASIS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Kalinchuk, A.; McCarley, R. W.; Basheer, R.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. [Porkka-Heiskanen, T.] Univ Helsinki, Inst Biomed, Helsinki, Finland. NR 0 TC 0 Z9 0 U1 1 U2 1 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 PY 2011 VL 34 SU S MA 0077 BP A30 EP A30 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400079 ER PT J AU Khawaja, IS Kunisaki, K Hurwitz, TD Thuras, P Schumacher, M Germain, A Amborn, B Sebesta, G Dieperink, ME AF Khawaja, I. S. Kunisaki, K. Hurwitz, T. D. Thuras, P. Schumacher, M. Germain, A. Amborn, B. Sebesta, G. Dieperink, M. E. TI IMPROVEMENT IN SLEEP QUALITY OF PATIENTS COMPLETING A PSYCHIATRY PARTIAL HOSPITALIZATION PROGRAM (PHP) SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Khawaja, I. S.; Kunisaki, K.; Hurwitz, T. D.; Thuras, P.; Schumacher, M.; Amborn, B.; Sebesta, G.; Dieperink, M. E.] VA Med Ctr, Dept Psychiat, Minneapolis, MN USA. [Khawaja, I. S.; Kunisaki, K.; Hurwitz, T. D.; Thuras, P.; Dieperink, M. E.] Univ Minnesota, Minneapolis, MN USA. [Germain, A.] VA Pittsburgh Healthcare Syst, Psychiat, Pittsburgh, PA USA. [Germain, A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0715 BP A246 EP A246 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400716 ER PT J AU Kozak, PJ Paer, A Jackson, NJ Chakravorty, S Grandner, MA AF Kozak, P. J. Paer, A. Jackson, N. J. Chakravorty, S. Grandner, M. A. TI ALCOHOL, SMOKING, CAFFEINE AND DRUG USE ASSOCIATED WITH SLEEP DURATION AND SLEEP QUALITY SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Kozak, P. J.; Paer, A.; Jackson, N. J.; Grandner, M. A.] Univ Penn, Div Sleep Med, Philadelphia, PA 19104 USA. [Chakravorty, S.] Philadelphia Vet Affairs Med Ctr, Dept Psychiat, Philadelphia, PA USA. NR 0 TC 1 Z9 1 U1 1 U2 8 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 PY 2011 VL 34 SU S MA 0017 BP A9 EP A9 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400019 ER PT J AU Laitman, BM Gajewski, ND Mann, GL Kubin, L Ross, RJ Morrison, AR AF Laitman, B. M. Gajewski, N. D. Mann, G. L. Kubin, L. Ross, R. J. Morrison, A. R. TI alpha-1 ADRENOCEPTOR ANTAGONIST PRAZOSIN REDUCES REM SLEEP (REMS) FRAGMENTATION AND NON-REM SLEEP (NREMS) LATENCY IN FEAR-CONDITIONED WISTAR-KYOTO RATS (WKY) SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Laitman, B. M.; Gajewski, N. D.; Mann, G. L.; Kubin, L.; Ross, R. J.; Morrison, A. R.] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Ross, R. J.] Philadelphia VA Med Ctr, Behav Hlth Serv, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0186 BP A67 EP A67 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400187 ER PT J AU Levine, CG Sher, AE Weaver, EM AF Levine, C. G. Sher, A. E. Weaver, E. M. TI SURGICAL TREATMENT FOR ADULT OBSTRUCTIVE SLEEP APNEA: A SYSTEMATIC REVIEW OF HIGH-LEVEL EVIDENCE SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Weaver, E. M.] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Weaver, E. M.] VA Puget Sound Hlth Care Syst, Otolaryngol Head & Neck Surg, Seattle, WA USA. [Sher, A. E.] Capital Reg Otolaryngol Head Neck Grp, Albany, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0429 BP A148 EP A148 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400430 ER PT J AU Martin, JL Hughes, J Jouldjian, S Washington, D Yosef, J Alessi, CA AF Martin, J. L. Hughes, J. Jouldjian, S. Washington, D. Yosef, J. Alessi, C. A. TI INSOMNIA AMONG WOMEN VETERANS: RESULTS OF A POSTAL SURVEY SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Martin, J. L.; Washington, D.; Alessi, C. A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Martin, J. L.; Hughes, J.; Jouldjian, S.; Washington, D.; Yosef, J.; Alessi, C. A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0919 BP A314 EP A314 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834401167 ER PT J AU McKenna, JT Abarr, KK Rigby, MS Yanagawa, Y McCarley, RW Brown, RE AF McKenna, J. T. Abarr, K. K. Rigby, M. S. Yanagawa, Y. McCarley, R. W. Brown, R. E. TI DISTRIBUTION AND INTERACTION BETWEEN CORTICALLY PROJECTING BASAL FOREBRAIN NEURONS INVESTIGATED USING MUTANT MOUSE STRAINS EXPRESSING FLUORESCENT PROTEINS IN GABAERGIC AND PARVALBUMIN NEURONS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [McKenna, J. T.; Abarr, K. K.; Rigby, M. S.; McCarley, R. W.; Brown, R. E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02401 USA. [Abarr, K. K.; Rigby, M. S.] Stonehill Coll, Easton, MA USA. [Yanagawa, Y.] Gunma Univ, Grad Sch Med, Maebashi, Gumma 371, Japan. [Yanagawa, Y.] Japan Sci & Technol Agcy, CREST, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0085 BP A32 EP A33 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400087 ER PT J AU Patil, SP Punjabi, NM Patel, SR Walia, H Mehra, R Chen, T Gottlieb, DJ Quan, SF Blumenthal, R Redline, S AF Patil, S. P. Punjabi, N. M. Patel, S. R. Walia, H. Mehra, R. Chen, T. Gottlieb, D. J. Quan, S. F. Blumenthal, R. Redline, S. TI EVALUATING FOR MODERATE-SEVERE SLEEP DISORDERED BREATHING IN PATIENTS WITH AT RISK FOR CORONARY HEART DISEASE SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Patil, S. P.; Punjabi, N. M.; Blumenthal, R.] Johns Hopkins Univ, Baltimore, MD USA. [Patel, S. R.; Quan, S. F.; Redline, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, T.; Gottlieb, D. J.] VA Boston Healthcare Syst, Boston, MA USA. [Walia, H.; Mehra, R.] Univ Hosp Case Med Syst, Cleveland, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0681 BP A235 EP A235 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400682 ER PT J AU Pavlova, I Lyamin, O Kosenko, P Mukhametov, L Siegel, J AF Pavlova, I Lyamin, O. Kosenko, P. Mukhametov, L. Siegel, J. TI REGIONAL DIFFERENCES IN THE CORTICAL EEG ASYMMETRY DURING SLOW WAVE SLEEP IN THE FUR SEAL SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Pavlova, I; Lyamin, O.; Mukhametov, L.] Utrish Dolphinarium Ltd, Moscow, Russia. [Lyamin, O.; Siegel, J.] Univ Calif Los Angeles, North Hills, CA USA. [Lyamin, O.; Siegel, J.] VA GLAHS Sepulveda, North Hills, CA USA. [Lyamin, O.; Mukhametov, L.] Severtsov Inst Ecol & Evolut, Moscow, Russia. [Kosenko, P.] S Fed Univ, Rostov Na Donu, Russia. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0101 BP A38 EP A38 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400103 ER PT J AU Peterson, VL Cameron, MH Lovera, J Boudreau, EA Kim, E McMillan, GP Turner, AP Haselkorn, JK Bourdette, D AF Peterson, V. L. Cameron, M. H. Lovera, J. Boudreau, E. A. Kim, E. McMillan, G. P. Turner, A. P. Haselkorn, J. K. Bourdette, D. TI POOR SLEEP QUALITY IS ASSOCIATED WITH REDUCED PARTICIPATION IN PEOPLE WITH MULTIPLE SCLEROSIS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Peterson, V. L.; Cameron, M. H.; Kim, E.; Bourdette, D.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Cameron, M. H.; Boudreau, E. A.; Kim, E.; Turner, A. P.; Haselkorn, J. K.; Bourdette, D.] Vet Hlth Adm, MS Ctr Excellence W, Seattle, WA USA. [Lovera, J.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [McMillan, G. P.] Portland VA Med Ctr, Natl Ctr Rehabil Auditory Res, Portland, OR USA. [Turner, A. P.; Haselkorn, J. K.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Haselkorn, J. K.] Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0621 BP A215 EP A215 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400622 ER PT J AU Phillips, A Klerman, EB Bianchi, MT AF Phillips, A. Klerman, E. B. Bianchi, M. T. TI NOISE INDUCED TRANSITIONS REPRODUCE REALISTIC SLEEP/WAKE ARCHITECTURE IN A MATHEMATICAL MODEL OF HUMAN SLEEP SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Phillips, A.; Klerman, E. B.] Harvard Univ, Brigham & Womens Hosp, Div Sleep Med, Sch Med, Boston, MA 02115 USA. [Bianchi, M. T.] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Sch Med,Sleep Div, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0096 BP A36 EP A36 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400098 ER PT J AU Richards, A Neylan, TC St-Hilaire, M Metzler, T Marmar, C AF Richards, A. Neylan, T. C. St-Hilaire, M. Metzler, T. Marmar, C. TI SLEEP QUALITY PREDICTS FUTURE POSITIVE AFFECT IN A PROSPECTIVE STUDY OF POLICE ACADEMY RECRUITS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Richards, A.; Neylan, T. C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Richards, A.; Neylan, T. C.; Metzler, T.] San Francisco VA Med Ctr, San Francisco, CA USA. [St-Hilaire, M.] Montreal Univ Hosp Ctr, Montreal, PQ, Canada. [Marmar, C.] NYU, Med Ctr, Dept Psychiat, New York, NY 10016 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0720 BP A248 EP A248 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400721 ER PT J AU Rumble, M Guo, M Phelan, CH Peppard, PE Benca, R AF Rumble, M. Guo, M. Phelan, C. H. Peppard, P. E. Benca, R. TI A PILOT RANDOMIZED CLINICAL EFFECTIVENESS TRIAL OF GROUP COGNITIVE-BEHAVIORAL THERAPY FOR INDIVIDUALS WITH PERSISTENT INSOMNIA FROM THE WISCONSIN SLEEP COHORT STUDY SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Rumble, M.; Guo, M.; Phelan, C. H.; Peppard, P. E.; Benca, R.] Univ Wisconsin, Madison, WI USA. [Phelan, C. H.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 PY 2011 VL 34 SU S MA 0528 BP A181 EP A181 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400529 ER PT J AU Seif, F Patel, SR Bhatt, DL Blumenthal, R Gottlieb, DJ Lewis, EF Patil, SP Quan, SF Redline, S Mehra, R AF Seif, F. Patel, S. R. Bhatt, D. L. Blumenthal, R. Gottlieb, D. J. Lewis, E. F. Patil, S. P. Quan, S. F. Redline, S. Mehra, R. TI OBSTRUCTIVE SLEEP APNEA AND NON-DIPPING NOCTURNAL BLOOD PRESSURE SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Seif, F.; Mehra, R.] Univ Hosp Case Med Ctr, Div Pulm Crit Care & Sleep Med, Cleveland, OH USA. [Patel, S. R.; Quan, S. F.; Redline, S.] Brigham & Womens Hosp, Div Sleep Med, Boston, MA 02115 USA. [Lewis, E. F.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Bhatt, D. L.] VA Boston Healthcare Syst, Div Cardiol, Boston, MA USA. [Gottlieb, D. J.] VA Boston Healthcare Syst, Div Pulm & Sleep Med, Boston, MA USA. [Blumenthal, R.] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Patil, S. P.] Johns Hopkins Univ, Div Pulm & Sleep Med, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0490 BP A168 EP A168 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400491 ER PT J AU Van Dort, CJ Flores, FJ Wilson, MA Brown, EN AF Van Dort, C. J. Flores, F. J. Wilson, M. A. Brown, E. N. TI ELECTROPHYSIOLOGICAL IDENTIFICATION OF SLEEP ACTIVE NEURONS IN RAT BASAL FOREBRAIN SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Van Dort, C. J.; Flores, F. J.; Brown, E. N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Van Dort, C. J.; Flores, F. J.; Wilson, M. A.; Brown, E. N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Wilson, M. A.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Brown, E. N.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 PY 2011 VL 34 SU S MA 0092 BP A35 EP A35 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400094 ER PT J AU Wu, F Nienhuis, R Lam, H Maidment, N Siegel, J AF Wu, F. Nienhuis, R. Lam, H. Maidment, N. Siegel, J. TI ROLE OF THE HYPOCRETIN (OREXIN) 2 RECEPTOR: NO EFFECT OF CATAPLEXY ALTERING DRUGS ON HYPOCRETIN (HCRT) LEVELS IN HCRT-R2 MUTANT NARCOLEPTIC DOGS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Wu, F.; Nienhuis, R.; Siegel, J.] VA GLAHS Sepulveda, North Hills, CA USA. [Wu, F.; Nienhuis, R.; Lam, H.; Maidment, N.; Siegel, J.] Univ Calif Los Angeles, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0003 BP A4 EP A4 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400005 ER PT J AU Xi, M Fung, SJ Chase, MH AF Xi, M. Fung, S. J. Chase, M. H. TI INTERACTIONS BETWEEN PROJECTIONS FROM THE AMYGDALA AND THE PEDUNCULOPONTINE TEGMENTAL NUCLEUS IN THE CONTROL OF ACTIVITY OF NEURONS IN THE NUCLEUS PONTIS ORALIS SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Xi, M.; Fung, S. J.; Chase, M. H.] WebSci Int, Los Angeles, CA USA. [Chase, M. H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Xi, M.; Fung, S. J.; Chase, M. H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0091 BP A34 EP A35 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400093 ER PT J AU Yang, C Yanagawa, Y McCarley, RW Brown, RE AF Yang, C. Yanagawa, Y. McCarley, R. W. Brown, R. E. TI ACETYLCHOLINE DIRECTLY AND INDIRECTLY INCREASES THE EXCITABILITY OF PARVALBUMIN-POSITIVE GABAERGIC NEURONS IN MOUSE BASAL FOREBRAIN SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Yang, C.; McCarley, R. W.; Brown, R. E.] VA Boston Healthcare Syst, Psychiat, Brockton, MA USA. [Yang, C.; McCarley, R. W.; Brown, R. E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [Yanagawa, Y.] Gunma Univ, Sch Med, Maebashi, Gumma 371, Japan. [Yanagawa, Y.] Japan Sci & Technol Agcy, CREST, Chiyoda Ku, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 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 PY 2011 VL 34 SU S MA 0090 BP A34 EP A34 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400092 ER PT J AU Zhang, J Xi, M Fung, SJ Sampogna, S Chase, MH AF Zhang, J. Xi, M. Fung, S. J. Sampogna, S. Chase, M. H. TI THE EPITHELIUM OF THE CHOROID PLEXUS IS INVOLVED IN THE HYPOCRETIN TRANSPORTATION FROM THE CSF TO THE CIRCULATORY SYSTEM SO SLEEP LA English DT Meeting Abstract CT 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) CY JUN 11-15, 2011 CL Minneapolis, MN SP Associated Profess Sleep Soc (APSS) C1 [Zhang, J.; Xi, M.; Fung, S. J.; Sampogna, S.; Chase, M. H.] Websci Int, Los Angeles, CA USA. [Zhang, J.; Xi, M.; Fung, S. J.; Chase, M. H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Chase, M. H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 PY 2011 VL 34 SU S MA 0138 BP A51 EP A51 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 886EG UT WOS:000299834400139 ER PT J AU Mendez, MF Manes, F AF Mendez, Mario F. Manes, Facundo TI The emerging impact of social neuroscience on neuropsychiatry and clinical neuroscience SO SOCIAL NEUROSCIENCE LA English DT Article C1 [Mendez, Mario F.] Univ Calif Los Angeles, David Geffen Sch Med, Sch Med, Los Angeles, CA 90095 USA. [Mendez, Mario F.] VA Greater Los Angeles Healthcare Syst, Neurobehav Unit, Los Angeles, CA USA. [Manes, Facundo] Favaloro Univ, Inst Neurosci, Buenos Aires, DF, Argentina. [Manes, Facundo] Inst Cognit Neurol INECO, Buenos Aires, DF, Argentina. RP Mendez, MF (reprint author), VAGLA, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM mmendez@ucla.edu FU NIA NIH HHS [R01 AG034499] NR 6 TC 3 Z9 3 U1 0 U2 2 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2011 VL 6 IS 5-6 SI SI BP 415 EP 419 DI 10.1080/17470919.2011.624806 PG 5 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 882NL UT WOS:000299570500001 PM 21970720 ER PT J AU Van den Stock, J de Jong, SJ Hodiamont, PPG de Gelder, B AF Van den Stock, Jan de Jong, Sjakko J. Hodiamont, Paul P. G. de Gelder, Beatrice TI Perceiving emotions from bodily expressions and multisensory integration of emotion cues in schizophrenia SO SOCIAL NEUROSCIENCE LA English DT Article DE Schizophrenia; Body; Emotion; Audiovisual ID DYNAMIC BODY EXPRESSIONS; EVENT-RELATED FMRI; FACIAL EMOTION; INFLUENCE RECOGNITION; SOCIAL COGNITION; FEAR CONTAGION; PERCEPTION; LANGUAGE; VOICE; FACE AB Most studies investigating emotion recognition in schizophrenia have focused on facial expressions and neglected bodily and vocal expressions. Furthermore, little is known about affective multisensory integration in schizophrenia. In the first experiment, the authors investigated recognition of static, face-blurred, whole-body expressions (instrumental, angry, fearful, and sad) with a two-alternative, forced-choice, simultaneous matching task in a sample of schizophrenia patients, nonschizophrenic psychotic patients, and matched controls. In the second experiment, dynamic, face-blurred, whole-body expressions (fearful and happy) were presented simultaneously with either congruent or incongruent human or animal vocalizations to schizophrenia patients and controls. Participants were instructed to categorize the emotion expressed by the body and to ignore the auditory information. The results of Experiment 1 show an emotion recognition impairment in the schizophrenia group and to a lesser extent in the nonschizophrenic psychosis group, and this for all four expressions. The findings of Experiment 2 show that schizophrenia patients are more influenced by the auditory information than controls, but only when the auditory information consists of human vocalizations. This shows that schizophrenia patients are impaired in recognizing whole-body expressions, and they show abnormal affective multisensory integration of bimodal stimuli originating from the same source. C1 [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Van den Stock, Jan; de Jong, Sjakko J.; Hodiamont, Paul P. G.; de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [Van den Stock, Jan; de Gelder, Beatrice] Katholieke Univ Leuven, Dept Neurosci, Louvain, Belgium. [de Jong, Sjakko J.] Breburg Grp, GGZ, Tilburg, Netherlands. [Hodiamont, Paul P. G.] Tilburg Univ, Dept Dev Clin & Cross Cultural Psychol, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Sch Med, Boston, MA USA. RP de Gelder, B (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Room 417,Bldg 36,1st St, Charlestown, MA 02129 USA. EM degelder@nmr.mgh.harvard.edu RI Van den Stock, Jan/F-1906-2014 OI Van den Stock, Jan/0000-0001-5756-3195 FU Human Frontiers Science Program [RGP0054/2004-C]; European Commission [FP6-2005-NEST-Path Imp 043403-COBOL]; NWO (Dutch Science Foundation) FX We are grateful to all participants, especially the patients for their willingness to volunteer for the study. Research was funded by a Human Frontiers Science Program grant (RGP0054/2004-C), a European Commission grant (FP6-2005-NEST-Path Imp 043403-COBOL) to B.d.G., and a NWO grant (Dutch Science Foundation). NR 52 TC 23 Z9 23 U1 2 U2 19 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2011 VL 6 IS 5-6 SI SI BP 537 EP 547 DI 10.1080/17470919.2011.568790 PG 11 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 882NL UT WOS:000299570500009 PM 21777157 ER PT J AU Lee, J Quintana, J Nori, P Green, MF AF Lee, Junghee Quintana, Javier Nori, Poorang Green, Michael F. TI Theory of mind in schizophrenia: Exploring neural mechanisms of belief attribution SO SOCIAL NEUROSCIENCE LA English DT Article DE Theory of mind; Belief attribution; Schizophrenia; fMRI; Social cognition ID TEMPORO-PARIETAL JUNCTION; SOCIAL COGNITION; NEUROCOGNITIVE DEFICITS; TEMPOROPARIETAL JUNCTION; BRAIN-REGIONS; FMRI; PEOPLE; PERCEPTION; ROBUST; OPTIMIZATION AB Background: Although previous behavioral studies have shown that schizophrenia patients have impaired theory of mind (ToM), the neural mechanisms associated with this impairment are poorly understood. This study aimed to identify the neural mechanisms of ToM in schizophrenia, using functional magnetic resonance imaging (fMRI) with a belief attribution task. Methods: In the scanner, 12 schizophrenia patients and 13 healthy control subjects performed the belief attribution task with three conditions: a false belief condition, a false photograph condition, and a simple reading condition. Results: For the false belief versus simple reading conditions, schizophrenia patients showed reduced neural activation in areas including the temporoparietal junction (TPJ) and medial prefrontal cortex (MPFC) compared with controls. Further, during the false belief versus false photograph conditions, we observed increased activations in the TPJ and the MPFC in healthy controls, but not in schizophrenia patients. For the false photograph versus simple reading condition, both groups showed comparable neural activations. Conclusions: Schizophrenia patients showed reduced task-related activation in the TPJ and the MPFC during the false belief condition compared with controls, but not for the false photograph condition. This pattern suggests that reduced activation in these regions is associated with, and specific to, impaired ToM in schizophrenia. C1 [Lee, Junghee; Quintana, Javier; Nori, Poorang; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Lee, Junghee; Quintana, Javier; Nori, Poorang; Green, Michael F.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Lee, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 300 Med Plaza,Room 2261, Los Angeles, CA 90095 USA. EM jungheelee@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 FU Veterans Integrated Service Network 22 Mental Illness Research, Education and Clinical Center; Veterans Administration Medical Research Service; NIMH [MH043292, MH065707] FX Support for this study came from the Veterans Integrated Service Network 22 Mental Illness Research, Education and Clinical Center (to Lee); a Merit Review Award from the Veterans Administration Medical Research Service (to Quintana); and NIMH grants MH043292 and MH065707 (to Green). We wish to thank Dr. Rebecca Saxe for providing the vignettes for the task. For generous support of the UCLA Brain Mapping Center, we also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, Ahmanson Foundation, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, and Northstar Fund. Financial disclosure: The authors have nothing to disclose. NR 60 TC 22 Z9 23 U1 3 U2 10 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI-UK JI Soc. Neurosci. PY 2011 VL 6 IS 5-6 SI SI BP 569 EP 581 DI 10.1080/17470919.2011.620774 PG 13 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 882NL UT WOS:000299570500012 PM 22050432 ER PT J AU Bell, ME Reardon, A AF Bell, Margret E. Reardon, Annemarie TI Experiences of Sexual Harassment and Sexual Assault in the Military Among OEF/OIF Veterans: Implications for Health Care Providers SO SOCIAL WORK IN HEALTH CARE LA English DT Article DE sexual assault; sexual harassment; sexual trauma; military; Veteran; OEF/OIF; health care ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD TRAUMA; WOMEN; PTSD; PREVALENCE; SERVICE; ABUSE; RISK AB Given the frequent occurrence and significant health impact of sexual harassment and sexual assault in the military, it is important that for health care providers working with Veterans to have at least some basic knowledge in this area. Targeting providers addressing mental health and psychosocial issues, but also applicable to clinicians working with survivors in a variety of capacities, this article provides an overview of clinical care with survivors of sexual trauma in the military, particularly those who are OEF/OIF Veterans. We cover basic background information, focusing primarily on the impact of sexual trauma in the military, how survivor's reactions are shaped by various aspects of the military context, and general principles to assist clinicians in working effectively with survivors, whatever their role. C1 [Bell, Margret E.] Dept Vet Affairs, Boston, MA USA. [Bell, Margret E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Reardon, Annemarie] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. RP Bell, ME (reprint author), VA Boston HCS, 150 S Huntington Ave,116B-3, Boston, MA 02130 USA. EM margret.bell@va.gov NR 33 TC 12 Z9 12 U1 1 U2 10 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0098-1389 J9 SOC WORK HEALTH CARE JI Soc. Work Health Care PY 2011 VL 50 IS 1 BP 34 EP 50 DI 10.1080/00981389.2010.513917 PG 17 WC Social Work SC Social Work GA 726GJ UT WOS:000287707600004 PM 21240770 ER PT J AU Skidmore, WC Roy, M AF Skidmore, W. Christopher Roy, Monica TI Practical Considerations for Addressing Substance Use Disorders in Veterans and Service Members SO SOCIAL WORK IN HEALTH CARE LA English DT Article DE substance use disorders; veterans; military; treatment; assessment ID POSTTRAUMATIC-STRESS-DISORDER; DIALECTICAL BEHAVIOR-THERAPY; ALCOHOL-USE DISORDERS; DRUG-ABUSE; ADDICTIVE DISORDERS; EXPOSURE THERAPY; CASE-MANAGEMENT; SCREENING-TEST; ILLICIT DRUG; COMORBIDITY AB Support and treatment for military veterans and active duty service members is a national priority. Furthermore, there is increased need for professionals with experience and interest in working with these brave individuals. Veterans and service members face significant challenges both during their service and after transitioning back to civilian settings. One such challenge for some veterans is substance use and its multidimensional effects on mental and physical health. The current article presents a brief but comprehensive overview of the prevalence and comorbidity of substance use disorders in veterans and service members. It also reviews practical information about assessment, treatment, and general clinical issues from the authors' clinical experience that is relevant to providers working with veterans and service members with substance use disorders. This information may be of particular interest to professionals with an interest in helping veterans, those who have limited experience working with veterans, or those who may work outside of standard military or Department of Veterans Affairs settings. Finally, future directions in this important area are discussed. C1 [Skidmore, W. Christopher] VA Boston Healthcare Syst, Psychol Serv 116B, Boston, MA 02130 USA. RP Skidmore, WC (reprint author), VA Boston Healthcare Syst, Psychol Serv 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM Chris.Skidmore@va.gov NR 80 TC 9 Z9 9 U1 2 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0098-1389 EI 1541-034X J9 SOC WORK HEALTH CARE JI Soc. Work Health Care PY 2011 VL 50 IS 1 BP 85 EP 107 DI 10.1080/00981389.2010.522913 PG 23 WC Social Work SC Social Work GA 726GJ UT WOS:000287707600007 PM 21240773 ER PT S AU Radu, A Hristescu, G Katsel, P Haroutunian, V Davis, KL AF Radu, Aurelian Hristescu, Gabriela Katsel, Pavel Haroutunian, Vahram Davis, Kenneth L. BE Arabnia, HR Tran, QN TI Microarray Database Mining and Cell Differentiation Defects in Schizophrenia SO SOFTWARE TOOLS AND ALGORITHMS FOR BIOLOGICAL SYSTEMS SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter ID ANTERIOR CINGULATE CORTEX; MYELINATION-RELATED GENES; PROGENITOR CELLS; OLIGODENDROCYTE DYSFUNCTION; MESSENGER-RNA; ADULT BRAIN; EXPRESSION; NEUROPATHOLOGY; POSTMORTEM; MATTER AB The causes of schizophrenia remain unknown, but a key role of oligodendrocytes and of the myelination process carried out by them has gained increasing support. The adult human brain parenchyma contains a relatively large population of progenitor cells that can generate oligodendrocytes. Defects in these adult oligodendrocyte progenitor cells (OPCs) or in their proliferation/differentiation have received little attention as potential causes of schizophrenia yet. We compared the set of genes whose expression is modified in schizophrenia, as revealed by our microarray studies, with genes specifically expressed in stem cells, as revealed by studies on human embryonic stem cells. We also evaluated the genes that are upregulated when stem cells engage in differentiation programs. These genes can be viewed as fingerprints or signatures for differentiation processes. The comparisons revealed that a substantial fraction of the genes downregulated in the brains of persons with schizophrenia belong to the differentiation signature. A plausible interpretation of our observations is that a cell differentiation process, possibly of adult OPCs to oligodendrocytes, is perturbed in schizophrenia. These observations constitute an incentive for a new direction of study, aimed at investigating the potential role of OPCs in schizophrenia. C1 [Radu, Aurelian] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Hristescu, Gabriela] Rowan Univ, Dept Comp Sci, Glassboro, NJ 08028 USA. [Katsel, Pavel; Haroutunian, Vahram] Bronx Vet Affairs Med Ctr, Mental Illness Res Ctr, Bronx, NY 10468 USA. [Katsel, Pavel; Haroutunian, Vahram] Bronx Vet Affairs Med Ctr, Educ Ctr, Bronx, NY 10468 USA. [Katsel, Pavel; Haroutunian, Vahram] Bronx Vet Affairs Med Ctr, Ctr Clin, Bronx, NY 10468 USA. [Katsel, Pavel; Haroutunian, Vahram; Davis, Kenneth L.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Radu, A (reprint author), Mt Sinai Sch Med, Dept Dev & Regenerat Biol, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM aurelian.radu@mssm.edu; hristescu@rowan.edu; pavel.katsel@mssm.edu; vahram.haroutunian@mssm.edu; kenneth.davis@mssm.edu FU NIMH NIH HHS [MH45212, MH064673] NR 31 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4419-7045-9 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2011 VL 696 BP 67 EP 74 DI 10.1007/978-1-4419-7046-6_7 D2 10.1007/978-1-4419-7046-6 PG 8 WC Biology; Mathematical & Computational Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Research & Experimental Medicine GA BUK92 UT WOS:000289694000007 PM 21431547 ER PT J AU Balboni, MJ Balboni, TA AF Balboni, Michael J. Balboni, Tracy A. BE Peteet, JR DAmbra, MN TI Spirituality and Biomedicine A History of Harmony and Discord SO SOUL OF MEDICINE: SPIRITUAL PERSPECTIVES AND CLINICAL PRACTICE LA English DT Article; Book Chapter C1 [Balboni, Michael J.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Balboni, Tracy A.] Harvard Univ, Sch Med, Boston, MA USA. RP Balboni, MJ (reprint author), Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. EM mjbalboni@partners.org; tbalboni@partners.org NR 63 TC 3 Z9 3 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA 2715 N CHARLES ST, BALTIMORE, MD 21218-4319 USA BN 978-1-4214-0299-4 PY 2011 BP 3 EP 22 PG 20 WC History & Philosophy Of Science; Religion SC History & Philosophy of Science; Religion GA BB1DY UT WOS:000341020500002 ER PT J AU Peteet, JR Balboni, MJ D'Ambra, MN AF Peteet, John R. Balboni, Michael J. D'Ambra, Michael N. BE Peteet, JR DAmbra, MN TI Approaching Spirituality in Clinical Practice SO SOUL OF MEDICINE: SPIRITUAL PERSPECTIVES AND CLINICAL PRACTICE LA English DT Article; Book Chapter ID QUALITY-OF-LIFE; ADVANCED CANCER; CARE; RELIGION; DEPRESSION; MEDICINE; THERAPY; ILLNESS; SCALE; NEEDS C1 [Peteet, John R.; D'Ambra, Michael N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Balboni, Michael J.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. RP Peteet, JR (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM jpeteet@partners.org; mjbalboni@partners.org; mdambra@partners.org NR 53 TC 5 Z9 5 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA 2715 N CHARLES ST, BALTIMORE, MD 21218-4319 USA BN 978-1-4214-0299-4 PY 2011 BP 23 EP 44 PG 22 WC History & Philosophy Of Science; Religion SC History & Philosophy of Science; Religion GA BB1DY UT WOS:000341020500003 ER PT J AU Balboni, MJ Bard, TR Liu, SW D'Ambra, MN Johnson, TD Moczynski, W Peteet, JR AF Balboni, Michael J. Bard, Terry R. Liu, Shan W. D'Ambra, Michael N. Johnson, Travis D. Moczynski, Walter Peteet, John R. BE Peteet, JR DAmbra, MN TI Ethical Considerations and Implications for Professionalism SO SOUL OF MEDICINE: SPIRITUAL PERSPECTIVES AND CLINICAL PRACTICE LA English DT Article; Book Chapter ID CONTROVERSIAL CLINICAL PRACTICES; MODERN MEDICINE; RELIGION; CARE; PHYSICIANS; CONSCIENCE; SPIRITUALITY; VIEWPOINT; OATH; BOUNDARIES C1 [Balboni, Michael J.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Bard, Terry R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Liu, Shan W.] Harvard Univ, Sch Med, Dept Emergency Med, Massachusetts Gen Hosp, Boston, MA USA. [D'Ambra, Michael N.; Peteet, John R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Johnson, Travis D.] Univ N Carolina, Hendersonville Family Med Residency Program, Hendersonville, NC USA. [Moczynski, Walter] Harvard Univ, Sch Divin, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Balboni, MJ (reprint author), Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. EM mjbalboni@partners.org; Terry_Bard@hms.harvard.edu; sliu1@partners.org; mdambra@partners.org; travisduanejohnson@gmail.com; wmoczynski@partners.org; jpeteet@partners.org NR 69 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA 2715 N CHARLES ST, BALTIMORE, MD 21218-4319 USA BN 978-1-4214-0299-4 PY 2011 BP 199 EP 224 PG 26 WC History & Philosophy Of Science; Religion SC History & Philosophy of Science; Religion GA BB1DY UT WOS:000341020500013 ER PT J AU Bard, TR Moczynski, W AF Bard, Terry R. Moczynski, Walter BE Peteet, JR DAmbra, MN TI Spiritual Care and Chaplaincy SO SOUL OF MEDICINE: SPIRITUAL PERSPECTIVES AND CLINICAL PRACTICE LA English DT Article; Book Chapter C1 [Bard, Terry R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Moczynski, Walter] Harvard Univ, Sch Divin, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bard, TR (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM Terry_Bard@hms.harvard.edu; wmoczynski@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA 2715 N CHARLES ST, BALTIMORE, MD 21218-4319 USA BN 978-1-4214-0299-4 PY 2011 BP 225 EP 236 PG 12 WC History & Philosophy Of Science; Religion SC History & Philosophy of Science; Religion GA BB1DY UT WOS:000341020500014 ER PT S AU Brice, SE Cowart, LA AF Brice, Sarah E. Cowart, L. Ashley BE Cowart, LA TI SPHINGOLIPID METABOLISM AND ANALYSIS IN METABOLIC DISEASE SO SPHINGOLIPIDS AND METABOLIC DISEASE SE Advances in Experimental Medicine and Biology LA English DT Article; Book Chapter ID INDUCED INSULIN-RESISTANCE; PROTEIN-KINASE-C; MAMMALIAN SERINE-PALMITOYLTRANSFERASE; NECROSIS-FACTOR-ALPHA; INDUCED MITOCHONDRIAL APOPTOSIS; ENDOPLASMIC-RETICULUM MEMBRANE; THIN-LAYER CHROMATOGRAPHY; SKELETAL-MUSCLE CELLS; SATURATED FATTY-ACIDS; CHAIN BASE SYNTHESIS AB Sphingolipids are an important class of structural and signaling molecules within the cell. As sphingolipids have been implicated in the development and pathogenesis of insulin resistance and the metabolic syndrome, it is important to understand their regulation and metabolism. Although these lipids are initially produced through a common pathway, there is no "generic" sphingolipid. Indeed, the biophysical and signaling properties of lipids may be manipulated by the subunit composition or isoform of their synthetic enzymes, via regulation of substrate integration. Functionally distinct pools of chemically-equivalent lipids may also be generated by de novo synthesis and recycling of existing complex sphingolipids. The highly integrated metabolism of the many bioactive sphingolipids means that manipulation of one enzyme or metabolite can result in a ripple effect, causing unforeseen changes in metabolite levels, enzyme activities, and cellular programmes. Fortunately, a suite of techniques, ranging from thin-layer chromatography to liquid chromatography-mass spectrometry approaches, allows investigators to undertake a functional characterization of all or part of the sphingolipidome in their systems of interest. C1 [Brice, Sarah E.; Cowart, L. Ashley] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Cowart, L. Ashley] Ralph H Johnson Vet Adm, Charleston, SC USA. RP Brice, SE (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. EM brices@musc.edu NR 172 TC 14 Z9 14 U1 1 U2 5 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4614-0649-5 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2011 VL 721 BP 1 EP 17 D2 10.1007/978-1-4614-0650-1 PG 17 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA BWF42 UT WOS:000293800300001 PM 21910079 ER PT J AU Wang, SL Wang, C Wood, KB Yan, M Zhou, HT AF Wang, Shenglin Wang, Chao Wood, Kirkham B. Yan, Ming Zhou, Haitao TI Radiographic Evaluation of the Technique for C1 Lateral Mass and C2 Pedicle Screw Fixation in Three Hundred Nineteen Cases SO SPINE LA English DT Article DE atlantoaxial fixation; C1 lateral mass screw; C2 pedicle screw; vertebral artery injury; computed tomography ID POSTERIOR ATLANTOAXIAL FIXATION; VERTEBRAL ARTERY; POLYAXIAL SCREW; C1-C2 COMPLEX; PLATE; PLACEMENT; STABILIZATION; ANGIOGRAPHY; FUSION; SAFETY AB Study Design. Retrospective radiographic study of the technique for C1 lateral mass screw (C1LMS) and C2 pedicle screw (C2PS) fixation. Objective. To evaluate (1) the accuracy of the C1LMS and C2PS placement; (2) the fusion rate between C1 and C2; (3) the risk for vertebral artery (VA) injury. Summary of Background Data. C1LMS and C2PS fixation is widely used when treating atlantoaxial instability. Several authors have reported their experience focusing on the technical outcomes, with many reporting fusion rates near 100%. However, most of them are relatively small series, and many have applied only plain postoperative radiographs instead of computed tomography (CT). Thus, we feel that the accuracy of C1LMS and C2PS placement has not been fully analyzed, as well as the anatomic relationship between the VA and the screws. Methods. Between December 2000 and September 2008, the fusion status and accuracy of the screws were evaluated on the postoperative reconstructive CT of 319 patients with atlantoaxial instability. Cases with malpositioned screws underwent CT angiography or magnetic resonance angiography after surgery, to evaluate potential VA injury. Results. C1LMS of 95.5% and C2PS of 92.8% were found to be in a "good" position. After 2007, six cases had malpositioned screws, which were all in the "out" or "down" area of the C2 pedicle. Five cases underwent CT angiography and 1 had magnetic resonance angiography to evaluate potential VA injury. No occlusion, associated aneurysm or fistula of the VA was found. All cases (100%) achieved solid fusion between C1 and C2. Conclusion. C1LMS of 95.5% and C2PS of 92.8% were confirmed to be in good position. None of the screws including the malpositioned caused VA injury, clinically or radiographically. The technique for C1LMS and C2PS fixation appears to be safe and effective. C1 [Wang, Shenglin; Wang, Chao; Yan, Ming; Zhou, Haitao] Peking Univ, Hosp 3, Dept Orthopaed, Beijing 100191, Peoples R China. [Wood, Kirkham B.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Wood, Kirkham B.] Harvard Univ, Sch Med, Boston, MA USA. RP Wang, C (reprint author), Peking Univ, Hosp 3, Dept Orthopaed, 49 N Garden St, Beijing 100191, Peoples R China. EM wangchaoo@ynet.com NR 25 TC 17 Z9 19 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JAN PY 2011 VL 36 IS 1 BP 3 EP 8 DI 10.1097/BRS.0b013e3181c97dc7 PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 700XL UT WOS:000285778700013 PM 20693942 ER PT J AU Suri, P Rainville, J Katz, JN Jouve, C Hartigan, C Limke, J Pena, E Li, L Swaim, B Hunter, DJ AF Suri, Pradeep Rainville, James Katz, Jeffrey N. Jouve, Cristin Hartigan, Carol Limke, Janet Pena, Enrique Li, Ling Swaim, Bryan Hunter, David J. TI The Accuracy of the Physical Examination for the Diagnosis of Midlumbar and Low Lumbar Nerve Root Impingement SO SPINE LA English DT Article DE physical examination; diagnostic; accuracy; sensitivity; specificity; lumbar; back pain; radiculop-athy; herniation; impingement ID LOW-BACK-PAIN; RESEARCH TRIAL SPORT; DISK HERNIATION; NONOPERATIVE TREATMENT; SURGICAL-MANAGEMENT; HISTORY; SPINE; SCIATICA; DEGENERATION; COMPRESSION AB Study Design. Cross-sectional study with prospective recruitment. Objective. To determine the accuracy of the physical examination for the diagnosis of midlumbar nerve root impingement (L2, L3, or L4), low lumbar nerve root impingement (L5 or S1) and level-specific lumbar nerve root impingement on magnetic resonance imaging, using in dividual tests and combinations of tests. Summary of Background Data. The sensitivity and specificity of the physical examination for the localization of nerve root impingement has not been previously studied. Methods. Sensitivities, specificities, and likelihood ratios (LRs) were calculated for the ability of individual tests and test combinations to predict the presence or absence of nerve root impingement at midlumbar, low lumbar, and specific nerve root levels. Results. LRs >= 5.0 indicate moderate to large changes from pre-test probability of nerve root impingement to post-test probability. For the diagnosis of midlumbar impingement, the femoral stretch test (FST), crossed FST, medial ankle pinprick sensation, and patellar reflex testing demonstrated LRs >= 5.0 (LR infinity). LRs >= 5.0 were ob served with the combinations of FST and either patellar reflex testing (LR 7.0; 95% confidence interval [CI] 2.3-21) or the sit-to-stand test (LR infinity). For the diagnosis of low lumbar impingement, the Achilles reflex test demonstrated an LR >= 5.0 (LR 7.1; 95% CI 0.96-53); test combinations did not increase LRs. For the diagnosis of level-specific impingement, LRs >= 5.0 were observed for anterior thigh sensation at L2 (LR 13; 95% CI 1.8-87); FST at L3 (LR 5.7; 95% CI 2.3-4.4); patellar reflex testing (LR 7.7; 95% CI 1.7-35), medial ankle sensation (LR infinity), or crossed FST (LR 13; 95% CI 1.8-87) at L4; and hip abductor strength at L5 (LR 11; 95% CI 1.3-84). Test combinations increased LRs for level-specific root impingement at the L4 level only. Conclusion. Individual physical examination tests may provide clinical information that substantially alters the likelihood that midlumbar impingement, low lumbar im pingement, or level-specific impingement is present. Test combinations improve diagnostic accuracy for midlum-bar impingement. C1 [Suri, Pradeep; Rainville, James; Jouve, Cristin; Hartigan, Carol; Limke, Janet; Pena, Enrique; Li, Ling; Swaim, Bryan; Hunter, David J.] New England Baptist Hosp, Div Res, Boston, MA 02130 USA. [Suri, Pradeep] Spaulding Rehabil Hosp, Boston, MA USA. [Suri, Pradeep; Rainville, James; Jouve, Cristin; Hartigan, Carol; Limke, Janet] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, Pradeep] VA Boston Healthcare Syst, Boston, MA USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy,Dept Med, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. RP Suri, P (reprint author), New England Baptist Hosp, Div Res, 125 Parker Hill Ave, Boston, MA 02130 USA. EM psuri@caregroup.harvard.edu RI Hunter, David/A-4622-2010 OI Hunter, David/0000-0003-3197-752X FU Rehabilitation Medicine Scientist Training Program (RMSTP); National Institutes of Health [K12 HD 01097]; NIH/NIAMS [K24 AR 02123] FX Funds were received to support this work from NIH. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Supported by the Rehabilitation Medicine Scientist Training Program (RMSTP) and the National Institutes of Health grant K12 HD 01097 (to P.S.), and, in part, by the grant NIH/NIAMS K24 AR 02123 (to J.N.K.). NR 37 TC 18 Z9 18 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JAN PY 2011 VL 36 IS 1 BP 63 EP 73 DI 10.1097/BRS.0b013e3181c953cc PG 11 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 700XL UT WOS:000285778700023 PM 20543768 ER PT J AU Sowa, GA Coelho, JP Bell, KM Zorn, AS Vo, NV Smolinski, P Niyonkuru, C Hartman, R Studer, RK Kang, JD AF Sowa, Gwendolyn A. Coelho, J. Paulo Bell, Kevin M. Zorn, Andrew S. Vo, Nam V. Smolinski, Patrick Niyonkuru, Christian Hartman, Robert Studer, Rebecca K. Kang, James D. TI Alterations in gene expression in response to compression of nucleus pulposus cells SO SPINE JOURNAL LA English DT Article DE Intervertebral disc; Gene expression; Compression ID LUMBAR INTERVERTEBRAL DISC; IN-VIVO; DYNAMIC COMPRESSION; PRESSURE MEASUREMENTS; FINITE-ELEMENT; SPINE; MODEL; DEGENERATION; FREQUENCY AB BACKGROUND CONTEXT: It is clear that mechanical forces are involved in initiating disc degeneration but also have the potential to exert beneficial effects. However, the signaling pathways initiated by mechanical stress and thresholds for these responses have not been elucidated. We have developed a metabolically active compression system with the advantages of having the ability to test cells in vitro as well as within their native matrix and control exposure to environmental factors. We hypothesized that nucleus pulposus cells would respond to compressive stress with different thresholds for alterations in catabolic and anabolic gene expression. PURPOSE: The purpose of the study was to establish the utility of a novel compression chamber and examine the effects of various magnitudes and durations of compression on nucleus pulposus inflammatory, catabolic, and anabolic gene expression. STUDY DESIGN: In vitro controlled examination of intervertebral disc cell responses to compression. METHODS: A chamber capable of imparting 0 to 20 MPa of hydrostatic compression onto nucleus pulposus cells was fabricated. Healthy rabbit nucleus pulposus cells were cultured in alginate beads and exposed to static compression at 0.7, 2, and 4 MPa for 4 or 24 hours. Gene expression analysis (real-time polymerase chain reaction) was performed to compare markers of inflammation (inducible nitric oxide synthase, cyclooxygenase-2), matrix catabolism (matrix metalloproteinase-3), and anticatabolic/anabolic metabolism (tissue inhibitor of metalloproteinase-1, aggrecan) in control and compressed cells. RESULTS: Compression resulted in magnitude-and duration-dependent changes in gene expression. Increasing magnitudes showed more anticatabolic gene expression changes, whereas increasing duration resulted in increases in procatabolic gene expression. CONCLUSION: These data demonstrate favorable effects of compression in relation to genes involved in matrix homeostasis and procatabolic gene expression in response to sustained loading levels, consistent with traumatic effects. These data provide an improved understanding of how compression affects cell signaling, which has the potential to be exploited to initiate repair and prevent matrix breakdown. (C) 2011 Elsevier Inc. All rights reserved. C1 [Sowa, Gwendolyn A.; Coelho, J. Paulo; Bell, Kevin M.; Zorn, Andrew S.; Vo, Nam V.; Hartman, Robert; Kang, James D.] Univ Pittsburgh, Dept Orthopaed Surg, Ferguson Lab Orthopaed Res, Pittsburgh, PA 15213 USA. [Sowa, Gwendolyn A.; Coelho, J. Paulo; Niyonkuru, Christian] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Smolinski, Patrick] Univ Pittsburgh, Dept Mech Engn, Pittsburgh, PA 15216 USA. [Studer, Rebecca K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Sowa, GA (reprint author), Univ Pittsburgh, Dept Orthopaed Surg, Ferguson Lab Orthopaed Res, 3471 5th Ave, Pittsburgh, PA 15213 USA. EM sowaga@upmc.edu FU DePuy Spine; CSRS FX Author disclosures: JDK (endowments, Pittsburgh Foundation; research support: staff/materials, J&J (ATRM Biologic), DePuy Spine; grants, CSRS). NR 31 TC 15 Z9 18 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 J9 SPINE J JI Spine Journal PD JAN PY 2011 VL 11 IS 1 BP 36 EP 43 DI 10.1016/j.spinee.2010.09.019 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 696AP UT WOS:000285414600010 PM 21056011 ER PT J AU Chartoff, EH Damez-Werno, D Sonntag, KC Hassinger, L Kaufmann, DE Peterson, J McPhie, D Cataldo, AM Cohen, BM AF Chartoff, Elena H. Damez-Werno, Diane Sonntag, Kai C. Hassinger, Linda Kaufmann, Daniel E. Peterson, Jesse McPhie, Donna Cataldo, Anne M. Cohen, Bruce M. TI Detection of Intranasally Delivered Bone Marrow-Derived Mesenchymal Stromal Cells in the Lesioned Mouse Brain: A Cautionary Report SO STEM CELLS INTERNATIONAL LA English DT Article AB Bone marrow-derived mesenchymal stromal cells (MSCs) hold promise for autologous treatment of neuropathologies. Intranasal delivery is relatively noninvasive and has recently been reported to result in transport of MSCs to the brain. However, the ability of MSCs to migrate from nasal passages to sites of neuropathology and ultimately survive has not been fully examined. In this paper, we harvested MSCs from transgenic mice expressing enhanced green fluorescent protein (cells hereafter referred to as MSC-EGFP) and delivered them intranasally to wild-type mice sustaining mechanical lesions in the striatum. Using fluorescent, colorimetric, and ultrastructural detection methods, GFP-expressing cells were undetectable in the brain from 3 hours to 2 months after MSC delivery. However, bright autofluorescence that strongly resembled emission from GFP was observed in the olfactory bulb and striatum of lesioned control and MSC-EGFP-treated mice. In a control experiment, we directly implanted MSC-EGFPs into the mouse striatum and detected robust GFP expression 1 and 7 days after implantation. These findings suggest that-under our conditions-intranasally delivered MSC-EGFPs do not survive or migrate in the brain. Furthermore, our observations highlight the necessity of including appropriate controls when working with GFP as a cellular marker. C1 [Chartoff, Elena H.; Damez-Werno, Diane; Sonntag, Kai C.; Hassinger, Linda; Peterson, Jesse; McPhie, Donna; Cataldo, Anne M.; Cohen, Bruce M.] Harvard Univ, McLean Hosp, Dept Psychiat, Sch Med, Belmont, MA 02478 USA. [Kaufmann, Daniel E.] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Charlestown, MA 02129 USA. RP Chartoff, EH (reprint author), Harvard Univ, McLean Hosp, Dept Psychiat, Sch Med, 115 Mill St, Belmont, MA 02478 USA. EM echartoff@mclean.harvard.edu OI Sonntag, Kai C./0000-0001-7979-8171 FU Center Grant, Stanley Medical Research Institute; Frazier Research Institute FX Center Grant, Stanley Medical Research Institute, and Frazier Research Institute (to B. M. Cohen) funded this paper. NR 43 TC 2 Z9 2 U1 0 U2 1 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1687-966X J9 STEM CELLS INT JI Stem Cells Int. PY 2011 AR UNSP 586586 DI 10.4061/2011/586586 PG 12 WC Cell & Tissue Engineering SC Cell Biology GA V29PM UT WOS:000208760300034 ER PT J AU Ronald, J Rajagopalan, R Cerrato, F Nord, AS Hatsukami, T Kohler, T Marcovina, S Heagerty, P Jarvik, GP AF Ronald, James Rajagopalan, Ramakrishnan Cerrato, Felecia Nord, Alex S. Hatsukami, Thomas Kohler, Ted Marcovina, Santica Heagerty, Patrick Jarvik, Gail P. TI Genetic Variation in LPAL2, LPA, and PLG Predicts Plasma Lipoprotein(a) Level and Carotid Artery Disease Risk SO STROKE LA English DT Article DE atherosclerosis; carotid stenosis; genomics; lipoprotein(a); risk factors ID CORONARY-HEART-DISEASE; INTIMA-MEDIA THICKNESS; APOLIPOPROTEIN(A) GENE; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; VASCULAR-DISEASE; ISCHEMIC-STROKE; GENOTYPE DATA; COPY NUMBER; POLYMORPHISM AB Background and Purpose-Lipoprotein(a) [Lp(a)] level is an established risk factor for coronary artery disease and has been implicated in carotid artery disease (CAAD). The relationship between genetic variation in the LPA gene region and CAAD risk remains unknown. Methods-We genotyped single nucleotide polymorphisms (SNPs) in the LPAL2, LPA, and PLG regions in 530 individuals with severe CAAD and 770 controls and kringle IV type 2 (KIV2) repeat length in a subset of 90 individuals. Results-Nine SNPs collectively accounted for 30% of the variance in Lp(a) level. Six SNPs were associated with Lp(a) level after accounting for KIV2 copy number, and the dominant KIV2 allele combined with these markers explained 60% of the variance in Lp(a) level. Five SNPs, including rs10455872, which had an odds ratio of 2.1 per minor allele and haplotypes formed by rs10455872, rs6919346, and rs3123629, were significant predictors of CAAD. After accounting for Lp(a) level, all evidence of CAAD-genotype association in the LPA region was eliminated. Conclusions-LPA region SNPs capture some but not all of the effect of KIV2 repeat length on Lp(a) level. There are associations between LPA region SNPs and CAAD that appear to be attributable to effects on Lp(a) level. (Stroke. 2011; 42: 2-9.) C1 [Jarvik, Gail P.] Univ Washington, Med Ctr, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Marcovina, Santica] Univ Washington, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98195 USA. [Nord, Alex S.] Univ Washington, Div Genome Sci, Dept Med, Seattle, WA 98195 USA. [Hatsukami, Thomas; Jarvik, Gail P.] Univ Washington, Div Vasc Surg, Dept Med, Seattle, WA 98195 USA. [Heagerty, Patrick] Univ Washington, Div Biostat, Dept Med, Seattle, WA 98195 USA. [Kohler, Ted] Vet Affairs Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA USA. RP Jarvik, GP (reprint author), Univ Washington, Med Ctr, Div Med Genet, Dept Med, Box 357720, Seattle, WA 98195 USA. EM pair@u.washington.edu RI Jarvik, Gail/N-6476-2014 OI Jarvik, Gail/0000-0002-6710-8708 FU National Institutes of Health (NIH) [PO1 HL 30086, RO1 HL67406]; VA Puget Sound Health Care System, Seattle, Washington including the Veteran Affairs Epidemiology Research and Information Center [CSP 701S] FX This work was funded by the National Institutes of Health (NIH) PO1 HL 30086 and RO1 HL67406. This work was supported in part by resources from the VA Puget Sound Health Care System, Seattle, Washington, including the Veteran Affairs Epidemiology Research and Information Center Program (award CSP 701S). NR 51 TC 19 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2011 VL 42 IS 1 BP 2 EP 9 DI 10.1161/STROKEAHA.110.591230 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 699AN UT WOS:000285636400008 PM 21127300 ER PT J AU Ning, MM Sarracino, DA Kho, AT Guo, S Lee, SR Krastins, B Buonanno, FS Vizcaino, JA Orchard, S McMullin, D Wang, XY Lo, EH AF Ning, MingMing Sarracino, David A. Kho, Alvin T. Guo, Shuzhen Lee, Sun-Ryung Krastins, Bryan Buonanno, Ferdinando S. Vizcaino, Juan A. Orchard, Sandra McMullin, David Wang, Xiaoying Lo, Eng H. TI Proteomic Temporal Profile of Human Brain Endothelium After Oxidative Stress SO STROKE LA English DT Article DE biomarker; cerebral ischemia; human brain endothelial cells; oxidative stress; proteomics ID ISCHEMIC-STROKE; HUMAN PLASMA; BLOOD; CELLS; ANGIOGENESIS; DISEASE; BARRIER; HEALTH AB Background and Purpose-Because brain endothelial cells exist at the neurovascular interface, they may serve as cellular reporters of brain dysfunction by releasing biomarkers into the circulation. Methods-We used proteomic techniques to screen conditioned media from human brain endothelial cultures subjected to oxidative stress induced by nitric oxide over 24 hours. Plasma samples from human stroke patients were analyzed by enzyme-linked immunosorbent assay. Results-In healthy endothelial cells, interaction mapping demonstrated cross-talk involving secreted factors, membrane receptors, and matrix components. In oxidatively challenged endothelial cells, networks of interacting proteins failed to emerge. Instead, inflammatory markers increased, secreted factors oscillated over time, and endothelial injury repair was manifested as changes in factors related to matrix integrity. Elevated inflammatory markers included heat shock protein, chemokine ligand-1, serum amyloid-A1, annexin-A5, and thrombospondin-1. Neurotrophic factors (prosaposin, nucleobindin-1, and tachykinin precursors) peaked at 12 hours, then rapidly decreased by 24 hours. Basement membrane components (fibronectin, desomoglein, profiling-1) were decreased. Cytoskeletal markers (actin, vimentin, nidogen, and filamin B) increased over time. From this initial analysis, the high-ranking candidate thrombospondin-1 was further explored in human plasma. Acute ischemic stroke patients had significantly higher thrombospondin-1 levels within 8 hours of symptom onset compared to controls with similar clinical risk factors (659 +/- 81 vs 1132 +/- 98 ng/mL; P < 0.05; n = 20). Conclusions-Screening of simplified cell culture systems may aid the discovery of novel biomarkers in clinical neurovascular injury. Further collaborative efforts are warranted to discover and validate more candidates of interest. (Stroke. 2011; 42: 37-43.) C1 [Ning, MingMing; Kho, Alvin T.; Buonanno, Ferdinando S.; McMullin, David; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Prote Res Ctr, Boston, MA USA. [Ning, MingMing; Guo, Shuzhen; Lee, Sun-Ryung; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab, Boston, MA USA. [Kho, Alvin T.] Childrens Hosp, CHIP, Boston, MA 02115 USA. [Sarracino, David A.; Krastins, Bryan] Harvard Partners Ctr Genet & Genom, Boston, MA USA. [Vizcaino, Juan A.; Orchard, Sandra] European Bioinformat Inst, EMBL, Cambridge, England. RP Lo, EH (reprint author), MGH E 149-2401, Charlestown, MA 02129 USA. EM Ning@hms.harvard.edu; Lo@helix.mgh.harvard.edu RI Vizcaino, Juan Antonio/C-3691-2009; OI Vizcaino, Juan Antonio/0000-0002-3905-4335; Orchard, Sandra/0000-0002-8878-3972 FU National Institutes for Neurological Disorders and Stroke [R21-NS052498, K23-NS051588, R01-NS48422, R37-NS37074, P01-NS55104, R01-NS067139] FX This work is supported in part by grants from the National Institutes for Neurological Disorders and Stroke (R21-NS052498, K23-NS051588, R01-NS48422, R37-NS37074, P01-NS55104, R01-NS067139). NR 26 TC 20 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2011 VL 42 IS 1 BP 37 EP 43 DI 10.1161/STROKEAHA.110.585703 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 699AN UT WOS:000285636400013 PM 21164131 ER PT J AU Poisson, SN Nguyen-Huynh, MN Johnston, SC Furie, KL Lev, MH Smith, WS AF Poisson, Sharon N. Nguyen-Huynh, Mai N. Johnston, S. Claiborne Furie, Karen L. Lev, Michael H. Smith, Wade S. TI Intracranial Large Vessel Occlusion as a Predictor of Decline in Functional Status After Transient Ischemic Attack SO STROKE LA English DT Article DE intracranial arterial diseases; prognosis; transient ischemic attack ID HIGH EARLY RISK; MINOR STROKE; VALIDATION; SCORE; ABCD; CT AB Background and Purpose-Clinical scores help predict outcome after transient ischemic attack (TIA), and imaging studies may improve the accuracy of predictions. Intracranial large vessel occlusion (LVO) predicts poor outcome after stroke, but the natural history of symptomatic intracranial LVO in patients with TIA is unknown. Methods-We studied patients presenting with TIA in the STOP Stroke Study, a prospective imaging-based study of stroke outcomes. All patients underwent brain CTA. If an intracranial vascular occlusion was found in an appropriate territory to account for clinical findings, then it was judged to be a symptomatic LVO. Baseline characteristics, follow-up events, and outcomes were collected. Characteristics of patients with and without LVO were compared using chi(2) and t tests. Predictors of LVO were analyzed by univariate and multivariate analysis. LVO was assessed as a predictor of asymptomatic outcome (modified Rankin scale [mRS] score, 0), poor outcome (mRS score <= 3), and increase in mRS score over the study period. Results-Of 97 patients with TIA, 13 (13%) had symptomatic intracranial LVO. Patients with LVO had higher baseline NIHSS on emergency department arrival, which was an independent predictor of LVO (OR, 1.15 per point; 95% CI, 1.02-1.29; P = 0.02). Patients with LVO were more likely to have an increase in mRS score during the 90-day follow-up (P = 0.03). LVO independently predicted an increase in mRS score (OR, 4.76; 95% CI, 1.23-18.43; P = 0.02) and was a borderline predictor of poor outcome (mRS score >= 3; OR, 5.07; 95% CI, 0.92-28.03; P = 0.06). Conclusions-LVO is found in >1 in 10 patients presenting with TIA and predicts a decline in functional status, likely attributable to new brain ischemia. (Stroke. 2011;42:44-47.) C1 [Poisson, Sharon N.; Nguyen-Huynh, Mai N.; Johnston, S. Claiborne; Smith, Wade S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Johnston, S. Claiborne] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Furie, Karen L.; Lev, Michael H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Poisson, SN (reprint author), 505 Parnassus Ave,Box 0114, San Francisco, CA 94143 USA. EM Sharon.Poisson@UCSFmedctr.org FU Department of Health and Human Services/AHRQ [R01-HSO11392-01A1] FX This study was funded by a grant from the Department of Health and Human Services/AHRQ, R01-HSO11392-01A1. NR 15 TC 19 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 2011 VL 42 IS 1 BP 44 EP 47 DI 10.1161/STROKEAHA.110.591099 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 699AN UT WOS:000285636400014 PM 21106958 ER PT B AU Ran, QT Liang, HY AF Ran, Qitao Liang, Hanyu BE Basu, S Wiklund, L TI The Use of Gpx4 Knockout Mice and Transgenic Mice to Study the Roles of Lipid Peroxidation in Diseases and Aging SO STUDIES ON EXPERIMENTAL MODELS SE Oxidative Stress in Applied Basic Research and Clinical Practice LA English DT Article; Book Chapter DE Aging; Glutathione peroxidase 4; Gpx4 isoforms; Lipid peroxidation ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; MILD COGNITIVE IMPAIRMENT; RAT-LIVER MITOCHONDRIA; IN-VIVO FORMATION; OXIDATIVE STRESS; ALZHEIMERS-DISEASE; CYTOCHROME-C; DNA-DAMAGE; SUPEROXIDE-DISMUTASE; SELENOPROTEIN PHGPX AB Lipid peroxidation, a primary event of oxidative stress, is considered to be important in disease pathogenesis and aging. Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that can directly reduce lipid hyproperoxides in membrane lipids. Several Gpx4 knockout mouse models and Gpx4 transgenic mouse models have been generated over the past 7 years, and data collected from those models indicate that Gpx4 plays an essential role in protecting against lipid peroxidation. Because Gpx4 knockout mice and Gpx4 transgenic mice show increased lipid peroxidation and decreased lipid peroxidation, respectively, those models were used to investigate the roles of lipid peroxidation in aging and disease. For example, lifespan studies showed that Gpx4 heterozygous knockout mice and Gpx4 transgenic mice altered lifespans, indicating that mild change in lipid peroxidation does not affect aging. However, studies using Gpx4 transgenic and knockout models showed that overexpression of Gpx4 protected against A beta toxicity and that deficiency of Gpx4 resulted in increased amyloidogenesis in brain, indicating that lipid peroxidation is important in the pathogenesis of Alzheimer's disease. Studies using Gpx4 transgenic mice also showed that overexpression of Gpx4 reduced atherosclerosis and attenuated cardiac ischemia/reperfusion injury, suggesting that lipid peroxidation is important in cardiovascular disease. Therefore, Gpx4 knockout and transgenic mouse models are useful in dissecting the in vivo roles of lipid peroxidation in diseases and aging. C1 [Ran, Qitao; Liang, Hanyu] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Ran, Qitao] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Ran, Qitao] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Ran, QT (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. EM RAN@uthscsa.edu NR 86 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-1-60761-955-0 J9 OXID STRESS APPL BAS JI Oxid. Stress Appl. Basic Res. Clin. Pract. PY 2011 BP 265 EP 278 DI 10.1007/978-1-60761-956-7_12 D2 10.1007/978-1-60761-956-7 PG 14 WC Biochemistry & Molecular Biology; Medicine, General & Internal SC Biochemistry & Molecular Biology; General & Internal Medicine GA BVJ58 UT WOS:000291666700012 ER PT J AU Broyles, LM Gordon, AJ Sereika, SM Ryan, CM Erlen, JA AF Broyles, Lauren Matukaitis Gordon, Adam J. Sereika, Susan M. Ryan, Christopher M. Erlen, Judith A. TI Do Words Matter? Incongruent Responses to Inconsistently Worded AUDIT-C Alcohol Screening Instruments SO SUBSTANCE ABUSE LA English DT Article DE Alcohol consumption; alcohol-related disorders; mass screening; psychometrics ID IDENTIFICATION TEST AUDIT; CONSUMPTION QUESTIONS; PROBLEM DRINKING; USE DISORDERS; PRIMARY-CARE; POPULATION; VALIDATION AB The first 3 questions of the Alcohol Use Disorders Identification Test (AUDIT-C) are often used as a brief alcohol screening instrument. However, the implications of common modifications made to the original AUDIT questions and response options have not been considered. The authors examined existing data from a randomized controlled trial of 310 persons with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) that was testing the efficacy of 2 antiretroviral medication adherence interventions. Logistic regression was used to model the probability of participants having inconsistent AUDIT-C item responses. Three patterns of conflicting responses to the AUDIT-C items were identified. Common item modifications resulted in 14% (n = 48) of the parent study sample reporting conflicting responses across related AUDIT-C items. The odds of having conflicting data were 3 times greater in opioid users (odds ratio [OR] = 3.139, 95% confidence interval [CI] = 1.267-7.777, P = .01) and greater in persons with higher levels of conscientiousness (OR = 1.053, 95% CI = 1.006-1.103, P = .03). Inconsistent question format and response options may impede proper scoring and interpretation of the AUDIT-C. Further discussion and consensus building are needed on the psychometrically ideal version of the AUDIT-C. C1 [Broyles, Lauren Matukaitis; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Dept Vet Affairs Med Ctr, Pittsburgh, PA 15206 USA. [Broyles, Lauren Matukaitis] VISN4 Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs Med Ctr, Pittsburgh, PA USA. [Broyles, Lauren Matukaitis; Gordon, Adam J.; Ryan, Christopher M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Broyles, Lauren Matukaitis; Sereika, Susan M.; Erlen, Judith A.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. RP Broyles, LM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Dept Vet Affairs Med Ctr, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM Lauren.Broyles@va.gov FU Ruth L. Kirschstein National Research Service Award (NRSA) from the National Institute of Nursing Research (NINR) [F31NR008822]; NINR [R01NR004749] FX This study was financially supported by a Ruth L. Kirschstein National Research Service Award (NRSA) to Dr. Broyles from the National Institute of Nursing Research (NINR, F31NR008822) and by NINR grant R01NR004749 to Dr. Erlen. The material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 15 TC 3 Z9 3 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PY 2011 VL 32 IS 4 BP 202 EP 209 DI 10.1080/08897077.2011.600673 PG 8 WC Substance Abuse SC Substance Abuse GA 888PO UT WOS:000300016200004 PM 22014250 ER PT J AU Broyles, LM Gordon, AJ Sereika, SM Ryan, CM Erlen, JA AF Broyles, Lauren Matukaitis Gordon, Adam J. Sereika, Susan M. Ryan, Christopher M. Erlen, Judith A. TI Predictive Utility of Brief Alcohol Use Disorders Identification Test (AUDIT) for Human Immunodeficiency Virus Antiretroviral Medication Nonadherence SO SUBSTANCE ABUSE LA English DT Article DE Acquired immunodeficiency syndrome; alcohol consumption; HIV infection; mass screening; patient adherence ID HIV-INFECTION; SCREENING SCORES; PRIMARY-CARE; DISEASE PROGRESSION; PROBLEM DRINKING; SUBSTANCE-ABUSE; MALE VETERANS; ADHERENCE; THERAPY; CONSUMPTION AB Alcohol use negatively affects adherence to antiretroviral therapy (ART), thus human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care providers need accurate, efficient assessments of alcohol use. Using existing data from an efficacy trial of 2 cognitive-behavioral ART adherence interventions, the authors sought to determine if results on 2 common alcohol screening tests (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] and its binge-related question [AUDIT-3]) predict ART nonadherence. Twenty-seven percent of the sample (n = 308) were positive on the AUDIT-C and 34% were positive on the AUDIT-3. In multivariate analyses, AUDIT-C-positive status predicted ART nonadherence after controlling for race, age, conscientiousness, and self-efficacy (P = .036). Although AUDIT-3-positive status was associated with ART nonadherence in unadjusted analyses, this relationship was not maintained in the final multivariate model. The AUDIT-C shows potential as an indirect screening tool for both at-risk drinking and ART nonadherence, underscoring the relationship between alcohol and chronic disease management. C1 [Broyles, Lauren Matukaitis; Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Dept Vet Affairs Med Ctr, Pittsburgh, PA 15206 USA. [Broyles, Lauren Matukaitis; Gordon, Adam J.; Ryan, Christopher M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Broyles, Lauren Matukaitis; Sereika, Susan M.; Erlen, Judith A.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. [Broyles, Lauren Matukaitis] VA Pittsburgh Healthcare Syst, VISN4 Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA 15206 USA. RP Broyles, LM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Dept Vet Affairs Med Ctr, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM Lauren.Broyles@va.gov FU National Institute of Nursing Research (NINR) [F31NR008822]; NINR [R01NR004749]; Health Services Research & Development Service of the US Department of Veterans Affairs; VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania FX This study was financially supported by a Ruth L. Kirschstein National Research Service Award (NRSA) to Dr. Broyles from the National Institute of Nursing Research (NINR, F31NR008822) and by NINR grant no. R01NR004749 to Dr. Erlen. Dr. Broyles is currently supported by a Career Development Award (CDA) from the Health Services Research & Development Service of the US Department of Veterans Affairs. The material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 35 TC 9 Z9 9 U1 1 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0889-7077 J9 SUBST ABUS JI Subst. Abus. PY 2011 VL 32 IS 4 BP 252 EP 261 DI 10.1080/08897077.2011.599255 PG 10 WC Substance Abuse SC Substance Abuse GA 888PO UT WOS:000300016200010 PM 22014256 ER PT J AU Piper, ME Loh, WY Smith, SS Japuntich, SJ Baker, TB AF Piper, Megan E. Loh, Wei-Yin Smith, Stevens S. Japuntich, Sandra J. Baker, Timothy B. TI Using Decision Tree Analysis to Identify Risk Factors for Relapse to Smoking SO SUBSTANCE USE & MISUSE LA English DT Article ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE DEPENDENCE; TOBACCO DEPENDENCE; VARIABLE SELECTION; CONTROLLED-TRIAL; SOCIAL-CLASS; CESSATION; PREDICTORS; SMOKERS; BUPROPION AB This research used classification tree analysis and logistic regression models to identify risk factors related to short- and long-term abstinence. Baseline and cessation outcome data from two smoking cessation trials, conducted from 2001 to 2002 in two Midwestern urban areas, were analyzed. There were 928 participants (53.1%% women, 81.8%% White) with complete data. Both analyses suggest that relapse risk is produced by interactions of risk factors and that early and late cessation outcomes reflect different vulnerability factors. The results illustrate the dynamic nature of relapse risk and suggest the importance of efficient modeling of interactions in relapse prediction.= 2 times/week) had a multivariate relative risk (RR) of gastrointestinal bleeding of 1.32 (95% confidence interval [CI], 1.12-1.55) compared to non-regular use. The association was particularly evident for upper gastrointestinal bleeding (multivariate RR, 1.49; 95% CI, 1.16-1.92). Compared to men who denied any aspirin use, multivariate RRs of upper gastrointestinal bleeding were 1.05 (95% CI 0.71-1.52) for men who used 0.5-1.5 standard tablets/week, 1.31 (95% CI 0.88-1.95) for 2-5 aspirin/week, 1.63 (95% CI, 1.15-2.32) for 6-14 aspirin/week and 2.40 (95% CI, 1.10-5.22) for >14 aspirin/week (P(trend) < 0.001). The relative risk also appeared to be dose-dependent among short-term users (>= 5 years; P(trend)<.001) and long-term users (>= 5 years; P(trend) = 0.015). In contrast, after controlling for dose, increasing duration of use did not appear to be associated with risk (P(trend) = 0.749). Conclusions: Regular aspirin use increases the risk of gastrointestinal bleeding, especially from the upper tract. However, risk of bleeding appears to be more strongly related to dose than to duration of use. Risk of bleeding should be minimized by using the lowest effective dose among short-term and long-term aspirin users. C1 [Huang, Edward S.; Chan, Andrew T.] Massachusetts Gen Hosp, Dept Med, Div Gastroenterol & Hepatol, Boston, MA 02114 USA. [Huang, Edward S.; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Strate, Lisa L.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. [Ho, Wendy W.] Univ Calif Los Angeles, Dept Med, Div Digest Dis, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Lee, Salina S.] Northwestern Univ, Dept Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Huang, ES (reprint author), Massachusetts Gen Hosp, Dept Med, Div Gastroenterol & Hepatol, Boston, MA 02114 USA. EM eshuang@partners.org FU Foundation for Digestive Health and Nutrition; American Gastroenterology Association FX Foundation for Digestive Health and Nutrition Pilot Research Award for this work. Dr. Chan is a Damon Runyon Clinical Investigator. Dr. Huang is supported by the American Gastroenterology Association Fellow to Faculty Transition Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 23 Z9 23 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 29 PY 2010 VL 5 IS 12 AR e15721 DI 10.1371/journal.pone.0015721 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 701CZ UT WOS:000285793200042 PM 21209949 ER PT J AU Eisen, HN Chakraborty, AK AF Eisen, Herman N. Chakraborty, Arup K. TI Evolving concepts of specificity in immune reactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T cells; peptide-MHC complexes; receptor-ligand interactions; antibody isomerism ID T-CELL-RECEPTOR; MAJOR HISTOCOMPATIBILITY COMPLEX; INDUCED CONFORMATIONAL TRANSITION; PEPTIDE-MHC COMPLEXES; MYELIN BASIC-PROTEIN; BENCE-JONES PROTEINS; MYELOMA PROTEINS; MOLECULAR MIMICRY; ANTIGEN-BINDING; MONOCLONAL-ANTIBODY AB Our goal is to provide a perspective on current understanding of the origins of specificity in immune reactions, a topic that has intrigued scientists for over a century. A fundamental property of adaptive immune responses is the ability to discriminate among an immense variety of substances by means of antibodies (Abs) and Ab-like receptors on T lymphocytes [T-cell receptors (TCRs)], each able to bind a particular chemical structure [the antigen (Ag)] and not, or only weakly, similar alternatives. Evidence has long existed, however, and has grown, especially recently, that while exhibiting remarkable specificity, many individual Abs and TCRs can also bind a variety of very different ligands. How can Ag recognition by these receptors exercise the great specificity for which they are renowned and yet react with a variety of different ligands (degeneracy)? We critically consider the mechanistic bases for this specificity/degeneracy enigma and also compare and contrast Ag recognition by Abs and TCRs. C1 [Eisen, Herman N.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Eisen, Herman N.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Eisen, Herman N.; Chakraborty, Arup K.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Eisen, Herman N.; Chakraborty, Arup K.] Harvard Univ, Boston, MA 02129 USA. RP Eisen, HN (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM hneisen@mit.edu FU National Institutes of Health [5-PO1-AI071195-02]; Cancer Core Grant FX A. K. C. is supported by National Institutes of Health Grants 5-PO1-AI071195-02 and the National Institutes of Health's Director's Pioneer Award. H.N.E. is supported by a Cancer Core Grant (to T. Jacks). We are grateful to an anonymous reviewer for valuable comments. NR 117 TC 38 Z9 38 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 28 PY 2010 VL 107 IS 52 BP 22373 EP 22380 DI 10.1073/pnas.1012051108 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699SX UT WOS:000285684200010 PM 21173256 ER PT J AU Ching, SN Cimenser, A Purdon, PL Brown, EN Kopell, NJ AF Ching, ShiNung Cimenser, Aylin Purdon, Patrick L. Brown, Emery N. Kopell, Nancy J. TI Thalamocortical model for a propofol-induced alpha-rhythm associated with loss of consciousness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE general anesthesia; oscillations; global coherence; GABA ID LESS-THAN-1 HZ OSCILLATION; INHIBITORY NEURONS; FRONTAL-LOBE; MU RHYTHM; EEG; MECHANISMS; ATTENTION; NETWORKS; BRAIN; SYNCHRONIZATION AB Recent data reveal that the general anesthetic propofol gives rise to a frontal alpha-rhythm at dose levels sufficient to induce loss of consciousness. In this work, a computational model is developed that suggests the network mechanisms responsible for such a rhythm. It is shown that propofol can alter the dynamics in thalamocortical loops, leading to persistent and synchronous alpha-activity. The synchrony that forms in the cortex by virtue of the involvement of the thalamus may impede responsiveness to external stimuli, thus providing a correlate for the unconscious state. C1 [Ching, ShiNung; Cimenser, Aylin; Purdon, Patrick L.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ching, ShiNung; Cimenser, Aylin; Purdon, Patrick L.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Ching, ShiNung; Kopell, Nancy J.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Ching, ShiNung; Kopell, Nancy J.] Boston Univ, Ctr BioDynam, Boston, MA 02215 USA. [Cimenser, Aylin; Purdon, Patrick L.; Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Ching, SN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM shinung@neurostat.mit.edu; nk@bu.edu FU National Institutes of Health [DP1-OD003646, K25-NS057580, DP2-OD006454]; National Science Foundation [DMS-0717670] FX This study was supported by National Institutes of Health Grants DP1-OD003646, K25-NS057580, and DP2-OD006454 and by National Science Foundation Grant DMS-0717670. NR 38 TC 90 Z9 91 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 28 PY 2010 VL 107 IS 52 BP 22665 EP 22670 DI 10.1073/pnas.1017069108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 699SX UT WOS:000285684200059 PM 21149695 ER PT J AU Siriussawakul, A Zaky, A Lang, JD AF Siriussawakul, Arunotai Zaky, Ahmed Lang, John D. TI Role of nitric oxide in hepatic ischemia-reperfusion injury SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Nitric oxide; Liver; Ischemia-reperfusion injury; Drug delivery ID ORTHOTOPIC LIVER-TRANSPLANTATION; NF-KAPPA-B; ISCHEMIA/REPERFUSION INJURY; S-NITROSYLATION; RAT-LIVER; SUPEROXIDE; APOPTOSIS; PROTECTS; SYNTHASE; ACTIVATION AB Hepatic ischemia-reperfusion injury (IRI) occurs upon restoration of hepatic blood flow after a period of ischemia. Decreased endogenous nitric oxide (NO) production resulting in capillary luminal narrowing is central in the pathogenesis of IRI. Exogenous NO has emerged as a potential therapy for IRI based on its role in decreasing oxidative stress, cytokine release, leukocyte endothelial-adhesion and hepatic apoptosis. This review will highlight the influence of endogenous NO on hepatic IRI, role of inhaled NO in ameliorating IRI, modes of delivery, donor drugs and potential side effects of exogenous NO. (C) 2010 Baishideng. All rights reserved. C1 [Siriussawakul, Arunotai; Zaky, Ahmed; Lang, John D.] Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA 98108 USA. [Siriussawakul, Arunotai; Zaky, Ahmed; Lang, John D.] Univ Washington, Sch Med, VA Puget Sound Healthcare Syst, Seattle, WA 98108 USA. RP Lang, JD (reprint author), Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA 98108 USA. EM jdlang@u.washington.edu NR 54 TC 36 Z9 38 U1 0 U2 2 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD DEC 28 PY 2010 VL 16 IS 48 BP 6079 EP 6086 DI 10.3748/wjg.v16.i48.6079 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 700JB UT WOS:000285733600006 PM 21182222 ER PT J AU Breuer, M Kolano, A Kwon, M Li, CC Tsai, TF Pellman, D Brunet, S Verlhac, MH AF Breuer, Manuel Kolano, Agnieszka Kwon, Mijung Li, Chao-Chin Tsai, Ting-Fen Pellman, David Brunet, Stephane Verlhac, Marie-Helene TI HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MOUSE OOCYTES; MICROTUBULE ORGANIZATION; HEPATOCELLULAR-CARCINOMA; METAPHASE SPINDLE; MEIOSIS-I; CHROMOSOMES; DYNAMICS; DIVISION; ROLES; MOTOR AB In contrast to somatic cells, formation of acentriolar meiotic spindles relies on the organization of microtubules (MTs) and MT-organizing centers (MTOCs) into a stable bipolar structure. The underlying mechanisms are still unknown. We show that this process is impaired in hepatoma up-regulated protein (Hurp) knockout mice, which are viable but female sterile, showing defective oocyte divisions. HURP accumulates on interpolar MTs in the vicinity of chromosomes via Kinesin-5 activity. By promoting MT stability in the spindle central domain, HURP allows efficient MTOC sorting into distinct poles, providing bipolarity establishment and maintenance. Our results support a new model for meiotic spindle assembly in which HURP ensures assembly of a central MT array, which serves as a scaffold for the genesis of a robust bipolar structure supporting efficient chromosome congression. Furthermore, HURP is also required for the clustering of extra centrosomes before division, arguing for a shared molecular requirement of MTOC sorting in mammalian meiosis and cancer cell division. C1 [Breuer, Manuel; Kolano, Agnieszka; Brunet, Stephane; Verlhac, Marie-Helene] Univ Paris 06, CNRS, Unite Mixte Rech 7622, F-75005 Paris, France. [Kwon, Mijung; Pellman, David] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Pediat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Chao-Chin; Tsai, Ting-Fen] Natl Yang Ming Univ, Dept Life Sci, Taipei 112, Taiwan. [Li, Chao-Chin; Tsai, Ting-Fen] Natl Yang Ming Univ, Inst Genome Sci, Taipei 112, Taiwan. RP Brunet, S (reprint author), Univ Paris 06, CNRS, Unite Mixte Rech 7622, F-75005 Paris, France. EM stephane.brunet@snv.jussieu.fr; marie-helene.verlhac@upmc.fr OI Breuer, Manuel/0000-0003-1982-2517; VERLHAC, Marie-Helene/0000-0001-8377-9010 FU Ligue Nationale Contre le Cancer [EL/2009/LNCC]; Leukemia and Lymphoma Society; Agence Nationale pour la Recherche [ANR08BLAN-0136-01]; National Health Research Institutes [NHRI-EX999837NI] FX M. Breuer is a recipient of a Ligue Nationale Contre le Cancer doctoral fellowship. M. Kwon is a recipient of a Special Fellow Award of the Leukemia and Lymphoma Society. S. Brunet is an Institut National de la Sante et de la Recherche Medicale fellow. This work was supported by grants from the Ligue Nationale Contre le Cancer (EL/2009/LNCC to M.-H. Verlhac), the Agence Nationale pour la Recherche (ANR08BLAN-0136-01 to M.-H. Verlhac), and the National Health Research Institutes (NHRI-EX999837NI to T.-F. Tsai). NR 32 TC 40 Z9 40 U1 0 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 27 PY 2010 VL 191 IS 7 BP 1251 EP 1260 DI 10.1083/jcb.201005065 PG 10 WC Cell Biology SC Cell Biology GA 699SR UT WOS:000285683600006 PM 21173113 ER PT J AU LoCascio, SA Morokata, T Chittenden, M Preffer, FI Dombkowski, DM Andreola, G Crisalli, K Kawai, T Saidman, SL Spitzer, TR Tolkoff-Rubin, N Cosimi, AB Sachs, DH Sykes, M AF LoCascio, Samuel A. Morokata, Tatsuaki Chittenden, Meredith Preffer, Frederic I. Dombkowski, David M. Andreola, Giovanna Crisalli, Kerry Kawai, Tatsuo Saidman, Susan L. Spitzer, Thomas R. Tolkoff-Rubin, Nina Cosimi, A. Benedict Sachs, David H. Sykes, Megan TI Mixed Chimerism, Lymphocyte Recovery, and Evidence for Early Donor-Specific Unresponsiveness in Patients Receiving Combined Kidney and Bone Marrow Transplantation to Induce Tolerance SO TRANSPLANTATION LA English DT Article DE Bone marrow transplantation; Tolerance; Immunosuppression; Kidney; Mixed chimerism ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; RENAL-ALLOGRAFT TOLERANCE; HUMANIZED ANTI-CD2 MAB; NK CELLS; IN-VIVO; RECIPIENTS; POPULATIONS; REJECTION; RESPONSES AB Background. We have previously reported operational tolerance in patients receiving human leukocyte antigen-mismatched combined kidney and bone marrow transplantation (CKBMT). We now report on transient multilineage hematopoietic chimerism and lymphocyte recovery in five patients receiving a modified CKBMT protocol and evidence for early donor-specific unresponsiveness in one of these patients. Methods. Five patients with end-stage renal disease received CKBMT from human leukocyte antigen-mismatched, haploidentical living-related donors after modified nonmyeloablative conditioning. Polychromatic flow cytometry was used to assess multilineage chimerism and lymphocyte recovery posttransplant. Limiting dilution analysis was used to assess helper T-lymphocyte reactivity to donor antigens. Results. Transient multilineage mixed chimerism was observed in all patients, but chimerism became undetectable by 2 weeks post-CKBMT. A marked decrease in T- and B-lymphocyte counts immediately after transplant was followed by gradual recovery. Initially, recovering T cells were depleted of CD45RA(+)/CD45RO(-) "naive-like" cells, which have shown strong recovery in two patients, and CD4:CD8 ratios increased immediately after transplant but then declined markedly. Natural killer cells were enriched in the peripheral blood of all patients after transplant. For subject 2, a pretransplant limiting dilution assay revealed T helper cells recognizing both donor and third-party peripheral blood mononuclear cells. However, the antidonor response was undetectable by day 24, whereas third-party reactivity persisted. Conclusion. These results characterize the transient multilineage mixed hematopoietic chimerism and recovery of lymphocyte subsets in patients receiving a modified CKBMT protocol. The observations are relevant to the mechanisms of donor-specific tolerance in this patient group. C1 [LoCascio, Samuel A.; Sykes, Megan] Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, New York, NY 10032 USA. [Morokata, Tatsuaki; Chittenden, Meredith; Andreola, Giovanna; Sachs, David H.; Sykes, Megan] Harvard Univ, Sch Med, Dept Surg, Transplantat Biol Res Ctr,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Preffer, Frederic I.; Dombkowski, David M.; Saidman, Susan L.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Crisalli, Kerry; Kawai, Tatsuo; Tolkoff-Rubin, Nina; Cosimi, A. Benedict] Harvard Univ, Sch Med, Dept Surg, Transplantat Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Spitzer, Thomas R.] Harvard Univ, Sch Med, Dept Med, Bone Marrow Transplantat Unit,Massachusetts Gen H, Boston, MA USA. RP Sykes, M (reprint author), Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, 622 W 168th St,PH 17-111, New York, NY 10032 USA. EM megan.sykes@columbia.edu FU Immune Tolerance Network (NIH) [N01 AI15416]; University of California San Francisco; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation; NIAID [R01 AI084074] FX This work was supported by a project of the Immune Tolerance Network (NIH Contract N01 AI15416), an international clinical research consortium headquartered at the University of California San Francisco; the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation; and NIAID grant R01 AI084074. NR 30 TC 36 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 27 PY 2010 VL 90 IS 12 BP 1607 EP 1615 DI 10.1097/TP.0b013e3181ffbaff PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 695NG UT WOS:000285377100056 PM 21085064 ER PT J AU Pitman, MB Genevay, M Yaeger, K Chebib, I Turner, BG Mino-Kenudson, M Brugge, WR AF Pitman, Martha Bishop Genevay, Muriel Yaeger, Kurt Chebib, Ivan Turner, Brian G. Mino-Kenudson, Mari Brugge, William R. TI High-Grade Atypical Epithelial Cells in Pancreatic Mucinous Cysts Are a More Accurate Predictor of Malignancy Than "Positive" Cytology SO CANCER CYTOPATHOLOGY LA English DT Article DE pancreas; mucinous cysts; cytology; mucinous cystic neoplasm; intraductal papillary mucinous neoplasm ID FINE-NEEDLE-ASPIRATION; UPDATED EXPERIENCE; NEOPLASMS; MANAGEMENT; LESIONS; CYTOMORPHOLOGY; DIAGNOSIS; FEATURES; FLUID; B72.3 AB BACKGROUND: The Sendai guidelines for risk assessment of malignancy in patients with mucinous cysts lists "positive" cytology as a high-risk feature. In the current study, the authors hypothesized that a cytological threshold of high-grade atypical epithelial cells (AEC) is a more accurate predictor of malignancy. METHODS: The clinical, radiological, and cytological data of 112 patients with histologically confirmed mucinous cysts of the pancreas were reviewed. Cytology slides were blindly reviewed and cells were classified as benign, AEC, or malignant. On histology, neoplasms were grouped as benign (low-grade and moderate dysplasia) and malignant (high-grade dysplasia/carcinoma in situ and invasive carcinoma). RESULTS: There were 92 patients with an intraductal papillary mucinous neoplasm (IPMN) and 20 with a mucinous cystic neoplasm; 39 were malignant and 73 were benign (42 with low-grade dysplasia and 31 with moderate dysplasia). Only 28% (11 of 39) of the malignant cysts were cytologically malignant with a sensitivity of 29%, a specificity of 100%, and an accuracy of 75%. AEC detected 17 additional cancers (44% of all malignant cysts; 16% more than detected on the basis of "positive" cytology). By using AEC as a surgical triage threshold, the sensitivity was 72%, the specificity was 85%, and the accuracy was 80%, with similar values for small (<= 3 cm) branch duct IPMN. Nine of 73 (12%) benign cysts were identified with AEC, 4 of which had moderate dysplasia. AEC had a positive predictive value of 87% for the detection of a mucinous cyst with moderate dysplasia or worse. CONCLUSIONS: AEC are a more accurate predictor of malignancy than "positive" cytology in aspirates of pancreatic mucinous cysts, including small branch duct IPMN. AEC warrant a "suspicious" interpretation for appropriate surgical triage. Cancer (Cancer Cytopathol) 2010; 118: 434-40. (C) 2010 American Cancer Society. C1 [Pitman, Martha Bishop; Genevay, Muriel; Yaeger, Kurt; Chebib, Ivan; Mino-Kenudson, Mari] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Labs, Boston, MA 02114 USA. [Turner, Brian G.; Brugge, William R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02114 USA. RP Pitman, MB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Labs, Warren 105-D,55 Fruit St, Boston, MA 02114 USA. EM mpitman@partners.org FU Foundation pour la Recherche Nuovo-Soldati FX Dr. Genevay is supported by the Foundation pour la Recherche Nuovo-Soldati. NR 22 TC 57 Z9 58 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD DEC 25 PY 2010 VL 118 IS 6 BP 434 EP 440 DI 10.1002/cncy.20118 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 693UU UT WOS:000285251700005 PM 20931638 ER PT J AU Kleene, KC Bagarova, J Hawthorne, SK Catado, LM AF Kleene, Kenneth C. Bagarova, Jana Hawthorne, Sabrina K. Catado, Leah M. TI Quantitative analysis of mRNA translation in mammalian spermatogenic cells with sucrose and Nycodenz gradients SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article ID Y-BOX PROTEIN; PREMATURE TRANSLATION; MOUSE; MICE; EXPRESSION; PATTERNS; SPERM; DIFFERENTIATION; TRANSCRIPTION; ACTIVATION AB Background: Developmental and global regulation of mRNA translation plays a major role in regulating gene expression in mammalian spermatogenic cells. Sucrose gradients are widely used to analyze mRNA translation. Unfortunately, the information from sucrose gradient experiments is often compromised by the absence of quantification and absorbance tracings, and confusion about the basic properties of sucrose gradients. Methods: The Additional Materials contain detailed protocols for the preparation and analysis of sucrose and Nycodenz gradients, obtaining absorbance tracings of sucrose gradients, aligning tracings and fractions, and extraction of equal proportions of RNA from all fractions. Results: The techniques described here have produced consistent measurements despite changes in personnel and minor variations in RNA extraction, gradient analysis, and mRNA quantification, and describes for the first time potential problems in using gradients to analyze mRNA translation in purified spermatogenic cells. Conclusions: Accurate quantification of the proportion of polysomal mRNA is useful in comparing translational activity at different developmental stages, different mRNAs, different techniques and different laboratories. The techniques described here are sufficiently accurate to elucidate the contributions of multiple regulatory elements of variable strength in regulating translation of the sperm mitochondria associated cysteine-rich protein (Smcp) mRNA in transgenic mice. C1 [Kleene, Kenneth C.; Bagarova, Jana; Hawthorne, Sabrina K.; Catado, Leah M.] Univ Massachusetts, Dept Biol, Boston, MA 02125 USA. [Bagarova, Jana] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Catado, Leah M.] Buckingham Browne & Nichols Sch, Upper Sch Sci Dept, Cambridge, MA 02138 USA. RP Kleene, KC (reprint author), Univ Massachusetts, Dept Biol, Boston, MA 02125 USA. EM kenneth.kleene@umb.edu FU National Science Foundation [MCB-0642128] FX This research was supported by Grant MCB-0642128 from the National Science Foundation. NR 38 TC 8 Z9 8 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD DEC 25 PY 2010 VL 8 AR 155 DI 10.1186/1477-7827-8-155 PG 8 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 708VH UT WOS:000286391900001 PM 21184686 ER PT J AU Stegmaier, K AF Stegmaier, Kimberly TI Chemical genomics and combo therapy SO BLOOD LA English DT Editorial Material ID MYELOGENOUS LEUKEMIA STEM; CONNECTIVITY MAP; PROGENITOR CELLS; MEK INHIBITORS; EXPRESSION; RESISTANCE; DISCOVERY; CANCERS; PI3K C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 23 PY 2010 VL 116 IS 26 BP 5786 EP 5788 DI 10.1182/blood-2010-10-312108 PG 5 WC Hematology SC Hematology GA 698GX UT WOS:000285583400002 PM 21183693 ER PT J AU Chang, WC White, MR Moyo, P McClear, S Thiel, S Hartshorn, KL Takahashi, K AF Chang, Wei-Chuan White, Mitchell R. Moyo, Patience McClear, Sheree Thiel, Steffen Hartshorn, Kevan L. Takahashi, Kazue TI Lack of the pattern recognition molecule mannose-binding lectin increases susceptibility to influenza A virus infection SO BMC IMMUNOLOGY LA English DT Article ID LEUKOCYTE ADHESION MOLECULES; INNATE IMMUNITY; DEFICIENT MICE; LUNG INJURY; BRONCHOALVEOLAR LAVAGE; SURFACTANT PROTEIN; COMPLEMENT; PATHWAY; CELLS; DEFENSE AB Background: Mannose-binding lectin (MBL), a pattern recognition innate immune molecule, inhibits influenza A virus infection in vitro. MBL deficiency due to gene polymorphism in humans has been associated with infection susceptibility. These clinical observations were confirmed by animal model studies, in which mice genetically lacking MBL were susceptible to certain pathogens, including herpes simplex virus 2. Results: We demonstrate that MBL is present in the lung of naive healthy wild type (WT) mice and that MBL null mice are more susceptible to IAV infection. Administration of recombinant human MBL (rhMBL) reverses the infection phenotype, confirming that the infection susceptibility is MBL-mediated. The anti-viral mechanisms of MBL include activation of the lectin complement pathway and coagulation, requiring serum factors. White blood cells (WBCs) in the lung increase in WT mice compared with MBL null mice on day 1 post-infection. In contrast, apoptotic macrophages (M Phi s) are two-fold higher in the lung of MBL null mice compared with WT mice. Furthermore, MBL deficient macrophages appear to be susceptible to apoptosis in vitro. Lastly, soluble factors, which are associated with lung injury, are increased in the lungs of MBL null mice during IAV infection. These results suggest that MBL plays a key role against IAV infection. Conclusion: MBL plays a key role in clearing IAV and maintaining lung homeostasis. In addition, our findings also suggest that MBL deficiency maybe a risk factor in IAV infection and MBL may be a useful adjunctive therapy for IAV infection. C1 [Chang, Wei-Chuan; Moyo, Patience; McClear, Sheree; Takahashi, Kazue] Harvard Univ, Sch Med, Program Dev Immunol, Dept Pediat,Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Mitchell R.; Hartshorn, Kevan L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Thiel, Steffen] Aarhus Univ, Dept Med Microbiol & Immunol, DK-8000 Aarhus, Denmark. RP Takahashi, K (reprint author), Harvard Univ, Sch Med, Program Dev Immunol, Dept Pediat,Massachusetts Gen Hosp, Boston, MA 02114 USA. EM ktakahashi1@partners.org OI Hartshorn, Kevan/0000-0002-7196-7433 FU NIH [UO1 AI074503-01, R21 AI077081-01A1] FX We would like to thank Enzon pharmaceuticals for providing rhMBL. The authors also thank NIH for funding (UO1 AI074503-01; R21 AI077081-01A1). The authors have no conflicting financial interests. NR 51 TC 36 Z9 38 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD DEC 23 PY 2010 VL 11 AR 64 DI 10.1186/1471-2172-11-64 PG 12 WC Immunology SC Immunology GA 706FO UT WOS:000286203500001 PM 21182784 ER PT J AU Bostrom, P Mann, N Wu, J Quintero, PA Plovie, ER Panakova, D Gupta, RK Xiao, CY MacRae, CA Rosenzweig, A Spiegelman, BM AF Bostroem, Pontus Mann, Nina Wu, Jun Quintero, Pablo A. Plovie, Eva R. Panakova, Daniela Gupta, Rana K. Xiao, Chunyang MacRae, Calum A. Rosenzweig, Anthony Spiegelman, Bruce M. TI C/EBP beta Controls Exercise-Induced Cardiac Growth and Protects against Pathological Cardiac Remodeling SO CELL LA English DT Article ID SERUM RESPONSE FACTOR; INSULIN SENSITIVITY; HEART; CARDIOMYOCYTES; HYPERTROPHY; INJURY; MUSCLE; TISSUE; ROLES AB The heart has the ability to growin size in response to exercise, but little is known about the transcriptional mechanisms underlying physiological hypertrophy. Adult cardiomyocytes have also recently been proven to hold the potential for proliferation, a process that could be of great importance for regenerative medicine. Using a unique RT-PCR-based screen against all transcriptional components, we showed that C/EBP beta was downregulated with exercise, whereas the expression of CITED4 was increased. Reduction of C/EBP beta in vitro and in vivo resulted in a phenocopy of endurance exercise with cardiomyocyte hypertrophy and proliferation. This proliferation was mediated, at least in part, by the increased CITED4. Importantly, mice with reduced cardiac C/EBP beta levels displayed substantial resistance to cardiac failure upon pressure overload. These data indicate that C/EBP beta represses cardiomyocyte growth and proliferation in the adult mammalian heart and that reduction in C/EBP beta is a central signal in physiologic hypertrophy and proliferation. C1 [Mann, Nina; Quintero, Pablo A.; Xiao, Chunyang; Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Mann, Nina; Quintero, Pablo A.; Xiao, Chunyang; Rosenzweig, Anthony] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Bostroem, Pontus; Wu, Jun; Gupta, Rana K.; Spiegelman, Bruce M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bostroem, Pontus; Wu, Jun; Gupta, Rana K.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Plovie, Eva R.; Panakova, Daniela; MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Rosenzweig, A (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, 330 Brookline Ave, Boston, MA 02215 USA. EM arosenzw@bidmc.harvard.edu; bruce_spiegelman@dfci.harvard.edu FU NIH [R01 HL085593]; Swedish Heart and Lung foundation; SSMF; Wenner-Gren Foundation; American Heart Association [09POST2010078]; Howard Hughes Postdoctoral Fellowship; T32 training grant; Leducq Foundation Network of Research Excellence; Maxwell Hurston Charitable Foundation FX We thank Shingo Kajimura for valuable discussion during the progression of the manuscript. This project was supported by NIH grant R01 HL085593. P. B. was supported by the Swedish Heart and Lung foundation, SSMF, and the Wenner-Gren Foundation. J.W. was supported by a postdoctoral fellowship from the American Heart Association (Founders Affiliate #09POST2010078). N.M. is a trainee the Harvard/MIT Health Sciences and Technology Program and is supported by a Howard Hughes Postdoctoral Fellowship. P. A. Q. is supported by a T32 training grant. This research was supported in part by a Leducq Foundation Network of Research Excellence (B. M. S. and A. R.) and grants from the NIH (A. R. and B. W. S.). A. R. also gratefully acknowledges support from Judith and David Ganz and the Maxwell Hurston Charitable Foundation. A. R. is a principal faculty member of the Harvard Stem Cell Institute. NR 27 TC 123 Z9 130 U1 0 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 23 PY 2010 VL 143 IS 7 BP 1072 EP 1083 DI 10.1016/j.cell.2010.11.036 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 698WO UT WOS:000285625400006 PM 21183071 ER PT J AU Gersbacher, MT Kim, DY Bhattacharyya, R Kovacs, DM AF Gersbacher, Manuel T. Kim, Doo Yeon Bhattacharyya, Raja Kovacs, Dora M. TI Identification of BACE1 cleavage sites in human voltage-gated sodium channel beta 2 subunit SO MOLECULAR NEURODEGENERATION LA English DT Article ID ALZHEIMERS-DISEASE; CELL-ADHESION; SECRETASE ACTIVITY; NEURITE OUTGROWTH; PROTEIN; BRAIN; MYELINATION; EXPRESSION; AUXILIARY; INJURY AB Background: The voltage-gated sodium channel beta 2 subunit (Nav beta 2) is a physiological substrate of BACE1 (beta-site APP cleaving enzyme) and gamma-secretase, two proteolytic enzymes central to Alzheimer's disease pathogenesis. Previously, we have found that the processing of Nav beta 2 by BACE1 and gamma-secretase regulates sodium channel metabolism in neuronal cells. In the current study we identified the BACE1 cleavage sites in human Nav beta 2. Results: We found a major (147-148 L down arrow M, where down arrow indicates the cleavage site) and a minor (144145 L down arrow Q) BACE1 cleavage site in the extracellular domain of human Nav beta 2 using a cell-free BACE1 cleavage assay followed by mass spectrometry. Next, we introduced two different double mutations into the identified major BACE1 cleavage site in human Nav beta 2: 147LM/VI and 147LM/AA. Both mutations dramatically decreased the cleavage of human Nav beta 2 by endogenous BACE1 in cell-free BACE1 cleavage assays. Neither of the two mutations affected subcellular localization of Nav beta 2 as confirmed by confocal fluorescence microscopy and subcellular fractionation of cholesterol-rich domains. Finally, wildtype and mutated Nav beta 2 were expressed along BACE1 in B104 rat neuroblastoma cells. In spite of alpha-secretase still actively cleaving the mutant proteins, Nav beta 2 cleavage products decreased by similar to 50% in cells expressing Nav beta 2 (147LM/VI) and similar to 75% in cells expressing Nav beta 2 (147LM/AA) as compared to cells expressing wildtype Nav beta 2. Conclusion: We identified a major (147-148 L down arrow M) and a minor (144-145 L down arrow Q) BACE1 cleavage site in human Nav beta 2. Our in vitro and cell-based results clearly show that the 147-148 L down arrow M is the major BACE1 cleavage site in human Nav beta 2. These findings expand our understanding of the role of BACE1 in voltage-gated sodium channel metabolism. C1 [Gersbacher, Manuel T.; Kim, Doo Yeon; Bhattacharyya, Raja; Kovacs, Dora M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Neurobiol Dis Lab, MassGen Inst Neurodegenerat Dis,Genet & Aging Res, Charlestown, MA 02129 USA. RP Kovacs, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Neurobiol Dis Lab, MassGen Inst Neurodegenerat Dis,Genet & Aging Res, Charlestown, MA 02129 USA. EM dora_kovacs@hms.harvard.edu FU NIH/NIA FX We would like to thank Drs. Aleister Saunders (Drexel University) and Rudolph E. Tanzi (Massachusetts General Hospital/Harvard Medical School) for the human BACE1 construct. This work is supported by grants from the NIH/NIA. NR 32 TC 18 Z9 18 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD DEC 23 PY 2010 VL 5 AR 61 DI 10.1186/1750-1326-5-61 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 708SG UT WOS:000286384000001 PM 21182789 ER PT J AU Filippakopoulos, P Qi, J Picaud, S Shen, Y Smith, WB Fedorov, O Morse, EM Keates, T Hickman, TT Felletar, I Philpott, M Munro, S McKeown, MR Wang, YC Christie, AL West, N Cameron, MJ Schwartz, B Heightman, TD La Thangue, N French, CA Wiest, O Kung, AL Knapp, S Bradner, JE AF Filippakopoulos, Panagis Qi, Jun Picaud, Sarah Shen, Yao Smith, William B. Fedorov, Oleg Morse, Elizabeth M. Keates, Tracey Hickman, Tyler T. Felletar, Ildiko Philpott, Martin Munro, Shonagh McKeown, Michael R. Wang, Yuchuan Christie, Amanda L. West, Nathan Cameron, Michael J. Schwartz, Brian Heightman, Tom D. La Thangue, Nicholas French, Christopher A. Wiest, Olaf Kung, Andrew L. Knapp, Stefan Bradner, James E. TI Selective inhibition of BET bromodomains SO NATURE LA English DT Article ID ABL TYROSINE KINASE; PROTEIN BRD4; P-TEFB; AGGRESSIVE CARCINOMA; MITOTIC CHROMOSOMES; SIGNAL-TRANSDUCTION; STRUCTURAL BASIS; CHEMICAL PROBES; IN-VIVO; LEUKEMIA AB Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family. C1 [Filippakopoulos, Panagis; Picaud, Sarah; Fedorov, Oleg; Keates, Tracey; Felletar, Ildiko; Philpott, Martin; Heightman, Tom D.; Knapp, Stefan] Univ Oxford, Struct Genom Consortium, Dept Clin Med, Oxford OX3 7DQ, England. [Qi, Jun; Smith, William B.; Morse, Elizabeth M.; McKeown, Michael R.; West, Nathan; Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shen, Yao; Wiest, Olaf] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Shen, Yao; Wiest, Olaf] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA. [Hickman, Tyler T.; Cameron, Michael J.; Schwartz, Brian; French, Christopher A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Munro, Shonagh; La Thangue, Nicholas; Knapp, Stefan] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England. [McKeown, Michael R.; Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wang, Yuchuan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Christie, Amanda L.; Kung, Andrew L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Kung, Andrew L.] Childrens Hosp, Boston, MA 02115 USA. RP Knapp, S (reprint author), Univ Oxford, Struct Genom Consortium, Dept Clin Med, Old Rd Campus,Roosevelt Dr, Oxford OX3 7DQ, England. EM stefan.knapp@sgc.ox.ac.uk; james_bradner@dfci.harvard.edu RI Fedorov, Oleg/B-6412-2014; OI Fedorov, Oleg/0000-0001-9004-1815; Wang, Yuchuan/0000-0001-5111-6562; Filippakopoulos, Panagis/0000-0002-1515-1317; Kung, Andrew/0000-0002-9091-488X; Knapp, Stefan/0000-0001-5995-6494 FU Canadian Institutes for Health Research [1097737]; Canadian Foundation for Innovation; Genome Canada through the Ontario Genomics Institute; GlaxoSmithKline; Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Merck Co., Inc.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust; University of Notre Dame; NIGMS [T32-075762]; DF/HCC; National Institutes of Health; Burroughs Wellcome Fund; Leukemia & Lymphoma Society FX We are grateful to U. Oppermann, S. Muller, S. Sallan, C. Lathan, P. Rahl, R. Young, K. Lee and K. Shaw for discussions and sharing unpublished information; K. Agu, S. Johnston and L. Li for analytical chemistry support; J. Daley for flow cytometry support; T. Bowman, T. Caron, C. Marvin and S. Rodig for immunohistochemistry; and A. Bass for sharing cell lines. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust. This research was supported by a Graduate Fellowship from the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, NIGMS T32-075762 (to Y.S.), the DF/HCC (to C. A. F. and J. E. B.), the National Institutes of Health, the Burroughs Wellcome Fund, and the Leukemia & Lymphoma Society (to J.E.B.). NR 43 TC 1047 Z9 1060 U1 39 U2 238 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 23 PY 2010 VL 468 IS 7327 BP 1067 EP 1073 DI 10.1038/nature09504 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697XT UT WOS:000285553800051 PM 20871596 ER PT J AU Shahian, DM Wolf, RE Iezzoni, LI Kirle, L Normand, SLT AF Shahian, David M. Wolf, Robert E. Iezzoni, Lisa I. Kirle, Leslie Normand, Sharon-Lise T. TI Variability in the Measurement of Hospital-wide Mortality Rates. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RISK-ADJUSTED MORTALITY; QUALITY-OF-CARE; DEATH RATES; PERFORMANCE; INDICATOR AB Background: Several countries use hospital-wide mortality rates to evaluate the quality of hospital care, although the usefulness of this metric has been questioned. Massachusetts policymakers recently requested an assessment of methods to calculate this aggregate mortality metric for use as a measure of hospital quality. Methods: The Massachusetts Division of Health Care Finance and Policy provided four vendors with identical information on 2,528,624 discharges from Massachusetts acute care hospitals from October 1, 2004, through September 30, 2007. Vendors applied their risk-adjustment algorithms and provided predicted probabilities of in-hospital death for each discharge and for hospital-level observed and expected mortality rates. We compared the numbers and characteristics of discharges and hospitals included by each of the four methods. We also compared hospitals' standardized mortality ratios and classification of hospitals with mortality rates that were higher or lower than expected, according to each method. Results: The proportions of discharges that were included by each method ranged from 28% to 95%, and the severity of patients' diagnoses varied widely. Because of their discharge-selection criteria, two methods calculated in-hospital mortality rates (4.0% and 5.9%) that were twice the state average (2.1%). Pairwise associations (Pearson correlation coefficients) of discharge-level predicted mortality probabilities ranged from 0.46 to 0.70. Hospital-performance categorizations varied substantially and were sometimes completely discordant. In 2006, a total of 12 of 28 hospitals that had higher-than-expected hospital-wide mortality when classified by one method had lower-than-expected mortality when classified by one or more of the other methods. Conclusions: Four common methods for calculating hospital-wide mortality produced substantially different results. This may have resulted from a lack of standardized national eligibility and exclusion criteria, different statistical methods, or fundamental flaws in the hypothesized association between hospital-wide mortality and quality of care. (Funded by the Massachusetts Division of Health Care Finance and Policy.) N Engl J Med 2010;363:2530-9. C1 [Shahian, David M.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Shahian, David M.; Wolf, Robert E.; Iezzoni, Lisa I.; Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Boston, MA USA. [Kirle, Leslie] Massachusetts Div Hlth Care Finance & Policy, Boston, MA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, Ctr Qual & Safety, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org FU DHCFP FX Supported by the DHCFP. NR 41 TC 96 Z9 97 U1 0 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 23 PY 2010 VL 363 IS 26 BP 2530 EP 2539 DI 10.1056/NEJMsa1006396 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 697YL UT WOS:000285555600008 PM 21175315 ER PT J AU Friedman, LS Gee, MS Misdraji, J AF Friedman, Lawrence S. Gee, Michael S. Misdraji, Joseph TI Case 39-2010: A 19-Year-Old Woman with Nausea, Jaundice, and Pruritus. Severe panlobular hepatitis, with features that were consistent with the acute onset of autoimmune hepatitis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WILSONS-DISEASE; LIVER-DISEASE; PREGNANCY; HEPATOTOXICITY; DIAGNOSIS; CIRRHOSIS; FULMINANT; SERUM; RISK C1 [Friedman, Lawrence S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Gee, Michael S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Friedman, Lawrence S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gee, Michael S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Misdraji, Joseph] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Friedman, Lawrence S.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Friedman, Lawrence S.] Newton Wellesley Hosp, Dept Med, Newton, MA USA. RP Friedman, LS (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 42 TC 5 Z9 6 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 23 PY 2010 VL 363 IS 26 BP 2548 EP 2557 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 697YL UT WOS:000285555600012 PM 21175318 ER PT J AU Annamalai, L Westmoreland, SV Domingues, HG Walsh, DG Gonzalez, G O'Neil, SP AF Annamalai, Lakshmanan Westmoreland, Susan V. Domingues, Heber G. Walsh, Dennis G. Gonzalez, Gilberto O'Neil, Shawn P. TI Myocarditis in CD8-Depleted SIV-Infected Rhesus Macaques after Short-Term Dual Therapy with Nucleoside and Nucleotide Reverse Transcriptase Inhibitors SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CORONARY-HEART-DISEASE; TUMOR-NECROSIS-FACTOR; ACTIVE ANTIRETROVIRAL THERAPY; LEFT-VENTRICULAR DYSFUNCTION; HIV-INFECTION; DILATED CARDIOMYOPATHY; PROTEASE INHIBITORS; CARDIOVASCULAR-DISEASE; CYTOKINE PRODUCTION AB Background: Although highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. Methodology/Principal Findings: We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/-)-beta-2',3'- dideoxy-5-fluoro-3'-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p, 0.05), but significantly greater quantities of TNF-alpha mRNA than either SIV-positive untreated animals or uninfected controls (p, 0.05). Interferon-gamma (IFN-gamma), IL-1 beta and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. Conclusions/Significance: These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection. C1 [Annamalai, Lakshmanan; Westmoreland, Susan V.; Domingues, Heber G.; Walsh, Dennis G.; O'Neil, Shawn P.] Harvard Univ, Sch Med, Div Comparat Pathol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Gonzalez, Gilberto] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Annamalai, L (reprint author), Oregon Natl Primate Res Ctr, Dept Anim Resources, Beaverton, OR USA. EM susan_westmoreland@hms.harvard.edu FU NIH NINDS; NIH, NCRR [RR000150, NS048831, NS05004] FX This study was supported in part by grants from NIH NINDS and NCRR, including RR000150 (SPO), NS048831 (SPO) and NS05004 (RGG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 6 Z9 6 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 23 PY 2010 VL 5 IS 12 AR e14429 DI 10.1371/journal.pone.0014429 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698FO UT WOS:000285579200010 PM 21203448 ER PT J AU Strata, F Stoianov, IP de Villers-Sidani, E Bonham, B Martone, T Kenet, T Chang, EF Vincenti, V Merzenich, MM AF Strata, Fabrizio Stoianov, Ivilin P. de Villers-Sidani, Etienne Bonham, Ben Martone, Tiziana Kenet, Tal Chang, Edward F. Vincenti, Vincenzo Merzenich, Michael M. TI Perinatal Asphyxia Affects Rat Auditory Processing: Implications for Auditory Perceptual Impairments in Neurodevelopmental Disorders SO PLOS ONE LA English DT Article ID CEREBRAL-PALSY; CORTEX NEURONS; BRAIN-STEM; AUTISM; INHIBITION; SYSTEM; BIRTH; ORGANIZATION; MONKEYS; CONSEQUENCES AB Perinatal asphyxia, a naturally and commonly occurring risk factor in birthing, represents one of the major causes of neonatal encephalopathy with long term consequences for infants. Here, degraded spectral and temporal responses to sounds were recorded from neurons in the primary auditory cortex (A1) of adult rats exposed to asphyxia at birth. Response onset latencies and durations were increased. Response amplitudes were reduced. Tuning curves were broader. Degraded successive-stimulus masking inhibitory mechanisms were associated with a reduced capability of neurons to follow higher-rate repetitive stimuli. The architecture of peripheral inner ear sensory epithelium was preserved, suggesting that recorded abnormalities can be of central origin. Some implications of these findings for the genesis of language perception deficits or for impaired language expression recorded in developmental disorders, such as autism spectrum disorders, contributed to by perinatal asphyxia, are discussed. C1 [Strata, Fabrizio] Univ Parma, Physiol Sect, Dept Neurosci, I-43100 Parma, Italy. [Strata, Fabrizio; Merzenich, Michael M.] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Coleman Mem Lab, Keck Ctr Integrat Neurosci, San Francisco, CA 94143 USA. [Stoianov, Ivilin P.] Univ Padua, Dept Gen Psychol, Padua, Italy. [de Villers-Sidani, Etienne] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. [Bonham, Ben] Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Epstein Labs, San Francisco, CA 94143 USA. [Martone, Tiziana] Univ Turin, Div Otolaryngol, Dept Clin Physiopathol, Turin, Italy. [Kenet, Tal] Massachusetts Gen Hosp, Dept Neurol, Athinoula A Martinos Ctr Biomed Imaging MGH Marti, Charlestown, MA USA. [Chang, Edward F.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA. [Vincenti, Vincenzo] Univ Parma, Dept Otolaryngol Head & Neck Surg, I-43100 Parma, Italy. RP Strata, F (reprint author), Univ Parma, Physiol Sect, Dept Neurosci, I-43100 Parma, Italy. EM fab@phy.ucsf.edu RI Stoianov, Ivilin/G-5904-2011 OI Stoianov, Ivilin/0000-0003-0642-259X FU National Institutes of Health Conte Center [MH77970]; John C. and Edward Coleman Memorial Fund; Italian Ministry of University and Research FX This work was supported by the National Institutes of Health Conte Center grant MH77970 (M.M.M.), the John C. and Edward Coleman Memorial Fund (M.M.M.), and the Italian Ministry of University and Research, PRIN 2009 (F.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 1 Z9 1 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 23 PY 2010 VL 5 IS 12 AR e15326 DI 10.1371/journal.pone.0015326 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698FO UT WOS:000285579200017 PM 21203459 ER PT J AU Wu, XY Ruvkun, G AF Wu, Xiaoyun Ruvkun, Gary TI Germ Cell Genes and Cancer SO SCIENCE LA English DT Editorial Material ID SOMATIC STEM-CELLS; C-ELEGANS; RNA INTERFERENCE; COMPLEX; ANTAGONIZE; EXPRESSION; PATHWAY; VASA C1 [Wu, Xiaoyun; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Wu, Xiaoyun; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Wu, XY (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM wux@molbio.mgh.harvard.edu; ruvkun@molbio.mgh.harvard.edu NR 19 TC 8 Z9 8 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 23 PY 2010 VL 330 IS 6012 BP 1761 EP 1762 DI 10.1126/science.1200772 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698OS UT WOS:000285603700026 PM 21205660 ER PT J AU Gerstein, MB Lu, ZJ Van Nostrand, EL Cheng, C Arshinoff, BI Liu, T Yip, KY Robilotto, R Rechtsteiner, A Ikegami, K Alves, P Chateigner, A Perry, M Morris, M Auerbach, RK Feng, X Leng, J Vielle, A Niu, W Rhrissorrakrai, K Agarwal, A Alexander, RP Barber, G Brdlik, CM Brennan, J Brouillet, JJ Carr, A Cheung, MS Clawson, H Contrino, S Dannenberg, LO Dernburg, AF Desai, A Dick, L Dose, AC Du, JA Egelhofer, T Ercan, S Euskirchen, G Ewing, B Feingold, EA Gassmann, R Good, PJ Green, P Gullier, F Gutwein, M Guyer, MS Habegger, L Han, T Henikoff, JG Henz, SR Hinrichs, A Holster, H Hyman, T Iniguez, AL Janette, J Jensen, M Kato, M Kent, WJ Kephart, E Khivansara, V Khurana, E Kim, JK Kolasinska-Zwierz, P Lai, EC Latorre, I Leahey, A Lewis, S Lloyd, P Lochovsky, L Lowdon, RF Lubling, Y Lyne, R MacCoss, M Mackowiak, SD Mangone, M Mckay, S Mecenas, D Merrihew, G Miller, DM Muroyama, A Murray, JI Ooi, SL Pham, H Phippen, T Preston, EA Rajewsky, N Ratsch, G Rosenbaum, H Rozowsky, J Rutherford, K Ruzanov, P Sarov, M Sasidharan, R Sboner, A Scheid, P Segal, E Shin, HJ Shou, C Slack, FJ Slightam, C Smith, R Spencer, WC Stinson, EO Taing, S Takasaki, T Vafeados, D Voronina, K Wang, GL Washington, NL Whittle, CM Wu, BJ Yan, KK Zeller, G Zha, Z Zhong, M Zhou, XL Ahringer, J Strome, S Gunsalus, KC Micklem, G Liu, XS Reinke, V Kim, SK Hillier, LW Henikoff, S Piano, F Snyder, M Stein, L Lieb, JD Waterston, RH AF Gerstein, Mark B. Lu, Zhi John Van Nostrand, Eric L. Cheng, Chao Arshinoff, Bradley I. Liu, Tao Yip, Kevin Y. Robilotto, Rebecca Rechtsteiner, Andreas Ikegami, Kohta Alves, Pedro Chateigner, Aurelien Perry, Marc Morris, Mitzi Auerbach, Raymond K. Feng, Xin Leng, Jing Vielle, Anne Niu, Wei Rhrissorrakrai, Kahn Agarwal, Ashish Alexander, Roger P. Barber, Galt Brdlik, Cathleen M. Brennan, Jennifer Brouillet, Jeremy Jean Carr, Adrian Cheung, Ming-Sin Clawson, Hiram Contrino, Sergio Dannenberg, Luke O. Dernburg, Abby F. Desai, Arshad Dick, Lindsay Dose, Andrea C. Du, Jiang Egelhofer, Thea Ercan, Sevinc Euskirchen, Ghia Ewing, Brent Feingold, Elise A. Gassmann, Reto Good, Peter J. Green, Phil Gullier, Francois Gutwein, Michelle Guyer, Mark S. Habegger, Lukas Han, Ting Henikoff, Jorja G. Henz, Stefan R. Hinrichs, Angie Holster, Heather Hyman, Tony Iniguez, A. Leo Janette, Judith Jensen, Morten Kato, Masaomi Kent, W. James Kephart, Ellen Khivansara, Vishal Khurana, Ekta Kim, John K. Kolasinska-Zwierz, Paulina Lai, Eric C. Latorre, Isabel Leahey, Amber Lewis, Suzanna Lloyd, Paul Lochovsky, Lucas Lowdon, Rebecca F. Lubling, Yaniv Lyne, Rachel MacCoss, Michael Mackowiak, Sebastian D. Mangone, Marco Mckay, Sheldon Mecenas, Desirea Merrihew, Gennifer Miller, David M., III Muroyama, Andrew Murray, John I. Ooi, Siew-Loon Pham, Hoang Phippen, Taryn Preston, Elicia A. Rajewsky, Nikolaus Raetsch, Gunnar Rosenbaum, Heidi Rozowsky, Joel Rutherford, Kim Ruzanov, Peter Sarov, Mihail Sasidharan, Rajkumar Sboner, Andrea Scheid, Paul Segal, Eran Shin, Hyunjin Shou, Chong Slack, Frank J. Slightam, Cindie Smith, Richard Spencer, William C. Stinson, E. O. Taing, Scott Takasaki, Teruaki Vafeados, Dionne Voronina, Ksenia Wang, Guilin Washington, Nicole L. Whittle, Christina M. Wu, Beijing Yan, Koon-Kiu Zeller, Georg Zha, Zheng Zhong, Mei Zhou, Xingliang Ahringer, Julie Strome, Susan Gunsalus, Kristin C. Micklem, Gos Liu, X. Shirley Reinke, Valerie Kim, Stuart K. Hillier, LaDeana W. Henikoff, Steven Piano, Fabio Snyder, Michael Stein, Lincoln Lieb, Jason D. Waterston, Robert H. CA modENCODE Consortium TI Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project SO SCIENCE LA English DT Article ID C. ELEGANS; NUCLEOSOME ORGANIZATION; TRANSCRIPTION FACTORS; RNA-SEQ; REVEALS; EXPRESSION; EMBRYOS; NETWORK; DNA; CHROMATIN AB We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome. C1 [Gerstein, Mark B.; Lu, Zhi John; Cheng, Chao; Yip, Kevin Y.; Robilotto, Rebecca; Alves, Pedro; Auerbach, Raymond K.; Leng, Jing; Alexander, Roger P.; Habegger, Lukas; Lochovsky, Lucas; Rozowsky, Joel; Sboner, Andrea; Shou, Chong; Yan, Koon-Kiu] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Gerstein, Mark B.; Lu, Zhi John; Cheng, Chao; Yip, Kevin Y.; Agarwal, Ashish; Alexander, Roger P.; Rozowsky, Joel; Sasidharan, Rajkumar; Sboner, Andrea; Yan, Koon-Kiu] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Gerstein, Mark B.; Agarwal, Ashish; Du, Jiang] Yale Univ, Dept Comp Sci, New Haven, CT 06511 USA. [Van Nostrand, Eric L.; Brdlik, Cathleen M.; Brouillet, Jeremy Jean; Kim, Stuart K.; Snyder, Michael] Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. [Arshinoff, Bradley I.; Perry, Marc; Feng, Xin; Kephart, Ellen; Lloyd, Paul; Ruzanov, Peter; Zha, Zheng; Stein, Lincoln] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Arshinoff, Bradley I.; Stein, Lincoln] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Liu, Tao; Shin, Hyunjin; Taing, Scott; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Tao; Shin, Hyunjin; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ikegami, Kohta; Brennan, Jennifer; Ercan, Sevinc; Jensen, Morten; Whittle, Christina M.; Zhou, Xingliang; Lieb, Jason D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Ikegami, Kohta; Brennan, Jennifer; Ercan, Sevinc; Jensen, Morten; Whittle, Christina M.; Zhou, Xingliang; Lieb, Jason D.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Chateigner, Aurelien; Carr, Adrian; Contrino, Sergio; Gullier, Francois; Lyne, Rachel; Rutherford, Kim; Smith, Richard; Micklem, Gos] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Chateigner, Aurelien; Carr, Adrian; Contrino, Sergio; Gullier, Francois; Lyne, Rachel; Rutherford, Kim; Smith, Richard; Micklem, Gos] Cambridge Syst Biol Ctr, Cambridge CB2 1QR, England. [Morris, Mitzi; Rhrissorrakrai, Kahn; Gutwein, Michelle; Khurana, Ekta; Mangone, Marco; Mecenas, Desirea; Scheid, Paul; Gunsalus, Kristin C.; Piano, Fabio] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Vielle, Anne; Cheung, Ming-Sin; Kolasinska-Zwierz, Paulina; Latorre, Isabel; Ahringer, Julie] Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England. [Niu, Wei; Euskirchen, Ghia; Zhong, Mei; Snyder, Michael] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06824 USA. [Niu, Wei; Janette, Judith; Wang, Guilin; Reinke, Valerie] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. [Dannenberg, Luke O.; Holster, Heather; Iniguez, A. Leo; Rosenbaum, Heidi] Roche NimbleGen, Madison, WI 53719 USA. [Dernburg, Abby F.; Dose, Andrea C.; Pham, Hoang] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Dernburg, Abby F.; Dose, Andrea C.; Pham, Hoang] Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Desai, Arshad; Gassmann, Reto; Muroyama, Andrew; Voronina, Ksenia] Univ Calif San Diego, Ludwig Inst Canc Res, Dept Cellular & Mol Med, San Diego, CA 92093 USA. [Ewing, Brent; Green, Phil; Leahey, Amber; MacCoss, Michael; Merrihew, Gennifer; Murray, John I.; Preston, Elicia A.; Vafeados, Dionne; Hillier, LaDeana W.; Waterston, Robert H.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Feingold, Elise A.; Good, Peter J.; Guyer, Mark S.; Lowdon, Rebecca F.] NHGRI, Div Extramural Res, NIH, Bethesda, MD 20892 USA. [Feng, Xin] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Han, Ting; Khivansara, Vishal; Kim, John K.] Univ Michigan, Inst Life Sci, Dept Human Genet, Ann Arbor, MI 48109 USA. [Henikoff, Jorja G.; Ooi, Siew-Loon; Henikoff, Steven] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Raetsch, Gunnar; Zeller, Georg] Max Planck Gesell, Friedrich Miescher Lab, D-72076 Tubingen, Germany. [Hyman, Tony; Sarov, Mihail] Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany. [Miller, David M., III; Spencer, William C.] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Kato, Masaomi; Slack, Frank J.] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. [Henz, Stefan R.] Max Planck Inst Dev Biol, D-72076 Tubingen, Germany. [Lai, Eric C.] Sloan Kettering Inst, New York, NY 10065 USA. [Lewis, Suzanna; Stinson, E. O.; Washington, Nicole L.] Lawrence Berkeley Natl Lab, Genom Div, Berkeley, CA 94720 USA. [Lubling, Yaniv; Segal, Eran] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel. [Mackowiak, Sebastian D.; Rajewsky, Nikolaus] Max Delbruck Ctr Mol Med, Div Syst Biol, D-13125 Berlin, Germany. [Mckay, Sheldon; Stein, Lincoln] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11542 USA. [Slightam, Cindie; Wu, Beijing; Kim, Stuart K.] Stanford Univ, Med Ctr, Dept Dev Biol, Stanford, CA 94305 USA. [Zeller, Georg] European Mol Biol Lab, D-69117 Heidelberg, Germany. [Gunsalus, Kristin C.; Piano, Fabio] NYU, Abu Dhabi, U Arab Emirates. [Dick, Lindsay] Rockefeller Univ, David Rockefeller Grad Program, New York, NY 10065 USA. RP Gerstein, MB (reprint author), Yale Univ, Program Computat Biol & Bioinformat, Bass 432,266 Whitney Ave, New Haven, CT 06520 USA. EM modencode.worm.pi@gersteinlab.org RI Spencer, William/E-8529-2010; yu, yan/C-2322-2012; Khurana, Ekta/C-4933-2013; Yan, Koon-Kiu/A-5940-2009; NUI, WEI/B-8300-2011; Gassmann, Reto/M-6488-2013; Zeller, Georg/M-6484-2013; Hyman, Anthony/B-3917-2017; Alexander, Roger/A-8643-2008; Liu, Tao/G-3585-2010; Sboner, Andrea/C-6487-2008; OI Rutherford, Kim/0000-0001-6277-726X; Micklem, Gos/0000-0002-6883-6168; Lewis, Suzanna/0000-0002-8343-612X; Liu, Tao/0000-0003-0446-9001; Lloyd, Paul/0000-0003-3508-5553; Segal, Eran/0000-0002-6859-1164; Hinrichs, Angie/0000-0002-1697-1130; Slack, Frank/0000-0001-8263-0409; Rozowsky, Joel/0000-0002-3565-0762; Dernburg, Abby/0000-0001-8037-1079; Mangone, Marco/0000-0001-7551-8793; Latorre, Isabel/0000-0003-0638-1783; Gassmann, Reto/0000-0002-0360-2977; Zeller, Georg/0000-0003-1429-7485; Hyman, Anthony/0000-0003-3664-154X; Alexander, Roger/0000-0002-2967-7395; Liu, Tao/0000-0002-8818-8313; Sboner, Andrea/0000-0001-6915-3070; McKay, Sheldon/0000-0002-4011-3160 FU NHGRI of the NIH [R01GM088565]; Muscular Dystrophy Association; Pew Charitable Trusts; Helmholtz-Alliance on Systems Biology (Max Delbruck Centrum Systems Biology Network); Wellcome Trust; William H. Gates III Endowed Chair of Biomedical Sciences FX Funding for this work came from the NHGRI of the NIH as part of the modENCODE project, NIH (grant R01GM088565), Muscular Dystrophy Association, and the Pew Charitable Trusts (J.K.K.); the Helmholtz-Alliance on Systems Biology (Max Delbruck Centrum Systems Biology Network) (S.D.M.); the Wellcome Trust (J.A.); the William H. Gates III Endowed Chair of Biomedical Sciences (R.H.W.); and the A. L. Williams Professorship (M.B.G.). M. Snyder has an advisory role with DNANexus, a DNA sequence storage and analysis company. Transfer of GFP-tagged fosmids requires a Materials Transfer Agreement with the Max Planck Institute of Molecular Cell Biology and Genetics. Raw microarray data are available from the Gene Expression Omnibus archive, and raw sequencing data are available from the SRA archive (accessions are in table S18). We appreciate help from S. Anthony, K. Bell, C. Davis, C. Dieterich, Y. Field, A. S. Hammonds, J. Jo, N. Kaplan, A. Manrai, B. Mathey-Prevot, R. McWhirter, S. Mohr, S. Von Stetina, J. Watson, K. Watkins, C. Xue, and Y. Zhang, and B. Carpenter. We thank C. Jan and D. Bartel for sharing data on poly(A) sites before publication, WormBase curator G. Williams for assistance in quality checking and preparing the transcriptomics data sets for publication, as well as his fellow curator P. Davis for reviewing and hand-checking the list of pseudogenes. NR 76 TC 458 Z9 462 U1 6 U2 90 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD DEC 23 PY 2010 VL 330 IS 6012 BP 1775 EP 1787 DI 10.1126/science.1196914 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698OS UT WOS:000285603700031 PM 21177976 ER PT J AU Roy, S Ernst, J Kharchenko, PV Kheradpour, P Negre, N Eaton, ML Landolin, JM Bristow, CA Ma, LJ Lin, MF Washietl, S Arshinoff, BI Ay, F Meyer, PE Robine, N Washington, NL Di Stefano, L Berezikov, E Brown, CD Candeias, R Carlson, JW Carr, A Jungreis, I Marbach, D Sealfon, R Tolstorukov, MY Will, S Alekseyenko, AA Artieri, C Booth, BW Brooks, AN Dai, Q Davis, CA Duff, MO Feng, X Gorchakov, AA Gu, TT Henikoff, JG Kapranov, P Li, RH MacAlpine, HK Malone, J Minoda, A Nordman, J Okamura, K Perry, M Powell, SK Riddle, NC Sakai, A Samsonova, A Sandler, JE Schwartz, YB Sher, N Spokony, R Sturgill, D van Baren, M Wan, KH Yang, L Yu, C Feingold, E Good, P Guyer, M Lowdon, R Ahmad, K Andrews, J Berger, B Brenner, SE Brent, MR Cherbas, L Elgin, SCR Gingeras, TR Grossman, R Hoskins, RA Kaufman, TC Kent, W Kuroda, MI Orr-Weaver, T Perrimon, N Pirrotta, V Posakony, JW Ren, B Russell, S Cherbas, P Graveley, BR Lewis, S Micklem, G Oliver, B Park, PJ Celniker, SE Henikoff, S Karpen, GH Lai, EC MacAlpine, DM Stein, LD White, KP Kellis, M AF Roy, Sushmita Ernst, Jason Kharchenko, Peter V. Kheradpour, Pouya Negre, Nicolas Eaton, Matthew L. Landolin, Jane M. Bristow, Christopher A. Ma, Lijia Lin, Michael F. Washietl, Stefan Arshinoff, Bradley I. Ay, Ferhat Meyer, Patrick E. Robine, Nicolas Washington, Nicole L. Di Stefano, Luisa Berezikov, Eugene Brown, Christopher D. Candeias, Rogerio Carlson, Joseph W. Carr, Adrian Jungreis, Irwin Marbach, Daniel Sealfon, Rachel Tolstorukov, Michael Y. Will, Sebastian Alekseyenko, Artyom A. Artieri, Carlo Booth, Benjamin W. Brooks, Angela N. Dai, Qi Davis, Carrie A. Duff, Michael O. Feng, Xin Gorchakov, Andrey A. Gu, Tingting Henikoff, Jorja G. Kapranov, Philipp Li, Renhua MacAlpine, Heather K. Malone, John Minoda, Aki Nordman, Jared Okamura, Katsutomo Perry, Marc Powell, Sara K. Riddle, Nicole C. Sakai, Akiko Samsonova, Anastasia Sandler, Jeremy E. Schwartz, Yuri B. Sher, Noa Spokony, Rebecca Sturgill, David van Baren, Marijke Wan, Kenneth H. Yang, Li Yu, Charles Feingold, Elise Good, Peter Guyer, Mark Lowdon, Rebecca Ahmad, Kami Andrews, Justen Berger, Bonnie Brenner, Steven E. Brent, Michael R. Cherbas, Lucy Elgin, Sarah C. R. Gingeras, Thomas R. Grossman, Robert Hoskins, Roger A. Kaufman, Thomas C. Kent, William Kuroda, Mitzi I. Orr-Weaver, Terry Perrimon, Norbert Pirrotta, Vincenzo Posakony, James W. Ren, Bing Russell, Steven Cherbas, Peter Graveley, Brenton R. Lewis, Suzanna Micklem, Gos Oliver, Brian Park, Peter J. Celniker, Susan E. Henikoff, Steven Karpen, Gary H. Lai, Eric C. MacAlpine, David M. Stein, Lincoln D. White, Kevin P. Kellis, Manolis CA modENCODE Consortium TI Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE SO SCIENCE LA English DT Article ID PREDICTIVE CHROMATIN SIGNATURES; TRANSCRIPTION FACTORS; SOMATIC-CELLS; HUMAN GENOME; DNA-BINDING; RNA PATHWAY; MELANOGASTER; SEQUENCE; REGIONS; NETWORK AB To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage-and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation. C1 [Roy, Sushmita; Ernst, Jason; Kheradpour, Pouya; Bristow, Christopher A.; Lin, Michael F.; Washietl, Stefan; Ay, Ferhat; Meyer, Patrick E.; Di Stefano, Luisa; Candeias, Rogerio; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Will, Sebastian; Berger, Bonnie; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Roy, Sushmita; Ernst, Jason; Kheradpour, Pouya; Bristow, Christopher A.; Lin, Michael F.; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Berger, Bonnie; Kellis, Manolis] MIT, Broad Inst, Cambridge, MA 02140 USA. [Roy, Sushmita; Ernst, Jason; Kheradpour, Pouya; Bristow, Christopher A.; Lin, Michael F.; Jungreis, Irwin; Marbach, Daniel; Sealfon, Rachel; Berger, Bonnie; Kellis, Manolis] Harvard Univ, Cambridge, MA 02140 USA. [Kharchenko, Peter V.; Tolstorukov, Michael Y.; Schwartz, Yuri B.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Negre, Nicolas; Ma, Lijia; Brown, Christopher D.; Spokony, Rebecca; Grossman, Robert; White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Dept Human Genet, Chicago, IL 60637 USA. [Eaton, Matthew L.; MacAlpine, Heather K.; Powell, Sara K.; MacAlpine, David M.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Landolin, Jane M.; Carlson, Joseph W.; Booth, Benjamin W.; Minoda, Aki; Sandler, Jeremy E.; Wan, Kenneth H.; Yu, Charles; Hoskins, Roger A.; Celniker, Susan E.; Karpen, Gary H.] Lawrence Berkeley Natl Lab, Dept Genome Dynam, Berkeley, CA 94720 USA. [Arshinoff, Bradley I.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Robine, Nicolas; Dai, Qi; Henikoff, Jorja G.; Okamura, Katsutomo; Lai, Eric C.] Sloan Kettering Inst, New York, NY 10065 USA. [Washington, Nicole L.; Lewis, Suzanna] LBNL, Genome Sci Div, Berkeley, CA 94720 USA. [Carr, Adrian; Russell, Steven; Micklem, Gos] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Carr, Adrian; Russell, Steven; Micklem, Gos] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge CB2 3EH, England. [Alekseyenko, Artyom A.; Gorchakov, Andrey A.; Kuroda, Mitzi I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Alekseyenko, Artyom A.; Gorchakov, Andrey A.; Kuroda, Mitzi I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. [Artieri, Carlo; Malone, John; Sturgill, David; Oliver, Brian] NIDDK, Sect Dev Genom, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Davis, Carrie A.; Feng, Xin; Gingeras, Thomas R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Duff, Michael O.; Yang, Li; Graveley, Brenton R.] Univ Connecticut, Stem Cell Inst, Dept Genet & Dev Biol, Farmington, CT 06030 USA. [Gu, Tingting; Riddle, Nicole C.; Elgin, Sarah C. R.] Washington Univ, Dept Biol, St Louis, MO 63130 USA. [Kapranov, Philipp; Gingeras, Thomas R.] Affymetrix, Santa Clara, CA 95051 USA. [Li, Renhua; Feingold, Elise; Good, Peter; Guyer, Mark; Lowdon, Rebecca] NHGRI, Div Extramural Res, NIH, Bethesda, MD 20892 USA. [Arshinoff, Bradley I.; Feng, Xin; Perry, Marc; Stein, Lincoln D.] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada. [Samsonova, Anastasia; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Samsonova, Anastasia; Perrimon, Norbert] Harvard Univ, Sch Med, Drosophila RNAi Screening Ctr, Boston, MA 02115 USA. [van Baren, Marijke; Brent, Michael R.] Washington Univ, Ctr Genome Sci, St Louis, MO 63108 USA. [Andrews, Justen; Cherbas, Lucy; Kaufman, Thomas C.; Cherbas, Peter] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Nordman, Jared; Sher, Noa; Orr-Weaver, Terry] Whitehead Inst, Cambridge, MA 02142 USA. [Berezikov, Eugene] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, Utrecht, Netherlands. [Berezikov, Eugene] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Cherbas, Lucy; Cherbas, Peter] Indiana Univ, Ctr Genom & Bioinformat, Bloomington, IN 47405 USA. [Henikoff, Steven] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Posakony, James W.; Ren, Bing] Univ Calif San Diego, Sect Cell & Dev Biol, Div Biol Sci, La Jolla, CA 92093 USA. [Pirrotta, Vincenzo] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08854 USA. [Brooks, Angela N.; Brenner, Steven E.; Karpen, Gary H.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Sakai, Akiko; Ahmad, Kami] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Meyer, Patrick E.] Univ Libre Brussels, Machine Learning Grp, B-1050 Brussels, Belgium. [Di Stefano, Luisa] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Brenner, Steven E.] Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. [Ay, Ferhat] Univ Florida, Gainesville, FL 32611 USA. [Kent, William] Univ Calif Santa Cruz, Sch Engn, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Kent, William] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 USA. [Feng, Xin] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. RP Kellis, M (reprint author), MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM celniker@fruitfly.org; steveh@fhcrc.org; karpen@fruitfly.org; laie@mskcc.org; david.macalpine@duke.edu; lincoln.stein@gmail.com; kpwhite@uchicago.edu; manoli@mit.edu RI Samsonova, Anastasia/Q-7591-2016; Minoda, Aki/D-5335-2017; Sakai, Akiko/A-8929-2010; Berezikov, Eugene/D-3363-2013; Brenner, Steven/A-8729-2008; Venken, Koen/B-9909-2013; Gorchakov, Andrey/N-5840-2015; Eaton, Matthew/C-4408-2011; jiang, lichun/F-3776-2012; White, Rob/G-4835-2012; Russell, Steve/A-4072-2011; Brooks, Angela/B-6173-2011; Graveley, Brenton/C-3108-2013; Hansen, Kasper/E-6094-2011 OI Meyer, Folker/0000-0003-1112-2284; Lloyd, Paul/0000-0003-3508-5553; Bellen, Hugo/0000-0001-5992-5989; Hinrichs, Angie/0000-0002-1697-1130; Negre, Nicolas/0000-0001-9727-3416; Robine, Nicolas/0000-0001-5698-8183; Brown, Christopher/0000-0002-3785-5008; Samsonova, Anastasia/0000-0002-9353-9173; Minoda, Aki/0000-0002-2927-5791; Gingeras, Thomas/0000-0001-9106-3573; Washington, Nicole/0000-0001-8936-9143; Grossman, Robert/0000-0003-3741-5739; Graveley, Brenton/0000-0001-5777-5892; Rutherford, Kim/0000-0001-6277-726X; McKay, Sheldon/0000-0002-4011-3160; Micklem, Gos/0000-0002-6883-6168; Lewis, Suzanna/0000-0002-8343-612X; Berezikov, Eugene/0000-0002-1145-2884; Brenner, Steven/0000-0001-7559-6185; Venken, Koen/0000-0003-0741-4698; Gorchakov, Andrey/0000-0003-2830-4236; jiang, lichun/0000-0003-2462-7636; Russell, Steve/0000-0003-0546-3031; Hansen, Kasper/0000-0003-0086-0687 FU National Human Genome Research Institute [RC2HG005639, U01HG004271, U01HG004258, U01HG004264, U01HG004279, U01HG004261, U01HG004274, U41HG004269]; LBNL [DE-AC02-05CH11231]; NSF [0937060, 0905968, 0644282]; Natural Sciences and Engineering Research Council of Canada (NSERC); Japan Society for the Promotion of Science; Swedish Research Council; NIH National Research Service; National Defense Science and Engineering; Austrian Fonds zur Forderung der wissenschaftlichen Forschung; Leukemia and Lymphoma Society; Lilly-Life Sciences Research Foundation; Affymetrix; Swiss National Science Foundation; German Research Foundation [WI 3628/1-1]; HHMI; Indiana Genomics Initiative; NIDDK genomics core laboratory; NIH [R01HG004037]; Sloan Foundation FX This work was supported by the National Human Genome Research Institute as part of the modENCODE project under RC2HG005639 (M.K.), U01HG004271 (S.E.C.), U01HG004258 (G.H.K.), U01HG004264 (K.P.W.), U01HG004279 (D.M.M.), U01HG004261 (E.L.), U01HG004274 (S.H.), and U41HG004269 (L.S.). Awards to S.E.C. and G.H.K. were carried out at LBNL under contract no. DE-AC02-05CH11231. Additional support was provided by the NSF under grant 0937060 to the Computing Research Association for the CIFellows Project (S.R.) and under award no. 0905968 (J.E.), a Natural Sciences and Engineering Research Council of Canada (NSERC) fellowship (B.A.), T. Kahveci (F.A.), the Japan Society for the Promotion of Science (K.O.), the Swedish Research Council (Q.D.), a NIH National Research Service Award postdoctoral fellowship (C.A.B.), a National Defense Science and Engineering Graduate Fellowship (R.S.), an Erwin Schrodinger Fellowship of the Austrian Fonds zur Forderung der wissenschaftlichen Forschung (S.W.), a Leukemia and Lymphoma Society fellowship (S.W.), a Lilly-Life Sciences Research Foundation fellowship (C.D.B.), a NSERC postdoctoral fellowship (C. G. A.), Affymetrix (T.G.R.), a fellowship from the Swiss National Science Foundation (D.M.), a German Research Foundation grant WI 3628/1-1 (S.W.), a HHMI Damon Runyon Cancer Research fellowship (J.T.N.), the Indiana Genomics Initiative (T.C.K.), H. Smith and the NIDDK genomics core laboratory (B.O.), NIH R01HG004037, NSF CAREER award 0644282, and the Sloan Foundation (M.K.). A full list of author contributions is available in the SOM. NR 69 TC 524 Z9 531 U1 17 U2 82 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 23 PY 2010 VL 330 IS 6012 BP 1787 EP 1797 DI 10.1126/science.1198374 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698OS UT WOS:000285603700032 ER PT J AU Braun, CR Mintseris, J Gavathiotis, E Bird, GH Gygi, SP Walensky, LD AF Braun, Craig R. Mintseris, Julian Gavathiotis, Evripidis Bird, Gregory H. Gygi, Steven P. Walensky, Loren D. TI Photoreactive Stapled BH3 Peptides to Dissect the BCL-2 Family Interactome SO CHEMISTRY & BIOLOGY LA English DT Article ID PROTEIN STRUCTURES; DOCKING APPROACH; BAX; ACTIVATION; PROTEOMICS; APOPTOSIS; DOMAINS; HELIX; NMR; INHIBITOR AB Defining protein interactions forms the basis for discovery of biological pathways, disease mechanisms, and opportunities for therapeutic intervention. To harness the robust binding affinity and selectivity of structured peptides for interactome discovery, we engineered photoreactive stapled BH3 peptide helices that covalently capture their physiologic BCL-2 family targets. The crosslinking alpha helices covalently trap both static and dynamic protein interactors, and enable rapid identification of interaction sites, providing a critical link between interactome discovery and targeted drug design. C1 [Braun, Craig R.; Gavathiotis, Evripidis; Bird, Gregory H.; Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Braun, Craig R.; Gavathiotis, Evripidis; Bird, Gregory H.; Walensky, Loren D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Braun, Craig R.; Gavathiotis, Evripidis; Bird, Gregory H.; Walensky, Loren D.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Mintseris, Julian; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Mintseris, Julian; Gygi, Steven P.] Harvard Univ, Sch Med, Taplin Biol Mass Spectrometry Facil, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM Loren_Walensky@dfci.harvard.edu FU NIH [5P01CA92625, 1R01GM090299]; Stand Up to Cancer Innovative Research Grant; National Sciences and Engineering Research Council of Canada FX We thank E. Smith for figure design and editorial assistance. This work was supported by NIH grant 5P01CA92625, 1R01GM090299, and a Stand Up to Cancer Innovative Research Grant to L.D.W., and a National Sciences and Engineering Research Council of Canada postgraduate scholarship to C.R.B. L.D.W. is a consultant and scientific advisory board member for Aileron Therapeutics. NR 34 TC 26 Z9 27 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD DEC 22 PY 2010 VL 17 IS 12 BP 1325 EP 1333 DI 10.1016/j.chembiol.2010.09.015 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 717BA UT WOS:000287016000010 PM 21168768 ER PT J AU Hayes, JP Morey, RA Petty, CM Seth, S Smoski, MJ McCarthy, G LaBar, KS AF Hayes, Jasmeet Pannu Morey, Rajendra A. Petty, Christopher M. Seth, Srishti Smoski, Moria J. McCarthy, Gregory LaBar, Kevin S. TI Staying cool when things get hot: emotion regulation modulates neural mechanisms of memory encoding SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE arousal; cognitive reappraisal; declarative memory; expressive suppression; subsequent memory paradigm; hippocampus; amygdala; left inferior frontal gyrus ID COGNITIVE CONSEQUENCES; NEGATIVE EMOTION; FMRI; EXPERIENCE; NEUROSCIENCE; SUPPRESSION; EXPRESSION; DEPRESSION; INFERENCE; AWARENESS AB During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala, and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes. C1 [Hayes, Jasmeet Pannu] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Hayes, Jasmeet Pannu] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Hayes, Jasmeet Pannu; Morey, Rajendra A.; Petty, Christopher M.; Seth, Srishti; McCarthy, Gregory; LaBar, Kevin S.] Duke Univ, Duke UNC Brain Imaging & Anal Ctr, Durham, NC USA. [Hayes, Jasmeet Pannu; Morey, Rajendra A.; McCarthy, Gregory] Durham VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Durham, NC USA. [Morey, Rajendra A.; Smoski, Moria J.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Morey, Rajendra A.; LaBar, Kevin S.] Duke Univ, Ctr Cognit Neurosci, Durham, NC USA. [McCarthy, Gregory] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Hayes, JP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B2, 150 S Huntington Ave, Boston, MA 02130 USA. EM jphayes@bu.edu FU Department of Veterans Affairs, Mental Illness Research Education and Clinical Center; US National Institutes of Health [K23 MH073091, K23 MH084013, 2 P01 NS041328] FX We would like to extend thanks to Jessica Nasser and Elizabeth Selgrade for their help with data collection and analysis, and Dan Dillon, Florin Dolcos, and Scott Hayes for helpful discussions regarding the project. This work was supported by the Department of Veterans Affairs, Mental Illness Research Education and Clinical Center Grant for Post-Deployment Mental Health, and US National Institutes of Health (grant numbers K23 MH073091, K23 MH084013, and 2 P01 NS041328. NR 46 TC 51 Z9 51 U1 7 U2 40 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD DEC 22 PY 2010 VL 4 AR 230 DI 10.3389/fnhum.2010.00230 PG 10 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 747TP UT WOS:000289342900001 PM 21212840 ER PT J AU Zhao, J Ohsumi, TK Kung, JT Ogawa, Y Grau, DJ Sarma, K Song, JJ Kingston, RE Borowsky, M Lee, JT AF Zhao, Jing Ohsumi, Toshiro K. Kung, Johnny T. Ogawa, Yuya Grau, Daniel J. Sarma, Kavitha Song, Ji Joon Kingston, Robert E. Borowsky, Mark Lee, Jeannie T. TI Genome-wide Identification of Polycomb-Associated RNAs by RIP-seq SO MOLECULAR CELL LA English DT Article ID EMBRYONIC STEM-CELLS; EZH2 HISTONE METHYLTRANSFERASE; H3 LYSINE 27; NONCODING RNAS; DEVELOPMENTAL REGULATORS; REPRESSIVE COMPLEX; CHROMATIN STATE; GENE-EXPRESSION; X-INACTIVATION; GROUP PROTEINS AB Polycomb proteins play essential roles in stem cell renewal and human disease. Recent studies of HOX genes and X inactivation have provided evidence for RNA cofactors in Polycomb repressive complex 2 (PRC2). Here we develop a RIP-seq method to capture the PRC2 transcriptome and identify a genome-wide pool of >9000 PRC2-interacting RNAs in embryonic stem cells. The transcriptome includes antisense, intergenic, and promoter-associated transcripts, as well as many unannotated RNAs. A large number of transcripts occur within imprinted regions, oncogene and tumor suppressor loci, and stem cell-related bivalent domains. We provide evidence for direct RNA-protein interactions, most likely via the Ezh2 subunit. We also identify Gtl2 RNA as a PRC2 cofactor that directs PRC2 to the reciprocally imprinted Dlk1 coding gene. Thus, Polycomb proteins interact with a genonne-wide family of RNAs, some of which may be used as biomarkers and therapeutic targets for human disease. C1 [Zhao, Jing; Kung, Johnny T.; Ogawa, Yuya; Sarma, Kavitha; Lee, Jeannie T.] Howard Hughes Med Inst, Boston, MA 02114 USA. [Zhao, Jing; Ohsumi, Toshiro K.; Kung, Johnny T.; Ogawa, Yuya; Grau, Daniel J.; Sarma, Kavitha; Kingston, Robert E.; Borowsky, Mark; Lee, Jeannie T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. [Song, Ji Joon] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Song, Ji Joon] Korea Adv Inst Sci & Technol, Grad Sch Nanosci & Technol, Taejon 305701, South Korea. RP Lee, JT (reprint author), Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu RI Song, Ji-Joon/C-1721-2011 FU Natural Sciences and Engineering Research Council of Canada; National Institutes of Health (NIH) [GM43901, RO1-GM090278]; Korean Ministry of Education, Science, and Technology FX S. Orkin generously provided the Ezh2-/- cell line. We thank M. Anguera for pEF1/V5/HisB and Xist E1 primers, B. del Rosario for Flag-GFP, and all members of the laboratory for many valuable discussions. J.T.K. is supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada; R.E.K. by the National Institutes of Health (NIH) (GM43901); J.J.S. by the Korean Ministry of Education, Science, and Technology; and J.T.L. by the NIH (RO1-GM090278). J.T.L. is an Investigator of the Howard Hughes Medical Institute. NR 59 TC 434 Z9 453 U1 1 U2 68 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC 22 PY 2010 VL 40 IS 6 BP 939 EP 953 DI 10.1016/j.molcel.2010.12.011 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 701NF UT WOS:000285823900012 PM 21172659 ER PT J AU Kaptchuk, TJ Friedlander, E Kelley, JM Sanchez, MN Kokkotou, E Singer, JP Kowalczykowski, M Miller, FG Kirsch, I Lembo, AJ AF Kaptchuk, Ted J. Friedlander, Elizabeth Kelley, John M. Sanchez, M. Norma Kokkotou, Efi Singer, Joyce P. Kowalczykowski, Magda Miller, Franklin G. Kirsch, Irving Lembo, Anthony J. TI Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome SO PLOS ONE LA English DT Article ID QUALITY-OF-LIFE; CLINICAL-TRIALS; END-POINT; METAANALYSIS; VALIDATION; DISORDERS; EFFICACY; BLIND AB Background: Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods: Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47 +/- 18 with IBS diagnosed by Rome III criteria and with a score >= 150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as "placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes" or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings: Open-label placebo produced significantly higher mean (+/- SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2 +/- 1.0 vs. 4.0 +/- 1.1, p<.001) and at 21-day endpoint (5.0 +/- 1.5 vs. 3.9 +/- 1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion: Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. C1 [Kaptchuk, Ted J.; Friedlander, Elizabeth; Sanchez, M. Norma; Kokkotou, Efi; Kowalczykowski, Magda; Lembo, Anthony J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Kaptchuk, Ted J.; Singer, Joyce P.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA 02215 USA. [Kelley, John M.] Endicott Coll, Dept Psychol, Beverly, MA USA. [Kelley, John M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. [Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Kirsch, Irving] Univ Hull, Dept Psychol, Kingston Upon Hull HU6 7RX, N Humberside, England. RP Kaptchuk, TJ (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. EM ted_kaptchuk@hms.harvard.edu FU National Center for Complementary and Alternative Medicine-NIH [K24 AT004095, R01 AT00402-01, R01AT004662] FX This study was partially supported by grant K24 AT004095, R01 AT00402-01 and R01AT004662 from National Center for Complementary and Alternative Medicine-NIH and in part from a gift from The Bernard Osher Foundation. The opinions expressed by the authors are their views alone and do not reflect the official views or policy of the National Center for Complementary and Alternative Medicine, National Institutes of Health, Public Health Service or the U.S. Department of Health and Human Services. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 196 Z9 197 U1 8 U2 52 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2010 VL 5 IS 12 AR e15591 DI 10.1371/journal.pone.0015591 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698FG UT WOS:000285578000036 PM 21203519 ER PT J AU Chao, MP Jaiswal, S Weissman-Tsukamoto, R Alizadeh, AA Gentles, AJ Volkmer, J Weiskopf, K Willingham, SB Raveh, T Park, CY Majeti, R Weissman, IL AF Chao, Mark P. Jaiswal, Siddhartha Weissman-Tsukamoto, Rachel Alizadeh, Ash A. Gentles, Andrew J. Volkmer, Jens Weiskopf, Kipp Willingham, Stephen B. Raveh, Tal Park, Christopher Y. Majeti, Ravindra Weissman, Irving L. TI Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47 SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID RECEPTOR-RELATED PROTEIN; ACUTE MYELOID-LEUKEMIA; INTEGRIN-ASSOCIATED PROTEIN; CLASS-I MOLECULES; STEM-CELLS; PROGNOSTIC-FACTOR; APOPTOTIC CELLS; TUMOR-GROWTH; EXPRESSION; SURFACE AB Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro-and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin's lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor-related protein, on phagocytic cells prevented anti-CD47 antibody-mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin's lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro-and anti-phagocytic signals in the immune evasion of cancer. C1 [Chao, Mark P.; Jaiswal, Siddhartha; Weissman-Tsukamoto, Rachel; Alizadeh, Ash A.; Volkmer, Jens; Weiskopf, Kipp; Willingham, Stephen B.; Raveh, Tal; Majeti, Ravindra; Weissman, Irving L.] Stanford Canc Ctr, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Chao, Mark P.; Jaiswal, Siddhartha; Weissman-Tsukamoto, Rachel; Alizadeh, Ash A.; Volkmer, Jens; Weiskopf, Kipp; Willingham, Stephen B.; Raveh, Tal; Majeti, Ravindra; Weissman, Irving L.] Ludwig Ctr, Stanford, CA 94305 USA. [Jaiswal, Siddhartha] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Alizadeh, Ash A.; Majeti, Ravindra] Stanford Univ, Div Hematol, Dept Internal Med, Palo Alto, CA 94304 USA. [Alizadeh, Ash A.] Stanford Univ, Div Oncol, Palo Alto, CA 94304 USA. [Gentles, Andrew J.] Stanford Univ, Dept Radiol, Palo Alto, CA 94304 USA. [Park, Christopher Y.] Mem Sloan Kettering Canc Ctr, Dept Pathol & Clin Labs, New York, NY 10065 USA. [Park, Christopher Y.] Mem Sloan Kettering Canc Ctr, Dept Human Oncol, New York, NY 10065 USA. [Park, Christopher Y.] Mem Sloan Kettering Canc Ctr, Pathogenesis Program, New York, NY 10065 USA. RP Chao, MP (reprint author), Stanford Canc Ctr, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. EM mpchao@stanford.edu OI Alizadeh, Arash Ash/0000-0002-5153-5625 FU Howard Hughes Medical Institute; National Cancer Institute, DHHS [CA09302]; Burroughs Wellcome Fund; National Cancer Institute (NCI)/NIH [KO8]; NCI [1U54CA149145-01]; American Association for Cancer Research; NIH [P01CA139490]; Ludwig Foundation FX M.P.C. is supported by a medical fellowship from the Howard Hughes Medical Institute and the Stanford Cancer Biology Program by PHS grant number CA09302, awarded by the National Cancer Institute, DHHS. R.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. C.Y.P. is supported by National Cancer Institute (NCI)/NIH (KO8). A.J.G. is supported by an NCI Integrative Cancer Biology Program grant 1U54CA149145-01. This work was supported in part by a grant from the American Association for Cancer Research to R.M., NIH grant P01CA139490 to I.L.W., and funding from the Ludwig Foundation. NR 55 TC 98 Z9 101 U1 4 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 22 PY 2010 VL 2 IS 63 AR 63ra94 DI 10.1126/scitranslmed.3001375 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735UK UT WOS:000288444900003 PM 21178137 ER PT J AU Volpp, KG Friedman, W Romano, PS Rosen, A Silber, JH AF Volpp, Kevin G. Friedman, William Romano, Patrick S. Rosen, Amy Silber, Jeffrey H. TI Residency Training at a Crossroads: Duty-Hour Standards 2010 SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID MORTALITY; INTERNS; REFORM; RISK; REGULATIONS; HANDOFFS; SLEEP; TIME AB In 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented a single duty-hour standard nationwide. The evidence to date suggests that this neither improved nor worsened patient outcomes. In June 2010, the ACGME proposed a new set of duty-hour standards for implementation in July 2011. The main disadvantage of this approach is that there is no ability to determine whether different standards would have worked better to reduce resident fatigue while improving patient safety. Many unanswered questions remain about how to design duty-hour standards, but relatively little evidence exists. In addition, the same approach may not work in all specialties and all hospitals. A more flexible, dynamic policy that emphasizes ongoing testing and evaluation would be more likely to achieve improvements in clinical and educational outcomes. C1 [Silber, Jeffrey H.] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. Univ Florida, Gainesville, FL 32610 USA. Univ Calif Davis, Sch Med, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. Vet Affairs Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Silber, JH (reprint author), Childrens Hosp Philadelphia, Ctr Outcomes Res, 3535 Market St,Suite 1029, Philadelphia, PA 19104 USA. EM silber@email.chop.edu RI Romano, Patrick/N-4225-2014 OI Romano, Patrick/0000-0001-6749-3979 FU National Heart, Lung, and Blood Institute [R01 HL082637] FX By grant R01 HL082637 from the National Heart, Lung, and Blood Institute. NR 22 TC 15 Z9 15 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 21 PY 2010 VL 153 IS 12 BP 826 EP + DI 10.7326/0003-4819-153-12-201012210-00287 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 696PL UT WOS:000285453700006 PM 20956679 ER PT J AU Nathan, DM Zheng, H AF Nathan, David M. Zheng, Hui TI Does the Relationship Between Hemoglobin A(1c) and Mean Glucose Levels Differ by Race? SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID A1C ASSAY C1 [Nathan, David M.; Zheng, Hui] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. NR 6 TC 1 Z9 1 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 21 PY 2010 VL 153 IS 12 BP 847 EP 848 DI 10.7326/0003-4819-153-12-201012210-00014 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 696PL UT WOS:000285453700010 PM 21173419 ER PT J AU Afgan, E Baker, D Coraor, N Chapman, B Nekrutenko, A Taylor, J AF Afgan, Enis Baker, Dannon Coraor, Nate Chapman, Brad Nekrutenko, Anton Taylor, James TI Galaxy CloudMan: delivering cloud compute clusters SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 11th Annual Bioinformatics Open Source Conference (BOSC) CY JUL 09-10, 2010 CL Boston, MA AB Background: Widespread adoption of high-throughput sequencing has greatly increased the scale and sophistication of computational infrastructure needed to perform genomic research. An alternative to building and maintaining local infrastructure is "cloud computing", which, in principle, offers on demand access to flexible computational infrastructure. However, cloud computing resources are not yet suitable for immediate "as is" use by experimental biologists. Results: We present a cloud resource management system that makes it possible for individual researchers to compose and control an arbitrarily sized compute cluster on Amazon's EC2 cloud infrastructure without any informatics requirements. Within this system, an entire suite of biological tools packaged by the NERC Bio-Linux team (http://nebc.nerc.ac.uk/tools/bio-linux) is available for immediate consumption. The provided solution makes it possible, using only a web browser, to create a completely configured compute cluster ready to perform analysis in less than five minutes. Moreover, we provide an automated method for building custom deployments of cloud resources. This approach promotes reproducibility of results and, if desired, allows individuals and labs to add or customize an otherwise available cloud system to better meet their needs. Conclusions: The expected knowledge and associated effort with deploying a compute cluster in the Amazon EC2 cloud is not trivial. The solution presented in this paper eliminates these barriers, making it possible for researchers to deploy exactly the amount of computing power they need, combined with a wealth of existing analysis software, to handle the ongoing data deluge. C1 [Afgan, Enis; Baker, Dannon; Taylor, James] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Afgan, Enis; Baker, Dannon; Taylor, James] Emory Univ, Dept Math & Comp Sci, Atlanta, GA 30322 USA. [Coraor, Nate; Nekrutenko, Anton] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. [Chapman, Brad] Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Ctr, Boston, MA 02114 USA. RP Taylor, J (reprint author), Emory Univ, Dept Biol, Atlanta, GA 30322 USA. EM james.taylor@emory.edu RI Taylor, James/F-1026-2011; zong, fico/H-4677-2011 OI Chapman, Brad/0000-0002-3026-1856; Nekrutenko, Anton/0000-0002-5987-8032; Taylor, James/0000-0001-5079-840X; FU NHGRI NIH HHS [HG004909, HG005133, HG005542] NR 10 TC 70 Z9 72 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 21 PY 2010 VL 11 SU 12 AR S4 DI 10.1186/1471-2105-11-S12-S4 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 759DA UT WOS:000290219600004 PM 21210983 ER PT J AU Ellenbogen, KA Gold, MR Meyer, TE Lozano, IF Mittal, S Waggoner, AD Lemke, B Singh, JP Spinale, FG Van Eyk, JE Whitehill, J Weiner, S Bedi, M Rapkin, J Stein, KM AF Ellenbogen, Kenneth A. Gold, Michael R. Meyer, Timothy E. Fernandez Lozano, Ignacio Mittal, Suneet Waggoner, Alan D. Lemke, Bernd Singh, Jagmeet P. Spinale, Francis G. Van Eyk, Jennifer E. Whitehill, Jeffrey Weiner, Stanislav Bedi, Maninder Rapkin, Joshua Stein, Kenneth M. TI Primary Results From the SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial A Randomized Trial Comparing Empirical, Echocardiography-Guided, and Algorithmic Atrioventricular Delay Programming in Cardiac Resynchronization Therapy SO CIRCULATION LA English DT Article DE clinical trials, randomized; echocardiography; electrophysiology; heart failure; implantable cardioverter-defibrillators ID CHRONIC HEART-FAILURE; VENTRICULAR CONDUCTION DELAY; SYSTOLIC FUNCTION; FOLLOW-UP; RATIONALE; EFFICACY; DESIGN; CARDIOMYOPATHY; DEFIBRILLATOR; STIMULATION AB Background-One variable that may influence cardiac resynchronization therapy response is the programmed atrioventricular (AV) delay. The SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy (SMART-AV) Trial prospectively randomized patients to a fixed empirical AV delay (120 milliseconds), echocardiographically optimized AV delay, or AV delay optimized with SmartDelay, an electrogram-based algorithm. Methods and Results-A total of 1014 patients (68% men; mean age, 66 +/- 11 years; mean left ventricular ejection fraction, 25 +/- 7%) who met enrollment criteria received a cardiac resynchronization therapy defibrillator, and 980 patients were randomized in a 1:1:1 ratio. All patients were programmed (DDD-60 or DDDR-60) and evaluated after implantation and 3 and 6 months later. The primary end point was left ventricular end-systolic volume. Secondary end points included New York Heart Association class, quality-of-life score, 6-minute walk distance, left ventricular end-diastolic volume, and left ventricular ejection fraction. The medians (quartiles 1 and 3) for change in left ventricular end-systolic volume at 6 months for the SmartDelay, echocardiography, and fixed arms were -21 mL (-45 and 6 mL), -19 mL (-45 and 6 mL), and -15 mL (-41 and 6 mL), respectively. No difference in improvement in left ventricular end-systolic volume at 6 months was observed between the SmartDelay and echocardiography arms (P=0.52) or the SmartDelay and fixed arms (P=0.66). Secondary end points, including structural (left ventricular end-diastolic volume and left ventricular ejection fraction) and functional (6-minute walk, quality of life, and New York Heart Association classification) measures, were not significantly different between arms. Conclusions-Neither SmartDelay nor echocardiography was superior to a fixed AV delay of 120 milliseconds. The routine use of AV optimization techniques assessed in this trial is not warranted. However, these data do not exclude possible utility in selected patients who do not respond to cardiac resynchronization therapy. C1 [Ellenbogen, Kenneth A.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Gold, Michael R.; Spinale, Francis G.] Med Univ S Carolina, Charleston, SC 29425 USA. [Meyer, Timothy E.; Rapkin, Joshua; Stein, Kenneth M.] Boston Sci, St Paul, MN USA. [Fernandez Lozano, Ignacio] Hosp Puerta Hierro, Madrid, Spain. [Mittal, Suneet] St Lukes Roosevelt Hosp, New York, NY USA. [Waggoner, Alan D.] Washington Univ, Sch Med, St Louis, MO USA. [Lemke, Bernd] Maerk Kliniken GmbH, Luedenscheid, Germany. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Whitehill, Jeffrey] Austin Heart Hosp, Austin, TX USA. [Weiner, Stanislav] Tyler Cardiovasc Consultants, Tyler, TX USA. [Bedi, Maninder] Washington Hosp, Washington, PA USA. RP Ellenbogen, KA (reprint author), Virginia Commonwealth Univ, Sch Med, Div Cardiol, POB 980053, Richmond, VA 23298 USA. EM kellenbogen@mcvh-vcu.edu FU Boston Scientific; St. Jude Medical; Biotronik; Sorin Biomedical; Medtronic FX This study was sponsored by Boston Scientific.; Dr Ellenbogen has received honoraria from Boston Scientific, St. Jude Medical, Biotronik, Sorin Biomedical, and Medtronic; received research grants from Medtronic, Boston Scientific and St. Jude Medical; and served on advisory boards for Boston Scientific, St. Jude Medical, Biotronik, Sorin Biomedical, and Medtronic. Dr Gold has received honoraria from Boston Scientific, Medtronic, St. Jude Medical, Sorin Biomedical, and Biotronik; received research grants from Boston Scientific, Medtronic, and St. Jude Medical; and served on advisory boards for Boston Scientific and Medtronic. Dr Meyer is an employee of and owns stock in Boston Scientific. Dr Lozano has received honoraria from St. Jude Medical and Biotronik, received fellowship support from Medtronic and St. Jude Medical, and served on the advisory boards for Boston Scientific and Sorin Biomedical. Dr Mittal has received honoraria from Boston Scientific, Medtronic, and St. Jude Medical; received fellowship support from Biotronik, St. Jude Medical, Medtronic, and Boston Scientific; and served on the advisory board for Biotronik. A. Waggoner has received honoraria from Boston Scientific and St. Jude Medical. Dr Weiner has received research support from Boston Scientific, Medtronic, St. Jude Medical, and Sorin Biomedical and served as a consultant to Boston Scientific. Professor Lemke has received honoraria from Boston Scientific, Medtronic, St. Jude Medical, Biotronik, and Sorin Biomedical. Dr Singh has received honoraria from Boston Scientific, St. Jude Medical, Biotronik, Sorin Biomedical, and Medtronic; received research grants from Medtronic, Boston Scientific, Biotronik, and St. Jude Medical; and served on the advisory boards for Boston Scientific, St. Jude Medical, Biotronik, Sorin Biomedical, and Medtronic. Dr Spinale has received honoraria from Boston Scientific and Acorn Cardiovascular (advisory board). Dr Van Eyk reports no conflicts. Dr Whitehill has received honoraria from Boston Scientific and St. Jude Medical; received research grants from Boston Scientific, Medtronic, and St. Jude Medical; and served on the advisory boards for Boston Scientific and St. Jude Medical). Dr Weiner has received research grants from Boston Scientific, Medtronic, St. Jude Medical, and Sorin Biomedical and has served on the advisory board for Boston Scientific. Dr Bedi has received honoraria from Boston Scientific and served on the advisory board for Boston Scientific. Dr Stein is an employee of and owns stock in Boston Scientific. Dr Ellenbogen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 46 TC 137 Z9 140 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 21 PY 2010 VL 122 IS 25 BP 2660 EP U126 DI 10.1161/CIRCULATIONAHA.110.992552 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 696PS UT WOS:000285454500011 PM 21098426 ER PT J AU Bednarz, B Daartz, J Paganetti, H AF Bednarz, Bryan Daartz, Juliane Paganetti, Harald TI Dosimetric accuracy of planning and delivering small proton therapy fields SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MONTE-CARLO SIMULATIONS; BRAGG PEAK FIELDS; DOSE CALCULATIONS; OUTPUT FACTORS; BEAM THERAPY; SETTINGS; GEANT4; NOZZLE; RANGE AB A detailed Monte Carlo model of a proton therapy treatment head was commissioned to simulate the delivery of small field proton treatments. Small fields are challenging in the planning and quality assurance process because of aperture scattering and dosimetric disequilibrium. Four patients with small fields used in all or parts of their treatment course were studied, including two stereotactic patients and two fractionated patients. For the two stereotactic patients the overall difference of the dose covering at least 95% of the gross tumor volume between the Monte Carlo calculations and the delivery was -0.2% and -1.6%, respectively. For the two fractionated patients the overall difference of the dose covering at least 95% of the clinical target volume was -3.0% and 1.0%, respectively. We have thus confirmed that our current planning and delivery process for small proton fields is accurate enough to treat small lesions in the patient. Furthermore, we studied the impact of field size corrections and identified limitations of the pencil beam algorithm for predicting hot and cold spots and range degradation in the target due scattering in heterogeneities. For the four cases studied in this paper, these limitations appear to impact individual field calculations, but do not have a significant impact on the prescribed dose over multiple fields. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Bednarz, B (reprint author), Univ Wisconsin, Wisconsin Inst Med Res, Dept Med Phys, Madison, WI 53703 USA. FU National Cancer Institute [P01CA021239, R01CA140735] FX The authors would like to thank Drs Martijn Engelsman, Hsiao-Ming Lu and Marc Bussiere of Massachusetts General Hospital for helpful discussions on proton treatment planning. The authors also thank the Partners Research Computing group at Massachusetts General Hospital for all their assistance with computing resources. This work was supported by award number P01CA021239 ('Proton Therapy Research') and R01CA140735 ('PBeam: Fast and Easy Monte Carlo System for Proton Therapy') from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 18 TC 11 Z9 11 U1 0 U2 8 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2010 VL 55 IS 24 BP 7425 EP 7438 DI 10.1088/0031-9155/55/24/003 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 688BT UT WOS:000284825200003 PM 21098920 ER PT J AU Espana, S Paganetti, H AF Espana, Samuel Paganetti, Harald TI The impact of uncertainties in the CT conversion algorithm when predicting proton beam ranges in patients from dose and PET-activity distributions SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; TISSUE PARAMETERS; IN-BEAM; THERAPY; VERIFICATION; NUMBERS; DELIVERY AB The advantages of a finite range of proton beams can only be partly exploited in radiation therapy unless the range can be predicted in patient anatomy with <2 mm accuracy (for non-moving targets). Monte Carlo dose calculation aims at 1-2 mm accuracy in dose prediction, and proton-induced PET imaging aims at similar to 2 mm accuracy in range verification. The latter is done using Monte Carlo predicted PET images. Monte Carlo methods are based on CT images to describe patient anatomy. The dose calculation algorithm and the CT resolution/artifacts might affect dose calculation accuracy. Additionally, when using Monte Carlo for PET range verification, the biological decay model and the cross sections for positron emitter production affect predicted PET images. The goal of this work is to study the effect of uncertainties in the CT conversion on the proton beam range predicted by Monte Carlo dose calculations and proton-induced PET signals. Conversion schemes to assign density and elemental composition based on a CT image of the patient define a unique Hounsfield unit (HU) to tissue parameters relationship. Uncertainties are introduced because there is no unique relationship between HU and tissue parameters. In this work, different conversion schemes based on a stoichiometric calibration method as well as different numbers of tissue bins were considered in three head and neck patients. For Monte Carlo dose calculation, the results show close to zero (<0.5 mm) differences in range using different conversion schemes. Further, a reduction of the number of bins used to define individual tissues down to 13 did not affect the accuracy. In the case of simulated PET images we found a more pronounced sensitivity on the CT conversion scheme with a mean fall-off position variation of about 1 mm. We conclude that proton dose distributions based on Monte Carlo calculation are only slightly affected by the uncertainty on density and elemental composition introduced by unique assignment to each HU if a stoichiometric calibration is used. Calculated PET images used for range verification are more sensitive to conversion uncertainties causing an intrinsic limitation due to CT conversion alone of at least 1 mm. C1 [Espana, Samuel] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Espana, S (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM sespana-palomares@partners.org RI Espana, Samuel/E-9240-2010 OI Espana, Samuel/0000-0001-9092-4597 FU National Cancer Institute [P01CA021239] FX The project described was supported by Award Number P01CA021239 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The authors also thank the Partners Research Computing group at Massachusetts General Hospital for all their assistance with computing resources and Dr Bryan Bednarz for helpful comments and suggestions regarding this manuscript. NR 24 TC 28 Z9 28 U1 0 U2 7 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2010 VL 55 IS 24 BP 7557 EP 7571 DI 10.1088/0031-9155/55/24/011 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 688BT UT WOS:000284825200011 PM 21098912 ER PT J AU Giallourakis, CC Franklin, A Guo, CG Cheng, HL Yoon, HS Gallagher, M Perlot, T Andzelm, M Murphy, AJ Macdonald, LE Yancopoulos, GD Alt, FW AF Giallourakis, Cosmas C. Franklin, Andrew Guo, Chunguang Cheng, Hwei-Ling Yoon, Hye Suk Gallagher, Michael Perlot, Thomas Andzelm, Milena Murphy, Andrew J. Macdonald, Lynn E. Yancopoulos, George D. Alt, Frederick W. TI Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epigenetic regulation; immunoglobulin genes; lymphocyte development ID HEAVY-CHAIN LOCUS; PRE-B-CELLS; INTERGENIC TRANSCRIPTION; NONCODING RNAS; GENE SEGMENTS; LYMPHOCYTE DEVELOPMENT; IMMUNOGLOBULIN LOCI; ALLELIC EXCLUSION; MYC EXPRESSION; T-CELLS AB Ig and T-cell receptor (TCR) variable-region gene exons are assembled from component variable (V), diversity (D) and joining (J) gene segments during early B and T cell development. The RAG1/2 endonuclease initiates V(D) J recombination by introducing DNA double-strand breaks at borders of the germ-line segments. In mice, the Ig heavy-chain (IgH) locus contains, from5' to 3', several hundred V(H) gene segments, 13 D segments, and 4 J(H) segments within a several megabase region. In developing B cells, IgH variable-region exon assembly is ordered with D to J(H) rearrangement occurring on both alleles before appendage of a V(H) segment. Also, IgH V(H) to DJ(H) rearrangement does not occur in T cells, even though DJ(H) rearrangements occur at low levels. In these contexts, V(D)J recombination is controlled by modulating substrate gene segment accessibility to RAG1/2 activity. To elucidate control elements, we deleted the 100-kb intergenic region that separates the V(H) and D clusters (generating Delta V(H)-D alleles). In both B and T cells, Delta V(H)-D alleles initiated high-level antisense and, at lower levels, sense transcription from within the downstream D cluster, with antisense transcripts extending into proximal V(H) segments. In developing T lymphocytes, activated germ-line antisense transcription was accompanied by markedly increased IgH D-to-J(H) rearrangement and substantial V(H) to DJ(H) rearrangement of proximal IgH V(H) segments. Thus, the V(H)-D intergenic region, and likely elements within it, can influence silencing of sense and antisense germ-line transcription from the IgH D cluster and thereby influence targeting of V(D)J recombination. C1 [Giallourakis, Cosmas C.; Franklin, Andrew; Guo, Chunguang; Cheng, Hwei-Ling; Yoon, Hye Suk; Gallagher, Michael; Perlot, Thomas; Andzelm, Milena; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Immune Dis Inst, Boston, MA 02115 USA. [Giallourakis, Cosmas C.; Franklin, Andrew; Guo, Chunguang; Cheng, Hwei-Ling; Yoon, Hye Suk; Gallagher, Michael; Perlot, Thomas; Andzelm, Milena; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Giallourakis, Cosmas C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Murphy, Andrew J.; Macdonald, Lynn E.; Yancopoulos, George D.] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Immune Dis Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu OI Murphy, Andrew/0000-0003-4152-4081 FU National Institutes of Health [AI20047, AI070839] FX We thank Drs. Kees Murre, David Schatz, Barry Sleckman, and Hidde Ploegh for critical review of this manuscript. This work was supported by National Institutes of Health Grant AI20047 (to F.W.A.) and K08 Grant AI070839 (to C.C.G.). C.G. is an Irvington Fellow of the Cancer Research Institute, and F.W.A. is an investigator of the Howard Hughes Medical Institute. NR 47 TC 24 Z9 25 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 21 PY 2010 VL 107 IS 51 BP 22207 EP 22212 DI 10.1073/pnas.1015954107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697OB UT WOS:000285521800051 PM 21123744 ER PT J AU Banks, WA Morley, JE Farr, SA Price, TO Ercal, N Vidaurre, I Schally, AV AF Banks, William A. Morley, John E. Farr, Susan A. Price, Tulin O. Ercal, Nuran Vidaurre, Irving Schally, Andrew V. TI Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Alzheimer's disease; learning; memory; peptide; sarcopenia ID REPEAT AMPLIFICATION PROTOCOL; AGED SAMP8 MICE; OBJECT RECOGNITION MEMORY; GENE-DISRUPTED MICE; ALPHA-LIPOIC ACID; GLUTATHIONE DISULFIDE; TRANSGENIC MICE; LIFE-SPAN; HIPPOCAMPUS; PROTEIN AB Both deficiency and excess of growth hormone (GH) are associated with increased mortality and morbidity. GH replacement in otherwise healthy subjects leads to complications, whereas individuals with isolated GH deficiency such as Laron dwarfs show increased life span. Here, we determined the effects of treatment with the GH-releasing hormone (GHRH) receptor antagonist MZ-5-156 on aging in SAMP8 mice, a strain that develops with aging cognitive deficits and has a shortened life expectancy. Starting at age 10 mo, mice received daily s.c. injections of 10 mu g/mouse of MZ-5-156. Mice treated for 4 mo with MZ-5-156 showed increased telomerase activity, improvement in some measures of oxidative stress in brain, and improved pole balance, but no change in muscle strength. MZ-5-156 improved cognition after 2 mo and 4 mo, but not after 7 mo of treatment (ages 12, 14 mo, and 17 mo, respectively). Mean life expectancy increased by 8 wk with no increase in maximal life span, and tumor incidence decreased from 10 to 1.7%. These results show that treatment with a GHRH antagonist has positive effects on some aspects of aging, including an increase in telomerase activity. C1 [Banks, William A.] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. [Banks, William A.] Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [Banks, William A.] Univ Washington, Sch Med, Dept Internal Med, Seattle, WA 98108 USA. [Morley, John E.; Farr, Susan A.; Price, Tulin O.] Vet Affairs Med Ctr, GRECC, St Louis, MO 63125 USA. [Morley, John E.; Farr, Susan A.] St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr Med, St Louis, MO 63104 USA. [Price, Tulin O.] St Louis Univ, Sch Med, Doisy Res Ctr, St Louis, MO 63104 USA. [Ercal, Nuran] Missouri Univ Sci & Technol, Dept Chem, Rolla, MO 65401 USA. [Vidaurre, Irving; Schally, Andrew V.] Vet Affairs Hosp, Inst Endocrine Polypeptide & Canc, Miami, FL 33125 USA. [Schally, Andrew V.] Univ Miami, Dept Pathol, Miami, FL 33101 USA. [Schally, Andrew V.] Univ Miami, Div Hematol, Dept Med, Miller Sch Med, Miami, FL 33101 USA. [Schally, Andrew V.] Univ Miami, Div Oncol, Dept Med, Miller Sch Med, Miami, FL 33101 USA. [Schally, Andrew V.] Univ Miami, Div Endocrinol, Dept Med, Miller Sch Med, Miami, FL 33101 USA. RP Banks, WA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA 98108 USA. EM wabanks1@u.washington.edu; andrew.schally@va.gov RI morley, john/F-9177-2011; OI morley, john/0000-0001-6444-2965; Schally, Andrew/0000-0003-1273-6747 FU Medical Research Service of the Veterans Affairs Department, the South Florida Veterans Affairs Foundation for Research and Education; University of Miami, Miller School of Medicine, Department of Pathology and Medicine, Division of Hematology/Oncology; VA Merit Review; National Institutes of Health [RO1 AG029839] FX The studies of A.V.S. were supported by the Medical Research Service of the Veterans Affairs Department, the South Florida Veterans Affairs Foundation for Research and Education, and the University of Miami, Miller School of Medicine, Department of Pathology and Medicine, Division of Hematology/Oncology (all to A.V.S.). Additional support was from VA Merit Review (W.A.B.) and National Institutes of Health Grant RO1 AG029839 (to. W.A.B.). NR 38 TC 26 Z9 26 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 21 PY 2010 VL 107 IS 51 BP 22272 EP 22277 DI 10.1073/pnas.1016369107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697OB UT WOS:000285521800062 PM 21135231 ER PT J AU Kunitake, H Zheng, P Yothers, G Land, SR Fehrenbacher, L Giguere, JK Wickerham, L Ganz, PA Ko, CY AF Kunitake, Hiroko Zheng, Ping Yothers, Greg Land, Stephanie R. Fehrenbacher, Louis Giguere, Jeffrey K. Wickerham, Lawrence Ganz, Patricia A. Ko, Clifford Y. TI Routine Preventive Care and Cancer Surveillance in Long-Term Survivors of Colorectal Cancer: Results From National Surgical Adjuvant Breast and Bowel Project Protocol LTS-01 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID STAGE-II; COLON; LEUCOVORIN; CARCINOMA; FLUOROURACIL; CHEMOTHERAPY; INSURANCE AB Purpose National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol LTS-01 examines routine preventive care and cancer surveillance in long-term colorectal cancer (CRC) survivors previously treated in NSABP adjuvant trials. Patients and Methods Long-term CRC survivors (>= 5 years) from five completed NSABP trials (Protocols C-05, C-06, C-07, R-02, and R-03) at 60 study sites were recruited and surveyed using preventive health care items from the National Health Interview Survey (NHIS). A 3: 1 comparison cohort case-matched by age, sex, race, and education was created from the 2005 NHIS. Contingency tables and multivariate models were used to compare cohorts and determine predictors of preventive care and cancer surveillance. Results A total of 708 patients in protocol LTS-01 (681 patients with colon cancer, 27 patients with rectal cancer) completed the interview: 57.1% male, mean age 66.2 years (standard deviation = 10.6), median survival 8 years. Patients in the LTS-01 protocol were more likely to have a usual source of health care (97.7% v 93.8%, P < .0001), have received a flu shot in the past 12 months (67.5% v 44.3%, P < .0001), and have undergone cancer screening by Pap smear (67.3% v 54.8%, P < .0001), mammogram (80.4% v 70.7%, P < .0001), and prostate-specific antigen test (84.5% v 74.5%, P < .0001) than patients in the NHIS cohort. For CRC surveillance, 96.5% of patients in protocol LTS-01 had a colonoscopy, 88.2% had a carcinoembryonic antigen test, and 66.4% had a computed tomography scan in the previous 5 years. Health insurance was the best predictor of cancer screening for all three methods (odds ratio = 2.6 to 4.5). No factor was uniformly associated with CRC surveillance. Conclusion This select population of long-term CRC survivors who participated in clinical trials achieved better routine preventive care and cancer screening than the general population and high rates of cancer surveillance. C1 [Kunitake, Hiroko] Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Kaiser Permanente Med Ctr, Vallejo, CA USA. Canc Ctr Carolinas, Greenville, SC USA. RP Kunitake, H (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRB 425, Boston, MA 02114 USA. EM hkunitake@hotmail.com OI Yothers, Greg/0000-0002-7965-7333 FU American Cancer Society [RSGPB-05-236-01-CPPB]; National Cancer Institute, Department of Health and Human Services [U10-CA-12027, U10-CA-69651, U10-CA-37377, U10-CA-69974] FX Supported by American Cancer Society Grant No. RSGPB-05-236-01-CPPB; Public Health Service Grants No. U10-CA-12027, U10-CA-69651, and U10-CA-37377; and Grant No. U10-CA-69974 from the National Cancer Institute, Department of Health and Human Services. NR 24 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2010 VL 28 IS 36 BP 5274 EP 5279 DI 10.1200/JCO.2010.30.1903 PG 6 WC Oncology SC Oncology GA 695PD UT WOS:000285383800016 PM 21079140 ER PT J AU Gong, C Yao, HR Liu, QA Chen, JQ Shi, JW Su, FX Song, EW AF Gong, Chang Yao, Herui Liu, Qiang Chen, Jingqi Shi, Junwei Su, Fengxi Song, Erwei TI Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer SO PLOS ONE LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; STEM-CELLS; SIDE POPULATION; RESISTANCE; THERAPEUTICS; CULTURE; NOTCH AB Purpose: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors. Methods: Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay. Results: ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non-CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold. Conclusions: These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies. C1 [Gong, Chang; Yao, Herui; Liu, Qiang; Chen, Jingqi; Shi, Junwei; Su, Fengxi; Song, Erwei] Sun Yat Sen Univ, Breast Tumor Ctr, Sun Yat Sen Mem Hosp, Guangzhou 510275, Guangdong, Peoples R China. [Liu, Qiang] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Song, Erwei] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510275, Guangdong, Peoples R China. RP Gong, C (reprint author), Sun Yat Sen Univ, Breast Tumor Ctr, Sun Yat Sen Mem Hosp, Guangzhou 510275, Guangdong, Peoples R China. EM songerwei02@yahoo.com.cn FU National Natural Science Foundation of China [30772550, 30801376, 30830110, 30831160515, 30921140312, 30973505]; Research Fund for the Doctoral Program of Higher Education (RFDP) [20070558248]; Sun Yat-Sen Excellent Medicine Youth Project [F002008010]; Ministry of Science and Technology of China [2010CB912800, 2009CB521706, 2005CB724605]; Science Foundation of Guangdong Province [8251008901000011, 2009B030801005]; foundation of Guangzhou Science and Technology Bureau [2009Y-C011-1] FX This work was supported by grants from the National Natural Science Foundation of China (30772550, 30801376, 30830110, 30831160515, 30921140312, 30973505), The Research Fund for the Doctoral Program of Higher Education (RFDP) (20070558248), Sun Yat-Sen Excellent Medicine Youth Project (F002008010), 973 (2010CB912800, 2009CB521706, 2005CB724605) Projects from Ministry of Science and Technology of China, Science Foundation of Guangdong Province (8251008901000011, 2009B030801005) and foundation of Guangzhou Science and Technology Bureau (2009Y-C011-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 27 Z9 29 U1 3 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 20 PY 2010 VL 5 IS 12 AR e15630 DI 10.1371/journal.pone.0015630 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698EM UT WOS:000285575200051 PM 21187973 ER PT J AU Rajicic, N Cuschieri, J Finkelstein, DM Miller-Graziano, CL Hayden, D Moldawer, LL Moore, E O'Keefe, G Pelik, K Warren, HS Schoenfeld, DA AF Rajicic, Natasa Cuschieri, Joseph Finkelstein, Dianne M. Miller-Graziano, Carol L. Hayden, Douglas Moldawer, Lyle L. Moore, Ernest O'Keefe, Grant Pelik, Kimberly Warren, H. Shaw Schoenfeld, David A. CA Inflammation Host Response Injury TI Identification and Interpretation of Longitudinal Gene Expression Changes in Trauma SO PLOS ONE LA English DT Article ID MULTIPLE ORGAN FAILURE; INJURY; INFLAMMATION; NEUTROPHILS; MICROARRAYS; RESPONSES; PATTERNS AB Rationale: The relationship between leukocyte gene expression and recovery of respiratory function after injury may provide information on the etiology of multiple organ dysfunction. Objectives: To find a list of genes for which expression after injury predicts respiratory recovery, and to identify which networks and pathways characterize these genes. Methods: Blood was sampled at 12 hours and at 1, 4, 7, 21 and 28 days from 147 patients who had been admitted to the hospital after blunt trauma. Leukocyte gene expression was measured using Affymetrix oligonucleotide arrays. A linear model, fit to each probe-set expression value, was used to impute the gene expression trajectory over the entire follow-up period. The proportional hazards model score test was used to calculate the statistical significance of each probe-set trajectory in predicting respiratory recovery. A list of genes was determined such that the expected proportion of false positive results was less than 10%. These genes were compared to the Gene Ontology for 'response to stimulus' and, using Ingenuity software, were mapped into networks and pathways. Measurements and Main Results: The median time to respiratory recovery was 6 days. There were 170 probe-sets representing 135 genes that were found to be related to respiratory recovery. These genes could be mapped to nine networks. Two known pathways that were activated were antigen processing and presentation and JAK-signaling. Conclusions: The examination of the relationship of gene expression over time with a patient's clinical course can provide information which may be useful in determining the mechanism of recovery or lack of recovery after severe injury. C1 [Rajicic, Natasa] Pfizer Inc, New York, NY 10017 USA. [Cuschieri, Joseph] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Finkelstein, Dianne M.; Hayden, Douglas; Pelik, Kimberly; Schoenfeld, David A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Miller-Graziano, Carol L.] Univ Rochester, Rochester, NY USA. [Moldawer, Lyle L.] Univ Florida, Shands Hosp, Gainesville, FL USA. [Moore, Ernest] Univ Colorado, Denver Hlth Med Ctr, Denver, CO 80202 USA. [O'Keefe, Grant] Univ Washington, Div Trauma & Gen Surg, Harborview, WA USA. [Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. RP Rajicic, N (reprint author), Pfizer Inc, New York, NY 10017 USA. EM Natasa.Rajicic@pfizer.com FU National Institute of General Medical Sciences [U54 GM-62119-02] FX This research was supported by a Large Scale Collaborative Research Grant from the National Institute of General Medical Sciences, U54 GM-62119-02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 7 Z9 7 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 20 PY 2010 VL 5 IS 12 AR e14380 DI 10.1371/journal.pone.0014380 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698EM UT WOS:000285575200007 PM 21187951 ER PT J AU Pacheco, B Finzi, A Stremlau, M Sodroski, J AF Pacheco, Beatriz Finzi, Andres Stremlau, Matthew Sodroski, Joseph TI Adaptation of HIV-1 to cells expressing rhesus monkey TRIM5 alpha SO VIROLOGY LA English DT Article DE Retrovirus; Restriction factor; Tripartite motif; Capsid; Cyclophilin-binding loop; Mutant ID IMMUNODEFICIENCY-VIRUS TYPE-1; SPECIES-SPECIFIC TROPISM; CYCLOPHILIN-A; SIMIAN CELLS; POSTENTRY RESTRICTION; REVERSE TRANSCRIPTION; INFECTION; PROTEIN; REPLICATION; APOBEC3G AB The cross-species transmission of retroviruses is limited by host restriction factors that exhibit inter-species diversity. For example, the TRIM5 alpha proteins of Old World monkeys block the early, post-entry steps in human immunodeficiency virus (HIV-1) infection. We adapted an HIV-1 isolate to replicate in cells expressing TRIM5 alpha(rh) from rhesus monkeys, an Old World species. A single amino acid change in the cyclophilin-binding loop of the HIV-1 capsid protein allowed virus replication in cells expressing TRIM5 alpha(rh). The capsid of the escape virus exhibited a reduced affinity for TRIM5 alpha(rh), but retained the ability to bind cyclophilin A efficiently. Thus, a preferred HIV-1 escape pathway involves decreased binding to TRIM5 alpha, a capsid-destabilizing factor, and retention of binding to cyclophilin A. a capsid-stabilizing factor. (C) 2010 Elsevier Inc. All rights reserved. C1 [Pacheco, Beatriz; Finzi, Andres; Stremlau, Matthew; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Pacheco, Beatriz; Finzi, Andres; Stremlau, Matthew; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Pathol, Div Aids, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU National Institutes of Health [AI063987]; National Institutes of Health (Center for AIDS Research) [AI060354] FX We thank Yvette McLaughlin and Elizabeth Carpelan for manuscript preparation. We acknowledge Angela Carville and the New England Primate Research Center for providing the rhesus monkey blood. We acknowledge Dr. Ronald Desrosiers from the New England Primate Research Center for kindly providing the 221-89 rhesus cell line. We acknowledge ATCC for the 293T, Cf2Th, MK2D and OMK cell lines. This work was supported by grants from the National Institutes of Health (AI063987 and a Center for AIDS Research Award AI060354) and a gift from the late William F. McCarty-Cooper. NR 66 TC 23 Z9 23 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2010 VL 408 IS 2 BP 204 EP 212 DI 10.1016/j.virol.2010.09.019 PG 9 WC Virology SC Virology GA 681IK UT WOS:000284304400010 PM 20956011 ER PT J AU Richardson, PG AF Richardson, Paul G. TI A new standard of care in newly diagnosed multiple myeloma SO LANCET LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; PLUS DEXAMETHASONE; ELDERLY-PATIENTS; CLINICAL-TRIAL; THALIDOMIDE; BORTEZOMIB; PREDNISONE; MELPHALAN; INDUCTION; THERAPY C1 [Richardson, Paul G.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Richardson, Paul G.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Richardson, PG (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu NR 16 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 0140-6736 J9 LANCET JI Lancet PD DEC 18 PY 2010 VL 376 IS 9758 BP 2043 EP 2044 DI 10.1016/S0140-6736(10)62177-0 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 702LA UT WOS:000285895000004 PM 21146204 ER PT J AU Qin, WP Pan, JP Wu, Y Bauman, WA Cardozo, C AF Qin, Weiping Pan, Jiangping Wu, Yong Bauman, William A. Cardozo, Christopher TI Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1 alpha SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Glucocorticoid; Testosterone; Muscle atrophy; Protein catabolism; Protein synthesis; FOXO1; PGC-1 alpha ID SKELETAL-MUSCLE; GLUCOCORTICOID-RECEPTOR; TRANSCRIPTION FACTORS; UBIQUITIN LIGASES; PROTEIN-SYNTHESIS; GENE-EXPRESSION; UP-REGULATION; MTOR; INVOLVE; PATHWAY AB Glucocorticoid-induced muscle atrophy results from muscle protein catabolism and reduced protein synthesis, associated with increased expression of two muscle-specific ubiquitin ligases (MAFbx and MuRF1), and of two inhibitors of protein synthesis, REDD1 and 4EBP1. MAFbx, MuRF1, REDD1 and 4EBP1 are up-regulated by the transcription factors FOXO1 and FOXO3A. The transcriptional co-activator PGC-1 alpha has been shown to attenuate many forms of muscle atrophy and to repress FOXO3A-mediated transcription of atrophy-specific genes. Dexamethasone-induced muscle atrophy can be prevented by testosterone, which blocks up-regulation by dexamethasone of FOXO1. Here, an animal model of dexamethasone-induced muscle atrophy was used to further characterize effects of testosterone to abrogate adverse actions of dexamethasone on FOXO1 levels and nuclear localization, and to determine how these agents affect PGC-1 alpha, and its upstream activators, p38 MAPK and AMPK. In rat gastrocnemius muscle, testosterone blunted the dexamethasone-mediated increase in levels of FOXO1 mRNA, and FOXO1 total and nuclear protein. Dexamethasone reduced total and nuclear PGC-1 alpha protein levels in the gastrocnemius: co-administration of testosterone with dexamethasone increased total and nuclear PGC-1 alpha levels above those present in untreated controls. Testosterone blocked dexamethasone-induced decreases in activity of p38 MARK in the gastrocnemius muscle. Regulation of FOXO1, PGC-1 alpha and p38 MARK by testosterone may represent a novel mechanism by which this agent protects against dexamethasone-induced muscle atrophy. Published by Elsevier Inc. C1 [Qin, Weiping; Pan, Jiangping; Wu, Yong; Bauman, William A.; Cardozo, Christopher] James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY USA. [Qin, Weiping; Bauman, William A.; Cardozo, Christopher] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bauman, William A.; Cardozo, Christopher] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. RP Qin, WP (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY USA. EM weiping.qin@mssm.edu; Chris.Cardozo@mssm.edu FU Department of Veterans Affairs Office of Research and Development, Rehabilitation Research and Development Service [B4162C, B3347K, B3522R] FX This work is supported by the Department of Veterans Affairs Office of Research and Development, Rehabilitation Research and Development Service, Grants B4162C, B3347K and B3522R. NR 35 TC 28 Z9 29 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 17 PY 2010 VL 403 IS 3-4 BP 473 EP 478 DI 10.1016/j.bbrc.2010.11.061 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 703ZS UT WOS:000286021300039 PM 21094144 ER PT J AU Black, YD Xiao, DQ Pellegrino, D Kachroo, A Brownell, AL Schwarzschild, MA AF Black, Yolanda D. Xiao, Danqing Pellegrino, Daniela Kachroo, Anil Brownell, Anna-Liisa Schwarzschild, Michael A. TI Protective effect of metabotropic glutamate mGluR5 receptor elimination in a 6-hydroxydopamine model of Parkinson's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Neuroprotection; mGluR5; Dopamine level; Behavioral tests; Parkinson s disease ID REDUCES NIGROSTRIATAL DEGENERATION; ADENOSINE A(2A) RECEPTORS; RODENT MODEL; BASAL GANGLIA; RAT MODEL; L-DOPA; METABOLIC-CHANGES; SUBSTANTIA-NIGRA; IN-VIVO; ANTAGONIST AB Pharmacologic or genetic blockade of metabotropic glutamate mGlu5 receptors (mGluR5) has been shown to attenuate parkinsonian motor deficits and protect nigrostriatal neurons from damage in the acute MPTP model of Parkinson s disease (PD) suggesting that therapeutically targeting the mGluR5 receptor may offer a novel approach to improving motor symptoms and/or slowing neurodegeneration in PD This study further explored the neuroprotective potential of targeting mGluR5 receptors We examined the behavioral and neurochemical effects of receptor elimination on toxicity induced by intra-striatal application of 6-hydroxydopamine (6-OHDA) thought to represent a comparatively progressive model of PD mGluR5 knockout (KO) mice and wild-type (WT) littermates received unilateral 6-OHDP infusions Reflecting the Imbalance expected following unilateral infusion WT but not KO mice demonstrated predominantly ipsilateral forepaw use and robust ipsilateral amphetamine-induced rotation Further performance on the vertical pole descent task was profoundly impaired in WT mice while KO mice completed the task significantly faster Consistent with the behavioral observations neurochemical analyses of striatal dopamine depletion showed significantly diminished severity in KO mice with only 64 % of striatal dopamine lost compared to 92% in WT mice The absence of brain mGluR5 receptors in living KO mice was verified using positron emission tomography (PET) Our findings substantiate the key role of mGluR5 receptors in animal models of PD strengthening the rationale for the development of mGluR5 antagonists for their neuroprotective as well as symptomatic benefit (C) 2010 Elsevier Ireland Ltd All rights reserved C1 [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Mol Neurobiol Lab, Dept Neurol, Charlestown, MA 02129 USA. [Pellegrino, Daniela; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Schwarzschild, MA (reprint author), Massachusetts Gen Hosp, Mol Neurobiol Lab, Dept Neurol, 114 16th St,Rm 3002, Charlestown, MA 02129 USA. FU National Institutes of Health (NIH) [NS054978, NS060991, NS60232]; DoD [W81XWH-04-1-0881] FX This work was supported by National Institutes of Health (NIH) grants NS054978 and NS060991 NS60232 DoD grant W81XWH-04-1-0881 NR 40 TC 15 Z9 15 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 17 PY 2010 VL 486 IS 3 BP 161 EP 165 DI 10.1016/j.neulet.2010.09.043 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 684RB UT WOS:000284565900010 PM 20854878 ER PT J AU Blackiston, D Shomrat, T Nicolas, CL Granata, C Levin, M AF Blackiston, Douglas Shomrat, Tal Nicolas, Cindy L. Granata, Christopher Levin, Michael TI A Second-Generation Device for Automated Training and Quantitative Behavior Analyses of Molecularly-Tractable Model Organisms SO PLOS ONE LA English DT Article ID ZEBRAFISH DANIO-RERIO; XENOPUS-LAEVIS TADPOLES; ABSTINENCE-INDUCED WITHDRAWAL; LEAD INHIBITS ACQUISITION; CENTRAL-NERVOUS-SYSTEM; LEFT-RIGHT ASYMMETRY; LARVAL ZEBRAFISH; CAENORHABDITIS-ELEGANS; NEURAL-NETWORK; C-ELEGANS AB A deep understanding of cognitive processes requires functional, quantitative analyses of the steps leading from genetics and the development of nervous system structure to behavior. Molecularly-tractable model systems such as Xenopus laevis and planaria offer an unprecedented opportunity to dissect the mechanisms determining the complex structure of the brain and CNS. A standardized platform that facilitated quantitative analysis of behavior would make a significant impact on evolutionary ethology, neuropharmacology, and cognitive science. While some animal tracking systems exist, the available systems do not allow automated training (feedback to individual subjects in real time, which is necessary for operant conditioning assays). The lack of standardization in the field, and the numerous technical challenges that face the development of a versatile system with the necessary capabilities, comprise a significant barrier keeping molecular developmental biology labs from integrating behavior analysis endpoints into their pharmacological and genetic perturbations. Here we report the development of a second-generation system that is a highly flexible, powerful machine vision and environmental control platform. In order to enable multidisciplinary studies aimed at understanding the roles of genes in brain function and behavior, and aid other laboratories that do not have the facilities to undergo complex engineering development, we describe the device and the problems that it overcomes. We also present sample data using frog tadpoles and flatworms to illustrate its use. Having solved significant engineering challenges in its construction, the resulting design is a relatively inexpensive instrument of wide relevance for several fields, and will accelerate interdisciplinary discovery in pharmacology, neurobiology, regenerative medicine, and cognitive science. C1 [Blackiston, Douglas; Shomrat, Tal; Nicolas, Cindy L.; Levin, Michael] Tufts Univ, Dept Biol, Medford, MA 02155 USA. [Blackiston, Douglas; Shomrat, Tal; Nicolas, Cindy L.; Levin, Michael] Tufts Univ, Ctr Regenerat & Dev Biol, Medford, MA 02155 USA. [Blackiston, Douglas] Forsyth Inst, Dept Regenerat & Dev Biol, Boston, MA USA. [Granata, Christopher] Boston Engn Corp, Waltham, MA USA. RP Blackiston, D (reprint author), Tufts Univ, Dept Biol, Medford, MA 02155 USA. EM michael.levin@tufts.edu OI Burne, Thomas/0000-0003-3502-9789 FU National Institutes of Health [T32-DE-007327]; G. Harold and Leila Y. Mathers Charitable Foundation FX D.B. was supported by National Institutes of Health T32-DE-007327; M.L. and T.S. were supported by the G. Harold and Leila Y. Mathers Charitable Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 187 TC 17 Z9 18 U1 3 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 17 PY 2010 VL 5 IS 12 AR e14370 DI 10.1371/journal.pone.0014370 PG 20 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698DS UT WOS:000285572900007 PM 21179424 ER PT J AU Leder, K Holland, EC Michor, F AF Leder, Kevin Holland, Eric C. Michor, Franziska TI The Therapeutic Implications of Plasticity of the Cancer Stem Cell Phenotype SO PLOS ONE LA English DT Article ID MYELOID-LEUKEMIA; BREAST-CANCER; IDENTIFICATION; HETEROGENEITY; MODEL AB The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra-or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer. C1 [Leder, Kevin; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Leder, Kevin; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Holland, Eric C.] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, Canc Biol & Genet Program, New York, NY 10021 USA. RP Leder, K (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu FU National Cancer Institute [U54CA143798] FX This work was supported by Award Number U54CA143798 from the National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 28 Z9 29 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 17 PY 2010 VL 5 IS 12 AR e14366 DI 10.1371/journal.pone.0014366 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 698DS UT WOS:000285572900005 PM 21179426 ER PT J AU Shao, HL Yoon, TJ Liong, M Weissleder, R Lee, H AF Shao, Huilin Yoon, Tae-Jong Liong, Monty Weissleder, Ralph Lee, Hakho TI Magnetic nanoparticles for biomedical NMR-based diagnostics SO BEILSTEIN JOURNAL OF NANOTECHNOLOGY LA English DT Review DE biosensor; diagnostics; magnetic nanoparticle; microfluidics; nuclear magnetic resonance AB Rapid and accurate measurements of protein biomarkers, pathogens and cells in biological samples could provide useful information for early disease diagnosis, treatment monitoring, and design of personalized medicine. In general, biological samples have only negligible magnetic susceptibility. Thus, using magnetic nanoparticles for biosensing not only enhances sensitivity but also effectively reduces sample preparation needs. This review focuses on the use of magnetic nanoparticles for in vitro detection of biomolecules and cells based on magnetic resonance effects. This detection platform, termed diagnostic magnetic resonance (DMR), exploits magnetic nanoparticles as proximity sensors, which modulate the spin-spin relaxation time of water molecules surrounding molecularly-targeted nanoparticles. By developing more effective magnetic nanoparticle biosensors, DMR detection limits for various target moieties have been considerably improved over the last few years. Already, a library of magnetic nanoparticles has been developed, in which a wide range of targets, including DNA/mRNA, proteins, small molecules/drugs, bacteria, and tumor cells, have been quantified. More recently, the capabilities of DMR technology have been further advanced with new developments such as miniaturized nuclear magnetic resonance detectors, better magnetic nanoparticles and novel conjugational methods. These developments have enabled parallel and sensitive measurements to be made from small volume samples. Thus, the DMR technology is a highly attractive platform for portable, low-cost, and efficient biomolecular detection within a biomedical setting. C1 [Shao, Huilin; Yoon, Tae-Jong; Liong, Monty; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Yoon, Tae-Jong] CHA Univ, Dept Appl Biosci, Seoul 135081, South Korea. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; hlee@mgh.harvard.edu FU NIH [2RO1EB004626, U01-HL080731, U54-CA119349, T32-CA79443]; Agency for Science, Technology and Research, Singapore FX The authors thank N. Sergeyev for providing cross-linked dextran-coated iron oxide nanoparticles; Y. Fisher-Jeffes for reviewing the manuscript. This work was supported in part by NIH Grants (2RO1EB004626, U01-HL080731, U54-CA119349 and T32-CA79443). H. Shao acknowledges financial support from the B.S.-Ph.D. National Science Scholarship awarded by the Agency for Science, Technology and Research, Singapore. NR 65 TC 33 Z9 33 U1 8 U2 40 PU BEILSTEIN-INSTITUT PI FRANKFURT AM MAIN PA TRAKEHNER STRASSE 7-9, FRANKFURT AM MAIN, 60487, GERMANY SN 2190-4286 J9 BEILSTEIN J NANOTECH JI Beilstein J. Nanotechnol. PD DEC 16 PY 2010 VL 1 BP 142 EP 154 DI 10.3762/bjnano.1.17 PG 13 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA V21NQ UT WOS:000208214700001 PM 21977404 ER PT J AU Tallman, MS Kim, HT Montesinos, P Appelbaum, FR de la Serna, J Bennett, JM Deben, G Bloomfield, CD Gonzalez, J Feusner, JH Gonzalez, M Gallagher, R Miguel, JDGS Larson, RA Milone, G Paietta, E Rayon, C Rowe, JM Rivas, C Schiffer, CA Vellenga, E Shepherd, L Slack, JL Wiernik, PH Willman, CL Sanz, MA AF Tallman, Martin S. Kim, Haesook T. Montesinos, Pau Appelbaum, Frederick R. de la Serna, Javier Bennett, John M. Deben, Guillermo Bloomfield, Clara D. Gonzalez, Jose Feusner, James H. Gonzalez, Marcos Gallagher, Robert Gonzalez-San Miguel, Jose D. Larson, Richard A. Milone, Gustavo Paietta, Elisabeth Rayon, Chelo Rowe, Jacob M. Rivas, Concha Schiffer, Charles A. Vellenga, Edo Shepherd, Lois Slack, James L. Wiernik, Peter H. Willman, Cheryl L. Sanz, Miguel A. TI Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group SO BLOOD LA English DT Article ID TRANS-RETINOIC ACID; RISK-ADAPTED TREATMENT; PML GENE BREAKPOINT; PROGNOSTIC-FACTORS; CD2 EXPRESSION; ANTHRACYCLINE MONOCHEMOTHERAPY; CYTOCHEMICAL CHARACTERISTICS; COMPETING RISK; AIDA PROTOCOL; FLT3 MUTATION AB Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-transretinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapeutica en Hemopatia Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL. (Blood. 2010; 116(25):5650-5659) C1 [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, Weill Cornell Med Coll, New York, NY 10065 USA. [Kim, Haesook T.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. [Montesinos, Pau; Sanz, Miguel A.] Hosp Univ La Fe, Valencia, Spain. [Appelbaum, Frederick R.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [de la Serna, Javier] Hosp 12 Octubre, E-28041 Madrid, Spain. [Bennett, John M.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Deben, Guillermo] Hosp Juan Canalejo, La Coruna, Spain. [Bloomfield, Clara D.] Ohio State Univ, Columbus, OH 43210 USA. [Gonzalez, Jose] Hosp Univ Virgen del Rocio, Seville, Spain. [Feusner, James H.] Childrens Hosp Res Ctr Oakland, Oakland, CA USA. [Gonzalez, Marcos] Hosp Univ Salamanca, Salamanca, Spain. [Gallagher, Robert] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Paietta, Elisabeth] Montefiore Med Ctr, North Div, Bronx, NY 10467 USA. [Gonzalez-San Miguel, Jose D.] Hosp Insular, Las Palmas Gran Canaria, Spain. [Larson, Richard A.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Milone, Gustavo] Fundaleu, Buenos Aires, DF, Argentina. [Rowe, Jacob M.] Technion Israel Inst Technol, Rambam Med Ctr, Haifa, Israel. [Rayon, Chelo] Univ Oviedo, Hosp Cent Asturias, E-33080 Oviedo, Spain. [Rivas, Concha] Gen Hosp, Alicante, Spain. [Schiffer, Charles A.] Wayne State Univ, Karmanos Canc Ctr, Detroit, MI USA. [Vellenga, Edo] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands. [Shepherd, Lois] NCIC Clin Trials Grp, Kingston, ON, Canada. [Slack, James L.] Mayo Clin, Scottsdale, AZ USA. [Wiernik, Peter H.] New York Med Coll, Our Lady Mercy Canc Ctr, Bronx, NY USA. [Willman, Cheryl L.] Univ New Mexico, Albuquerque, NM 87131 USA. RP Tallman, MS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, Weill Cornell Med Coll, 1275 York Ave,Box 380, New York, NY 10065 USA. EM tallmanm@mskcc.org RI IBSAL, Secretaria/H-3719-2011; OI Larson, Richard/0000-0001-9168-3203; Gonzalez Diaz, Marcos/0000-0001-6637-1072 FU Public Health Service [CA23318, CA66636, CA21115, CA17145, CA31936, CA33601, CA32102, CA38926, CA20319, CA12213, CA14028, CA56771]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services FX This work was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants ECOG CA23318, CA66636, CA21115, CA17145, CALGB CA31936 and CA33601, SWOG Grant CA32102, CA38926, CA20319, CA12213, CA14028, CA56771, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 42 TC 11 Z9 11 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 16 PY 2010 VL 116 IS 25 BP 5650 EP 5659 DI 10.1182/blood-2010-02270819 PG 10 WC Hematology SC Hematology GA 695PE UT WOS:000285383900029 PM 20858857 ER PT J AU Liu, Z Kearney, CM AF Liu, Zun Kearney, Christopher M. TI An efficient Foxtail mosaic virus vector system with reduced environmental risk SO BMC BIOTECHNOLOGY LA English DT Article ID TRIPLE GENE BLOCK; DEPENDENT RNA-POLYMERASE; CELL-TO-CELL; EXPRESSION SYSTEM; TRANSGENIC PLANTS; SILENCING SUPPRESSION; TRANSIENT EXPRESSION; VIRAL VECTOR; IN-VIVO; POTEXVIRUSES AB Background: Plant viral vectors offer high-yield expression of pharmaceutical and commercially important proteins with a minimum of cost and preparation time. The use of Agrobacterium tumefaciens has been introduced to deliver the viral vector as a transgene to each plant cell via a simple, nonsterile infiltration technique called "agroinoculation". With agroinoculation, a full length, systemically moving virus is no longer necessary for excellent protein yield, since the viral transgene is transcribed and replicates in every infiltrated cell. Viral genes may therefore be deleted to decrease the potential for accidental spread and persistence of the viral vector in the environment. Results: In this study, both the coat protein (CP) and triple gene block (TGB) genetic segments were eliminated from Foxtail mosaic virus to create the "FECT" vector series, comprising a deletion of 29% of the genome. This viral vector is highly crippled and expresses little or no marker gene within the inoculated leaf. However, when co-agroinoculated with a silencing suppressor (p19 or HcPro), FECT expressed GFP at 40% total soluble protein in the tobacco host, Nicotiana benthamiana. The modified FoMV vector retained the full-length replicase ORF, the TGB1 subgenomic RNA leader sequence and either 0, 22 or 40 bases of TGB1 ORF (in vectors FECT0, FECT22 and FECT40, respectively). As well as N. benthamiana, infection of legumes was demonstrated. Despite many attempts, expression of GFP via syringe agroinoculation of various grass species was very low, reflecting the low Agrobacterium-mediated transformation rate of monocots. Conclusions: The FECT/40 vector expresses foreign genes at a very high level, and yet has a greatly reduced biohazard potential. It can form no virions and can effectively replicate only in a plant with suppressed silencing. C1 [Liu, Zun; Kearney, Christopher M.] Baylor Univ, Dept Biol, Waco, TX 76798 USA. [Liu, Zun] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Liu, Zun] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. RP Kearney, CM (reprint author), Baylor Univ, Dept Biol, 1 Bear Pl 7388, Waco, TX 76798 USA. EM chris_kearney@baylor.edu OI Kearney, Christopher/0000-0002-1945-7815 NR 48 TC 9 Z9 9 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD DEC 16 PY 2010 VL 10 AR 88 DI 10.1186/1472-6750-10-88 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 706CK UT WOS:000286194100001 PM 21162736 ER PT J AU Johannessen, CM Boehm, JS Kim, SY Thomas, SR Wardwell, L Johnson, LA Emery, CM Stransky, N Cogdill, AP Barretina, J Caponigro, G Hieronymus, H Murray, RR Salehi-Ashtiani, K Hill, DE Vidal, M Zhao, JJ Yang, XP Alkan, O Kim, S Harris, JL Wilson, CJ Myer, VE Finan, PM Root, DE Roberts, TM Golub, T Flaherty, KT Dummer, R Weber, BL Sellers, WR Schlegel, R Wargo, JA Hahn, WC Garraway, LA AF Johannessen, Cory M. Boehm, Jesse S. Kim, So Young Thomas, Sapana R. Wardwell, Leslie Johnson, Laura A. Emery, Caroline M. Stransky, Nicolas Cogdill, Alexandria P. Barretina, Jordi Caponigro, Giordano Hieronymus, Haley Murray, Ryan R. Salehi-Ashtiani, Kourosh Hill, David E. Vidal, Marc Zhao, Jean J. Yang, Xiaoping Alkan, Ozan Kim, Sungjoon Harris, Jennifer L. Wilson, Christopher J. Myer, Vic E. Finan, Peter M. Root, David E. Roberts, Thomas M. Golub, Todd Flaherty, Keith T. Dummer, Reinhard Weber, Barbara L. Sellers, William R. Schlegel, Robert Wargo, Jennifer A. Hahn, William C. Garraway, Levi A. TI COT drives resistance to RAF inhibition through MAP kinase pathway reactivation SO NATURE LA English DT Article ID B-RAF; TUMOR PROGRESSION; SIGNALING PATHWAY; KAPPA-B; BRAF; MUTATIONS; CANCER; CELLS; GENE; TRANSFORMATION AB Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas(1). Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma(2-6)-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials(7-9). However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance(10-12). Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies(13). Here we expressed similar to 600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies. C1 [Johannessen, Cory M.; Boehm, Jesse S.; Kim, So Young; Thomas, Sapana R.; Johnson, Laura A.; Stransky, Nicolas; Barretina, Jordi; Hieronymus, Haley; Yang, Xiaoping; Alkan, Ozan; Root, David E.; Golub, Todd; Hahn, William C.; Garraway, Levi A.] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Johannessen, Cory M.; Kim, So Young; Thomas, Sapana R.; Wardwell, Leslie; Johnson, Laura A.; Emery, Caroline M.; Barretina, Jordi; Hahn, William C.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, So Young; Murray, Ryan R.; Salehi-Ashtiani, Kourosh; Hill, David E.; Vidal, Marc; Hahn, William C.] Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. [Cogdill, Alexandria P.; Flaherty, Keith T.; Wargo, Jennifer A.] Massachusetts Gen Hosp, Div Surg Oncol Med Oncol & Dermatol, Boston, MA 02114 USA. [Barretina, Jordi; Golub, Todd; Hahn, William C.; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Caponigro, Giordano; Wilson, Christopher J.; Myer, Vic E.; Finan, Peter M.; Weber, Barbara L.; Sellers, William R.; Schlegel, Robert] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Hieronymus, Haley; Golub, Todd] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Murray, Ryan R.; Salehi-Ashtiani, Kourosh; Hill, David E.; Vidal, Marc; Zhao, Jean J.; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Murray, Ryan R.; Salehi-Ashtiani, Kourosh; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kim, Sungjoon; Harris, Jennifer L.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. RP Garraway, LA (reprint author), Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM Levi_Garraway@dfci.harvard.edu RI Hill, David/B-6617-2011; OI Boehm, Jesse/0000-0002-6795-6336; Cogdill, Alexandria/0000-0001-8917-9462; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243 FU NIH [CA134502]; Novartis Institutes for Biomedical Research; Melanoma Research Alliance; Starr Cancer Consortium; US National Cancer Institute [R33 CA128625, RC2 CA148268]; Swiss National Foundation [310040-103671]; Gottfried and Julia Bangerter Rhyner Stiftung; Ellison Foundation; DFCI Strategic Initiative FX We thank members of the Broad Institute/Novartis Cancer Cell Line Encyclopedia (CCLE) for contributing cell line genomic data, expression data and pharmacological cell line sensitivity data; J. Thibault and A. Shipway for CCLE related tissue culture; R. Depinho, G. Dunn, S. Ethier, H. Greulich, A. Henderson, D. Kaplan, R. Levine, C. Miller, H. Piwnica-Worms, H. Suzuki, M. Vigny, D. Vollrath and the Harvard Institute of Proteomics for contributing templates for the kinase collection; J. Du and D. B. Wheeler for assistance with functional testing of kinases; D. A. Barbie for helpful discussions, S. E. Moody and H. W. Cheung for technical assistance, and J. K. Grenier and S. J. Silver for compiling and annotating the list of kinases. This work was supported by the NIH Director's New Innovator Award (L. A. G.), grants from the Novartis Institutes for Biomedical Research (L. A. G.), Melanoma Research Alliance (L. A. G.), Starr Cancer Consortium(L. A. G.) the US National Cancer Institute (R33 CA128625, RC2 CA148268) (W. C. H.), NIH (CA134502) (J.J.Z) the Swiss National Foundation (310040-103671) (R. D.), the Gottfried and Julia Bangerter Rhyner Stiftung (R. D.) the Ellison Foundation (M. V. and CCSB) and institute sponsored research funds from the DFCI Strategic Initiative (M. V. and CCSB). NR 29 TC 716 Z9 730 U1 4 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 16 PY 2010 VL 468 IS 7326 BP 968 EP U370 DI 10.1038/nature09627 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 695BC UT WOS:000285344600048 PM 21107320 ER PT J AU Cannon, CP Shah, S Dansky, HM Davidson, M Brinton, EA Gotto, AM Stepanavage, M Liu, SX Gibbons, P Ashraf, TB Zafarino, J Mitchel, Y Barter, P AF Cannon, Christopher P. Shah, Sukrut Dansky, Hayes M. Davidson, Michael Brinton, Eliot A. Gotto, Antonio M., Jr. Stepanavage, Michael Liu, Sherry Xueyu Gibbons, Patrice Ashraf, Tanya B. Zafarino, Jennifer Mitchel, Yale Barter, Philip CA DEFINE Investigators TI Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ESTER TRANSFER PROTEIN; CHOLESTEROL EFFLUX; BLOOD-PRESSURE; TORCETRAPIB; ATORVASTATIN; LIPOPROTEIN; INHIBITION; STATINS; TRIALS; HDL AB Background: Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. Results: A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001) -- a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001) -- a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P=0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. Conclusions: Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.) N Engl J Med 2010;363:2406-15. C1 [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Shah, Sukrut; Dansky, Hayes M.; Stepanavage, Michael; Liu, Sherry Xueyu; Gibbons, Patrice; Ashraf, Tanya B.; Zafarino, Jennifer; Mitchel, Yale] Merck Res Labs, Rahway, NJ USA. [Davidson, Michael] Radiant Res, Chicago, IL USA. [Brinton, Eliot A.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Gotto, Antonio M., Jr.] Weill Cornell Med Coll, New York, NY USA. [Barter, Philip] Heart Res Inst, Sydney, NSW, Australia. RP Cannon, CP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,1st Fl, Boston, MA 02115 USA. EM cpcannon@partners.org FU Merck Research Laboratories FX Supported by Merck Research Laboratories. NR 23 TC 433 Z9 443 U1 6 U2 32 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 16 PY 2010 VL 363 IS 25 BP 2406 EP 2415 DI 10.1056/NEJMoa1009744 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 694ZK UT WOS:000285340200006 PM 21082868 ER PT J AU Misra, M Parangi, S Ross, DS Shailam, R Sadow, PM AF Misra, Madhusmita Parangi, Sareh Ross, Douglas S. Shailam, Randheer Sadow, Peter M. TI Case 38-2010: A 13-Year-Old Girl with an Enlarging Neck Mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PAPILLARY THYROID-CARCINOMA; DIFFUSE SCLEROSING VARIANT; RECURRENT LARYNGEAL NERVE; FINE-NEEDLE-ASPIRATION; LYMPHOCYTIC THYROIDITIS; SINGLE INSTITUTION; PSAMMOMA BODY; BRAF MUTATION; CANCER; NODULES C1 [Misra, Madhusmita] Massachusetts Gen Hosp, Serv Pediat, Boston, MA 02114 USA. [Parangi, Sareh] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Ross, Douglas S.] Massachusetts Gen Hosp, Thyroid Unit, Boston, MA 02114 USA. [Shailam, Randheer] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sadow, Peter M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Misra, Madhusmita] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Parangi, Sareh] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Ross, Douglas S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Shailam, Randheer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Serv Pediat, Boston, MA 02114 USA. FU Ipsen; Tercica; Genentech; Genzyme; Abbott Laboratories FX Dr. Misra reports receiving consulting fees from Ipsen, and honoraria and grant support from Tercica and Genentech. Dr. Ross reports receiving grant support from Genzyme and consulting fees from Abbott Laboratories. No other potential conflict of interest relevant to this article was reported. NR 43 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 16 PY 2010 VL 363 IS 25 BP 2446 EP 2455 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 694ZK UT WOS:000285340200012 ER PT J AU Shannon, K Armstrong, SA AF Shannon, Kevin Armstrong, Scott A. TI Genetics, Epigenetics, and Leukemia. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SOMATIC MUTATIONS; HEMATOPOIETIC STEM; EZH2 C1 [Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Shannon, Kevin] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. [Armstrong, Scott A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Armstrong, Scott A.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Shannon, K (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. FU NCI NIH HHS [R01 CA072614, R37 CA072614] NR 10 TC 5 Z9 6 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 16 PY 2010 VL 363 IS 25 BP 2460 EP 2461 DI 10.1056/NEJMe1012071 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 694ZK UT WOS:000285340200015 PM 21067376 ER PT J AU Fromson, JA Kenney, LK AF Fromson, John A. Kenney, Linda K. TI The Disclosure Dilemma - Large-Scale Adverse Events SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Fromson, John A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kenney, Linda K.] Medically Induced Trauma Support Serv, Chestnut Hill, MA USA. RP Fromson, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 16 PY 2010 VL 363 IS 25 BP 2471 EP 2471 DI 10.1056/NEJMc1011109 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 694ZK UT WOS:000285340200032 PM 21158676 ER PT J AU Bolondi, G Garuti, C Corradini, E Zoller, H Vogel, W Finkenstedt, A Babitt, JL Lin, HY Pietrangelo, A AF Bolondi, Giuliano Garuti, Cinzia Corradini, Elena Zoller, Heinz Vogel, Wolfgang Finkenstedt, Armin Babitt, Jodie L. Lin, Herbert Y. Pietrangelo, Antonello TI Altered hepatic BMP signaling pathway in human HFE hemochromatosis SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Iron overload; Bone morphogenetic proteins; Hepcidin ID ANTIMICROBIAL PEPTIDE HEPCIDIN; IRON OVERLOAD; JUVENILE HEMOCHROMATOSIS; HEREDITARY HEMOCHROMATOSIS; MOUSE-LIVER; EXPRESSION; GENE; METABOLISM; SMAD7; HEMOJUVELIN AB Human hemochromatosis (HC) has been associated with the common C282Y polymorphism of HFE or rare pathogenic mutations of TfR2, HJV, FPN and HAMP. All forms of human HC seem to be caused by low or inadequate levels of hepcidin, the iron hormone. We and others have recently shown that Hfe(-/-) mice exhibit an impairment in the bone morphogenetic protein (BMP) signaling pathway controlling hepcidin. However, all data indicating the central role of BMPs in hepcidin regulation and an impaired BMP/SMAD signaling in HC have been collected in mice. In this study we investigated whether also in humans the expression of BMP signaling targets, SMAD7 and Id1, are associated with liver iron concentration (LIC) and whether such regulation is disrupted in HFE-HC. We correlated the mRNA expression, assessed by RT-PCR, of HAMP, SMAD7 and Id1 with LIC in liver biopsies from patients with normal iron status. HFE-HC or non-HC hepatic iron overload. We found that in human liver, not only HAMP, but also SMAD7 and Id1 mRNA significantly correlate with the extent of hepatic iron burden. However, this correlation is lost in patients with HFE-HC, but maintained in subjects with non-hemochromatotic iron overload. These data indicate that in human HFE-HC a disrupted BMP/SMAD signaling in the liver is key in the pathogenesis of the disease. (C) 2010 Elsevier Inc. All rights reserved. C1 [Bolondi, Giuliano; Garuti, Cinzia; Corradini, Elena; Pietrangelo, Antonello] Univ Hosp Modena, Ctr Hemochromatosis, I-41100 Modena, Italy. [Zoller, Heinz; Vogel, Wolfgang; Finkenstedt, Armin] Med Univ Innsbruck, Dept Med 2, Innsbruck, Austria. [Babitt, Jodie L.; Lin, Herbert Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Membrane Biol,Nephrol Div,Ctr Syst Biol, Boston, MA USA. RP Pietrangelo, A (reprint author), Univ Hosp Modena, Ctr Hemochromatosis, Via Pozzo 71, I-41100 Modena, Italy. EM antonello.pietrangelo@unimore.it RI Corradini, Elena/O-4167-2016; Pietrangelo, Antonello/K-1517-2016 OI Corradini, Elena/0000-0001-9477-2164; Pietrangelo, Antonello/0000-0002-7411-935X FU Italian University and Research Council [PRIN-08]; Austrian Science Fund [P195579]; NIH [K08 DK075846, RO1 DK087727, RO1 DK-069533, RO1 DK-071837]; Fondazione Telethon FX This study was supported by the Italian University and Research Council grant PRIN-08 and the Telethon 2010 grant to AP, the Austrian Science Fund FWF Project P195579 to HZ, NIH grants K08 DK075846 and RO1 DK087727 to JLB and RO1 DK-069533 and RO1 DK-071837 grants to HYL. NR 33 TC 26 Z9 26 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD DEC 15 PY 2010 VL 45 IS 4 BP 308 EP 312 DI 10.1016/j.bcmd.2010.08.010 PG 5 WC Hematology SC Hematology GA 690UI UT WOS:000285033500010 PM 20863724 ER PT J AU Tejwani, A Kobayashi, W Chen, YLE Rosenberg, AE Yoon, S Raskin, KA Rosenthal, DI Nielsen, GP Hornicek, FJ DeLaney, TF AF Tejwani, Ajay Kobayashi, Wendy Chen, Yen Lin Evelyn Rosenberg, Andrew E. Yoon, Sam Raskin, Kevin A. Rosenthal, Daniel I. Nielsen, Gunnlaugur P. Hornicek, Francis J. DeLaney, Thomas F. TI Management of Acral Myxoinflammatory Fibroblastic Sarcoma SO CANCER LA English DT Article DE acral myxoinflammatory; fibroblastic sarcoma; sarcoma; radiotherapy; surgical resection ID SOFT-TISSUE SARCOMA; IMMUNOHISTOCHEMICAL ANALYSIS; EXTREMITY PRESERVATION; RADIATION-THERAPY; LOCAL-CONTROL; TUMOR; FOOT; HAND; RADIOTHERAPY; SURGERY AB BACKGROUND Acral myxoinflammatory fibroblastic sarcoma (AMFS) is a rare low-grade sarcoma that commonly affects the distal extremities From the published cases therapy for AMFS to date has been comprised of excision or amputation with limited use of radiotherapy (PT) or chemotherapy In this report the outcome of 17 patients with AMFS treated at the study institution was reported METHODS A retrospective review of all cases of AMFS identified in the Sarcoma Database in the Department of Radiation Oncology at the study institution was conducted Treatment records and data from follow-up visits of patients were reviewed RESULTS Seventeen patients were identified All the patients underwent surgical resection (15 excisions and 2 amputations) Positive surgical margins after excisions were noted in 5 patients and were widely positive in 1 patient Of the 17 patients 14 patients received some form of PT The average total dose was 564 Gray (Gy) Eight patients received preoperative PT alone 5 patients received preoperative PT and postoperative PT and 1 patient received preoperative PT and intraoperative RT Median follow-up was 24 5 months One patient presented with recurrent disease and was treated with resection and both pre- and postoperative PT He was free of disease 23 months after his last treatment No local recurrence was noted in the remaining patients Of the 14 patients undergoing preoperative PT complete pathologic necrosis or no tumor was noted in 1 of the patients No metastatic disease was observed in any of the patients There was no significant radiation toxicity observed in any of the patients CONCLUSIONS Data were consistent with local control of distal extremity sarcomas with resection and PT suggesting that limb-sparing surgery with this treatment combination is an appropriate option in the limb sparing control of patients with AMFS even those with positive surgical margins Cancer 2010,116 5733-9 (C) 2010 American Cancer Society C1 [Kobayashi, Wendy; Chen, Yen Lin Evelyn; DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Rosenberg, Andrew E.; Nielsen, Gunnlaugur P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yoon, Sam] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Raskin, Kevin A.; Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Tejwani, Ajay] New York Methodist Hosp, Dept Radiat Oncol, Brooklyn, NY USA. [Tejwani, Ajay; Chen, Yen Lin Evelyn; Rosenberg, Andrew E.; Yoon, Sam; Raskin, Kevin A.; Rosenthal, Daniel I.; Nielsen, Gunnlaugur P.; Hornicek, Francis J.; DeLaney, Thomas F.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. RP DeLaney, TF (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. NR 22 TC 10 Z9 10 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2010 VL 116 IS 24 BP 5733 EP 5739 DI 10.1002/cncr.25567 PG 7 WC Oncology SC Oncology GA 692PO UT WOS:000285165100023 PM 20737559 ER PT J AU Bernards, R Filipowicz, W Livingston, DM Mihich, E AF Bernards, Rene Filipowicz, Witold Livingston, David M. Mihich, Enrico TI Twenty-Second Annual Pezcoller Symposium: RNA Biology and Cancer SO CANCER RESEARCH LA English DT Article AB The 22nd annual Pezcoller Symposium titled "RNA Biology and Cancer" was held in Trento, Italy, on June 1012, 2010. The program of the symposium was developed by Drs. Rene Bernards, Witold Filipowicz, and David Livingston; they cochaired the meeting in cooperation with Dr. Enrico Mihich. The topics discussed included the opportunities offered by small RNA as tools for cancer drug development, the role of noncoding RNAs, the biochemistry of small RNAs, the function of micro RNA in cancer, and RNAs as diagnostics and therapeutics in cancer. Cancer Res; 70(24); 10034-7. (C) 2010 AACR. C1 [Livingston, David M.; Mihich, Enrico] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bernards, Rene] Netherlands Canc Inst, Amsterdam, Netherlands. [Filipowicz, Witold] Friedrich Miescher Inst Biomed Res, Basel, Switzerland. RP Mihich, E (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM enrico.mihich@roswellpark.org OI Bernards, Rene/0000-0001-8677-3423 NR 0 TC 2 Z9 2 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10034 EP 10037 DI 10.1158/0008-5472.CAN-10-2978 PG 4 WC Oncology SC Oncology GA 694XD UT WOS:000285334200004 PM 21159628 ER PT J AU Sasaki, T Okuda, K Zheng, W Butrynski, J Capelletti, M Wang, LP Gray, NS Wilner, K Christensen, JG Demetri, G Shapiro, GI Rodig, SJ Eck, MJ Janne, PA AF Sasaki, Takaaki Okuda, Katsuhiro Zheng, Wei Butrynski, James Capelletti, Marzia Wang, Liping Gray, Nathanael S. Wilner, Keith Christensen, James G. Demetri, George Shapiro, Geoffrey I. Rodig, Scott J. Eck, Michael J. Jaenne, Pasi A. TI The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers SO CANCER RESEARCH LA English DT Article ID ANAPLASTIC LYMPHOMA KINASE; CHRONIC MYELOID-LEUKEMIA; EML4-ALK FUSION GENE; LUNG-CANCER; CHRONIC-PHASE; C-MET; IDENTIFICATION; IMATINIB; DOMAIN; NPM AB The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers. Cancer Res; 70(24); 10038-43. (C) 2010 AACR. C1 [Sasaki, Takaaki; Okuda, Katsuhiro; Capelletti, Marzia; Wang, Liping; Shapiro, Geoffrey I.; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Sasaki, Takaaki; Okuda, Katsuhiro; Butrynski, James; Capelletti, Marzia; Wang, Liping; Demetri, George; Shapiro, Geoffrey I.; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zheng, Wei; Gray, Nathanael S.; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zheng, Wei; Gray, Nathanael S.; Eck, Michael J.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Butrynski, James; Demetri, George] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Wilner, Keith; Christensen, James G.] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla, CA USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Shapiro, Geoffrey I.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D820,44 Binney St, Boston, MA 02115 USA. EM pjanne@partners.org OI Sasaki, Takaaki/0000-0002-6505-8786 FU NCI [P50CA090578]; [NIHR01CA136851]; [R01CA135257] FX This study was supported by NIHR01CA136851 (N.S. Gray and P.A. Janne) and R01CA135257 (P.A. Janne) and by the NCI Lung SPORE P50CA090578 (P.A. Janne and G.I. Shapiro). NR 20 TC 149 Z9 153 U1 4 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10038 EP 10043 DI 10.1158/0008-5472.CAN-10-2956 PG 6 WC Oncology SC Oncology GA 694XD UT WOS:000285334200005 PM 21030459 ER PT J AU Hyrien, O Dietrich, J Noble, M AF Hyrien, Ollivier Dietrich, Joerg Noble, Mark TI Mathematical and Experimental Approaches to Identify and Predict the Effects of Chemotherapy on Neuroglial Precursors SO CANCER RESEARCH LA English DT Article ID DEPENDENT BRANCHING-PROCESS; ASTROCYTE PROGENITOR CELLS; HIGH-DOSE CHEMOTHERAPY; GENERATION IN-VITRO; STOCHASTIC-MODEL; OLIGODENDROCYTE DIFFERENTIATION; THYROID-HORMONE; GROWTH-FACTOR; CLONAL DATA; CULTURE AB The adverse effects of chemotherapy on normal cells of the body create substantial clinical problems for many cancer patients. However, relatively little is known about the effects, other than promotion of cell death, of such agents on the function of normal precursor cells critical in tissue homeostasis and repair. We have combined mathematical and experimental analyses to identify the effects of sublethal doses of chemotherapy on glial precursor cells of the central nervous system. We modeled the temporal development of a population of precursor and terminally differentiated cells exposed to sublethal doses of carmustine (BCNU), a classic alkylating chemotherapeutic agent used in treatment of gliomas and non-Hodgkin's lymphomas, as a multitype age-dependent branching process. We fitted our model to data from in vitro clonal experiments using the method of pseudo-likelihood. This approach identifies several novel drug effects, including modification of the cell cycle length, the time between division and differentiation, and alteration in the probability of undergoing self-renewal division in precursor cells. These changes of precursor cell function in the chemotherapy-exposed brain may have profound clinic implications. Major Findings: We applied our computational approach to analyze the effects of BCNU on clonal cultures of oligodendrocyte progenitor cells-one of the best-characterized neural progenitor cells in the mammalian brain. Our analysis reveals that transient exposures to BCNU increased the cell cycle length of progenitor cells and decreased their time to differentiation, while also decreasing the likelihood that they will undergo self-renewing divisions. By investigating the behavior of our mathematical model, we demonstrate that precursor cell populations should recover spontaneously from transient modifications of the timing of division and of differentiation, but such recovery will not happen after alteration of cell fate. These studies identify means by which precursor cell function can be critically compromised by transient exposure to chemotherapy with long-term consequences on the progenitor cell pool even in the absence of drug-induced apoptosis. These analyses also provide novel tools that apply broadly to identify effects of chemotherapeutic agents and other physiological stressors. Cancer Res; 70(24); 10051-9. (C) 2010 AACR. C1 [Hyrien, Ollivier] Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [Dietrich, Joerg; Noble, Mark] Univ Rochester, Med Ctr, Dept Biomed Genet, Rochester, NY 14642 USA. [Dietrich, Joerg] Harvard Univ, Sch Med, Dept Neurol, Div Neurooncol,Massachusetts Gen Hosp,Canc Ctr, Boston, MA 02115 USA. RP Hyrien, O (reprint author), Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, 601 Elmwood Ave, Rochester, NY 14642 USA. EM Ollivier_Hyrien@urmc.rochester.edu FU NIH [R01-CA134839, R01-NS39511, P30-ES001247, NS44701, K12]; Stephen E. and Catherine Pappas Foundation FX This work is supported by NIH Grants R01-CA134839, R01-NS39511, P30-ES001247, and NS44701. J.D. is a recipient of the Paul Calabresi Career Development Award for Clinical Oncology (NIH-K12) and the Stephen E. and Catherine Pappas Foundation Award for Brain Tumor Research. NR 43 TC 16 Z9 16 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10051 EP 10059 DI 10.1158/0008-5472.CAN-10-1400 PG 9 WC Oncology SC Oncology GA 694XD UT WOS:000285334200007 PM 21056994 ER PT J AU Schoenfeld, J Jinushi, M Nakazaki, Y Wiener, D Park, J Soiffer, R Neuberg, D Mihm, M Hodi, FS Dranoff, G AF Schoenfeld, Jonathan Jinushi, Masahisa Nakazaki, Yukoh Wiener, Daniel Park, Joosang Soiffer, Robert Neuberg, Donna Mihm, Martin Hodi, F. Stephen Dranoff, Glenn TI Active Immunotherapy Induces Antibody Responses That Target Tumor Angiogenesis SO CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; LYMPHOCYTE-ASSOCIATED ANTIGEN-4; AUGMENTS ANTITUMOR IMMUNITY; ENDOTHELIAL GROWTH-FACTOR; METASTATIC MELANOMA; CELLS; VACCINATION; THERAPY; CANCER; TUMORIGENESIS AB The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF-secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment. Cancer Res; 70(24); 10150-60. (C) 2010 AACR. C1 [Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Hodi, F. Stephen; Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Hodi, F. Stephen; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Hodi, F. Stephen; Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Schoenfeld, Jonathan; Jinushi, Masahisa; Nakazaki, Yukoh; Wiener, Daniel; Park, Joosang; Soiffer, Robert; Neuberg, Donna; Mihm, Martin; Hodi, F. Stephen; Dranoff, Glenn] Harvard Univ, Sch Med, Boston, MA USA. [Schoenfeld, Jonathan] Harvard Radiat Oncol Program, Boston, MA USA. [Jinushi, Masahisa] Hokkaido Univ, Res Ctr Infect Associated Canc, Inst Med Genet, Sapporo, Hokkaido, Japan. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mihm, Martin] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dana 520C,44 Binney St, Boston, MA 02115 USA. EM glenn_dranoff@dfci.harvard.edu RI Jinushi, Masahisa/A-4311-2012 FU HHMI; Uehara Memorial Foundation; Kanae Foundation for the Promotion of Medical Sciences [CA78378, CA111506, CA143083, AI29530]; Leukemia & Lymphoma Society; Melanoma Research Alliance; Research Foundation for the Treatment of Ovarian Cancer FX Supported by the HHMI (J. Schoenfeld), Uehara Memorial Foundation, the Kanae Foundation for the Promotion of Medical Sciences (M. Jinushi), CA78378, CA111506, CA143083, AI29530, the Leukemia & Lymphoma Society, the Melanoma Research Alliance, and the Research Foundation for the Treatment of Ovarian Cancer (G. Dranoff). NR 40 TC 38 Z9 42 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10150 EP 10160 DI 10.1158/0008-5472.CAN-10-1852 PG 11 WC Oncology SC Oncology GA 694XD UT WOS:000285334200017 PM 21159637 ER PT J AU Moriceau, G Ory, B Mitrofan, L Riganti, C Blanchard, F Brion, R Charrier, C Battaglia, S Pilet, P Denis, MG Shultz, LD Monkkonen, J Redini, F Heymann, D AF Moriceau, Gatien Ory, Benjamin Mitrofan, Laura Riganti, Chiara Blanchard, Frederic Brion, Regis Charrier, Celine Battaglia, Severine Pilet, Paul Denis, Marc G. Shultz, Leonard D. Monkkonen, Jukka Redini, Francoise Heymann, Dominique TI Zoledronic Acid Potentiates mTOR Inhibition and Abolishes the Resistance of Osteosarcoma Cells to RAD001 (Everolimus): Pivotal Role of the Prenylation Process SO CANCER RESEARCH LA English DT Article ID MAMMALIAN TARGET; BONE-TUMORS; RAPAMYCIN INHIBITION; RAT OSTEOSARCOMA; BISPHOSPHONATES; CANCER; THERAPY; GROWTH; AGENTS; LINE AB Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. In this study, we investigated in vivo the effects of RAD001 (Everolimus), a new orally available mTOR inhibitor, on the growth of human and mouse osteosarcoma cells either alone or in combination with zoledronate (ZOL), an anti-osteoporotic drug used to treat bone metastases. RAD001 inhibited osteosarcoma cell proliferation in a dose-and time-dependent manner with no modification of cell-cycle distribution. Combination with ZOL augmented this inhibition of cell proliferation, decreasing PI3K/mTOR signaling compared with single treatments. Notably, in contrast to RAD001, ZOL downregulated isoprenylated membrane-bound Ras concomitantly with an increase of nonisoprenylated cytosolic Ras in sensitive and resistant osteosarcoma cell lines to both drugs. Moreover, ZOL and RAD001 synergized to decrease Ras isoprenylation and GTP-bound Ras levels. Further, the drug combination reduced tumor development in two murine models of osteoblastic or osteolytic osteosarcoma. We found that ZOL could reverse RAD001 resistance in osteosarcoma, limiting osteosarcoma cell growth in combination with RAD001. Our findings rationalize further study of the applications of mTOR and mevalonate pathway inhibitors that can limit protein prenylation pathways. Cancer Res; 70(24); 10329-39. (C)2010 AACR. C1 [Heymann, Dominique] INSERM, Fac Med, UMR 957, F-44035 Nantes 1, France. [Moriceau, Gatien; Ory, Benjamin; Blanchard, Frederic; Brion, Regis; Charrier, Celine; Battaglia, Severine; Redini, Francoise; Heymann, Dominique] Univ Nantes, Nantes Atlantique Univ, Nantes, France. [Ory, Benjamin] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Ory, Benjamin] Harvard Univ, Sch Med, Boston, MA USA. [Mitrofan, Laura; Monkkonen, Jukka] Univ Kuopio, Dept Pharmaceut, FIN-70211 Kuopio, Finland. [Riganti, Chiara] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Pilet, Paul] INSERM, UMR 791, F-44035 Nantes 1, France. [Denis, Marc G.] INSERM, UMR 913, F-44035 Nantes 1, France. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Heymann, D (reprint author), INSERM, Fac Med, UMR 957, 1 Rue Gaston Veil, F-44035 Nantes 1, France. EM dominique.heymann@univ-nantes.fr RI ory, benjamin/K-8231-2015; Charrier, Celine/K-9198-2015; REDINI, Francoise/K-7981-2015; Blanchard, Frederic/K-8018-2015; Denis, Marc/K-8049-2015; BATTAGLIA, Severine/K-8715-2015 OI Denis, Marc/0000-0001-5865-3248; Riganti, Chiara/0000-0001-9787-4836; FU Pharma Novartis (Rueil-Malmaison, France); NIH [CA34196] FX This work was supported by a grant from Pharma Novartis (Rueil-Malmaison, France) and by a NIH Cancer Core grant CA34196. NR 44 TC 43 Z9 44 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10329 EP 10339 DI 10.1158/0008-5472.CAN-10-0578 PG 11 WC Oncology SC Oncology GA 694XD UT WOS:000285334200034 PM 20971812 ER PT J AU Sablina, AA Hector, M Colpaert, N Hahn, WC AF Sablina, Anna A. Hector, Melissa Colpaert, Nathalie Hahn, William C. TI Identification of PP2A Complexes and Pathways Involved in Cell Transformation SO CANCER RESEARCH LA English DT Article ID PROTEIN PHOSPHATASE 2A; SMALL-T-ANTIGEN; MIDDLE TUMOR-ANTIGEN; MAP KINASE PATHWAY; CATALYTIC SUBUNIT; BETA-CATENIN; C-MYC; ONCOGENIC TRANSFORMATION; REGULATORY SUBUNIT; EPITHELIAL-CELLS AB The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine-threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56 alpha, B56 gamma, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56 alpha, B56 gamma, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation. Cancer Res; 70(24); 10474-84. (C)2010 AACR. C1 [Sablina, Anna A.; Hector, Melissa; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA USA. [Sablina, Anna A.; Colpaert, Nathalie] KULeuven, Ctr Human Genet, VIB Inst, Leuven, Belgium. [Hahn, William C.] Broad Inst Harvard, Cambridge, MA USA. [Hahn, William C.] MIT, Cambridge, MA 02139 USA. [Sablina, Anna A.; Hector, Melissa; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hahn, WC (reprint author), Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 1538, Boston, MA 02115 USA. EM Anna.Sablina@cme.vib-kuleuven.be; William_Hahn@dfci.harvard.edu OI Hector-Greene, Melissa/0000-0001-7263-1440 FU U.S. National Cancer Institute [P01 CA050661, 1K99 CA125974-01A2] FX Supported in part by grants from the U.S. National Cancer Institute P01 CA050661 (W.C. Hahn) and 1K99 CA125974-01A2 (A.A. Sablina). NR 50 TC 66 Z9 69 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 IS 24 BP 10474 EP 10484 DI 10.1158/0008-5472.CAN-10-2855 PG 11 WC Oncology SC Oncology GA 694XD UT WOS:000285334200048 PM 21159657 ER PT J AU Anderson, JM Yoshizawa, C Winer, EP Watson, D Millward, C Tan, V Shak, S Baehner, FL AF Anderson, J. M. Yoshizawa, C. Winer, E. P. Watson, D. Millward, C. Tan, V. Shak, S. Baehner, F. L. TI Quantitative Gene Expression by RT-PCR in Classic and Variant Forms of Lobular Carcinoma in Estrogen Receptor Positive Invasive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Genom Hlth, Redwood City, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-10-15 DI 10.1158/0008-5472.SABCS10-P3-10-15 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801226 ER PT J AU Baselga, J Bradbury, I Eidtmann, H Di Cosimo, S Aura, C De Azambuja, E Gomez, H Dinh, P Fauria, K Van Dooren, V Paoletti, P Goldhirsch, A Chang, TW Lang, I Untch, M Gelber, RD Piccart-Gebhart, M AF Baselga, J. Bradbury, I. Eidtmann, H. Di Cosimo, S. Aura, C. De Azambuja, E. Gomez, H. Dinh, P. Fauria, K. Van Dooren, V. Paoletti, P. Goldhirsch, A. Chang, T-W Lang, I. Untch, M. Gelber, R. D. Piccart-Gebhart, M. TI First Results of the NeoALTTO Trial (BIG 01-06/EGF 106903): A Phase III, Randomized, Open Label, Neoadjuvant Study of Lapatinib, Trastuzumab, and Their Combination Plus Paclitaxel in Women with HER2-Positive Primary Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Vall dHebron Univ Hosp, NeoALTTO Study Team, Barcelona, Spain. FSS Ltd, Kincraig, Scotland. Univ Hosp Kiel, Kiel, Germany. Vall dHebron Univ Hosp, Breast Canc Ctr, Barcelona, Spain. SOLTI Spanish Breast Canc Res Grp, Barcelona, Spain. Inst Jules Bordet, B-1000 Brussels, Belgium. Breast European Adjuvant Study Team, Brussels, Belgium. Inst Nacl Enfermedades Neoplas, Lima, Peru. Breast Int Grp, Brussels, Belgium. GlaxoSmithKline, Collegeville, PA USA. European Inst Oncol, Milan, Italy. Natl Cheng Kung Univ Hosp, Tainan 70428, Taiwan. Natl Inst Oncol, Budapest, Hungary. Charite, Acad Hosp, D-13353 Berlin, Germany. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 3 Z9 3 U1 2 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA S3-3 DI 10.1158/0008-5472.SABCS10-S3-3 PG 2 WC Oncology SC Oncology GA V43QL UT WOS:000209695802005 ER PT J AU Burstein, HJ Barry, WT Cirrincione, C Chew, HK Tolaney, S Lake, D Pluard, T Blackwell, K Winer, EP Hudis, CA AF Burstein, H. J. Barry, W. T. Cirrincione, C. Chew, H. K. Tolaney, S. Lake, D. Pluard, T. Blackwell, K. Winer, E. P. Hudis, C. A. TI CALGB 40302: Fulvestrant with or without Lapatinib as Therapy for Hormone Receptor Positive Advanced Breast Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Study SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. CALGB Stat Ctr, Durham, NC USA. Univ Calif Davis, Davis, CA 95616 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Washington Univ, Sch Med, St Louis, MO USA. Duke Univ, Med Ctr, Durham, NC USA. NR 0 TC 1 Z9 1 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA PD05-01 DI 10.1158/0008-5472.SABCS10-PD05-01 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801407 ER PT J AU Ghazoui, Z Anderson, H Dunbier, A Anderson, E Lindemann, J Wellings, B Walker, J Kuter, I Dowsett, M AF Ghazoui, Z. Anderson, H. Dunbier, A. Anderson, E. Lindemann, J. Wellings, B. Walker, J. Kuter, I. Dowsett, M. TI Transcriptional Changes Induced by Anastrozole and Fulvestrant Treatment in ER-Positive Breast Cancers SO CANCER RESEARCH LA English DT Meeting Abstract C1 Breakthrough Breast Canc Res Ctr, London, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. Royal Marsden Hosp, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P1-12-02 DI 10.1158/0008-5472.SABCS10-P1-12-02 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800490 ER PT J AU Goodwin, RA Jamal, R Booth, CM Goss, PE Eisenhauer, EA Tu, D Shepherd, LE AF Goodwin, R. A. Jamal, R. Booth, C. M. Goss, P. E. Eisenhauer, E. A. Tu, D. Shepherd, L. E. TI Effects of Diabetes (DM), Hypertension (HTN) and Coronary Artery Disease (CAD) on Prognosis after 5 Years of Adjuvant Tamoxifen (TAM) and on Treatment Outcomes with the Use of Extended Letrozole (LET): NCIC CTG MA.17 SO CANCER RESEARCH LA English DT Meeting Abstract C1 Queens Univ, Kingston, ON, Canada. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA PD03-04 DI 10.1158/0008-5472.SABCS10-PD03-04 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801392 ER PT J AU Goss, PE Ingle, JN Chapman, JAW Ellis, MJ Sledge, GW Budd, GT Rabaglio, M Gelmon, K Shepherd, L Pritchard, KI AF Goss, P. E. Ingle, J. N. Chapman, J-A W. Ellis, M. J. Sledge, G. W. Budd, G. T. Rabaglio, M. Gelmon, K. Shepherd, L. Pritchard, K. I. TI Final Analysis of NCIC CTG MA.27: A Randomized Phase III Trial of Exemestane Versus Anastrozole in Postmenopausal Women with Hormone Receptor Positive Primary Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. Queens Univ, Kingston, ON, Canada. Washington Univ, St Louis, MO USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Cleveland Clin, Cleveland, OH USA. Univ Bern, Inst Med Oncol, Inselspital, Bern, Switzerland. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA S1-1 DI 10.1158/0008-5472.SABCS10-S1-1 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801487 ER PT J AU Habin, KR Shannon, K Ryan, PD Lundquist, D Banister, GE Bauer-Wu, S Post, KE Forcier, AG Woodford, ML Schapira, L AF Habin, K. R. Shannon, K. Ryan, P. D. Lundquist, D. Banister, G. E. Bauer-Wu, S. Post, K. E. Forcier, A. G. Woodford, M. L. Schapira, L. TI Genetic Information for Treatment, Surveillance and Support [GIFTSS]: Initial Evaluation of a Program for the Underserved SO CANCER RESEARCH LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Canc Resource Fdn Inc, Marlborough, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Emory Univ, Atlanta, GA 30322 USA. Northeastern Univ, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P1-10-01 DI 10.1158/0008-5472.SABCS10-P1-10-01 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800453 ER PT J AU Halasz, LM Sreedhara, M Chen, YH Harris, JR Brock, JE AF Halasz, L. M. Sreedhara, M. Chen, Y-H Harris, J. R. Brock, J. E. TI Improved Outcomes of Breast-Conserving Surgery (BCS) and Radiation Therapy (RT) for Ductal Carcinoma In Situ (DCIS) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P1-15-07 DI 10.1158/0006-5472.SABCS10-P1-15-07 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801020 ER PT J AU Harris, LN Liu, Z Li, A Sprecher, E Sarkar, S Lezon-Geyda, K Krop, I Winer, EP Tuck, DR AF Harris, L. N. Liu, Z. Li, A. Sprecher, E. Sarkar, S. Lezon-Geyda, K. Krop, I. Winer, E. P. Tuck, D. R. TI Integrated Genomic Analysis before and after Brief Exposure to Trastuzumab (T): The 11q13 and 17q12 Amplicons Are Associated with Response to T plus Chemotherapy in Early Stage HER2 Positive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Yale Univ, Sch Med, New Haven, CT USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA PD07-08 DI 10.1158/0008-5472.SABCS10-PD07-08 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801436 ER PT J AU Krop, IE Modi, S Elias, A LoRusso, P Choi, YJ Lu, M AF Krop, I. E. Modi, S. Elias, A. LoRusso, P. Choi, Y. J. Lu, M. TI A Dose-Escalation Study of Trastuzumab-DM1 (T-DM1), Paclitaxel (T), and Pertuzumab (P) in Patients with HER2-Positive, Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with a Trastuzumab-Containing Regimen SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Colorado, Sch Med, Aurora, CO USA. Wayne State Univ, Detroit, MI USA. Genentech Inc, San Francisco, CA 94080 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-14-10 DI 10.1158/0008-5472.SABCS10-P3-14-10 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801299 ER PT J AU Krop, IE Wolff, AC Winer, EP Miller, KD Park, BH Ware, J Holden, S Levy, GG Derynck, M Storniolo, AM AF Krop, I. E. Wolff, A. C. Winer, E. P. Miller, K. D. Park, B. H. Ware, J. Holden, S. Levy, G. G. Derynck, M. Storniolo, A. M. TI A Phase lb Study Evaluating Safety, Tolerability, Pharmacokinetics (PK), and Activity of the Phosphoinositide-3 Kinase (PI3K) Inhibitor GDC-0941 in Combination with Trastuzumab-MCC-DM1 (T-DM1) in Patients with Advanced HER2-Positive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Kimmel Canc Ctr, Baltimore, MD USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Genentech Inc, San Francisco, CA 94080 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P6-15-02 DI 10.1158/0008-5472.SABCS10-P6-15-02 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800328 ER PT J AU Ligibel, JA O'Malley, A Fisher, M Daniel, G Winer, EP Keating, NL AF Ligibel, J. A. O'Malley, A. Fisher, M. Daniel, G. Winer, E. P. Keating, N. L. TI Aromatase Inhibitors and Risk of Myocardial Infarction, Stroke and Fracture SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA S2-6 DI 10.1158/0008-5472.SABCS10-S2-6 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801499 ER PT J AU Ligibel, JA Meyerhardt, J Najita, J Shockro, L Campbell, N Pierce, J Paskett, E Shapiro, C AF Ligibel, J. A. Meyerhardt, J. Najita, J. Shockro, L. Campbell, N. Pierce, J. Paskett, E. Shapiro, C. TI Impact of a Telephone-Based Exercise Intervention on Physical Activity Behaviors and Fitness in a Cooperative Group Setting SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA USA. Moores UCSD Canc Ctr, San Diego, CA USA. Ohio State Med Ctr, Columbus, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA PD08-09 DI 10.1158/0008-5472.SABCS10-PD08-09 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801447 ER PT J AU Lim, E Wu, D Pal, B Bouras, T Asselin-Labat, ML Vaillant, F Yagita, H Lindeman, GJ Smyth, GK Visvader, JE AF Lim, E. Wu, D. Pal, B. Bouras, T. Asselin-Labat, M-L Vaillant, F. Yagita, H. Lindeman, G. J. Smyth, G. K. Visvader, J. E. TI Transcriptome Analyses of Mouse and Human Mammary Cell Subpopulations Reveals Multiple Conserved Genes and Pathways SO CANCER RESEARCH LA English DT Meeting Abstract C1 Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. Dana Farber Canc Inst, Boston, MA 02115 USA. Juntendo Univ, Sch Med, Tokyo 113, Japan. Royal Melbourne Hosp, Melbourne, Vic, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P4-04-03 DI 10.1158/0008-5472.SABCS10-P4-04-03 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801358 ER PT J AU Lin, NU Beliakoff, J Foley, KP Whitesell, L Lindquist, S AF Lin, N. U. Beliakoff, J. Foley, K. P. Whitesell, L. Lindquist, S. TI Heat Shock Protein 90 Inhibition Limits the Emergence of Tamoxifen Resistance SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Imclone Syst, Bridgewater, NJ USA. Synta Pharmaceut Corp, Lexington, MA USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P6-15-06 DI 10.1158/0008-5472.SABCS10-P6-15-06 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800333 ER PT J AU Lobb, R Opdyke, KM McDonnell, CJ Pagaduan, MG Hurlbert, M Gates-Ferris, K Chi, B Allen, JD AF Lobb, R. Opdyke, K. M. McDonnell, C. J. Pagaduan, M. G. Hurlbert, M. Gates-Ferris, K. Chi, B. Allen, J. D. TI Organizational Use of Evidence-Based Strategies To Promote Timely Mammography among Medically Underserved Clients Recruited through the Avon Breast Health Outreach Program SO CANCER RESEARCH LA English DT Meeting Abstract C1 St Michaels Hosp, Ctr Res Inner City Hlth, Toronto, ON, Canada. Dana Farber Canc Inst, Boston, MA USA. Cicatelli Associates Inc, New York, NY USA. James Bell Associates, New York, NY USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P1-10-10 DI 10.1158/0008-5472.SABCS10-P1-10-10 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800462 ER PT J AU Lu, D Krop, I Modi, S Elias, A LoRusso, P Huang, J Lu, M Girish, S AF Lu, D. Krop, I. Modi, S. Elias, A. LoRusso, P. Huang, J. Lu, M. Girish, S. TI Pharmacokinetics (PK) of Trastuzumab-DM1 (T-DM1) and Paclitaxel (T) in Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with a Trastuzumab-Containing Regimen SO CANCER RESEARCH LA English DT Meeting Abstract C1 Genentech Inc, San Francisco, CA 94080 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Colorado, Sch Med, Aurora, CO USA. Wayne State Univ, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-14-22 DI 10.1158/0008-5472.SABCS10-P3-14-22 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801311 ER PT J AU Mayer, EL Shak, S Miller, K Rugo, H Carey, L Ryabin, N Pomeroy, C Yoshizawa, C Winer, EP Burstein, HJ AF Mayer, E. L. Shak, S. Miller, K. Rugo, H. Carey, L. Ryabin, N. Pomeroy, C. Yoshizawa, C. Winer, E. P. Burstein, H. J. TI Prognostic Value of Genomic Analysis after Neoadjuvant Chemotherapy for Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Genom Hlth Inc, Redwood City, CA USA. Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-10-13 DI 10.1158/0008-5472.SABCS10-P3-10-13 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801224 ER PT J AU Mayer, EL Scheulen, M Beckman, J Richly, H Poli, A Bhargava, P Duarte, A Cotreau, M Al-Adhami, M Dickler, M AF Mayer, E. L. Scheulen, M. Beckman, J. Richly, H. Poli, A. Bhargava, P. Duarte, A. Cotreau, M. Al-Adhami, M. Dickler, M. TI Combination of Tivozanib, an Oral Inhibitor of VEGFR, with Weekly Paclitaxel for Metastatic Breast Cancer: Preliminary Results of an Ongoing Phase 1 Study SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Essen Gesamthsch, Sch Med, West German Canc Ctr, Essen, Germany. Brigham & Womens Hosp, Boston, MA 02115 USA. AVEO Pharmaceut Inc, Cambridge, MA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P2-16-10 DI 10.1158/0008-5472.SABCS10-P2-16-10 PG 2 WC Oncology SC Oncology GA V43QL UT WOS:000209695801153 ER PT J AU McCullough, AE Dell'Orto, P Reinholz, MM Gelber, RD Dueck, AC Russo, L Jenkins, RB Andrighetto, S Chen, B Lingle, WL Jackisch, C Perez, EA Piccart-Gebhart, MJ Viale, G AF McCullough, A. E. Dell'Orto, P. Reinholz, M. M. Gelber, R. D. Dueck, A. C. Russo, L. Jenkins, R. B. Andrighetto, S. Chen, B. Lingle, W. L. Jackisch, C. Perez, E. A. Piccart-Gebhart, M. J. Viale, G. TI Concordance of HER2 Central Assessment by Two International Central Laboratories: A Ring Study within the Framework of the Adjuvant HER2-Positive ALTTO Trial (BIG2-06/N063D/EGF106708) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Mayo Clin Rochester, Rochester, MN USA. European Inst Oncol, Milan, Italy. Mayo Clin Arizona, Scottsdale, AZ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Klinikum Offenbach, Offenbach, Germany. Univ Libre Bruxelles, Inst Jules Bordet, Brussels, Belgium. Mayo Clin Florida, Jacksonville, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-10-36 DI 10.1158/0008-5472.SABCS10-P3-10-36 PG 2 WC Oncology SC Oncology GA V43QL UT WOS:000209695801247 ER PT J AU Olson, EM Lin, NU DiPiro, PJ Najita, J Krop, IE Winer, EP Burstein, HJ AF Olson, E. M. Lin, N. U. DiPiro, P. J. Najita, J. Krop, I. E. Winer, E. P. Burstein, H. J. TI Responses to Subsequent Anti-HER2 Therapy after Treatment with Trastuzumab-DM1 in Women with HER2-Positive Metastatic Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Olson, E. M.; Lin, N. U.; DiPiro, P. J.; Najita, J.; Krop, I. E.; Winer, E. P.; Burstein, H. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-14-08 DI 10.1158/0008-5472.SABCS10-P3-14-08 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801297 ER PT J AU Ozanne, EM Bechtold, T Boortz, S Esserman, LJ AF Ozanne, E. M. Bechtold, T. Boortz, S. Esserman, L. J. TI Wide Scale, Automated Breast Cancer Risk Assessment and Decision Support for High Risk Women: www.BreastHealthDecisions.org SO CANCER RESEARCH LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P6-09-11 DI 10.1158/0008-5472.SABCS10-P6-09-11 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800268 ER PT J AU Partridge, AH Gelber, S Piccart, M Focant, F Scullion, M Winer, E Gelber, R AF Partridge, A. H. Gelber, S. Piccart, M. Focant, F. Scullion, M. Winer, E. Gelber, R. TI The Effect of Age on Breast Cancer Outcomes in Women with Her-2 Positive Breast Cancer: Results from the HERA Trial SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, HERA Trial Study Team, Boston, MA 02115 USA. Inst Jules Bordet, B-1000 Brussels, Belgium. Roche Prod Ltd, Welwyn Garden City AL7 3AY, Herts, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P4-09-12 DI 10.1158/0008-5472.SABCS10-P4-09-12 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800100 ER PT J AU Perlmutter, J Frank, E LeStage, B Esserman, L AF Perlmutter, J. Frank, E. LeStage, B. Esserman, L. TI I-SPY 2 Clinical Trial: Advocate Involvement in Protocol, Informed Consent and Patient Support Materials Development SO CANCER RESEARCH LA English DT Meeting Abstract C1 Gemini Grp, Ann Arbor, MI USA. Dana Farber Canc Ctr, Boston, MA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P5-07-02 DI 10.1158/0008-5472.SABCS10-P5-07-02 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800029 ER PT J AU Ramsey, B Newell, AH Troxell, M Olson, S Keenan, E Luoh, SW AF Ramsey, B. Newell, A. Hanlon Troxell, M. Olson, S. Keenan, E. Luoh, S-W. TI False Positive HER-2 Testing by Fluorescence In Situ Hybridization in Human Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P4-08-03 DI 10.1158/0008-5472.SABCS10-P4-08-03 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800107 ER PT J AU Ruddy, KJ Meyer, ME Giobbie-Hurder, A Emmons, KM Weeks, JC Winer, EP Partridge, AH AF Ruddy, K. J. Meyer, M. E. Giobbie-Hurder, A. Emmons, K. M. Weeks, J. C. Winer, E. P. Partridge, A. H. TI Long-Term Risk Perceptions and Quality of Life of Women with Ductal Carcinoma In Situ SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Ruddy, K. J.; Meyer, M. E.; Giobbie-Hurder, A.; Emmons, K. M.; Weeks, J. C.; Winer, E. P.; Partridge, A. H.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P2-15-01 DI 10.1158/0008-5472.SABCS10-P2-15-01 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801143 ER PT J AU Ruddy, KJ Archer, LE Cohen, HJ Winer, EP Hudis, CA Muss, HB Partridge, AH AF Ruddy, K. J. Archer, L. E. Cohen, H. J. Winer, E. P. Hudis, C. A. Muss, H. B. Partridge, A. H. TI Adherence, Persistence and Toxicity with Oral CMF in Older Women with Early Stage Breast Cancer in CALGB 49907 (Adherence Companion Study 60104) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Med Ctr, Durham, NC USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ N Carolina, Chapel Hill, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P5-10-12 DI 10.1158/0008-5472.SABCS10-P5-10-12 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800046 ER PT J AU Schott, AF Chang, JC Krop, IE Griffith, KA Layman, RM Hayes, DF Wicha, MS AF Schott, A. F. Chang, J. C. Krop, I. E. Griffith, K. A. Layman, R. M. Hayes, D. F. Wicha, M. S. TI Phase lb Trial of the Gamma Secretase Inhibitor (GSI), MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor, MI 48109 USA. Baylor Coll Med, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Ohio State Univ, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P6-15-03 DI 10.1158/0008-5472.SABCS10-P6-15-03 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800329 ER PT J AU Sgroi, DC Finkelstein, DM Shepherd, L Ingle, JN Rimm, DL Sasano, H Porter, P Pins, M Paik, S Ristimaki, A Pritchard, KI Tu, D Goss, PE AF Sgroi, D. C. Finkelstein, D. M. Shepherd, L. Ingle, J. N. Rimm, D. L. Sasano, H. Porter, P. Pins, M. Paik, S. Ristimaki, A. Pritchard, K. I. Tu, D. Goss, P. E. TI Quantitative Protein and Gene Expression Biomarkers of Tamoxifen and Letrozole Recurrence in the NCIC CTG MA.17 Cohort SO CANCER RESEARCH LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Queens Univ, Kingston, ON, Canada. Mayo Clin, Rochester, MN USA. Yale Univ, Sch Med, New Haven, CT USA. Tohoku Univ, Sch Med, Sendai, Miyagi 980, Japan. Univ Washington Med, Seattle, WA USA. Advocate Lutheran Gen Hosp, Park Ridge, IL USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ Helsinki, FIN-00014 Helsinki, Finland. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P3-10-26 DI 10.1158/0008-5472.SABCS10-P3-10-26 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801237 ER PT J AU Silver, DP AF Silver, D. P. TI DNA Repair and Breast Cancer: Therapeutic Opportunities SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Silver, D. P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA ES2-2 DI 10.1158/0008-5472.SABCS10-ES2-2 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800358 ER PT J AU Tevaarwerk, AJ Lee, JW Sesto, MC Cleeland, CS Wagner, LI Chang, VTS Fisch, M AF Tevaarwerk, A. J. Lee, J-W Sesto, M. C. Cleeland, C. S. Wagner, L. I. Chang, V. T. S. Fisch, M. TI Predictors of Employment Outcomes in Breast Cancer (BrCa) Patients: An Analysis from E2Z02 (ECOG's SOAPP Study) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Wisconsin, Madison, WI 53706 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. VA New Jersey Hlth Care Syst, E Orange, NJ USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P2-14-07 DI 10.1158/0008-5472.SABCS10-P2-14-07 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801137 ER PT J AU Vachon, CM Brandt, KR Suman, VJ Weinshilboum, R Kosel, ML Wu, F Serie, DJ Olson, JE Buzdar, AU Shepherd, LE Goss, PE Ingle, JN AF Vachon, C. M. Brandt, K. R. Suman, V. J. Weinshilboum, R. Kosel, M. L. Wu, F. Serie, D. J. Olson, J. E. Buzdar, A. U. Shepherd, L. E. Goss, P. E. Ingle, J. N. TI Mammographic Density Response to Aromatase Inhibitor Therapy SO CANCER RESEARCH LA English DT Meeting Abstract C1 Mayo Clin, Rochester, MN USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P2-09-03 DI 10.1158/0008-5472.SABCS10-P2-09-03 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801080 ER PT J AU Walker, SR Nelson, EA Chaudhury, M Madoux, F Subramaniam, P Chase, P Koenig, M Roush, WR Hodder, P Frank, DA AF Walker, S. R. Nelson, E. A. Chaudhury, M. Madoux, F. Subramaniam, P. Chase, P. Koenig, M. Roush, W. R. Hodder, P. Frank, D. A. TI Preclinical Evaluation of a STAT3 Inhibitor in Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Scripps Florida, Jupiter, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P6-15-12 DI 10.1158/0008-5472.SABCS10-P6-15-12 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695800339 ER PT J AU Wong, JS Smith, BL Troyan, SL Gadd, MA Gelman, R Lester, SC Schnitt, SJ Sgroi, DC Chen, YH Silver, BJ Harris, JR AF Wong, J. S. Smith, B. L. Troyan, S. L. Gadd, M. A. Gelman, R. Lester, S. C. Schnitt, S. J. Sgroi, D. C. Chen, Y-H Silver, B. J. Harris, J. R. TI Eight-Year Update of a Prospective Study of Wide Excision Alone for Ductal Carcinoma In Situ (DCIS) of the Breast SO CANCER RESEARCH LA English DT Meeting Abstract C1 Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2010 VL 70 SU 24 MA P1-15-03 DI 10.1158/0008-5472.SABCS10-P1-15-03 PG 1 WC Oncology SC Oncology GA V43QL UT WOS:000209695801016 ER PT J AU Dominy, JE Puigserver, P AF Dominy, John E. Puigserver, Pere TI Nuclear FoxO1 inflames insulin resistance SO EMBO JOURNAL LA English DT Editorial Material ID OBESITY; INFLAMMATION AB Chronic activation of macrophage-mediated inflammatory signals in insulin-sensitive metabolic tissues is thought to be one of the causes of insulin resistance-one of the hallmarks of the metabolic syndrome. However, the mechanisms, components and dynamics by which this inflammatory response is spatially and temporally regulated are not completely understood. In this issue of The EMBO Journal, Olefsky and colleagues (Fan et al, 2010) report that FoxO1, which is suppressed by the action of AKT, triggers the Tlr4 inflammatory signalling pathway in macrophages. The authors further establish that inflammatory signalling pathways are also able to signal back to and suppress the activity of FoxO1 through AKT. The findings of this paper suggest an intriguing regulatory transcriptional/signalling loop in macrophages that may contribute to maintain and exacerbate inflammation and insulin resistance in other cell types such as adipocytes. C1 [Dominy, John E.; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Dominy, John E.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Puigserver, P (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu NR 11 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 15 PY 2010 VL 29 IS 24 BP 4068 EP 4069 DI 10.1038/emboj.2010.305 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695XX UT WOS:000285407200003 PM 21157481 ER PT J AU Shan, WH Zhong, WX Zhao, R Oberley, TD AF Shan, Weihua Zhong, Weixiong Zhao, Rui Oberley, Terry D. TI Thioredoxin 1 as a subcellular biomarker of redox imbalance in human prostate cancer progression SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Thioredoxin 1; Reactive oxygen species; Redox state; Prostate cancer; Androgen; Free radicals ID MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; EPITHELIAL-CELLS; EXPRESSION; NUCLEAR; GLUTATHIONE; COMPARTMENTATION; ACTIVATION; RESISTANCE; INHIBITOR AB We determined protein levels and subcellular distribution of thioredoxin 1 (Trx1) in human prostate tissues using tissue microarrays and analyzed redox changes in Trx1 in the nucleus and cytoplasm in cell culture models with a redox Western blot technique We demonstrated increased nuclear Trx1 levels in high- versus low-grade human prostate cancers Despite Increased protein levels the oxidized forms of nuclear Trx1 were higher in prostate cancer cell lines compared to their benign counterparts suggesting that nuclear redox imbalance occurred selectively in cancer cells A growth-stimulating dose of androgen caused transient oxidation of Trx1 in androgen-responsive prostate cancer cells only suggesting a loss of both androgen and redox-signaling mechanisms during cancer progression Androgen independent PC3 cells showed a significant Increase in nuclear and cytoplasmic Trx1 protein levels but a significant decrease in total Trx activity Trx1 redox state and activity correlated with the sensitivity of prostate cancer cells to pro-oxidant agents and downregulation of Trx1 sensitized cancer cells to these agents Our findings suggest that loss of Trx function because of oxidation and corresponding redox imbalance may play important roles in prostate cancer progression and response to therapies and Trx1 may serve as a biomarker of subcellular redox imbalance in prostate cancer Published by Elsevier Inc C1 [Shan, Weihua; Zhong, Weixiong; Oberley, Terry D.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Shan, Weihua; Oberley, Terry D.] Univ Wisconsin, Sch Med & Publ Hlth, Mol & Environm Toxicol Ctr, Madison, WI 53705 USA. [Zhong, Weixiong; Oberley, Terry D.] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Madison, WI 53705 USA. [Zhao, Rui] Univ Wisconsin, Sch Vet Med, Dept Comparat Biosci, Madison, WI 53706 USA. RP Oberley, TD (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI 53705 USA. FU University of Wisconsin Department of Pathology Research and Development Committee; National Cancer Institute [P30 CA014520]; NIH [RO1 CA073599, RO1 CA194853, RO1 AG012350, RO1 CA115801] FX The authors thank the laboratory of Dr Dean P Jones for technical advice Joan Sempf and Jamie Swanlund for technical assistance and Dr Lukasana Chaiswing for sending the cells to Biosynthesis Inc (Lewisville TX USA) to authenticate cell identity The contents do not represent the views of the U S Department of Veterans Affairs This work was supported by funds from the University of Wisconsin Department of Pathology Research and Development Committee Grant P30 CA014520 from the National Cancer Institute NIH Grants RO1 CA073599 RO1 CA194853 RO1 AG012350 and RO1 CA115801 and resources and facilities at the William S Middleton Memorial Veterans Hospital (Madison WI USA) NR 28 TC 31 Z9 35 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC 15 PY 2010 VL 49 IS 12 BP 2078 EP 2087 DI 10.1016/j.freeradbiomed.2010.10.691 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 696MH UT WOS:000285445000026 PM 20955789 ER PT J AU Schmid, AA Andersen, J Kent, T Williams, LS Damush, TM AF Schmid, Arlene A. Andersen, Jane Kent, Thomas Williams, Linda S. Damush, Teresa M. TI Using intervention mapping to develop and adapt a secondary stroke prevention program in Veterans Health Administration medical centers SO IMPLEMENTATION SCIENCE LA English DT Article ID CLINICAL-PRACTICE GUIDELINE; AMERICAN-HEART-ASSOCIATION; TRANSIENT ISCHEMIC ATTACK; OCCUPATIONAL-THERAPY; REHABILITATION CARE; SELF-MANAGEMENT; 1ST-EVER STROKE; BLOOD-PRESSURE; OLDER-ADULTS; RISK-FACTORS AB Secondary stroke prevention is championed by the stroke guidelines; however, it is rarely systematically delivered. We sought to develop a locally tailored, evidence-based secondary stroke prevention program. The purpose of this paper was to apply intervention mapping (IM) to develop our locally tailored stroke prevention program and implementation plan. We completed a needs assessment and the five Steps of IM. The needs assessment included semi-structured interviews of 45 providers; 26 in Indianapolis and 19 in Houston. We queried frontline clinical providers of stroke care using structured interviews on the following topics: current provider practices in secondary stroke risk factor management; barriers and needs to support risk factor management; and suggestions on how to enhance secondary stroke risk factor management throughout the continuum of care. We then describe how we incorporated each of the five Steps of IM to develop locally tailored programs at two sites that will be evaluated through surveys for patient outcomes, and medical records chart abstraction for processes of care. C1 [Schmid, Arlene A.; Williams, Linda S.; Damush, Teresa M.] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Schmid, Arlene A.; Williams, Linda S.; Damush, Teresa M.] Hlth Serv Res & Dev HSR&D Ctr Implementing Eviden, Indianapolis, IN 46202 USA. [Schmid, Arlene A.; Williams, Linda S.; Damush, Teresa M.] VA Stroke Qual Enhancement Res Initiat QUERI, Indianapolis, IN 46202 USA. [Schmid, Arlene A.] Indiana Univ, Sch Hlth & Rehabil Sci, Dept Occupat Therapy, Indianapolis, IN 46202 USA. [Schmid, Arlene A.; Damush, Teresa M.] Indiana Univ, Ctr Aging Res, Indianapolis, IN 46202 USA. [Andersen, Jane; Kent, Thomas] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Schmid, Arlene A.; Williams, Linda S.; Damush, Teresa M.] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Williams, Linda S.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN 46202 USA. [Damush, Teresa M.] Indiana Univ Sch Med, Dept Gen Internal & Geriatr, Indianapolis, IN 46202 USA. RP Schmid, AA (reprint author), Richard L Roudebush Vet Adm Med Ctr, 1481 W 10th St,11 H, Indianapolis, IN 46202 USA. EM arlene.schmid@va.gov OI Kent, Thomas/0000-0002-9877-7584 FU VA HSRD [IIR-05-297-2] FX We thank Angela Harris, Danielle Sager, Barbara Kimmel, Christi Murphy, and Ellen Matthiesen for conducting the provider interviews at the Indianapolis and Houston VAMC. We are grateful for the time and effort provided by the clinical providers of both the Indianapolis and Houston VAMC to complete these interviews. Support was provided by VA HSR&D funding IIR-05-297-2 'Adapting Tools to Implement Stroke Risk Management to Veterans' to Dr. Damush and in part by VA RR&D funding CDA D6174W to Dr. Schmid. NR 41 TC 13 Z9 13 U1 3 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD DEC 15 PY 2010 VL 5 AR 97 DI 10.1186/1748-5908-5-97 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 707JJ UT WOS:000286282000001 PM 21159171 ER PT J AU Sprenger, CC Plymate, SR Reed, MJ AF Sprenger, Cynthia C. Plymate, Stephen R. Reed, May J. TI Aging-related alterations in the extracellular matrix modulate the microenvironment and influence tumor progression SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; microenvironment; senescence; extracellular matrix; matricellular proteins ID PROSTATE-CANCER CELLS; ENDOTHELIAL GROWTH-FACTOR; AGE-DEPENDENT CHANGES; CARCINOMA-CELLS; GENE-EXPRESSION; DIFFERENTIAL EXPRESSION; MATRICELLULAR PROTEIN; IMPAIRED ANGIOGENESIS; HYALURONAN SYNTHESIS; HYAL1 HYALURONIDASE AB Age is the greatest risk factor for the development of epithelial cancers. In this minireview, we will examine key extracellular matrix and matricellular components, their changes with aging, and discuss how these alterations might influence the subsequent progression of cancer in the aged host. Because of the tight correlation between advanced age and the prevalence of prostate cancer, we will use prostate cancer as the model throughout this minireview. C1 [Reed, May J.] Univ Washington, Dept Med, Harborview Med Ctr, Div Gerontol, Seattle, WA 98104 USA. [Plymate, Stephen R.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA USA. RP Reed, MJ (reprint author), Univ Washington, Dept Med, Harborview Med Ctr, Div Gerontol, 325 9th Ave,Box 359625, Seattle, WA 98104 USA. EM mjr@u.washington.edu FU NIH [U54 CA126540, R01 AG015837]; Department of Defense [W81XWH-09-1-0177] FX Grant sponsor: NIH; Grant numbers: U54 CA126540, R01 AG015837;; Grant sponsor: Prostate Cancer Research Program (Department of Defense); Grant number: W81XWH-09-1-0177 NR 118 TC 21 Z9 22 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2010 VL 127 IS 12 BP 2739 EP 2748 DI 10.1002/ijc.25615 PG 10 WC Oncology SC Oncology GA 680CA UT WOS:000284208400001 PM 21351253 ER PT J AU Sherman, KE Andersen, JW Butt, AA Umbleja, T Alston, B Koziel, MJ Peters, MG Sulkowski, M Goodman, ZD Chung, RT AF Sherman, Kenneth E. Andersen, Janet W. Butt, Adeel A. Umbleja, Triin Alston, Beverly Koziel, Margaret J. Peters, Marion G. Sulkowski, Mark Goodman, Zachary D. Chung, Raymond T. CA AIDS Clinical Trials Grp A5178 Stu TI Sustained Long-Term Antiviral Maintenance Therapy in HCV/HIV-Coinfected Patients (SLAM-C) SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE fibrosis; HCV; HIV; maintenance; racial disparity ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; PROTEASE INHIBITOR THERAPY; ALPHA-2A PLUS RIBAVIRIN; LIVER-DISEASE; INTERFERON THERAPY; HEPATOCELLULAR-CARCINOMA; ANTIRETROVIRAL THERAPY; FIBROSIS PROGRESSION AB Background: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network. Methods: HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 > 200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. Results: Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. Conclusions: Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy. C1 [Sherman, Kenneth E.] Univ Cincinnati, Coll Med, Div Digest Dis, Dept Internal Med, Cincinnati, OH 45267 USA. [Andersen, Janet W.; Umbleja, Triin] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Butt, Adeel A.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Alston, Beverly] NIAID, Div Aids, Bethesda, MD 20892 USA. [Koziel, Margaret J.] Beth Israel Deaconess Med Ctr, Harvard Inst Med, Boston, MA 02215 USA. [Peters, Marion G.] Univ Calif San Francisco, Dept Gastroenterol, San Francisco, CA 94143 USA. [Sulkowski, Mark] Johns Hopkins Univ, Div Infect Dis & Gastroenterol Hepatol, Baltimore, MD USA. [Goodman, Zachary D.] Armed Forces Inst Pathol, Washington, DC 20306 USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Sherman, KE (reprint author), Univ Cincinnati, Coll Med, Div Digest Dis, Dept Internal Med, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM kenneth.sherman@uc.edu FU National Institute of Allergy and Infectious Diseases [U01 AI068634, U01 AI38858, U01 AI068636]; NIDDK [K24 DK070528, RO1 16065]; National Center for Research Resources; Roche Pharmaceuticals FX The project described was supported by National Institute of Allergy and Infectious Diseases funding to the AIDS Clinical Trials Group including U01 AI068634, U01 AI38858, U01 AI068636, an NIDDK K24 DK070528 to K.E.S., and an RO1 16065 to M.S. Also supported in part by the General Clinical Research Center Units funded by the National Center for Research Resources. Study drug and other support was provided by Roche Pharmaceuticals. Statistical analysis of the entire data sets pertaining to efficacy and safety have been independently confirmed by a biostatistician who is not employed by the corporate entity. NR 32 TC 17 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2010 VL 55 IS 5 BP 597 EP 605 DI 10.1097/QAI.0b013e3181f6d916 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 679FR UT WOS:000284147500011 PM 20921898 ER PT J AU Triant, VA Regan, S Lee, H Sax, PE Meigs, JB Grinspoon, SK AF Triant, Virginia A. Regan, Susan Lee, Hang Sax, Paul E. Meigs, James B. Grinspoon, Steven K. TI Association of Immunologic and Virologic Factors With Myocardial Infarction Rates in a US Healthcare System SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; myocardial infarction; immune function; cardiovascular risk factors ID CARDIOVASCULAR-DISEASE EVENTS; HIV-INFECTED PATIENTS; T-CELL COUNT; ANTIRETROVIRAL THERAPY; RISK-FACTORS; IMMUNODEFICIENCY; DRUGS AB Background: The effects of immunologic and virologic factors on acute myocardial infarction (AMI) rates in patients with HIV are unclear. Methods: HIV-infected patients in a US healthcare system were assessed for AMI. Results: Of 6517 patients with HIV, 273 (4.2%) had an AMI. In a model adjusting for cardiovascular risk factors, antiretroviral medications, and HIV parameters, CD4 count less than 200/mm(3) (odds ratio, 1.74; 95% confidence interval, 1.07 to 2.81; P = 0.02) predicted AMI. Increased HIV viral load was associated with AMI accounting for cardiovascular disease risk factors and antiretroviral medications but was not significant when CD4 count was considered. Conclusions: Immunologic control appears to be the most important HIV-related factor associated with AMI. C1 [Triant, Virginia A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Regan, Susan; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Sax, Paul E.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Sax, Paul E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Grinspoon, Steven K.] Harvard Univ, Sch Med, Boston, MA USA. RP Triant, VA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,Longfellow 207, Boston, MA 02114 USA. EM vtriant@partners.org FU [K01 AI073109]; [K24 DK080140]; [K24 DK064545] FX Funded in part by K01 AI073109 (V.A.T.), K24 DK080140 (J.B.M.), and K24 DK064545 (S.K.G.). NR 18 TC 70 Z9 70 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2010 VL 55 IS 5 BP 615 EP 619 DI 10.1097/QAI.0b013e3181f4b752 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 679FR UT WOS:000284147500014 PM 20827215 ER PT J AU Safren, SA Reisner, SL Herrick, A Mimiaga, MI Stall, RD AF Safren, Steven A. Reisner, Sari L. Herrick, Amy Mimiaga, Matthew I. Stall, Ronald D. TI Mental Health and HIV Risk in Men Who Have Sex With Men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE mental health; HIV; MSM ID BEHAVIORAL INTERVENTIONS; COGNITIVE MODEL; UNITED-STATES; SUBSTANCE USE; INFECTED MSM; DRUG-USE; PREVALENCE; DEPRESSION; DISORDERS; EXPLORE AB Evidence-based HIV prevention interventions with men who have sex with men (MSM) in the United States have moderate effect sizes in reducing HIV sexual risk behavior. Mental health and psychosocial problems, which both disproportionately affect MSM populations and are implicated in HIV transmission risk behaviors, also likely interfere with the uptake of HIV behavioral interventions. Moreover, given that mental health and psychosocial problems such as depression, substance use, and violence frequently co-occur for many MSM (eg, as syndemic conditions), what is probably needed are combination prevention efforts, or prevention "cocktails," similar to treatment "cocktails," that address the psychological and behavioral mechanisms that interact to produce elevated risk for HIV. Such interventions should incorporate a holistic framework to address the sexual health and overall well being of MSM. Addressing co-occurring psychosocial risk factors is apt to improve effect sizes of current HIV prevention interventions and allow for more effective uptake by MSM. C1 [Safren, Steven A.; Mimiaga, Matthew I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Safren, Steven A.; Reisner, Sari L.; Mimiaga, Matthew I.] Fenway Inst, Boston, MA USA. [Reisner, Sari L.; Mimiaga, Matthew I.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Herrick, Amy; Stall, Ronald D.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA USA. RP Safren, SA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ssafren@partners.org FU National Institute of Mental Health [MH084757]; National Institute of Drug Abuse [DA022936] FX Some of the funding for investigator time to prepare this article comes from grants MH084757 (Dr S.A.S) from the National Institute of Mental Health and DA022936 (Dr R.S.) from the National Institute of Drug Abuse. NR 40 TC 61 Z9 62 U1 18 U2 35 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2010 VL 55 SU 2 BP S74 EP S77 DI 10.1097/QAI.0b013e3181fbc939 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 689YD UT WOS:000284966100004 PM 21406991 ER PT J AU Suri, P Rainville, J Kalichman, L Katz, JN AF Suri, Pradeep Rainville, James Kalichman, Leonid Katz, Jeffrey N. TI Does This Older Adult With Lower Extremity Pain Have the Clinical Syndrome of Lumbar Spinal Stenosis? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LOW-BACK-PAIN; DIAGNOSIS SUPPORT TOOL; LEG PAIN; CLASSIFICATION; CLAUDICATION; PREVALENCE; MANAGEMENT; FEATURES; TRIAL AB Context The clinical syndrome of lumbar spinal stenosis (LSS) is a common diagnosis in older adults presenting with lower extremity pain. Objective To systematically review the accuracy of the clinical examination for the diagnosis of the clinical syndrome of LSS. Data Sources MEDLINE, EMBASE, and CINAHL searches of articles published from January 1966 to September 2010. Study Selection Studies were included if they contained adequate data on the accuracy of the history and physical examination for diagnosing the clinical syndrome of LSS, using a reference standard of expert opinion with radiographic or anatomic confirmation. Data Extraction Two authors independently reviewed each study to determine eligibility, extract data, and appraise levels of evidence. Data Synthesis Four studies evaluating 741 patients were identified. Among patients with lower extremity pain, the likelihood of the clinical syndrome of LSS was increased for individuals older than 70 years (likelihood ratio [LR], 2.0; 95% confidence interval [CI], 1.6-2.5), and was decreased for those younger than 60 years (LR, 0.40; 95% CI, 0.29-0.57). The most useful symptoms for increasing the likelihood of the clinical syndrome of LSS were having no pain when seated (LR, 7.4; 95% CI, 1.9-30), improvement of symptoms when bending forward (LR, 6.4; 95% CI, 4.1-9.9), the presence of bilateral buttock or leg pain (LR, 6.3; 95% CI, 3.1-13), and neurogenic claudication (LR, 3.7; 95% CI, 2.9-4.8). Absence of neurogenic claudication (LR, 0.23; 95% CI, 0.17-0.31) decreased the likelihood of the diagnosis. A wide-based gait (LR, 13; 95% CI, 1.9-95) and abnormal Romberg test result (LR, 4.2; 95% CI, 1.4-13) increased the likelihood of the clinical syndrome of LSS. A score of 7 or higher on a diagnostic support tool including history and examination findings increased the likelihood of the clinical syndrome of LSS (LR, 3.3; 95% CI, 2.7-4.0), while a score lower than 7 made the diagnosis much less likely (LR, 0.10; 95% CI, 0.06-0.16). Conclusions The diagnosis of the clinical syndrome of LSS requires the appropriate clinical picture and radiographic findings. Absence of pain when seated and improvement of symptoms when bending forward are the most useful individual findings. Combinations of findings are most useful for identifying patients who are unlikely to have the diagnosis. JAMA. 2010; 304(23): 2628-2636 C1 [Suri, Pradeep] Spaulding Rehabil Hosp, Boston, MA 02114 USA. [Suri, Pradeep; Rainville, James] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Phys Med & Rehabil, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg,Div Rheumatol Immunol & Allerg, Boston, MA 02115 USA. [Suri, Pradeep] VA Boston Healthcare Syst, Boston, MA USA. [Suri, Pradeep; Rainville, James; Kalichman, Leonid] New England Baptist Hosp, Boston, MA USA. [Kalichman, Leonid] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Phys Therapy, IL-84105 Beer Sheva, Israel. RP Suri, P (reprint author), Spaulding Rehabil Hosp, Room 753,125 Nashua St, Boston, MA 02114 USA. EM psuri@partners.org OI Kalichman, Leonid/0000-0003-2987-4396 FU National Institutes of Health [K12 HD 01097]; Rehabilitation Medicine Scientist Training Program (RMSTP) [K12 HD 01097]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR 02124, P60 AR 47782] FX Dr Suri is funded by grant K12 HD 01097 from the National Institutes of Health and the Rehabilitation Medicine Scientist Training Program (RMSTP). Dr Katz is also funded in part by grants K24 AR 02124 and P60 AR 47782 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. NR 42 TC 54 Z9 56 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 15 PY 2010 VL 304 IS 23 BP 2628 EP 2636 DI 10.1001/jama.2010.1833 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 694MX UT WOS:000285303400026 PM 21156951 ER PT J AU Vilardaga, JP Agnati, LF Fuxe, K Ciruela, F AF Vilardaga, Jean-Pierre Agnati, Luigi F. Fuxe, Kjell Ciruela, Francisco TI G-protein-coupled receptor heteromer dynamics SO JOURNAL OF CELL SCIENCE LA English DT Article DE G-protein-coupled receptors; Heterodimers; Signaling ID PARATHYROID-HORMONE RECEPTOR; ADENOSINE A(2A) RECEPTORS; HIGHER-ORDER OLIGOMERS; ALLOSTERIC MODULATION; INTEGRATIVE MECHANISM; MAMMALIAN SWEET; ENERGY-TRANSFER; NEUROPEPTIDE-Y; LIVING CELLS; IN-VIVO AB G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors, and have evolved to detect and transmit a large palette of extracellular chemical and sensory signals into cells. Activated receptors catalyze the activation of heterotrimeric G proteins, which modulate the propagation of second messenger molecules and the activity of ion channels. Classically thought to signal as monomers, different GPCRs often pair up with each other as homo-and heterodimers, which have been shown to modulate signaling to G proteins. Here, we discuss recent advances in GPCR heteromer systems involving the kinetics of the early steps in GPCR signal transduction, the dynamic property of receptor-receptor interactions, and how the formation of receptor heteromers modulate the kinetics of G-protein signaling. C1 [Vilardaga, Jean-Pierre] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. [Vilardaga, Jean-Pierre] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Vilardaga, Jean-Pierre] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Agnati, Luigi F.] IRCCS, San Camillo, Lido Venezia, Italy. [Fuxe, Kjell] Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden. [Ciruela, Francisco] Univ Barcelona, Fac Med, Dept Pathol & Expt Therapy, Pharmacol Unit, Barcelona 08907, Spain. RP Vilardaga, JP (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. EM jpv@pitt.edu RI Ciruela, Francisco/A-5096-2013; OI Ciruela, Francisco/0000-0003-0832-3739; Fuxe, Kjell/0000-0001-8491-4288 FU National Institutes of Health [R01DK087688] FX This work was supported by the National Institutes of Health grant R01DK087688 (to J.-P.V). Deposited in PMC for release after 12 months. NR 63 TC 25 Z9 27 U1 1 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC 15 PY 2010 VL 123 IS 24 BP 4215 EP 4220 DI 10.1242/jcs.063354 PG 6 WC Cell Biology SC Cell Biology GA 688GF UT WOS:000284837100003 PM 21123619 ER PT J AU Kasperkovitz, PV Cardenas, ML Vyas, JM AF Kasperkovitz, Pia V. Cardenas, Michael L. Vyas, Jatin M. TI TLR9 Is Actively Recruited to Aspergillus fumigatus Phagosomes and Requires the N-Terminal Proteolytic Cleavage Domain for Proper Intracellular Trafficking SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; BETA-GLUCAN RECEPTOR; DENDRITIC CELLS; CYTOKINE PRODUCTION; MURINE MACROPHAGES; CPG DNA; RECOGNITION; ACTIVATION; DECTIN-1; CONIDIA AB TLR9 recognizes unmethylated CpG DNA and induces innate immune responses. TLR9 activation is a multistep process requiring proteolytic cleavage and trafficking to endolysosomal compartments for ligand-induced signaling. However, the rules that govern the dynamic subcellular trafficking for TLR9 after pathogen uptake have not been established. In this study, we demonstrate that uptake of Aspergillus fumigatus conidia induced drastic spatial redistribution of TLR9 to the phagosomal membrane of A. fumigatus-containing phagosomes but not to bead-containing phagosomes in murine macrophages. Specific TLR9 recruitment to the fungal phagosome was consistent using A. fumigatus spores at different germination stages and selected mutants affecting the display of Ags on the fungal cell surface. Spatiotemporal regulation of TLR9 compartmentalization to the A. fumigatus phagosome was independent of TLR2, TLR4, and downstream TLR signaling. Our data demonstrate that the TLR9 N-terminal proteolytic cleavage domain was critical for successful intracellular trafficking and accumulation of TLR9 in CpG-containing compartments and A. fumigatus phagosomal membranes. Our study provides evidence for a model in which A. fumigatus spore phagocytosis by macrophages specifically induces TLR9 recruitment to A. fumigatus phagosomes and may thereby mediate TLR9-induced antifungal innate immune responses. The Journal of Immunology, 2010, 185: 7614-7622. C1 [Kasperkovitz, Pia V.; Cardenas, Michael L.; Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Kasperkovitz, Pia V.; Vyas, Jatin M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Vyas, JM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. EM jvyas@partners.org RI Vyas, Jatin/Q-1627-2016 OI Vyas, Jatin/0000-0002-9985-9565 FU National Institutes of Health [K08 AI-057999]; Massachusetts General Hospital Department of Medicine FX This work was supported in part by National Institutes of Health Grant K08 AI-057999 (to J.M.V.). J.M.V., P. V. K., and M. L. C. were supported by Massachusetts General Hospital Department of Medicine start-up funds. NR 50 TC 39 Z9 40 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 DEC 15 PY 2010 VL 185 IS 12 BP 7614 EP 7622 DI 10.4049/jimmunol.1002760 PG 9 WC Immunology SC Immunology GA 688UF UT WOS:000284878700060 PM 21059889 ER PT J AU Herschhorn, A Marasco, WA Hizi, A AF Herschhorn, Alon Marasco, Wayne A. Hizi, Amnon TI Antibodies and Lentiviruses That Specifically Recognize a T Cell Epitope Derived from HIV-1 Nef Protein and Presented by HLA-C SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLASS-I; REVERSE-TRANSCRIPTASE; CTL RESPONSE; EXPRESSION; TYPE-1; INFECTION; PEPTIDE; ANTIGEN; SURFACE AB HIV selectively downregulates HLA-A and -B from the surfaces of infected cells to avoid detection by the immune system. In contrast, the HLA-C molecules are highly resistant to this downregulation. High expression level of HLA-C on the cell surface, which correlates with a single nucleotide polymorphism, is also associated with lower viral loads and slower progression to AIDS. These findings strongly suggest that HIV-1-derived peptides are efficiently presented by HLA-C and trigger the elimination of infected cells. Accordingly, the ability to detect these HLA-C-peptide complexes may be used for therapeutic targeting of HIV-1-infected cells and for measuring effective presentation of vaccine candidates after immunization with HIV-1-related proteins or genes. However, low level of HLA-C expression on the cell surface has impeded the development of such complex-recognizing reagents. In this study, we describe the development of a high-affinity human Ab that specifically interacts, at low pM concentrations, with a conserved viral T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. The human Ab selectively detects this complex on different cells and does not interact with a control complex that differed only in the presented peptide. Engineering lentiviruses to display this Ab endowed them with the same specificity as the Ab, whereas coexpressing the Ab and Fas ligand enables the lentiviruses to kill specifically Nef-presenting cells. Abs and pseudoviruses with such specificity are likely to be highly valuable as building blocks for specific targeting and killing of HIV-1-infected cells. The Journal of Immunology, 2010, 185: 7623-7632. C1 [Herschhorn, Alon; Hizi, Amnon] Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. [Marasco, Wayne A.] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hizi, A (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel. EM ahizy@post.tau.ac.il FU Tel Aviv University FX This work was performed in partial fulfillment of the requirements for a Ph.D. degree of A. Herschhorn. A. Herschhorn was supported by the Tel Aviv University President and Rector Scholarship for excellence. A. Hizi is the Incumbent of the Gregorio and Dora Shapira Chair for the Research of Malignancies. NR 43 TC 5 Z9 5 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2010 VL 185 IS 12 BP 7623 EP 7632 DI 10.4049/jimmunol.1001561 PG 10 WC Immunology SC Immunology GA 688UF UT WOS:000284878700061 PM 21076072 ER PT J AU Giordano, TP Tropea, TF Satpute, SS Sinnegger-Brauns, MJ Striessnig, J Kosofsky, BE Rajadhyaksha, AM AF Giordano, Thomas P. Tropea, Thomas F. Satpute, Shirish S. Sinnegger-Brauns, Martina J. Striessnig, Joerg Kosofsky, Barry E. Rajadhyaksha, Anjali M. TI Molecular Switch from L-Type Ca(v)1.3 to Ca(v)1.2 Ca2+ Channel Signaling Underlies Long-Term Psychostimulant-Induced Behavioral and Molecular Plasticity SO JOURNAL OF NEUROSCIENCE LA English DT Article ID VENTRAL TEGMENTAL AREA; CALCIUM-CHANNELS; CREB PHOSPHORYLATION; NUCLEUS-ACCUMBENS; GENE-EXPRESSION; COCAINE REWARD; SENSITIZATION; PROTEIN; ADDICTION; DOPAMINE AB L-type Ca2+ channel (LTCC)-activated signaling cascades contribute significantly to psychostimulant-induced locomotor sensitization; however, the precise contribution of the two brain-specific subunits Ca(v)1.2 and Ca(v)1.3 remains mostly unknown. In this study, by using amphetamine and cocaine locomotor sensitization in mutant mice expressing dihydropyridine (DHP)-insensitive Ca(v)1.2 LTCCs (Ca(v)1.2DHP(-/-)), we find that, as opposed to a previously identified role of the Ca(v)1.3 subunit of LTCCs in development of sensitization, the Ca(v)1.2 subunit mediates expression of amphetamine and cocaine sensitization when examined after a 14 d drug-free period. Molecular studies to further elucidate the role of Ca(v)1.2 versus Ca(v)1.3 LTCCs in activating signaling pathways in the nucleus accumbens (NAc) of drug-naive versus drug-preexposed mice examined 14 d later revealed that an acute amphetamine and cocaine challenge in drug-naive mice increases Ser133 cAMP response element-binding protein (CREB) phosphorylation in the NAc via Ca(v)1.3 channels and via a dopamine D-1-dependent mechanism, independent of the extracellular signal-regulated kinase (ERK) pathway, an important mediator of psychostimulant-induced plasticity. In contrast, in amphetamine-and cocaine-preexposed mice, an amphetamine or cocaine challenge no longer activates CREB unless Ca(v)1.2 LTCCs are blocked. This Ca(v)1.2-dependent blunting of CREB activation that underlies expression of locomotor sensitization occurs only after extended drug-free periods and involves recruitment of D-1 receptors and the ERK pathway. Thus, our results demonstrate that specific LTCC subunits are required for the development (Ca(v)1.3) versus expression (Ca(v)1.2) of psychostimulant sensitization and that subunit-specific signaling pathways recruited by psychostimulants underlies long-term drug-induced behavioral responses. C1 [Giordano, Thomas P.; Tropea, Thomas F.; Kosofsky, Barry E.; Rajadhyaksha, Anjali M.] New York Presbyterian Hosp, Div Pediat Neurol, Dept Pediat, New York, NY 10065 USA. [Kosofsky, Barry E.; Rajadhyaksha, Anjali M.] Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. [Giordano, Thomas P.; Satpute, Shirish S.; Kosofsky, Barry E.; Rajadhyaksha, Anjali M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Mol & Dev Neurosci, Charlestown, MA 02129 USA. [Giordano, Thomas P.; Satpute, Shirish S.; Kosofsky, Barry E.; Rajadhyaksha, Anjali M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging,Dept Radiol, Charlestown, MA 02129 USA. [Sinnegger-Brauns, Martina J.; Striessnig, Joerg] Univ Innsbruck, Inst Pharm, Dept Pharmacol & Toxicol, A-6020 Innsbruck, Austria. [Sinnegger-Brauns, Martina J.; Striessnig, Joerg] Univ Innsbruck, Ctr Mol Biosci Innsbruck, A-6020 Innsbruck, Austria. RP Rajadhyaksha, AM (reprint author), Weill Cornell Med Coll, 1300 York Ave,Box 91, New York, NY 10065 USA. EM amr2011@med.cornell.edu OI Brauns, Martina/0000-0002-0547-2731; Striessnig, Joerg/0000-0002-9406-7120 FU National Institute on Drug Abuse [K01 DA14057, R21 DA023686]; Austrian Science Fund [P20670] FX This work was supported by National Institute on Drug Abuse Grants K01 DA14057 (A.M.R.) and R21 DA023686 (A.M.R.), and the Austrian Science Fund P20670 (J.S.). We thank Herbert E. Covington III for help with statistical analyses and helpful suggestions in manuscript preparation, Kathryn Schierberl for her help with manuscript preparation, and Susan M. Ferguson for technical help with SL327 pharmacological experiments. NR 46 TC 23 Z9 25 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 15 PY 2010 VL 30 IS 50 BP 17051 EP 17062 DI 10.1523/JNEUROSCI.2255-10.2010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 695AF UT WOS:000285342300030 PM 21159975 ER PT J AU Weiss, J Sos, ML Seidel, D Peifer, M Zander, T Heuckmann, JM Ullrich, RT Menon, R Maier, S Soltermann, A Moch, H Wagener, P Fischer, F Heynck, S Koker, M Schottle, J Leenders, F Gabler, F Dabow, I Querings, S Heukamp, LC Balke-Want, H Ansen, S Rauh, D Baessmann, I Altmuller, J Wainer, Z Conron, M Wright, G Russell, P Solomon, B Brambilla, E Brambilla, C Lorimier, P Sollberg, S Brustugun, OT Engel-Riedel, W Ludwig, C Petersen, I Sanger, J Clement, J Groen, H Timens, W Sietsma, H Thunnissen, E Smit, E Heideman, D Cappuzzo, F Ligorio, C Damiani, S Hallek, M Beroukhim, R Pao, W Klebl, B Baumann, M Buettner, R Ernestus, K Stoelben, E Wolf, J Nurnberg, P Perner, S Thomas, RK AF Weiss, Jonathan Sos, Martin L. Seidel, Danila Peifer, Martin Zander, Thomas Heuckmann, Johannes M. Ullrich, Roland T. Menon, Roopika Maier, Sebastian Soltermann, Alex Moch, Holger Wagener, Patrick Fischer, Florian Heynck, Stefanie Koker, Mirjam Schoettle, Jakob Leenders, Frauke Gabler, Franziska Dabow, Ines Querings, Silvia Heukamp, Lukas C. Balke-Want, Hyatt Ansen, Sascha Rauh, Daniel Baessmann, Ingelore Altmueller, Janine Wainer, Zoe Conron, Matthew Wright, Gavin Russell, Prudence Solomon, Ben Brambilla, Elisabeth Brambilla, Christian Lorimier, Philippe Sollberg, Steinar Brustugun, Odd Terje Engel-Riedel, Walburga Ludwig, Corinna Petersen, Iver Saenger, Joerg Clement, Joachim Groen, Harry Timens, Wim Sietsma, Hannie Thunnissen, Erik Smit, Egbert Heideman, Danielle Cappuzzo, Federico Ligorio, Claudia Damiani, Stefania Hallek, Michael Beroukhim, Rameen Pao, William Klebl, Bert Baumann, Matthias Buettner, Reinhard Ernestus, Karen Stoelben, Erich Wolf, Juergen Nuernberg, Peter Perner, Sven Thomas, Roman K. TI Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID KINASE INHIBITORS; BREAST-CANCER; MUTATIONS; GEFITINIB; SENSITIVITY; CARCINOMAS; TUMOR; GENE; ADENOCARCINOMA; IDENTIFICATION AB Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients. C1 [Weiss, Jonathan; Sos, Martin L.; Seidel, Danila; Peifer, Martin; Heuckmann, Johannes M.; Ullrich, Roland T.; Fischer, Florian; Heynck, Stefanie; Koker, Mirjam; Schoettle, Jakob; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Querings, Silvia; Balke-Want, Hyatt; Thomas, Roman K.] Univ Cologne, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, Max Planck Soc, D-50931 Cologne, Germany. [Weiss, Jonathan; Sos, Martin L.; Seidel, Danila; Peifer, Martin; Heuckmann, Johannes M.; Ullrich, Roland T.; Fischer, Florian; Heynck, Stefanie; Koker, Mirjam; Schoettle, Jakob; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Querings, Silvia; Balke-Want, Hyatt; Thomas, Roman K.] Univ Cologne, Fac Med, D-50931 Cologne, Germany. [Seidel, Danila; Leenders, Frauke; Gabler, Franziska; Dabow, Ines; Wolf, Juergen; Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol Koln Bonn, Lab Translat Canc Genom, D-50924 Cologne, Germany. [Zander, Thomas; Ansen, Sascha; Hallek, Michael; Wolf, Juergen; Thomas, Roman K.] Univ Cologne, Dept Internal Med, D-50924 Cologne, Germany. [Menon, Roopika; Maier, Sebastian; Perner, Sven] Univ Tubingen Hosp, Ctr Comprehens Canc, Inst Pathol, D-72076 Tubingen, Germany. [Soltermann, Alex; Moch, Holger] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland. [Wagener, Patrick] Cornell Univ, Weill Med Coll, Dept Surg, New York, NY 10065 USA. [Heukamp, Lukas C.; Buettner, Reinhard] Univ Bonn, Inst Pathol, D-53123 Bonn, Germany. [Rauh, Daniel; Nuernberg, Peter; Thomas, Roman K.] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany. [Baessmann, Ingelore; Altmueller, Janine] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany. [Baessmann, Ingelore; Altmueller, Janine] Univ Cologne, Inst Genet, D-50931 Cologne, Germany. [Wainer, Zoe; Conron, Matthew; Wright, Gavin] Peter MacCallum Canc Inst, Dept Surg Oncol, Melbourne, Vic 3002, Australia. [Russell, Prudence] St Vincents Hosp, Dept Pathol, Fitzroy, Vic 3065, Australia. [Solomon, Ben] Peter MacCallum Canc Ctr, Dept Haematol & Oncol, Melbourne, Vic 3002, Australia. [Brambilla, Elisabeth; Brambilla, Christian; Lorimier, Philippe] Univ Grenoble 1, Dept Pathol, F-38041 Grenoble, France. [Brambilla, Elisabeth; Brambilla, Christian] Univ Grenoble 1, Inst Albert Bonniot, INSERM, U823, F-38042 Grenoble, France. [Sollberg, Steinar] Oslo Univ Hosp, Dept Thorac Surg, Rikshosp, N-0027 Oslo, Norway. [Brustugun, Odd Terje] Norwegian Radium Hosp, Dept Radiat Biol, N-0310 Oslo, Norway. [Brustugun, Odd Terje] Oslo Univ Hosp, Dept Oncol, Radiumhosp, N-0310 Oslo, Norway. [Engel-Riedel, Walburga; Ludwig, Corinna; Stoelben, Erich] Kliniken Stadt Koln gGmbH, Lungenklin Merheim, D-51109 Cologne, Germany. [Petersen, Iver] Univ Jena, Jena Univ Hosp, Inst Pathol, D-07743 Jena, Germany. [Saenger, Joerg] Inst Pathol Bad Berka, D-99438 Bad Berka, Germany. [Clement, Joachim] Univ Jena, Univ Clin Jena, Dept Internal Med 2, D-07740 Jena, Germany. [Groen, Harry] Univ Groningen, Univ Med Ctr Groningen, Dept Pulm Dis, NL-9713 GZ Groningen, Netherlands. [Timens, Wim; Sietsma, Hannie] Univ Med Ctr Groningen, Dept Pathol, NL-9713 GZ Groningen, Netherlands. [Thunnissen, Erik; Heideman, Danielle] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands. [Smit, Egbert] Vrije Univ Amsterdam, Med Ctr, Dept Pulm Dis, NL-1007 MB Amsterdam, Netherlands. [Cappuzzo, Federico] Osped Civile, Dept Med Oncol, I-57100 Livorno, Italy. [Ligorio, Claudia; Damiani, Stefania] Univ Hosp Bologna, Dept Haematol & Oncol Sci, I-40138 Bologna, Italy. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Broad Inst, Canc Program, Cambridge, MA 02115 USA. [Pao, William] Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA. [Klebl, Bert; Baumann, Matthias] Lead Discovery Ctr GmbH, D-44227 Dortmund, Germany. [Ernestus, Karen] Kliniken Stadt Koln gGmbH, Hosp Merheim, Dept Pathol, D-51109 Cologne, Germany. RP Sos, ML (reprint author), Univ Cologne, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, Max Planck Soc, D-50931 Cologne, Germany. EM martin.sos@nf.mpg.de; nini@nf.mpg.de RI Rauh, Daniel/G-1595-2013; Timens, Wim/K-5570-2013; Heukamp, Lukas/A-8338-2013; Brambilla, Elisabeth/L-8796-2013; BRAMBILLA, CHRISTIAN/K-2285-2013; OI Timens, Wim/0000-0002-4146-6363; Thunnissen, Erik/0000-0001-5355-8508; DAMIANI, STEFANIA/0000-0002-2757-5985; Cappuzzo, Federico/0000-0002-6295-6767; Wright, Gavin/0000-0002-7000-9305; Rauh, Daniel/0000-0002-1970-7642 FU Deutsche Krebshilfe [107954]; German Ministry of Science and Education (BMBF) [01GS08100, 01GS08101]; Max Planck Society [M.I.F.A.NEUR8061]; Deutsche Forschungsgemeinschaft (DFG) through SFB [TP6, TP5]; Ministry for Innovation, Science, Research and Technology of the State of Nordrhein-Westfalen (MIWT) [4000-12 09]; International Association for the Study of Lung Cancer; NIH National Cancer Institute; Royal Australasian College of Surgeons; Australasian Society of Cardiac and Thoracic Surgeons Foundation; Peter MacCallum Foundation; Sequenom; Sanofi-Aventis; Merck; Roche; Infinity; Boehringer; AstraZeneca; ATLAS Biolabs; Novartis; Novartis Institutes for BioMedical Research; Molecular MD; BMS; Symphony Evolution; Eli Lilly; Boehringer Ingelheim through the University Medical Center Groningen; [2008] FX This work was supported by the Deutsche Krebshilfe (grant 107954 to R. K. T.); the German Ministry of Science and Education (BMBF) as part of the NGFNplus program (grants 01GS08100 to R. K. T. and 01GS08101 to J. Wolf and P.N.); the Max Planck Society (M.I.F.A.NEUR8061 to R. K. T.); the Deutsche Forschungsgemeinschaft (DFG) through SFB (TP6 to R. K. T. and R. T. U.; TP5 to L. C. H. and R. Buettner); the Ministry for Innovation, Science, Research and Technology of the State of Nordrhein-Westfalen (MIWT, 4000-12 09 to R. K. T. and B. K.); and an anonymous foundation to R. K. T. E. B. and C. B. were supported by the PNES INCA grant 2008. B. S. was supported by the International Association for the Study of Lung Cancer Young Investigator Award. W. P. was supported by a grant from the NIH National Cancer Institute. Z.W. was supported by the Royal Australasian College of Surgeons and a Raelene Boyle Scholarship. G. W. was supported by the Australasian Society of Cardiac and Thoracic Surgeons Foundation Grant, Peter MacCallum Foundation Grant, and a private research donation from family and friends of former patients.; R.K.T. receives consulting and lecture fees from Sequenom, Sanofi-Aventis, Merck, Roche, Infinity, Boehringer, AstraZeneca, and ATLAS Biolabs, as well as research support from Novartis and AstraZeneca. J. Wolf is a member of advisory boards of Roche, AstraZeneca, Novartis, Amgen, Bayer, and Merck and has received lecture fees from Roche, AstraZeneca, and Merck. R. Beroukhim receives consulting fees for Novartis Institutes for BioMedical Research. W. P. receives consulting fees from Molecular MD, AstraZeneca, BMS, and Symphony Evolution. H. G. received research support from Eli Lilly, Roche, and Boehringer Ingelheim through the University Medical Center Groningen. The other authors declare that they have no competing interests. Accession numbers: All raw data are publicly available (GEO; GSE25016). NR 33 TC 324 Z9 340 U1 5 U2 34 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 15 PY 2010 VL 2 IS 62 AR 62ra93 DI 10.1126/scitranslmed.3001451 PG 7 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 735UG UT WOS:000288444300004 PM 21160078 ER PT J AU Veiga, P Gallini, CA Beal, C Michaud, M Delaney, ML DuBois, A Khlebnikov, A Vlieg, JETV Punit, S Glickman, JN Onderdonk, A Glimcher, LH Garrett, WS AF Veiga, Patrick Gallini, Carey Ann Beal, Chloe Michaud, Monia Delaney, Mary L. DuBois, Andrea Khlebnikov, Artem Vlieg, Johan E. T. van Hylckama Punit, Shivesh Glickman, Jonathan N. Onderdonk, Andrew Glimcher, Laurie H. Garrett, Wendy S. TI Bifidobacterium animalis subsp. lactis fermented milk product reduces inflammation by altering a niche for colitogenic microbes (vol 107, pg 18132, 2010) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Correction C1 [Veiga, Patrick; Gallini, Carey Ann; Michaud, Monia; Punit, Shivesh; Glimcher, Laurie H.; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Veiga, Patrick; Beal, Chloe; Khlebnikov, Artem; Vlieg, Johan E. T. van Hylckama] Danone Res, F-91767 Palaiseau, France. [Delaney, Mary L.; DuBois, Andrea; Glickman, Jonathan N.; Onderdonk, Andrew; Glimcher, Laurie H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Khlebnikov, Artem] Dannon Co Inc, White Plains, NY 10603 USA. [Glickman, Jonathan N.; Onderdonk, Andrew; Glimcher, Laurie H.; Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Glimcher, Laurie H.] MIT & Harvard, Ragon Inst MGH, Charlestown, MA 02129 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Veiga, P (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. RI Veiga, Patrick/A-9862-2011; Khlebnikov, Artem/K-4780-2012; Beal, Chloe/N-1992-2014 OI Veiga, Patrick/0000-0001-6318-8547; Khlebnikov, Artem/0000-0002-1866-234X; Beal, Chloe/0000-0002-4154-4720 NR 1 TC 0 Z9 0 U1 0 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 DEC 14 PY 2010 VL 107 IS 50 BP 21943 EP 21943 DI 10.1073/pnas.1017174108 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500128 ER PT J AU Veiga, P Gallini, CA Beal, C Michaud, M Delaney, ML DuBois, A Khlebnikov, A Vlieg, JETV Punit, S Glickman, JN Onderdonk, A Glimcher, LH Garrett, WS AF Veiga, Patrick Gallini, Carey Ann Beal, Chloe Michaud, Monia Delaney, Mary L. DuBois, Andrea Khlebnikov, Artem Vlieg, Johan E. T. van Hylckama Punit, Shivesh Glickman, Jonathan N. Onderdonk, Andrew Glimcher, Laurie H. Garrett, Wendy S. TI Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation (vol 107, pg 18575, 2010) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Correction C1 [Veiga, Patrick; Gallini, Carey Ann; Michaud, Monia; Punit, Shivesh; Glimcher, Laurie H.; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Veiga, Patrick; Beal, Chloe; Khlebnikov, Artem; Vlieg, Johan E. T. van Hylckama] Danone Res, F-91767 Palaiseau, France. [Delaney, Mary L.; DuBois, Andrea; Glickman, Jonathan N.; Onderdonk, Andrew; Glimcher, Laurie H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Khlebnikov, Artem] Dannon Co Inc, White Plains, NY 10603 USA. [Glickman, Jonathan N.; Onderdonk, Andrew; Glimcher, Laurie H.; Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Glimcher, Laurie H.] MIT & Harvard, Ragon Inst MGH, Charlestown, MA 02129 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Veiga, P (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. RI Khlebnikov, Artem/K-4780-2012; Beal, Chloe/N-1992-2014; OI Khlebnikov, Artem/0000-0002-1866-234X; Beal, Chloe/0000-0002-4154-4720; Veiga, Patrick/0000-0001-6318-8547 NR 1 TC 0 Z9 0 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21943 EP 21943 DI 10.1073/pnas.1016618107 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500127 ER PT J AU Leong, NL Buijze, GA Fu, EC Stockmans, F Jupiter, JB AF Leong, Natalie L. Buijze, Geert A. Fu, Eric C. Stockmans, Filip Jupiter, Jesse B. CA Distal Radius Malunion DiRaM TI Computer-assisted versus non-computer-assisted preoperative planning of corrective osteotomy for extra-articular distal radius malunions: a randomized controlled trial SO BMC MUSCULOSKELETAL DISORDERS LA English DT Article ID COLLES FRACTURE; WRIST AB Background: Malunion is the most common complication of distal radius fracture. It has previously been demonstrated that there is a correlation between the quality of anatomical correction and overall wrist function. However, surgical correction can be difficult because of the often complex anatomy associated with this condition. Computer assisted surgical planning, combined with patient-specific surgical guides, has the potential to improve pre-operative understanding of patient anatomy as well as intra-operative accuracy. For patients with malunion of the distal radius fracture, this technology could significantly improve clinical outcomes that largely depend on the quality of restoration of normal anatomy. Therefore, the objective of this study is to compare patient outcomes after corrective osteotomy for distal radius malunion with and without preoperative computer-assisted planning and peri-operative patient-specific surgical guides. Methods/Design: This study is a multi-center randomized controlled trial of conventional planning versus computer-assisted planning for surgical correction of distal radius malunion. Adult patients with extra-articular malunion of the distal radius will be invited to enroll in our study. After providing informed consent, subjects will be randomized to two groups: one group will receive corrective surgery with conventional preoperative planning, while the other will receive corrective surgery with computer-assisted pre-operative planning and peri-operative patient specific surgical guides. In the computer-assisted planning group, a CT scan of the affected forearm as well as the normal, contralateral forearm will be obtained. The images will be used to construct a 3D anatomical model of the defect and patient-specific surgical guides will be manufactured. Outcome will be measured by DASH and PRWE scores, grip strength, radiographic measurements, and patient satisfaction at 3, 6, and 12 months postoperatively. Discussion: Computer-assisted surgical planning, combined with patient-specific surgical guides, is a powerful new technology that has the potential to improve the accuracy and consistency of orthopaedic surgery. To date, the role of this technology in upper extremity surgery has not been adequately investigated, and it is unclear whether its use provides any significant clinical benefit over traditional preoperative imaging protocols. Our study will represent the first randomized controlled trial investigating the use of computer assisted surgery in corrective osteotomy for distal radius malunions. C1 [Leong, Natalie L.; Buijze, Geert A.; Fu, Eric C.; Jupiter, Jesse B.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Stockmans, Filip] AZ Groeninge, Handgrp Groeninge, Kortrijk, Belgium. RP Buijze, GA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St,YAW-2-2C, Boston, MA 02114 USA. EM gbuijze@partners.org OI Leong, Natalie/0000-0001-6556-9781 FU AO Foundation [F-08-18J] FX We acknowledge the AO Foundation, for their sponsorship of this study. Project no. F-08-18J was supported by the AO Research Fund of the AO Foundation. We also thank Materialise for generously providing the surgical guides at no cost to our participating surgeons or study subjects. NR 23 TC 11 Z9 11 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2474 J9 BMC MUSCULOSKEL DIS JI BMC Musculoskelet. Disord. PD DEC 14 PY 2010 VL 11 AR 282 DI 10.1186/1471-2474-11-282 PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 703HA UT WOS:000285967800001 PM 21156074 ER PT J AU Figueroa, ME Abdel-Wahab, O Lu, C Ward, PS Patel, J Shih, A Li, YS Bhagwat, N Vasanthakumar, A Fernandez, HF Tallman, MS Sun, ZX Wolniak, K Peeters, JK Liu, W Choe, SE Fantin, VR Paietta, E Lowenberg, B Licht, JD Godley, LA Delwel, R Valk, PJM Thompson, CB Levine, RL Melnick, A AF Figueroa, Maria E. Abdel-Wahab, Omar Lu, Chao Ward, Patrick S. Patel, Jay Shih, Alan Li, Yushan Bhagwat, Neha Vasanthakumar, Aparna Fernandez, Hugo F. Tallman, Martin S. Sun, Zhuoxin Wolniak, Kristy Peeters, Justine K. Liu, Wei Choe, Sung E. Fantin, Valeria R. Paietta, Elisabeth Lowenberg, Bob Licht, Jonathan D. Godley, Lucy A. Delwel, Ruud Valk, Peter J. M. Thompson, Craig B. Levine, Ross L. Melnick, An TI Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACQUIRED MUTATIONS; DNA; GENOME; DEMETHYLATION; METHYLATION; CONVERSION; PROTEINS; GLIOMAS; HELP AB Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the alpha-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect. C1 [Lu, Chao; Ward, Patrick S.; Thompson, Craig B.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Figueroa, Maria E.; Li, Yushan; Melnick, An] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY 10065 USA. [Abdel-Wahab, Omar; Patel, Jay; Shih, Alan; Bhagwat, Neha; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Abdel-Wahab, Omar; Shih, Alan; Tallman, Martin S.; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA. [Vasanthakumar, Aparna; Godley, Lucy A.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Fernandez, Hugo F.] H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Bone Marrow Transplantat, Tampa, FL 33612 USA. [Sun, Zhuoxin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02445 USA. [Wolniak, Kristy; Licht, Jonathan D.] Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. [Peeters, Justine K.; Lowenberg, Bob; Delwel, Ruud; Valk, Peter J. M.] Erasmus Univ, Med Ctr, Dept Hematol, NL-3000 CA Rotterdam, Netherlands. [Liu, Wei; Choe, Sung E.; Fantin, Valeria R.] Agios Pharmaceut, Cambridge, MA 02139 USA. [Paietta, Elisabeth] Montefiore Med Ctr, Ctr Canc, North Div, Bronx, NY 10466 USA. RP Thompson, CB (reprint author), Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. EM craig@mail.med.upenn.edu; leviner@mskcc.org; amm2014@med.cornell.edu RI Lu, Chao/E-8047-2012; Ward, Patrick/H-2361-2014; OI Ward, Patrick/0000-0001-6437-8174; Abdel-Wahab, Omar/0000-0002-3907-6171 FU Leukemia and Lymphoma Society; Sackler Center for Biomedical and Physical Sciences; NIH [R01 HL082950]; NCI [U54CA143798-01, CA21115, CA 114737]; University of Pennsylvania; Starr Cancer Consortium; Howard Hughes Medical Institute; Agios FX M.E.F. is funded by a Leukemia and Lymphoma Society Special Fellow award. A.M. is funded by a Leukemia and Lymphoma Society SCOR and TRP award, and is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. A.M. and M.E.F. are also supported by the Sackler Center for Biomedical and Physical Sciences. J.D.L. is funded by NIH grant R01 HL082950. C.B.T., C.L., and P.S.W. are supported in part by grants from the NCI and NIH. P.S.W. is also supported in part by the University of Pennsylvania Medical Scientist Training Program. This work was supported in part by U54CA143798-01 from the National Cancer Institute (to R.L.L.) and by a grant from the Starr Cancer Consortium (to R.L.L. and A.M.). R.L.L. is an Early Career Award Recipient of the Howard Hughes Medical Institute and is a Geoffrey Beene Junior Faculty Chair at Memorial Sloan-Kettering Cancer Center. E.P. is supported by NCI CA21115 and CA 114737. We would like to thank Adriana Heguy and Igor Dolgalev for assistance with DNA resequencing, and also thank Hans-Guido Wendel and Dino Mavrakis for assistance with TET2 shRNA construction. We thank Justin Cross and Dan Zlotoff for technical help and Sachie Marubayashi for assistance with murine bone marrow studies. W.L., S.E.C., V.R.F., and C.B.T. are employees or consultants of Agios Pharmaceuticals and have financial interest in Agios. NR 29 TC 933 Z9 961 U1 14 U2 89 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 14 PY 2010 VL 18 IS 6 BP 553 EP 567 DI 10.1016/j.ccr.2010.11.015 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 697PL UT WOS:000285527300007 PM 21130701 ER PT J AU Mandelbaum, J Bhagat, G Tang, HY Mo, TW Brahmachary, M Shen, QO Chadburn, A Rajewsky, K Tarakhovsky, A Pasqualucci, L Dalla-Favera, R AF Mandelbaum, Jonathan Bhagat, Govind Tang, Hongyan Mo, Tongwei Brahmachary, Manisha Shen, Qiong Chadburn, Amy Rajewsky, Klaus Tarakhovsky, Alexander Pasqualucci, Laura Dalla-Favera, Riccardo TI BLIMP1 Is a Tumor Suppressor Gene Frequently Disrupted in Activated B Cell-like Diffuse Large B Cell Lymphoma SO CANCER CELL LA English DT Article ID DEREGULATED BCL6 EXPRESSION; PLASMA-CELLS; HODGKIN LYMPHOMA; DOWN-REGULATION; KAPPA-B; C-MYC; DIFFERENTIATION; TRANSCRIPTION; MUTATIONS; REPRESSION AB Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease composed of at least two distinct subtypes: germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. These phenotypic subtypes segregate with largely unique genetic lesions, suggesting the involvement of different pathogenetic mechanisms. In this report we show that the BLIMP1/PRDM1 gene is inactivated by multiple mechanisms, including homozygous deletions, truncating or missense mutations, and transcriptional repression by constitutively active BCL6, in similar to 53% of ABC-DLBCL. In vivo, conditional deletion of Blimp1 in mouse B cells promotes the development of lymphoproliferative disorders recapitulating critical features of the human ABC-DLBCL. These results demonstrate that BLIMP1 is a bona fide tumor-suppressor gene whose loss contributes to lymphomagenesis by blocking plasma cell differentiation. C1 [Mandelbaum, Jonathan; Bhagat, Govind; Tang, Hongyan; Mo, Tongwei; Brahmachary, Manisha; Shen, Qiong; Pasqualucci, Laura; Dalla-Favera, Riccardo] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA. [Mandelbaum, Jonathan; Bhagat, Govind; Tang, Hongyan; Mo, Tongwei; Brahmachary, Manisha; Shen, Qiong; Chadburn, Amy; Pasqualucci, Laura; Dalla-Favera, Riccardo] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. [Mandelbaum, Jonathan] Columbia Univ, Integrated Program Cellular Mol & Biomed Studies, New York, NY 10032 USA. [Bhagat, Govind; Pasqualucci, Laura; Dalla-Favera, Riccardo] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Dalla-Favera, Riccardo] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. [Chadburn, Amy] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Rajewsky, Klaus] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Tarakhovsky, Alexander] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10065 USA. RP Pasqualucci, L (reprint author), Columbia Univ, Inst Canc Genet, New York, NY 10032 USA. EM lp171@columbia.edu; rd10@columbia.edu OI Bhagat, Govind/0000-0001-6250-048X FU N.I.H. [CA-092625, CA-37295]; Leukemia & Lymphoma Society; Stewart Trust FX We thank U. Klein, D. Dominguez-Sola, and M. Saito for helpful discussions; A. Grunn for help with the sequencing analysis; J. Piskurich for providing the CIITA luciferase reporter; and G. Bornkamm for the bicistronic expression cassette. We also thank the Flow Cytometry, Transgenic Mouse and Genomics Shared Resources of the Herbert Irving Comprehensive Cancer Center. This work was supported by N.I.H. Grants CA-092625 and CA-37295, by a Specialized Center of Research grant from the Leukemia & Lymphoma Society, and by the Stewart Trust Fund. L.P. is on leave from the University of Perugia. The authors declare no conflicts of interest. NR 52 TC 102 Z9 106 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 14 PY 2010 VL 18 IS 6 BP 568 EP 579 DI 10.1016/j.ccr.2010.10.030 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 697PL UT WOS:000285527300008 PM 21156281 ER PT J AU Calado, DP Zhang, BC Srinivasan, L Sasaki, Y Seagal, J Unitt, C Rodig, S Kutok, J Tarakhovsky, A Schmidt-Supprian, M Rajewsky, K AF Calado, Dinis Pedro Zhang, Baochun Srinivasan, Lakshmi Sasaki, Yoshiteru Seagal, Jane Unitt, Christine Rodig, Scott Kutok, Jeffery Tarakhovsky, Alexander Schmidt-Supprian, Marc Rajewsky, Klaus TI Constitutive Canonical NF-kappa B Activation Cooperates with Disruption of BLIMP1 in the Pathogenesis of Activated B Cell-like Diffuse Large Cell Lymphoma SO CANCER CELL LA English DT Article ID GENE-EXPRESSION; MOLECULAR SUBTYPES; MULTIPLE-MYELOMA; IN-VIVO; LYMPHOCYTES; MUTATIONS; TRANSCRIPTION; INACTIVATION; SUBGROUPS; PATHWAYS AB Diffuse large B cell lymphoma (DLBCL) comprises disease entities with distinct genetic profiles, including germinal center B cell (GCB)-like and activated B cell (ABC)-like DLBCLs. Major differences between these two subtypes include genetic aberrations leading to constitutive NF-kappa B activation and interference with terminal B cell differentiation through BLIMP1 inactivation, observed in ABC- but not GCB-DLBCL. Using conditional gain-of-function and/or loss-of-function mutagenesis in the mouse, we show that constitutive activation of the canonical NF-kappa B pathway cooperates with disruption of BLIMP1 in the development of a lymphoma that resembles human ABC-DLBCL. Our work suggests that both NE-kappa B signaling, as an oncogenic event, and BLIMP1, as a tumor suppressor, play causal roles in the pathogenesis of ABC-DLBCL. C1 [Calado, Dinis Pedro; Zhang, Baochun; Srinivasan, Lakshmi; Sasaki, Yoshiteru; Seagal, Jane; Schmidt-Supprian, Marc; Rajewsky, Klaus] Harvard Univ, Childrens Hosp, Sch Med, Program Cellular & Mol Med, Boston, MA 02115 USA. [Calado, Dinis Pedro; Zhang, Baochun; Srinivasan, Lakshmi; Sasaki, Yoshiteru; Seagal, Jane; Schmidt-Supprian, Marc; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Unitt, Christine; Rodig, Scott; Kutok, Jeffery] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Tarakhovsky, Alexander] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10065 USA. [Sasaki, Yoshiteru] Riken Ctr Dev Biol, Kobe, Hyogo 6500047, Japan. [Schmidt-Supprian, Marc] Max Planck Inst Biochem, D-82152 Martinsried, Germany. RP Rajewsky, K (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Program Cellular & Mol Med, Boston, MA 02115 USA. EM rajewsky@idi.harvard.edu RI Schmidt-Supprian, Marc/F-5893-2011 OI Schmidt-Supprian, Marc/0000-0002-8543-6166 FU National Cancer Institute [P01CA092625]; Leukemia & Lymphoma Society FX We thank D. Ghitza, A. Pellerin, J. Grundy, and J. Xia for technical assistance, M. Ottaviano for administrative assistance, K.R. laboratory members, M. Janz and S.A. Godinho for critical comments and suggestions, S. Koralov for help with sequence analysis, and S. Peng for HPRT qRT-PCR primers. K.R. is supported by the National Cancer Institute through P01CA092625 and an LLS SCOR grant, and D.P.C. and B.Z. by postdoctoral fellowships of the Leukemia & Lymphoma Society. The authors declare no conflict of interest. NR 37 TC 74 Z9 75 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 14 PY 2010 VL 18 IS 6 BP 580 EP 589 DI 10.1016/j.ccr.2010.11.024 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 697PL UT WOS:000285527300009 PM 21156282 ER PT J AU Fearon, WF Bornschein, B Tonino, PAL Gothe, RM De Bruyne, B Pijls, NHJ Siebert, U AF Fearon, William F. Bornschein, Bernhard Tonino, Pim A. L. Gothe, Raffaella M. De Bruyne, Bernard Pijls, Nico H. J. Siebert, Uwe CA Fractional Flow Reserve Versus Ang TI Economic Evaluation of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients With Multivessel Disease SO CIRCULATION LA English DT Article DE angiography; coronary disease; cost-benefit analysis; fractional flow reserve, myocardial; physiology; stents ID COST-EFFECTIVENESS; ANGIOGRAPHY; MEDICARE; STENOSIS; TRIAL; FAME AB Background-The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study demonstrated significantly improved health outcomes at 1 year in patients randomized to multivessel percutaneous coronary intervention guided by fractional flow reserve (FFR) compared with percutaneous coronary intervention guided by angiography alone. The economic impact of routine measurement of FFR in this setting is not known. Methods and Results-In this study, 1005 patients were randomly assigned to FFR-guided or angiography-guided percutaneous coronary intervention and followed up for 1 year. A prospective cost-utility analysis comparing costs and quality-adjusted life-years was performed with a time horizon of 1 year. Quality-adjusted life-years were calculated with the use of utilities determined by the EuroQuol 5 dimension health survey with US weights. Direct medical costs included those of the index procedure and hospitalization and costs for major adverse cardiac events during follow-up. Confidence intervals for both quality-adjusted life-years and costs were estimated by the bootstrap percentile method. Major adverse cardiac events at 1 year occurred in 13.2% of those in the FFR-guided arm and 18.3% of those in the angiography-guided arm (P=0.02). Quality-adjusted life-years were slightly greater in the FFR-guided arm (0.853 versus 0.838; P=0.2). Mean overall costs at 1 year were significantly less in the FFR-guided arm ($14 315 versus $16 700; P<0.001). Bootstrap simulation indicated that the FFR-guided strategy was cost-saving in 90.74% and cost-effective at a threshold of US $50 000 per quality-adjusted life-years in 99.96%. Sensitivity analyses demonstrated robust results. Conclusion-Economic evaluation of the FAME study reveals that FFR-guided percutaneous coronary intervention in patients with multivessel coronary disease is one of those rare situations in which a new technology not only improves outcomes but also saves resources. C1 [Fearon, William F.] Stanford Univ, Med Ctr, Div Cardiovasc Med, Stanford, CA 94305 USA. [Bornschein, Bernhard; Gothe, Raffaella M.; Siebert, Uwe] Univ Hlth Sci Med Informat & Technol, Hall In Tirol, Austria. [Tonino, Pim A. L.; Pijls, Nico H. J.] Catharina Hosp, Eindhoven, Netherlands. [De Bruyne, Bernard] Cardiovasc Ctr Aalst, Aalst, Belgium. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Fearon, WF (reprint author), Stanford Univ, Med Ctr, Div Cardiovasc Med, 300 Pasteur Dr,H2103, Stanford, CA 94305 USA. EM wfearon@stanford.edu FU St. Jude Medical; Meijer Lavino Foundation for Cardiac Research FX Dr Pijls reports receiving an institutional research grant for the Catharina Hospital Eindhoven from St. Jude Medical. Dr De Bruyne reports receiving research grants from the Meijer Lavino Foundation for Cardiac Research. The FAME study was sponsored by St. Jude Medical. NR 21 TC 136 Z9 142 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 14 PY 2010 VL 122 IS 24 BP 2545 EP 2550 DI 10.1161/CIRCULATIONAHA.109.925396 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 693RN UT WOS:000285243200013 PM 21126973 ER PT J AU Ghali, JK Massie, BM Mann, DL Rich, MW AF Ghali, Jalal K. Massie, Barry M. Mann, Douglas L. Rich, Michael W. TI Heart Failure Guidelines, Performance Measures, and the Practice of Medicine Mind the Gap SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE guidelines; performance measures; practice of medicine ID LEFT-VENTRICULAR DYSFUNCTION; THERAPY; CARE; SPIRONOLACTONE; DEFIBRILLATORS; IMPROVEMENT; ADHERENCE; DIAGNOSIS; OUTCOMES; REGISTRY AB Guidelines have rather quickly assumed a central role in health care delivery in the U.S. They have become the foundation on which performance measures are built and, therefore, a major player in assessing the quality of care provided by individuals and institutions, the ramifications of which involve reputation, reimbursement, and litigation. We are concerned, however, that in our enthusiasm for collectively endorsing these guidelines, we are marginalizing the importance of physician judgment and inadvertently risking the conversion of guidelines into "cookbooks." We believe that this viewpoint, while unequivocally acknowledging the fundamental importance of guidelines, simultaneously provides a critically important perspective on the potential for misuse of both guidelines and performance measures. Further, we hope that publication of this viewpoint will help temper enthusiasm for overzealous conversion of guidelines into performance measures, thereby restoring the vital role of physician judgment and insight into patient management. (J Am Coll Cardiol 2010;56:2077-80) (C) 2010 by the American College of Cardiology Foundation C1 [Ghali, Jalal K.] Wayne State Univ, DMC Cardiovasc Inst, Detroit, MI 48201 USA. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Mann, Douglas L.; Rich, Michael W.] Washington Univ, Sch Med, St Louis, MO USA. RP Ghali, JK (reprint author), Wayne State Univ, DMC Cardiovasc Inst, 3990 John R St,Suite 9370, Detroit, MI 48201 USA. EM JGhali@dmc.org OI Mann, Douglas /0000-0002-2516-0145 NR 31 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 14 PY 2010 VL 56 IS 25 BP 2077 EP 2080 DI 10.1016/j.jacc.2010.07.013 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 691MI UT WOS:000285084000004 PM 21144966 ER PT J AU Rajesh, M Mukhopadhyay, P Batkai, S Patel, V Saito, K Matsumoto, S Kashiwaya, Y Horvath, B Mukhopadhyay, B Becker, L Hasko, G Liaudet, L Wink, DA Veves, A Mechoulam, R Pacher, P AF Rajesh, Mohanraj Mukhopadhyay, Partha Batkai, Sandor Patel, Vivek Saito, Keita Matsumoto, Shingo Kashiwaya, Yoshihiro Horvath, Bela Mukhopadhyay, Bani Becker, Lauren Hasko, Gyoergy Liaudet, Lucas Wink, David A. Veves, Aristidis Mechoulam, Raphael Pacher, Pal TI Cannabidiol Attenuates Cardiac Dysfunction, Oxidative Stress, Fibrosis, and Inflammatory and Cell Death Signaling Pathways in Diabetic Cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cannabinoids; diabetic complications; inflammation; oxidative stress ID NF-KAPPA-B; ENDOCANNABINOID SYSTEM; MITOCHONDRIAL; PROTECTS; DISEASE; METALLOTHIONEIN; CANNABINOIDS; CONSTITUENT; INHIBITION; ANTAGONISM AB Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-kappa B and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38 alpha) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-alpha, markers of fibrosis (transforming growth factor-beta, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-kappa B activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis. (J Am Coll Cardiol 2010;56:2115-25) (C) 2010 by the American College of Cardiology Foundation C1 [Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Kashiwaya, Yoshihiro] NIAAA, Lab Metab Control, NIH, Bethesda, MD 20892 USA. [Saito, Keita; Matsumoto, Shingo; Wink, David A.] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Liaudet, Lucas] Univ Lausanne Hosp, Dept Intens Care Med, Lausanne, Switzerland. [Veves, Aristidis] Harvard Univ, Sch Med, Microcirculat Lab, Boston, MA USA. [Veves, Aristidis] Harvard Univ, Beth Israel Deaconess Med Ctr, Joslin Beth Israel Deaconess Foot Ctr, Sch Med, Boston, MA 02215 USA. [Mechoulam, Raphael] Hebrew Univ Jerusalem, Dept Med Chem & Nat Prod, Fac Med, Jerusalem, Israel. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, 5625 Fishers Lane,MSC 9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Horvath, Bela/A-7368-2009; Batkai, Sandor/G-3889-2010; MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Liaudet, Lucas/0000-0003-2670-4930 FU NIH/NIAAA; NIDA [DA9789]; Hungarian Research Council (EU) [MB08 80238]; Novartis FX This study was supported by the Intramural Research Program of the NIH/NIAAA (to Dr. Pacher) and NIDA Grant DA9789 (to Dr. Mechoulam). Dr. Horvath is a recipient of a Hungarian Research Council Scientific Research Fund Fellowship (NKTH OTKA EU, MB08 80238). Dr. Veves receives funding from Novartis for an investigator-initiated research grant, unrelated to this study. Dr. Mechoulam is a consultant for GW Pharmaceuticals, United Kingdom, which is not involved in this publication and is unaware of it. All other authors have reported that they have no relationships to disclose. NR 33 TC 101 Z9 105 U1 4 U2 38 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 14 PY 2010 VL 56 IS 25 BP 2115 EP 2125 DI 10.1016/j.jacc.2010.07.033 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 691MI UT WOS:000285084000011 PM 21144973 ER PT J AU Giugliano, RP Braunwald, E AF Giugliano, Robert P. Braunwald, Eugene TI The Year in Non-ST-Segment Elevation Acute Coronary Syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute coronary syndrome(s); non-ST-segment; year in ID PROTON-PUMP INHIBITORS; ACUITY ACUTE CATHETERIZATION; GROWTH-DIFFERENTIATION FACTOR-15; OPTIMIZING PLATELET INHIBITION; AMERICAN HEART ASSOCIATIONS; CARDIAC COMPUTED-TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; DUAL ANTIPLATELET THERAPY; INTENSIVE STATIN THERAPY; LOW-DENSITY-LIPOPROTEIN C1 [Giugliano, Robert P.; Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Div Cardiovasc Med, Sch Med, Boston, MA 02115 USA. RP Braunwald, E (reprint author), TIMI Study Off, 350 Longwood Ave,1st Floor Offices, Boston, MA 02115 USA. EM ebraunwald@partners.org FU Daiichi-Sankyo; Merck; AstraZeneca; Bayer; Daiichi Sankyo; Eli Lilly; GlaxoSmithKline; Johnson Johnson; Sanofi-Aventis FX Dr. Giugliano receives research grant support from Daiichi-Sankyo and Merck; and honoraria for lectures/consultancies from Bristol-Myers Squibb, Daiichi-Sankyo, Merck, Ortho McNeil, Regeneron, and Sanofi-Aventis. Dr. Braunwald receives grant support from AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, and Sanofi-Aventis; and consults for or serves on the advisory board of Merck, Daiichi Sankyo, and Eli Lilly. NR 142 TC 2 Z9 2 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 DEC 14 PY 2010 VL 56 IS 25 BP 2126 EP 2138 DI 10.1016/j.jacc.2010.09.016 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 691MI UT WOS:000285084000012 PM 21144974 ER PT J AU Kegel, KB Sapp, E Alexander, J Reeves, P Bleckmann, D Sobin, L Masso, N Valencia, A Jeong, H Krainc, D Palacino, J Curtis, D Kuhn, R Betschart, C Sena-Esteves, M Aronin, N Paganetti, P DiFiglia, M AF Kegel, Kimberly B. Sapp, Ellen Alexander, Jonathan Reeves, Patrick Bleckmann, Dorothee Sobin, Linsday Masso, Nicholas Valencia, Antonio Jeong, Hyunkyung Krainc, Dimitri Palacino, James Curtis, Daniel Kuhn, Rainer Betschart, Claudia Sena-Esteves, Miguel Aronin, Neil Paganetti, Paolo DiFiglia, Marian TI Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors SO MOLECULAR NEURODEGENERATION LA English DT Article ID LENGTH MUTANT HUNTINGTIN; INTRANUCLEAR INCLUSIONS; POLYGLUTAMINE EXPANSION; PLASMA-MEMBRANE; TRANSGENIC MICE; LIPID RAFTS; MOUSE MODEL; IN-VITRO; DISEASE; PROTEOLYSIS AB Background: The mutation in Huntington's disease is a polyglutamine expansion near the N-terminus of huntingtin. Huntingtin expressed in immortalized neurons is cleaved near the N-terminus to form N-terminal polypeptides known as cleavage products A and B (cpA and cpB). CpA and cpB with polyglutamine expansion form inclusions in the nucleus and cytoplasm, respectively. The formation of cpA and cpB in primary neurons has not been established and the proteases involved in the formation of these fragments are unknown. Results: Delivery of htt cDNA into the mouse striatum using adeno-associated virus or into primary cortical neurons using lentivirus generated cpA and cpB, indicating that neurons in brain and in vitro can form these fragments. A screen of small molecule protease inhibitors introduced to clonal striatal X57 cells and HeLa cells identified compounds that reduced levels of cpA and are inhibitors of the aspartyl proteases cathepsin D and cathepsin E. The most effective compound, P1-N031, is a transition state mimetic for aspartyl proteases. By western blot analysis, cathepsin D was easily detected in clonal striatal X57 cells, mouse brain and primary neurons, whereas cathepsin E was only detectible in clonal striatal X57 cells. In primary neurons, levels of cleavage product A were not changed by the same compounds that were effective in clonal striatal cells or by mRNA silencing to partially reduce levels of cathepsin D. Instead, treating primary neurons with compounds that are known to inhibit gamma secretase activity either indirectly (Imatinib mesylate, Gleevec) or selectively (LY-411,575 or DAPT) reduced levels of cpA. LY-411,575 or DAPT also increased survival of primary neurons expressing endogenous full-length mutant huntingtin. Conclusion: We show that cpA and cpB are produced from a larger huntingtin fragment in vivo in mouse brain and in primary neuron cultures. The aspartyl protease involved in forming cpA has cathepsin-D like properties in immortalized neurons and gamma secretase-like properties in primary neurons, suggesting that cell type may be a critical factor that specifies the aspartyl protease responsible for cpA. Since gamma secretase inhibitors were also protective in primary neurons, further study of the role of gamma-secretase activity in HD neurons is justified. C1 [Kegel, Kimberly B.; Sapp, Ellen; Alexander, Jonathan; Reeves, Patrick; Sobin, Linsday; Masso, Nicholas; Valencia, Antonio; Jeong, Hyunkyung; Krainc, Dimitri; Sena-Esteves, Miguel; DiFiglia, Marian] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Bleckmann, Dorothee; Kuhn, Rainer; Betschart, Claudia; Paganetti, Paolo] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4002 Basel, Switzerland. [Palacino, James; Curtis, Daniel] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Aronin, Neil] Univ Massachusetts, Sch Med, Dept Med & Cell Biol, Worcester, MA 01655 USA. RP Kegel, KB (reprint author), Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. EM kkegel@partners.org FU Huntington's Disease Society of America; MGH-MIT-NIBR BEAT HD Collaboration funds FX We thank Rudy Tanzi for helpful discussions about gamma-secretase. This work was supported by grants from the Huntington's Disease Society of America to MD and the MGH-MIT-NIBR BEAT HD Collaboration funds to MD. Neil Aronin is a member of the UMass DERC (DK32520). NR 62 TC 8 Z9 8 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD DEC 14 PY 2010 VL 5 AR 58 DI 10.1186/1750-1326-5-58 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 704SF UT WOS:000286072000001 PM 21156064 ER PT J AU Bechtel, N Scahill, RI Rosas, HD Acharya, T van den Bogaard, SJA Jauffret, C Say, MJ Sturrock, A Johnson, H Onorato, CE Salat, DH Durr, A Leavitt, BR Roos, RAC Landwehrmeyer, GB Langbehn, DR Stout, JC Tabrizi, SJ Reilmann, R AF Bechtel, N. Scahill, R. I. Rosas, H. D. Acharya, T. van den Bogaard, S. J. A. Jauffret, C. Say, M. J. Sturrock, A. Johnson, H. Onorato, C. E. Salat, D. H. Durr, A. Leavitt, B. R. Roos, R. A. C. Landwehrmeyer, G. B. Langbehn, D. R. Stout, J. C. Tabrizi, S. J. Reilmann, R. TI Tapping linked to function and structure in premanifest and symptomatic Huntington disease SO NEUROLOGY LA English DT Article ID CEREBRAL-BLOOD-FLOW; AGE-OF-ONSET; SIMPLE MOVEMENTS; PREDICT-HD; DYSFUNCTION; PERFORMANCE; PROGRESSION; IMPAIRMENT; HANDEDNESS; PATHOLOGY AB Objective: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. Methods: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAGrepeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. Results: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. Conclusion: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study. Neurology (R) 2010;75:2150-2160 C1 [Reilmann, R.] Univ Munster, Dept Neurol, Univ Clin Munster UKM, EHDN Huntington Ctr Munster, D-48129 Munster, Germany. [Scahill, R. I.; Say, M. J.; Tabrizi, S. J.] UCL, Inst Neurol, London, England. [Rosas, H. D.; Onorato, C. E.; Salat, D. H.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Rosas, H. D.] Harvard Univ, Sch Med, Charlestown, MA USA. [Acharya, T.; Johnson, H.; Langbehn, D. R.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Langbehn, D. R.] Univ Iowa, Dept Biostat Secondary, Iowa City, IA USA. [van den Bogaard, S. J. A.; Roos, R. A. C.] Leiden Univ, Dept Neurol, Med Ctr, Leiden, Netherlands. [Jauffret, C.; Durr, A.] Grp Hosp Pitie Salpetriere, CRICM UPMC Inserm, UMR S975, F-75634 Paris, France. [Sturrock, A.; Leavitt, B. R.] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. [Landwehrmeyer, G. B.] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany. [Durr, A.] Hop La Pitie Salpetriere, APHP, Dept Genet & Cytogenet, Paris, France. [Stout, J. C.] Monash Univ, Sch Psychol & Psychiat, Clayton, Vic 3800, Australia. RP Reilmann, R (reprint author), Univ Munster, Dept Neurol, Univ Clin Munster UKM, EHDN Huntington Ctr Munster, Albert Schweitzer Str 33, D-48129 Munster, Germany. EM r.reilmann@uni-muenster.de RI Leavitt, Blair/G-1934-2012; Johnson, Hans/M-7039-2015 OI Johnson, Hans/0000-0001-9513-2660 FU CHDI/ HighQ Foundation; NIH [P01NS058793, R01NS042861, RO1 NG HG003330-01A1]; NIH (NINDS) [P01 NS058793, R01 NS042861, NS40068]; Temmler Pharma GmbH Co.; Juvenile Huntington's Disease (Oxford University); Novartis; Medivation, Inc.; Horizon Pharma, Inc.; Neurarin Corporation; CHDI Foundation, Inc.; Eli Lilly and Company; NIH (NIDA) [R01 DAO5821]; NINDS [1R01 NS40068-1, R01 NS054893-01A1]; European Huntington's Disease Network FX Study funding: Supported by the CHDI/ HighQ Foundation, a non-for-profit organization dedicated to finding treatments for HD. The cortical thickness imaging work was additionally supported by NIH P01NS058793 and R01NS042861.; Dr. Bechtel receives research support from the CHDI/HighQ Foundation, Inc. Dr. Scahill receives research support from the CHDI/HighQ Foundation, Inc. Dr. Rosas receives research support from the NIH (NINDS P01 NS058793 [Co-PI] and NIH NINDS R01 NS042861 [PI]) and the CHDI/HighQ Foundation, Inc. T. Acharya, Dr. van den Bogaard, C. Jauffret, M.J. Say, Dr. Sturrock, Dr. Johnson, Dr. Onorato, Dr. Salat, Dr. Durr, Dr. Leavitt, and Dr. Roos report no disclosures. Dr. Landwehrmeyer serves on scientific advisory boards for Trophos and Siena Biotech S.p.A.; has received funding for travel from Temmler Pharma GmbH & Co. KG; receives royalties from the publication of oSearch, AmJuvenile Huntington's Disease (Oxford University Press, 2009); and receives research support from Novartis, Medivation, Inc., Horizon Pharma, Inc., Neurarin Corporation, and CHDI Foundation, Inc. Dr. Langbehn receives/has received research support from Eli Lilly and Company, the NIH (NIDA R01 DAO5821 [biostatistician, coinvestigator], NINDS 1R01 NS40068-1 [biostatistician, coinvestigator], NINDS R01 NS054893-01A1 [biostatistician], and NIH RO1 NG HG003330-01A1 [biostatistician]), CHDI Foundation, Inc., and from the Michael J. Fox Foundation. Dr. Stout has served as a consultant for and received funding for travel from Medivation, Inc.; serves on the editorial advisory boards of the Journal of the International Neuropsychological Society and Brain Imaging and Behavior; and receives research support from the NIH (NINDS NS40068 [coinvestigator]), and CHDI Foundation, Inc. Prof. Tabrizi receives research support from the CHDI, Wellcome Trust, and MRC. Dr. Reilmann serves on scientific advisory boards for Wyeth, the CHDI, Novartis, Siena Biotech S. p. A., and Neurosearch; holds a patent re: Glossomotography; received speaker honoraria from Temmler Pharma GmbH & Co. KG, Neurosearch and the Huntington Study Group; and receives research support from the European Huntington's Disease Network and the CHDI/HighQ Foundation, Inc. NR 40 TC 50 Z9 50 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 14 PY 2010 VL 75 IS 24 BP 2150 EP 2160 DI 10.1212/WNL.0b013e3182020123 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 694JJ UT WOS:000285292700007 PM 21068430 ER PT J AU Perez, DL Haldar, A Rotenberg, A Kothare, SV AF Perez, David L. Haldar, Amit Rotenberg, Alexander Kothare, Sanjeev V. TI Teaching Video NeuroImages: Complex partial seizure evolving into a psychogenic nonepileptic seizure SO NEUROLOGY LA English DT Editorial Material C1 [Perez, David L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Perez, David L.; Haldar, Amit; Rotenberg, Alexander; Kothare, Sanjeev V.] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Perez, David L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Perez, DL (reprint author), Brigham & Womens Hosp, Dept Neurol, 75 Francis St, Boston, MA 02115 USA. EM david.lperez@gmail.com NR 1 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 14 PY 2010 VL 75 IS 24 BP E98 EP E98 DI 10.1212/WNL.0b013e31820203db PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 694JJ UT WOS:000285292700002 PM 21172839 ER PT J AU Mroz, P Szokalska, A Wu, MX Hamblin, MR AF Mroz, Pawel Szokalska, Angelika Wu, Mei X. Hamblin, Michael R. TI Photodynamic Therapy of Tumors Can Lead to Development of Systemic Antigen-Specific Immune Response SO PLOS ONE LA English DT Article ID CYTOLYTIC T-LYMPHOCYTES; ANTITUMOR IMMUNITY; HUMAN-MELANOMA; SOLID TUMORS; INFILTRATING LYMPHOCYTES; COMPLEMENT ACTIVATION; HLA-A2 MELANOMAS; DENDRITIC CELLS; COLON-TUMOR; IFN-GAMMA AB Background: The mechanism by which the immune system can effectively recognize and destroy tumors is dependent on recognition of tumor antigens. The molecular identity of a number of these antigens has recently been identified and several immunotherapies have explored them as targets. Photodynamic therapy (PDT) is an anti-cancer modality that uses a non-toxic photosensitizer and visible light to produce cytotoxic reactive oxygen species that destroy tumors. PDT has been shown to lead to local destruction of tumors as well as to induction of anti-tumor immune response. Methodology/Principal Findings: We used a pair of equally lethal BALB/c colon adenocarcinomas, CT26 wild-type (CT26WT) and CT26.CL25 that expressed a tumor antigen, beta-galactosidase (beta-gal), and we treated them with vascular PDT. All mice bearing antigen-positive, but not antigen-negative tumors were cured and resistant to rechallenge. T lymphocytes isolated from cured mice were able to specifically lyse antigen positive cells and recognize the epitope derived from beta-galactosidase antigen. PDT was capable of destroying distant, untreated, established, antigen-expressing tumors in 70% of the mice. The remaining 30% escaped destruction due to loss of expression of tumor antigen. The PDT anti-tumor effects were completely abrogated in the absence of the adaptive immune response. Conclusion: Understanding the role of antigen-expression in PDT immune response may allow application of PDT in metastatic as well as localized disease. To the best of our knowledge, this is the first time that PDT has been shown to lead to systemic, antigen-specific anti-tumor immunity. C1 [Mroz, Pawel; Szokalska, Angelika; Wu, Mei X.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mroz, Pawel; Wu, Mei X.; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Szokalska, Angelika] Med Univ Warsaw, Dept Immunol, Warsaw, Poland. [Wu, Mei X.; Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Mroz, P (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI Muchowicz, Angelika/J-7494-2012; OI Hamblin, Michael/0000-0001-6431-4605 FU US NIH National Cancer Institute [RO1CA/AI838801, R01AI050875]; Genzyme-Partners Translational Research Grant; Foundation for Polish Science, International Union Against Cancer and European Structural Fund FX Supported by US NIH National Cancer Institute (grants RO1CA/AI838801 and R01AI050875 to MRH). P.M. was partly supported by Genzyme-Partners Translational Research Grant. A.S. was supported by the Foundation for Polish Science, International Union Against Cancer and European Structural Fund: "Mazowieckie Stypendium Doktoranckie." The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 46 Z9 47 U1 4 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 14 PY 2010 VL 5 IS 12 AR e15194 DI 10.1371/journal.pone.0015194 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 694JH UT WOS:000285292500016 PM 21179470 ER PT J AU Pan, YP Zhang, K Qi, JP Yue, JA Springer, TA Chen, JF AF Pan, YouDong Zhang, Kun Qi, JunPeng Yue, Jiao Springer, Timothy A. Chen, JianFeng TI Cation-pi interaction regulates ligand-binding affinity and signaling of integrin alpha(4)beta(7) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SPECIFICITY-DETERMINING LOOP; I-LIKE DOMAIN; CELL-MIGRATION; BETA-SUBUNIT; STRUCTURAL BASIS; CYTOPLASMIC DOMAIN; CRYSTAL-STRUCTURE; ALPHA-SUBUNIT; HYBRID DOMAIN; ACTIVATION AB Integrin alpha(4)beta(7) mediates rolling and firm adhesion of leucocytes, two of the critical steps in leukocyte migration and tissue specific homing. Affinity of alpha(4)beta(7) for ligand is dynamically regulated by three interlinked metal ion-binding sites in beta(7)-subunit I domain. In this study, we found that Phe185 (F185), a highly conserved aromatic residue in beta(7)-subunit, links the specificity-determining loop and the synergistic metal ion-binding site (SyMBS) through cation-pi interaction. Mutations of F185 that disrupted the SyMBS cation-F185 interaction led to deficient firm cell adhesion mediated by high affinity alpha(4)beta(7), and only slightly affected rolling adhesion mediated by low affinity alpha(4)beta(7). Disruption of SyMBS cation-F185 interaction induced partial extension of integrin ectodomain and separation of cytoplasmic tails, and impaired alpha(4)beta(7)-mediated bidirectional signaling. In addition, loss of SyMBS cation-F185 interaction increased paxillin expression and promoted paxillin-integrin binding, leading to deficient cell spreading. Furthermore, integrin alpha(4)beta(7)-mediated cell migration was decreased by the abolishment of SyMBS cation-F185 interaction. Thus, these findings reveal a cation-pi interaction playing vital roles in the regulation of integrin affinity, signaling, and biological functions. C1 [Springer, Timothy A.] Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Pan, YouDong; Zhang, Kun; Qi, JunPeng; Yue, Jiao; Chen, JianFeng] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Mol Cell Biol Lab, Shanghai 200031, Peoples R China. RP Springer, TA (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM springer@idi.harvard.edu; jfchen@sibs.ac.cn FU National Institute of Health (NIH) [HLB-48675]; Ministry of Science and Technology [2010CB529703]; National Natural Science Foundation of China [30700119, 30970604]; Shanghai Pujiang Program [08PJ14106]; Chinese Academy of Sciences [KSCX2-YW-R-67]; Novo Nordisk-CAS Research Foundation [NN-CAS 2008-1] FX We thank Dr. Minsoo Kim (University of Rochester Medical Center) for kindly providing talin-GFP and Dr. Gaoxiang Ge and Dr. Dangsheng Li for discussion. This work was supported by grants from National Institute of Health (NIH) (HLB-48675), Ministry of Science and Technology 973 project (2010CB529703), National Natural Science Foundation of China (30700119, 30970604), Shanghai Pujiang Program (08PJ14106), Chinese Academy of Sciences (KSCX2-YW-R-67), and Novo Nordisk-CAS Research Foundation (NN-CAS 2008-1). NR 42 TC 11 Z9 13 U1 0 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21388 EP 21393 DI 10.1073/pnas.1015487107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500033 PM 21098296 ER PT J AU Enshell-Seijffers, D Lindon, C Wu, E Taketo, MM Morgan, BA AF Enshell-Seijffers, David Lindon, Catherine Wu, Eleanor Taketo, Makoto M. Morgan, Bruce A. TI beta-Catenin activity in the dermal papilla of the hair follicle regulates pigment-type switching SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pheomelanin; eumelanin ID MOUSE AGOUTI GENE; COAT-COLOR; DOMESTIC DOGS; MICE; MUTATION; ATTRACTIN; PROTEIN; EXPRESSION; MELANISM; PATHWAY AB The switch between black and yellow pigment is mediated by the interaction between Melanocortin receptor 1 (Mc1r) and its antagonist Agouti, but the genetic and developmental mechanisms that modify this interaction to obtain different coat color in distinct environments are poorly understood. Here, the role of Wnt/beta-catenin signaling in the regulation of pigment-type switching was studied. Loss and gain of function of beta-catenin in the dermal papilla (DP) of the hair follicle results in yellow and black animals, respectively. beta-Catenin activity in the DP suppresses Agouti expression and activates Corin, a negative regulator of Agouti activity. In addition, beta-catenin activity in the DP regulates melanocyte activity by a mechanism that is independent of both Agouti and Corin. The coordinate and inverse regulation of Agouti and Corin renders pelage pigmentation sensitive to changes in beta-catenin activity in the DP that do not alter pelage structure. As a result, the signals that specify two biologically distinct quantitative traits are partially uncoupled despite their common regulation by the beta-catenin pathway in the same cells. C1 [Enshell-Seijffers, David; Lindon, Catherine; Wu, Eleanor; Morgan, Bruce A.] Harvard Univ, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Enshell-Seijffers, David; Lindon, Catherine; Wu, Eleanor; Morgan, Bruce A.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Taketo, Makoto M.] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. RP Enshell-Seijffers, D (reprint author), Harvard Univ, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM david.enshell@cbrc2.mgh.harvard.edu; bruce.morgan@cbrc2.mgh.harvard.edu OI Enshell-Seijffers, David/0000-0002-8228-2659 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR055256] FX We thank David E. Fisher and Vincent Hearing for providing the C5 anti-Mitf and alpha PEP7 anti-Tyr antibodies, respectively, and R. Czyzewski for technical assistance. This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 1R01AR055256 (to B.A.M.). NR 31 TC 24 Z9 24 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21564 EP 21569 DI 10.1073/pnas.1007326107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500063 PM 21098273 ER PT J AU Elpek, KG Rubinstein, MP Bellemare-Pelletier, A Goldrath, AW Turley, SJ AF Elpek, Kutlu G. Rubinstein, Mark P. Bellemare-Pelletier, Angelique Goldrath, Ananda W. Turley, Shannon J. TI Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15R alpha complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokine complexes; natural killer cell dysfunction; end-stage cells ID MOUSE NK CELLS; DENDRITIC CELLS; IN-VIVO; IMMUNE-RESPONSES; T-CELLS; ACTIVATION; IL-15; IMMUNOTHERAPY; MATURATION; INFECTION AB Cytotoxic lymphocytes such as natural killer (NK) and CD8T cells play important roles in immunosurveillance by killing virally infected or malignant cells. The homeostatic cytokine, IL-15, promotes the development, function, and survival of NK and CD8 T cells. IL-15 is normally presented in trans as a surface complex with IL-15 receptor-alpha-chain (IL-15R alpha) by dendritic cells (DCs) and monocytes. Signaling by IL-15 occurs via the IL-2/IL-15 receptor beta-chain (CD122) which is expressed primarily by NK1.1(+) cells and CD8 T cells. The use of preformed complexes of IL-15 with soluble IL-15R alpha complexes to boost the effector function of CD122(+) cytolytic lymphocytes such as NK and CD8 T cells has recently gained considerable attention. Here we describe the impact of transient and prolonged in vivo stimulation by IL-15/IL-15R alpha complexes on NK and CD8 T cells. Whereas transitory stimulation increased the number of activated NK cells and significantly enhanced their effector function, prolonged stimulation by IL-15/IL-15R alpha complexes led to a marked accumulation of mature NK cells with considerably impaired activation, cytotoxicity, and proliferative activity, and an altered balance of activating and inhibitory receptors. In contrast to NK cells, CD8 T cells exhibited an activated phenotype and robust T cell receptor stimulation and effector function upon chronic stimulation with IL15/IL-15R alpha complexes. Thus, prolonged stimulation with the strong activating signal leads to a preferential accrual of mature NK cells with altered activation and diminished functional capacity. These findings point to a negative feedback mechanism to preferentially counterbalance excessive NK cell activity and may have important implications for cytokine immunotherapy. C1 [Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Rubinstein, Mark P.; Goldrath, Ananda W.] Univ Calif San Diego, Div Biol, La Jolla, CA 92093 USA. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Turley, SJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM shannon_turley@dfci.harvard.edu FU American Association for Cancer Research Centennial; American Cancer Society Research; National Institutes of Health [AI067545]; Cancer Research Institute FX We thank Dr. Jerry Ritz for critically reading this manuscript. This study was supported in part by research funding from an American Association for Cancer Research Centennial Postdoctoral Fellowship in Cancer Research to K.G.E.), an American Cancer Society Research Scholar Award to S.J.T.), National Institutes of Health Grant AI067545 to A.W.G.), and a Cancer Research Institute Scholar Award to A.W.G.). NR 41 TC 39 Z9 41 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21647 EP 21652 DI 10.1073/pnas.1012128107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500077 PM 21098276 ER PT J AU Duda, DG Duyverman, AMMJ Kohno, M Snuderl, M Steller, EJA Fukumura, D Jain, RK AF Duda, Dan G. Duyverman, Annique M. M. J. Kohno, Mitsutomo Snuderl, Matija Steller, Ernst J. A. Fukumura, Dai Jain, Rakesh K. TI Malignant cells facilitate lung metastasis by bringing their own soil SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CANCER METASTASIS; STROMAL CELLS; TUMORS; CARCINOMA; VESSELS; LINES; MICE AB Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil-stromal components including activated fibroblasts-from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated in heterotypic tumor-stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic cancer cells, significantly decreases the number of metastases and extends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has important conceptual and clinical implications for the colonization step in tumor progression. C1 [Duda, Dan G.; Duyverman, Annique M. M. J.; Kohno, Mitsutomo; Steller, Ernst J. A.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Snuderl, Matija] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Snuderl, Matija] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. EM dai@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu OI Snuderl, Matija/0000-0003-0752-0917 FU National Institutes of Health [R01CA085140, P01CA080124, R01CA115767, R01CA126642, R01CA096915]; Department of Defense [W81XWH-06-1-0781]; Japanese Ministry of Health and Welfare FX We thank Drs. I. J. Fidler, Y. Izumi, and B. Seed for useful suggestions; L. Xu, K. S. Cohen, M. R. Dawson, N. Hosseini, P. Huang, J. Kahn, M. Kim, S. Roberge, and C. Smith for invaluable help with the experiments; and M. Ancukiewicz for statistical analysis. This study was performed with support provided by Grant R01CA085140 (to R.K.J.) and was partially supported by Grants P01CA080124, R01CA115767, R01CA126642 (all to R.K.J.), and R01CA096915 (to D.F.), all from the National Institutes of Health. A.M.M.J.D. received Department of Defense Fellowship W81XWH-06-1-0781. M.K. received a research fellowship from the Japanese Ministry of Health and Welfare. NR 23 TC 160 Z9 171 U1 2 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21677 EP 21682 DI 10.1073/pnas.1016234107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500082 PM 21098274 ER PT J AU Trichonas, G Murakami, Y Thanos, A Morizane, Y Kayama, M Debouck, CM Hisatomi, T Miller, JW Vavvas, DG AF Trichonas, George Murakami, Yusuke Thanos, Aristomenis Morizane, Yuki Kayama, Maki Debouck, Christine M. Hisatomi, Toshio Miller, Joan W. Vavvas, Demetrios G. TI Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE degenerations; necroptosis ID NONAPOPTOTIC CELL-DEATH; PROGRAMMED NECROSIS; TNF-ALPHA; IN-VIVO; MITOCHONDRIAL APOPTOSIS; EXPERIMENTAL-MODEL; ACTIVATION; DEGENERATION; INFLAMMATION; PATHWAY AB Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders. C1 [Trichonas, George; Murakami, Yusuke; Thanos, Aristomenis; Morizane, Yuki; Kayama, Maki; Hisatomi, Toshio; Miller, Joan W.; Vavvas, Demetrios G.] Massachusetts Eye & Ear Infirm, Retina Serv, Angiogenesis Lab, Boston, MA 02114 USA. [Trichonas, George; Murakami, Yusuke; Morizane, Yuki; Kayama, Maki; Hisatomi, Toshio; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Debouck, Christine M.] TetraLog Pharmaceut, Malvern, PA 19355 USA. [Hisatomi, Toshio] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka 8128582, Japan. RP Vavvas, DG (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, Angiogenesis Lab, Boston, MA 02114 USA. EM demetrios_vavvas@meei.harvard.edu OI Hisatomi, Toshio/0000-0003-2552-9595; Vavvas, Demetrios/0000-0002-8622-6478 FU Bacardi Fund; Research to Prevent Blindness Foundation; Lions Eye Research Fund; Onassis Foundation; Fight For Sight; Harvard Ophthalmology Department; Bausch and Lomb; National Eye Institute [EY014104] FX We thank N. Michaud (Massachusetts Eye and Ear Infirmary) and F. Morikawa (Kyushu University) for technical assistance. This work was supported by the Bacardi Fund (D.G.V.), the Research to Prevent Blindness Foundation (D.G.V.), the Lions Eye Research Fund (D.G.V.), the Onassis Foundation (D.G.V.), a grant-in-aid from Fight For Sight (D.G.V.), the Harvard Ophthalmology Department (D.G.V.), a Vitreoretinal Fellowship from Bausch and Lomb (to Y. Morizane), and National Eye Institute Grant EY014104 (Massachusetts Eye and Ear Infirmary core grant). NR 48 TC 138 Z9 147 U1 5 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21695 EP 21700 DI 10.1073/pnas.1009179107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500085 PM 21098270 ER PT J AU Schwer, B Schumacher, B Lombard, DB Xiao, CY Kurtev, MV Gao, J Schneider, JI Chai, H Bronson, RT Tsai, LH Deng, CX Alt, FW AF Schwer, Bjoern Schumacher, Bjoern Lombard, David B. Xiao, Cuiying Kurtev, Martin V. Gao, Jun Schneider, Jennifer I. Chai, Hua Bronson, Roderick T. Tsai, Li-Huei Deng, Chu-Xia Alt, Frederick W. TI Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NERVOUS-SYSTEM; DEACETYLATION; MICE; DISRUPTION; CHROMATIN; MOUSE; GENE AB In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1-Sirt7) have been implicated as NAD(+)-dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity. C1 [Schwer, Bjoern; Lombard, David B.; Chai, Hua; Alt, Frederick W.] Harvard Univ, Childrens Hosp,Dept Genet, Sch Med,Immune Dis Inst, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. [Schumacher, Bjoern; Schneider, Jennifer I.] Univ Cologne, Inst Genet, D-50674 Cologne, Germany. [Xiao, Cuiying; Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Kurtev, Martin V.] Harvard Univ, Sch Med, Dept Neurol & Neurobiol, Boston, MA 02115 USA. [Gao, Jun; Tsai, Li-Huei] MIT, Howard Hughes Med Inst, Picower Inst Learning & Memory, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tsai, Li-Huei] Harvard Univ, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. RP Alt, FW (reprint author), Harvard Univ, Childrens Hosp,Dept Genet, Sch Med,Immune Dis Inst, Howard Hughes Med Inst,Program Cellular & Mol Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI deng, chuxia/N-6713-2016; Schumacher, Bjorn/I-4829-2013 OI Schumacher, Bjorn/0000-0001-6097-5238 FU Ellison Medical Foundation/American Federation for Aging; Ellison Foundation; National Institute on Aging/National Institutes of Health (NIH) [AG022325]; Hartford Foundation; Deutsche Forschungsgemeinschaft; Marie Curie European Reintegration Grant [PERG04-GA-2008-239330]; German-Israeli Foundation [YIG 2213]; NIH [PO1 AG027916] FX We thank Hwei-Ling Cheng and members of the F.W.A. laboratory for helpful discussions and Amanda Donahue and Melissa Cummings (Children's Hospital Boston) for help with DXA. We thank Bruce Yankner (Harvard Medical School) for comments on the manuscript. This work was supported by an Ellison Medical Foundation/American Federation for Aging Research Senior Postdoctoral Fellow Research Grant (to B. Schwer), an Ellison Foundation Senior Scholar Award (to F.W.A), a National Institute on Aging/National Institutes of Health (NIH) K08 Award (AG022325) and Hartford Foundation Grant (to D.B.L), Deutsche Forschungsgemeinschaft (Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases and Sonderforschungsbereich 829), Marie Curie European Reintegration Grant (PERG04-GA-2008-239330) and German-Israeli Foundation (YIG 2213) grants (to B. Schumacher), and NIH Grant PO1 AG027916 (to L.-H.T.). F.W.A. and L.-H.T. are Investigators of the Howard Hughes Medical Institute. NR 30 TC 78 Z9 85 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21790 EP 21794 DI 10.1073/pnas.1016306107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500101 PM 21098266 ER PT J AU Rasbach, KA Gupta, RK Ruas, JL Wu, J Naseri, E Estall, JL Spiegelman, BM AF Rasbach, Kyle A. Gupta, Rana K. Ruas, Jorge L. Wu, Jun Naseri, Elnaz Estall, Jennifer L. Spiegelman, Bruce M. TI PGC-1 alpha regulates a HIF2 alpha-dependent switch in skeletal muscle fiber types SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; TUMOR-SUPPRESSOR PROTEIN; GENE-EXPRESSION; RECEPTOR-ALPHA; DNA-BINDING; IN-VIVO; CALCINEURIN; GAMMA; HIF AB The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1 alpha has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1 alpha in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 alpha (HIF2 alpha) as a major PGC-1 alpha target in skeletal muscle that is positively regulated by both exercise and beta-adrenergic signaling. This transcriptional regulation of HIF2 alpha is completely dependent on the PGC-1 alpha/ERR alpha complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2 alpha target genes in primary myotubes suggested an unexpected role for HIF2 alpha in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1 alpha-mediated switch to slow, oxidative fibers in vitro is dependent on HIF2 alpha, and mice with a muscle-specific knockout of HIF2 alpha increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2 alpha acts downstream of PGC-1 alpha as a key regulator of a muscle fiber-type program and the adaptive response to exercise. C1 [Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Bruce_Spiegelman@dfci.harvard.edu OI Ruas, Jorge/0000-0002-1110-2606 FU American Heart Association [09POST2010078]; [DK54477]; [DK61562] FX This work was supported by Grants DK54477 and DK61562 (to B.M.S., Harvard Medical School, Boston). J.W. was supported by a postdoctoral fellowship from the American Heart Association (Founders Affiliate 09POST2010078). NR 55 TC 51 Z9 57 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21866 EP 21871 DI 10.1073/pnas.1016089107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500114 PM 21106753 ER PT J AU Gao, XB Eladari, D Leviel, F Tew, BY Miro-Julia, C Cheema, F Miller, L Nelson, R Paunescu, TG McKee, M Brown, D Al-Awqati, Q AF Gao, XiaoBo Eladari, Dominique Leviel, Francoise Tew, Ben Yi Miro-Julia, Cristina Cheema, Faisal Miller, Lance Nelson, Raoul Paunescu, Teodor G. McKee, Mary Brown, Dennis Al-Awqati, Qais TI Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CORTICAL COLLECTING DUCT; CIS-TRANS ISOMERASE; VACUOLAR H+-ATPASE; METABOLIC-ACIDOSIS; EPITHELIAL-CELLS; URINARY ACIDIFICATION; CL-/HCO3-EXCHANGER; ANION-EXCHANGER; MOUSE KIDNEY; RAT AB Acid-base transport in the renal collecting tubule is mediated by two canonical cell types: the beta-intercalated cell secretes HCO3 by an apical Cl:HCO3 named pendrin and a basolateral vacuolar (V)-ATPase. Acid secretion is mediated by the alpha-intercalated cell, which has an apical V-ATPase and a basolateral Cl:HCO3 exchanger (kAE1). We previously suggested that the beta-cell converts to the alpha-cell in response to acid feeding, a process that depended on the secretion and deposition of an extracellular matrix protein termed hensin (DMBT1). Here, we show that deletion of hensin from intercalated cells results in the absence of typical alpha-intercalated cells and the consequent development of complete distal renal tubular acidosis (dRTA). Essentially all of the intercalated cells in the cortex of the mutant mice are canonical beta-type cells, with apical pendrin and basolateral or diffuse/bipolar V-ATPase. In the medulla, however, a previously undescribed cell type has been uncovered, which resembles the cortical beta-intercalated cell in ultrastructure, but does not express pendrin. Polymerization and deposition of hensin (in response to acidosis) requires the activation of beta 1 integrin, and deletion of this gene from the intercalated cell caused a phenotype that was identical to the deletion of hensin itself, supporting its critical role in hensin function. Because previous studies suggested that the conversion of beta- to alpha-intercalated cells is a manifestation of terminal differentiation, the present results demonstrate that this differentiation proceeds from HCO3 secreting to acid secreting phenotypes, a process that requires deposition of hensin in the ECM. C1 [Gao, XiaoBo; Tew, Ben Yi; Miro-Julia, Cristina; Cheema, Faisal; Al-Awqati, Qais] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Gao, XiaoBo; Tew, Ben Yi; Miro-Julia, Cristina; Cheema, Faisal; Al-Awqati, Qais] Columbia Univ Coll Phys & Surg, Dept Physiol & Cellular Biophys, New York, NY 10032 USA. [Eladari, Dominique; Leviel, Francoise] Univ Paris 06, F-75006 Paris, France. [Eladari, Dominique; Leviel, Francoise] Ctr Rech Cordeliers, Inst Natl Sante & Rech Med, Unite Mixte Rech Sci 872, Team 3, F-75006 Paris, France. [Eladari, Dominique; Leviel, Francoise] Ctr Rech Cordeliers, Ctr Natl Rech Sci, Lab Genom Physiol & Physiopathol Renales, ERL7226, F-75006 Paris, France. [Eladari, Dominique; Leviel, Francoise] Univ Paris 05, Fac Med Paris Descartes, F-75006 Paris, France. [Miller, Lance; Nelson, Raoul] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84132 USA. [Paunescu, Teodor G.; McKee, Mary; Brown, Dennis] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. RP Al-Awqati, Q (reprint author), Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. EM qa1@columbia.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [20999]; American Heart Association; Fondation Leducq; l'Agence Nationale de la Recherche [PHYSIO 2007-RPV07084]; National Institutes of Health [R37 DK42956]; Boston Area Diabetes and Endocrinology Center [DK-57521]; MGH Center for the Study of Inflammatory Bowel Disease [DK-43341]; Spanish Ministry of Education [FPU AP2007-02223]; [DK-73266] FX We are grateful to Ombeline de La Rochefoucauld, Wei Dong, and Elizabeth S. Olson for performance of the studies on auditory nerve responses, which are described in the SI Text. X.G. and Q.A.-A. are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (20999) and the American Heart Association; D.E. was funded by the Fondation Leducq, and by Grant PHYSIO 2007-RPV07084 from l'Agence Nationale de la Recherche; D.B. is supported by National Institutes of Health (R37 DK42956). T.G.P. is supported by DK-73266. D.B. is additionally supported for his work in the Microscopy Core of the Massachusetts General Hospital (MGH) Program in Membrane Biology by grants from the Boston Area Diabetes and Endocrinology Center (DK-57521) and by the MGH Center for the Study of Inflammatory Bowel Disease (DK-43341). C.M.-J. is a recipient of a fellowship from the Spanish Ministry of Education (FPU AP2007-02223). NR 33 TC 32 Z9 32 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 14 PY 2010 VL 107 IS 50 BP 21872 EP 21877 DI 10.1073/pnas.1010364107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 697NY UT WOS:000285521500115 PM 21098262 ER PT J AU Harris, JB LaRocque, RC Charles, RC Mazumder, RN Khan, AI Bardhan, PK AF Harris, Jason B. LaRocque, Regina C. Charles, Richelle C. Mazumder, Ramendra N. Khan, Azharul I. Bardhan, Pradip K. TI Cholera's western front SO LANCET LA English DT Editorial Material ID TETRACYCLINE; BANGLADESH; VACCINES C1 [Harris, Jason B.; LaRocque, Regina C.; Charles, Richelle C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [LaRocque, Regina C.; Charles, Richelle C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Mazumder, Ramendra N.; Khan, Azharul I.; Bardhan, Pradip K.] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM jbharris@partners.org FU FIC NIH HHS [K01 TW007409]; NIAID NIH HHS [K08 AI089721] NR 15 TC 30 Z9 32 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD DEC 11 PY 2010 VL 376 IS 9757 BP 1961 EP 1965 DI 10.1016/S0140-6736(10)62172-1 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 701GZ UT WOS:000285807700004 PM 21112083 ER PT J AU Conrad, C AF Conrad, Claudius TI The art of medicine Music for healing: from magic to medicine SO LANCET LA English DT Editorial Material C1 [Conrad, Claudius] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Conrad, Claudius] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Dept Surg, Boston, MA 02114 USA. RP Conrad, C (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM cconrad1@partners.org NR 7 TC 12 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD DEC 11 PY 2010 VL 376 IS 9757 BP 1980 EP 1981 DI 10.1016/S0140-6736(10)62251-9 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 701GZ UT WOS:000285807700013 PM 21171230 ER PT J AU Mochida, GH Ganesh, VS Felie, JM Gleason, D Hill, RS Clapham, KR Rakiec, D Tan, WH Akawi, N Al-Saffar, M Partlow, JN Tinschert, S Barkovich, AJ Ali, B Al-Gazali, L Walsh, CA AF Mochida, Ganeshwaran H. Ganesh, Vijay S. Felie, Jillian M. Gleason, Danielle Hill, R. Sean Clapham, Katie Rose Rakiec, Daniel Tan, Wen-Hann Akawi, Nadia Al-Saffar, Muna Partlow, Jennifer N. Tinschert, Sigrid Barkovich, A. James Ali, Bassam Al-Gazali, Lihadh Walsh, Christopher A. TI A Homozygous Mutation in the Tight-Junction Protein JAM3 Causes Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ADHESION MOLECULE-C; INFECTION-LIKE SYNDROME; RETINAL-PIGMENT EPITHELIUM; NANCE-HORAN-SYNDROME; INTRACRANIAL CALCIFICATION; PSEUDO-TORCH; COL4A1 MUTATION; CELL JUNCTIONS; EXPRESSION; GENE AB The tight junction, or zonula occludens, is a specialized cell-cell junction that regulates epithelial and endothelial permeability, and it is an essential component of the blood-brain barrier in the cerebrovascular endothelium. In addition to functioning as a diffusion barrier, tight junctions are also involved in signal transduction. In this study, we identified a homozygous mutation in the tight-junction protein gene JAM3 in a large consanguineous family from the United Arab Emirates. Some members of this family had a rare autosomal-recessive syndrome characterized by severe hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Their clinical presentation overlaps with some reported cases of pseudo-TORCH syndrome as well as with cases involving mutations in occludin, another component of the tight-junction complex. However, massive intracranial hemorrhage distinguishes these patients from others. Homozygosity mapping identified the disease locus in this family on chromosome 11q25 with a maximum multipoint LOD score of 6.15. Sequence analysis of genes in the candidate interval uncovered a mutation in the canonical splice-donor site of intron 5 of JAM3. RT-PCR analysis of a patient lymphoblast cell line confirmed abnormal splicing, leading to a frameshift mutation with early termination. JAM3 is known to be present in vascular endothelium, although its roles in cerebral vasculature have not been implicated. Our results suggest that JAM3 is essential for maintaining the integrity of the cerebrovascular endothelium as well as for normal lens development in humans. C1 [Al-Gazali, Lihadh] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Paediat, Al Ain, U Arab Emirates. [Mochida, Ganeshwaran H.; Ganesh, Vijay S.; Felie, Jillian M.; Gleason, Danielle; Hill, R. Sean; Clapham, Katie Rose; Rakiec, Daniel; Tan, Wen-Hann; Al-Saffar, Muna; Partlow, Jennifer N.; Walsh, Christopher A.] Manton Ctr Orphan Dis Res, Div Genet, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Ganesh, Vijay S.; Felie, Jillian M.; Gleason, Danielle; Hill, R. Sean; Clapham, Katie Rose; Rakiec, Daniel; Tan, Wen-Hann; Al-Saffar, Muna; Partlow, Jennifer N.; Walsh, Christopher A.] Childrens Hosp Boston, Howard Hughes Med Inst, Dept Med, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Hill, R. Sean; Walsh, Christopher A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.; Hill, R. Sean; Walsh, Christopher A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Mochida, Ganeshwaran H.] Massachusetts Gen Hosp, Dept Neurol, Pediat Neurol Unit, Boston, MA 02114 USA. [Akawi, Nadia; Ali, Bassam] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Pathol, Al Ain, U Arab Emirates. [Tinschert, Sigrid] Tech Univ Dresden, Med Fak Carl Gustav Carus, Inst Klin Genet, D-01307 Dresden, Germany. [Barkovich, A. James] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Walsh, Christopher A.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. RP Al-Gazali, L (reprint author), United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Paediat, POB 17666, Al Ain, U Arab Emirates. EM l.algazali@uaeu.ac.ae; christopher.walsh@childrens.harvard.edu RI Ali, Bassam/J-7014-2012 FU National Institute of Neurological Disorders and Stroke [5R01NS035129-13]; Fogarty International Center [5R21TW008223-02]; Nancy Lurie Marks Family Foundation; Dubai Harvard Foundation for Medical Research; Simons Foundation; Manton Center for Orphan Disease Research; National Alliance for Research on Schizophrenia and Depression (NARSAD) FX We would like to thank the family for their participation in this research. SNP genotyping was performed at The W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University through the National Institutes of Health Neuroscience Microarray Consortium. We thank the Partners Health Care Center for Personalized Genetic Medicine for establishing the lymphoblast cell lines. We thank Brenda J. Barry for coordinating patient studies and Philippe Schroter and Juliane Artelt for help with cell culture. This research was supported by grants from the National Institute of Neurological Disorders and Stroke (5R01NS035129-13) and Fogarty International Center (5R21TW008223-02) to C.A.W. and by the Nancy Lurie Marks Family Foundation, the Dubai Harvard Foundation for Medical Research, the Simons Foundation, and the Manton Center for Orphan Disease Research. G.H.M. was supported by the Young Investigator Award of the National Alliance for Research on Schizophrenia and Depression (NARSAD) as a NARSAD Lieber Investigator. C.A.W. is an Investigator of the Howard Hughes Medical Institute. NR 45 TC 24 Z9 26 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 10 PY 2010 VL 87 IS 6 BP 882 EP 889 DI 10.1016/j.ajhg.2010.10.026 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 698AT UT WOS:000285564600016 PM 21109224 ER PT J AU Christie, MA Mc Carley, RW Strecker, RE AF Christie, Michael A. Mc Carley, Robert W. Strecker, Robert E. TI Twenty-four hours, or five days, of continuous sleep deprivation or experimental sleep fragmentation do not alter thirst or motivation for water reward in rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Rat; sleep; sleep deprivation; sleep fragmentation; thirst; motivation; feeding; hyperphagia ID PSYCHOMOTOR VIGILANCE TASK; BASAL FOREBRAIN; BODY-WEIGHT; OBESITY; BEHAVIOR; RISK; IMPAIRMENTS; PERFORMANCE; ADENOSINE; COCAINE AB Sleep disruption results in an increased demand for energy, which typically causes hyperphagia in an attempt to redress the energy metabolism imbalance. Therefore, experiments combining food reward and sleep disruption may underestimate the effect of sleep disruption due to their contradictory influences on behavior (for example on operant measures of attention). In contrast, water is not a central component of energy metabolism and thus thirst may not be affected by sleep disruption. However, little work has been done examining the effect of sleep disruption on thirst and motivation for water. The effect of total sleep deprivation (SD) and experimental sleep fragmentation (SF) on thirst and motivation for water was assessed. In experiment 1 (using 22 month old male Fisher-Norway rats) the amount of water consumed during a 15 min period immediately following a period of 24 h SD or SF (in which water was not available) was measured, and, in a separate session, the amount of water consumed during the 24 h of SD or SF was measured. Thereafter, the effect of 5 days SD or SF on motivation for water was assessed with the progressive ratio task (using water reward), which is widely used to assess motivation. Experiment 2 (using 6 month, and 22 month, old male Sprague- Dawley rats) followed an identical design except that the SF condition was dropped (due to a lack of any difference between the SD and SF conditions in experiment 1), and only the 6 month old rats experienced the full 5 day SD condition. Daily measurements of body weight and food consumption were recorded in experiment 2 in order to confirm previously published findings that food consumption goes up and body weight declines in sleep deprived rats. In both experiments the quantity of water rats consumed during a 15 min period immediately following the 24 h period of sleep disruption, or consumed during the 24 h period of SD or SF, did not change compared to control rats. Furthermore, 5 days of SD or SF had no effect on breakpoint in the progressive ratio task indicating that 5 days of SD or SF did not alter motivation for water reward. As previously reported, food consumption increased and body weight decreased during the 5 days of SD. in experiment 2. The findings indicate that although sleep disruption increases food consumption and decreases body weight, it does not alter thirst or motivation for water reward. Thus, water restriction is well suited for experiments examining the effect of sleep disruption on reward motivated behavioral tests in rats. (C) 2010 Elsevier B.V. All rights reserved. C1 [Christie, Michael A.] VA Boston Healthcare Syst, Brockton, MA USA. Harvard Univ, Sch Med, Brockton, MA 02401 USA. RP Christie, MA (reprint author), VA Boston Healthcare Syst, Brockton, MA USA. EM michael_christie@hms.harvard.edu; robert_strecker@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU Department of Veterans Affairs Medical Research Service [P50 HL060292, R01 MH039683, T32 HL07901] FX We thank Lauren Kane, Kathryn Dugger, Sabrina Taylor, Jessin Varghese, Melissa Chace, Elizabeth Davis, Courtney Earle, Brittany Roy, Timothy Connors, Molly Little, and Nina Connolly for technical assistance, and John Franco for care of the animals. We thank Lauren Shifflett and James McKenna for careful proofreading of the manuscript. This research was supported by the Department of Veterans Affairs Medical Research Service Award to RES, P50 HL060292 (RES & RWM), R01 MH039683 (RWM), T32 HL07901 (MAC). NR 36 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD DEC 10 PY 2010 VL 214 IS 2 BP 180 EP 186 DI 10.1016/j.bbr.2010.05.020 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 643SJ UT WOS:000281318700004 PM 20493906 ER PT J AU Hashem, AM Van Domselaar, G Li, CG Wang, JZ She, YM Cyr, TD Sui, JH He, RT Marasco, WA Li, XG AF Hashem, Anwar M. Van Domselaar, Gary Li, Changgui Wang, Junzhi She, Yi-Min Cyr, Terry D. Sui, Jianhua He, Runtao Marasco, Wayne A. Li, Xuguang TI Universal antibodies against the highly conserved influenza fusion peptide cross-neutralize several subtypes of influenza A virus SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Influenza virus; Universal antibodies; Fusion peptide; Cross-protection ID MONOCLONAL-ANTIBODIES; VIRAL HEMAGGLUTININS; ANTIVIRAL THERAPY; AVIAN INFLUENZA; H5N1 INFECTION; BROAD-SPECTRUM; VACCINE; IMMUNIZATION; PROTECTION; SUBUNITS AB The fusion peptide of influenza viral hemagglutinin plays a critical role in virus entry by facilitating membrane fusion between the virus and target cells. As the fusion peptide is the only universally conserved epitope in all influenza A and B viruses, it could be an attractive target for vaccine-induced immune responses. We previously reported that antibodies targeting the first 14 amino acids of the N-terminus of the fusion peptide could bind to virtually all influenza virus strains and quantify hemagglutinins in vaccines produced in embryonated eggs. Here we demonstrate that these universal antibodies bind to the viral hemagglutinins in native conformation presented in infected mammalian cell cultures and neutralize multiple subtypes of virus by inhibiting the pH-dependant fusion of viral and cellular membranes. These results suggest that this unique, highly-conserved linear sequence in viral hemagglutinin is exposed sufficiently to be attacked by the antibodies during the course of infection and merits further investigation because of potential importance in the protection against diverse strains of influenza viruses. Crown Copyright (C) 2010 Published by Elsevier Inc. All rights reserved. C1 [Hashem, Anwar M.; She, Yi-Min; Cyr, Terry D.; Li, Xuguang] Hlth Canada, Ctr Vaccine Evaluat, Biol & Genet Therapies Directorate, HPFB, Ottawa, ON K1A 0K9, Canada. [Hashem, Anwar M.] King Abdulaziz Univ, Dept Microbiol, Fac Med, Jeddah 21413, Saudi Arabia. [Li, Changgui; Wang, Junzhi] Natl Inst Control Pharmaceut & Biol Prod, Beijing, Peoples R China. [Van Domselaar, Gary; He, Runtao] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada. [Hashem, Anwar M.; Li, Xuguang] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada. [Sui, Jianhua; Marasco, Wayne A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Med, Boston, MA 02115 USA. RP Li, XG (reprint author), Hlth Canada, Ctr Vaccine Evaluat, Biol & Genet Therapies Directorate, HPFB, AL 2201E, Ottawa, ON K1A 0K9, Canada. EM Sean.Li@hc-sc.gc.ca RI Hashem, Anwar/E-9411-2011 FU King Abdulaziz University; Saudi Arabian Cultural Bureau in Canada FX We thank Caroline Gravel for technical assistance and Monika Tocchi for editorial help. Drs. Richard Isbrucker and Shiv Prasad (Health Canada) are acknowledged for their critical review of the manuscript. AMH is supported by a Scholarship from King Abdulaziz University, through the Saudi Arabian Cultural Bureau in Canada. NR 33 TC 31 Z9 32 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 10 PY 2010 VL 403 IS 2 BP 247 EP 251 DI 10.1016/j.bbrc.2010.11.030 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 697RT UT WOS:000285534500017 PM 21078301 ER PT J AU Akavia, UD Litvin, O Kim, J Sanchez-Garcia, F Kotliar, D Causton, HC Pochanard, P Mozes, E Garraway, LA Pe'er, D AF Akavia, Uri David Litvin, Oren Kim, Jessica Sanchez-Garcia, Felix Kotliar, Dylan Causton, Helen C. Pochanard, Panisa Mozes, Eyal Garraway, Levi A. Pe'er, Dana TI An Integrated Approach to Uncover Drivers of Cancer SO CELL LA English DT Article ID GENE-EXPRESSION; MALIGNANT-MELANOMA; GENOME; MITF; IDENTIFICATION; TRANSFORMATION; INTERFERENCE; REGULATORS; SIGNATURE; PROFILES AB Systematic characterization of cancer genomes has revealed a staggering number of diverse aberrations that differ among individuals, such that the functional importance and physiological impact of most tumor genetic alterations remain poorly defined. We developed a computational framework that integrates chromosomal copy number and gene expression data for detecting aberrations that promote cancer progression. We demonstrate the utility of this framework using a melanoma data set. Our analysis correctly identified known drivers of melanoma and predicted multiple tumor dependencies. Two dependencies, TBC1D16 and RAB27A, confirmed empirically, suggest that abnormal regulation of protein trafficking contributes to proliferation in melanoma. Together, these results demonstrate the ability of integrative Bayesian approaches to identify candidate drivers with biological, and possibly therapeutic, importance in cancer. C1 [Akavia, Uri David; Litvin, Oren; Sanchez-Garcia, Felix; Kotliar, Dylan; Causton, Helen C.; Mozes, Eyal; Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Akavia, Uri David; Litvin, Oren; Pe'er, Dana] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [Kim, Jessica; Pochanard, Panisa; Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, Jessica; Pochanard, Panisa; Garraway, Levi A.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Biol Sci, 1212 Amsterdam Ave, New York, NY 10027 USA. EM dpeer@biology.columbia.edu OI Pe'er, Dana/0000-0002-9259-8817 FU National Institutes of Health Roadmap Initiative; NIH [1-DP2-OD002414-01]; National Centers for Biomedical Computing [1U54CA121852-01A1]; Burroughs Wellcome Fund; Packard Fellowship for Science and Engineering FX The authors will like to thank Nir Hacohen, Antonio Iavarone, Daphne Koller, Liz Miller, Itsik Pe'er, Suzanne Pfeffer, Neal Rosen, and Olga Troyanskaya for valuable comments. This research was supported by the National Institutes of Health Roadmap Initiative, NIH Director's New Innovator Award Program through grant number 1-DP2-OD002414-01, and National Centers for Biomedical Computing Grant 1U54CA121852-01A1. D.P. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and Packard Fellowship for Science and Engineering. NR 42 TC 223 Z9 227 U1 2 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 10 PY 2010 VL 143 IS 6 BP 1005 EP 1017 DI 10.1016/j.cell.2010.11.013 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 692VB UT WOS:000285182600016 PM 21129771 ER PT J AU Hariharan, N Maejima, Y Nakae, J Paik, J DePinho, RA Sadoshima, J AF Hariharan, Nirmala Maejima, Yasuhiro Nakae, Jun Paik, Jihye DePinho, Ronald A. Sadoshima, Junichi TI Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes SO CIRCULATION RESEARCH LA English DT Article DE autophagy; starvation; FoxO; Sirt1; Rab7; deacetylation ID FORKHEAD TRANSCRIPTION FACTOR; CELL-SURVIVAL; IN-VIVO; PROTEIN; HEART; MATURATION; STRESS AB Rationale: Autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood. Objective: We investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy. Methods and Results: Glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome-lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c-FoxO1(-/-)), and beclin1(+/-) mice, in which autophagy is significantly inhibited. Conclusions: These results suggest that Sirt1-mediated deacetylation of FoxO1 and upregulation of Rab7 play an important role in mediating starvation-induced increases in autophagic flux, which in turn plays an essential role in maintaining left ventricular function during starvation. (Circ Res. 2010; 107: 1470-1482.) C1 [Hariharan, Nirmala; Maejima, Yasuhiro; Sadoshima, Junichi] Univ Med & Dent New Jersey, Cardiovasc Res Inst, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. [Nakae, Jun] Keio Univ, Sch Med, Div Endocrinol Metab & Nephrol, Dept Internal Med, Tokyo, Japan. [Paik, Jihye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med Oncol, Boston, MA 02115 USA. RP Sadoshima, J (reprint author), Univ Med & Dent New Jersey, Cardiovasc Res Inst, New Jersey Med Sch, Dept Cell Biol & Mol Med, 185 S Orange Ave,MSB G609, Newark, NJ 07103 USA. EM sadoshju@umdnj.edu RI Hariharan, Nirmala/J-6736-2013 FU US Public Health Service [HL59139, HL67724, HL69020, HL91469, HL102738, AG27211]; Foundation of Leducq Transatlantic Network of Excellence FX This work was supported in part by US Public Health Service grants HL59139, HL67724, HL69020, HL91469, HL102738, and AG27211 and the Foundation of Leducq Transatlantic Network of Excellence. NR 24 TC 210 Z9 226 U1 8 U2 35 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD DEC 10 PY 2010 VL 107 IS 12 BP 1470 EP 1482 DI 10.1161/CIRCRESAHA.110.227371 PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 692HD UT WOS:000285143000010 PM 20947830 ER PT J AU Balakrishnan, A Stearns, AT Park, PJ Dreyfuss, JM Ashley, SW Rhoads, DB Tavakkolizadeh, A AF Balakrishnan, Anita Stearns, Adam T. Park, Peter J. Dreyfuss, Jonathan M. Ashley, Stanley W. Rhoads, David B. Tavakkolizadeh, Ali TI MicroRNA mir-16 is anti-proliferative in enterocytes and exhibits diurnal rhythmicity in intestinal crypts SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE MicroRNA; Diurnal; Proliferation; Enterocyte ID EPITHELIAL-CELL PROLIFERATION; CIRCADIAN GENE-EXPRESSION; CYCLIN D1 EXPRESSION; POSTTRANSCRIPTIONAL REGULATION; CAENORHABDITIS-ELEGANS; MICROARRAY ANALYSIS; TARGETING BCL2; CANCER CELLS; SMALL RNAS; C-ELEGANS AB Background and aims: The intestine exhibits profound diurnal rhythms in function and morphology, in part due to changes in enterocyte proliferation. The regulatory mechanisms behind these rhythms remain largely unknown. We hypothesized that microRNAs are involved in mediating these rhythms, and studied the role of microRNAs specifically in modulating intestinal proliferation. Methods: Diurnal rhythmicity of microRNAs in rat jejunum was analyzed by microarrays and validated by qPCR. Temporal expression of diurnally rhythmic mir-16 was further quantified in intestinal crypts, villi, and smooth muscle using laser capture microdissection and qPCR. Morphological changes in rat jejunum were assessed by histology and proliferation by immunostaining for bromodeoxyuridine. In IEC-6 cells stably overexpressing mir-16, proliferation was assessed by cell counting and MTS assay, cell cycle progression and apoptosis by flow cytometry, and cell cycle gene expression by qPCR and immunoblotting. Results: mir-16 peaked 6 hours after light onset (HALO 6) with diurnal changes restricted to crypts. Crypt depth and villus height peaked at HALO 13-14 in antiphase to mir-16. Overexpression of mir-16 in IEC-6 cells suppressed specific G1/S regulators (cyclins D1-3, cyclin El and cyclin-dependent kinase 6) and produced G1 arrest. Protein expression of these genes exhibited diurnal rhythmicity in rat jejunum, peaking between HALO 11 and 17 in antiphase to mir-16. Conclusions: This is the first report of circadian rhythmicity of specific microRNAs in rat jejunum. Our data provide a link between anti-proliferative mir-16 and the intestinal proliferation rhythm and point to mir-16 as an important regulator of proliferation in jejunal crypts. This function may be essential to match proliferation and absorptive capacity with nutrient availability. (C) 2010 Elsevier Inc. All rights reserved. C1 [Balakrishnan, Anita; Stearns, Adam T.; Ashley, Stanley W.; Tavakkolizadeh, Ali] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Balakrishnan, Anita; Stearns, Adam T.; Ashley, Stanley W.; Rhoads, David B.; Tavakkolizadeh, Ali] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Balakrishnan, Anita] Univ Liverpool, Sch Clin Sci, Div Gastroenterol, Liverpool L69 3GE, Merseyside, England. [Stearns, Adam T.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 2JD, England. [Park, Peter J.; Dreyfuss, Jonathan M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Rhoads, David B.] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. RP Balakrishnan, A (reprint author), Brigham & Womens Hosp, Dept Surg, Thorn 1503,20 Shattuck St, Boston, MA 02115 USA. EM anita.balakrishnan@doctors.org.uk; atavakkoli@partners.org OI Stearns, Adam/0000-0003-4327-7360; Dreyfuss, Jonathan/0000-0001-7242-3991 FU NIDDK NIH HHS [R01 DK047326-10, P30 DK040561, R01 DK047326] NR 61 TC 19 Z9 21 U1 0 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD DEC 10 PY 2010 VL 316 IS 20 BP 3512 EP 3521 DI 10.1016/j.yexcr.2010.07.007 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 684CC UT WOS:000284523600019 PM 20633552 ER PT J AU Farhat, GN Walker, R Buist, DSM Onega, T Kerlikowske, K AF Farhat, Ghada N. Walker, Rod Buist, Diana S. M. Onega, Tracy Kerlikowske, Karla TI Changes in Invasive Breast Cancer and Ductal Carcinoma In Situ Rates in Relation to the Decline in Hormone Therapy Use SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN PLUS PROGESTIN; HEALTHY POSTMENOPAUSAL WOMEN; UNITED-STATES; REPLACEMENT THERAPY; SCREENING MAMMOGRAPHY; POPULATION; DECREASE; IMPACT; TRIAL; FALL AB Purpose To assess trends in invasive breast cancer and ductal carcinoma in situ (DCIS) incidence in association with changes in hormone therapy (HT) use in regular mammography screeners. Methods We included 2,071,814 screening mammography examinations performed between January 1997 and December 2006 on 696,385 women age 40 to 79 years; 9,586 breast cancers were diagnosed within 12 months of a screening examination. We calculated adjusted annual rates (mammogram level) for prevalent HT use, incident invasive breast cancer (overall and by tumor histology and estrogen receptor [ER] status), and incident DCIS. Results After a precipitous decrease in HT use in 2002, the incidence of invasive breast cancer decreased significantly in 2002 to 2006 among women age 50 to 69 years (Ptrend(2002-2006) = .005) and 70 to 79 years (Ptrend(2002-2006) = .003) but not in women age 40 to 49 years (Ptrend(2002-2006) = .45). DCIS rates significantly decreased in women age 50 to 69 years after 2002 (Ptrend(2002-2006) = .02). Invasive ductal tumors significantly declined in women age 50 to 69 years and 70 to 79 years in 2002 to 2006. In women age 50 to 69 years, invasive lobular and ER-positive cancer rates declined steadily in 2002 to 2005 (Ptrend(2002-2005) = .02 and .03, respectively), but an elevated rate in 2006 rendered the overall trend nonsignificant (Ptrend(2002-2006) = .89 and .91, respectively). Conclusion In parallel to the sharp decline in HT use in women undergoing regular mammography screening, invasive breast cancer rates decreased in women age 50 to 69 and 70 to 79 years after 2002, and DCIS rates decreased in women age 50 to 69 years, consistent with evidence that HT cessation reduces breast cancer risk. However, the decrease in incidence may have started to level off in 2006; this finding has not been uniformly reported in other populations, warranting further investigation. C1 Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Kerlikowske, Karla] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Grp Hlth Res Inst, Seattle, WA USA. Norris Cotton Canc Ctr, Dartmouth Med Sch, Lebanon, NH USA. RP Kerlikowske, K (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM karla.kerlikowske@ucsf.edu FU National Cancer Institute [U01CA63740, U01CA86076, U01CA86082, U01CA70013, U01CA63731, U01CA70040] FX Supported by the National Cancer Institute-funded Breast Cancer Surveillance Consortium co-operative agreement (Grants No. U01CA63740, U01CA86076, U01CA86082, U01CA70013, U01CA63731, and U01CA70040). The collection of cancer incidence data was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, please see the following Web site: http://breastscreening.cancer.gov/work/acknowledgement.html. NR 33 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2010 VL 28 IS 35 BP 5140 EP 5146 DI 10.1200/JCO.2010.29.5121 PG 7 WC Oncology SC Oncology GA 691PH UT WOS:000285092800014 PM 21060026 ER PT J AU MacConaill, LE Garraway, LA AF MacConaill, Laura E. Garraway, Levi A. TI Clinical Implications of the Cancer Genome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SMALL-CELL LUNG; ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CONSENSUS CODING SEQUENCES; ADVANCED COLORECTAL-CANCER; LINEAGE-SURVIVAL ONCOGENE; RESECTED COLON-CANCER; TRANS RETINOIC ACID; C-MYC; HUMAN BREAST AB Cancer is a disease of the genome. Most tumors harbor a constellation of structural genomic alterations that may dictate their clinical behavior and treatment response. Whereas elucidating the nature and importance of these genomic alterations has been the goal of cancer biologists for several decades, ongoing global genome characterization efforts are revolutionizing both tumor biology and the optimal paradigm for cancer treatment at an unprecedented scope. The pace of advance has been empowered, in large part, through disruptive technological innovations that render complete cancer genome characterization feasible on a large scale. This article highlights cardinal biologic and clinical insights gleaned from systematic cancer genome characterization. We also discuss how the convergence of cancer genome biology, technology, and targeted therapeutics articulates a cohesive framework for the advent of personalized cancer medicine. C1 [Garraway, Levi A.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Canc Genome Discovery, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Broad Inst, Cambridge, MA USA. RP Garraway, LA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Canc Genome Discovery, 44 Binney St, Boston, MA 02115 USA. EM Levi_Garraway@dfci.harvard.edu FU National Cancer Institute [R21CA126674]; Starr Cancer Consortium; Dana-Farber Cancer Institute FX This work was supported by the National Cancer Institute (Grant No. R21CA126674); the Starr Cancer Consortium (L.A.G.); and the Dana-Farber Cancer Institute. NR 89 TC 91 Z9 91 U1 0 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2010 VL 28 IS 35 BP 5219 EP 5227 DI 10.1200/JCO.2009.27.4944 PG 9 WC Oncology SC Oncology GA 691PH UT WOS:000285092800025 PM 20975063 ER PT J AU Gimenez-Cassina, A Danial, NN AF Gimenez-Cassina, Alfredo Danial, Nika N. TI Noxa: A Sweet Twist to Survival and More SO MOLECULAR CELL LA English DT Editorial Material ID BAD AB The BCL-2 family member Noxa induces apoptosis by antagonizing the prosurvival protein MCL-1. In this issue of Molecular Cell, Lowman et al. (2010) uncover a glucose-dependent phosphoregulatory mechanism that inactivates Noxa's apoptotic function and triggers its capacity to modulate glucose metabolism. C1 [Gimenez-Cassina, Alfredo; Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gimenez-Cassina, Alfredo; Danial, Nika N.] Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA. [Gimenez-Cassina, Alfredo; Danial, Nika N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Danial, NN (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nika_danial@dfci.harvard.edu OI Gimenez-Cassina, Alfredo/0000-0002-2768-2350 NR 9 TC 5 Z9 5 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC 10 PY 2010 VL 40 IS 5 BP 687 EP 688 DI 10.1016/j.molcel.2010.11.037 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695XL UT WOS:000285405800003 PM 21145478 ER PT J AU Black, JC Allen, A Van Rechem, C Forbes, E Longworth, M Tschop, K Rinehart, C Quiton, J Walsh, R Smallwood, A Dyson, NJ Whetstine, JR AF Black, Joshua C. Allen, Andrew Van Rechem, Capucine Forbes, Emily Longworth, Michelle Tschoep, Katrin Rinehart, Claire Quiton, Jonathan Walsh, Ryan Smallwood, Andrea Dyson, Nicholas J. Whetstine, Johnathan R. TI Conserved Antagonism between JMJD2A/KDM4A and HP1 gamma during Cell Cycle Progression SO MOLECULAR CELL LA English DT Article ID HISTONE H3 LYSINE-9; BETA-GLOBIN LOCUS; PERICENTRIC HETEROCHROMATIN; CAENORHABDITIS-ELEGANS; DNA-REPLICATION; C-ELEGANS; MAMMALIAN-CELLS; FISSION YEAST; HP1 PROTEINS; S-PHASE AB The KDM4/JMJD2 family of histone demethylases is amplified in human cancers. However, little is known about their physiologic or tumorigenic roles. We have identified a conserved and unappreciated role for the JMJD2A/KDM4A H3K9/36 tridemethylase in cell cycle progression. We demonstrate that JMJD2A protein levels are regulated in a cell cycle-dependent manner and that JMJD2A overexpression increased chromatin accessibility, S phase progression, and altered replication timing of specific genomic loci. These phenotypes depended on JMJD2A enzymatic activity. Strikingly, depletion of the only C. elegans homolog, JMJD-2, slowed DNA replication and increased ATR/p53-dependent apoptosis. Importantly, overexpression of HP1 gamma antagonized JMJD2A-dependent progression through S phase, and depletion of HPL-2 rescued the DNA replication-related phenotypes in jmjd-2(-/-) animals. Our findings describe a highly conserved model whereby JMJD2A regulates DNA replication by antagonizing HP1 gamma and controlling chromatin accessibility. C1 [Black, Joshua C.; Allen, Andrew; Van Rechem, Capucine; Forbes, Emily; Longworth, Michelle; Tschoep, Katrin; Walsh, Ryan; Dyson, Nicholas J.; Whetstine, Johnathan R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Charlestown, MA 02129 USA. [Black, Joshua C.; Allen, Andrew; Van Rechem, Capucine; Forbes, Emily; Longworth, Michelle; Tschoep, Katrin; Walsh, Ryan; Dyson, Nicholas J.; Whetstine, Johnathan R.] Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. [Rinehart, Claire] Western Kentucky Univ, Dept Biol, Bowling Green, KY 42101 USA. [Quiton, Jonathan] Western Kentucky Univ, Dept Math & Comp Sci, Bowling Green, KY 42101 USA. [Smallwood, Andrea] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. RP Whetstine, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, 13th St, Charlestown, MA 02129 USA. EM jwhetstine@hms.harvard.edu RI Black, Joshua/Q-2484-2015 FU Ellison Medical Foundation; Milton Fund; Astra Zeneca MGH Alliance; Howard Goodman Fellowship; Jane Coffin Childs Memorial Fund for Medical Research FX We are grateful to Ravi Mylvaganam and the MGH Flow Cytometry core for assistance with the FAGS analysis. We would like to thank Sigrid Jacobshagen for technical assistance and Othon Iliopoulos for helpful discussions and comments on the manuscript. We thank Jane Hubbard for suggestions and technical advice regarding mitotic germline nuclei. We thank Steve Smale for providing antibodies to HP1 alpha and HP1 beta, and Adriana La Volpe for providing antibody to RAD-51. We thank Dr. Shohei Mitani of the National Bioresource Project for the tm2966 deletion allele and the CGC for additional C. elegans mutant strains. This work was supported by funding to J.R.W. from the Ellison Medical Foundation, Milton Fund, Astra Zeneca MGH Alliance, and the Howard Goodman Fellowship. J.C.B. is a Fellow of The Jane Coffin Childs Memorial Fund for Medical Research. This investigation has been aided by a grant from The Jane Coffin Childs Memorial Fund for Medical Research. NR 45 TC 76 Z9 78 U1 3 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC 10 PY 2010 VL 40 IS 5 BP 736 EP 748 DI 10.1016/j.molcel.2010.11.008 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695XL UT WOS:000285405800008 PM 21145482 ER PT J AU Levy, C Khaled, M Iliopoulos, D Janas, MM Schubert, S Pinner, S Chen, PH Li, SQ Fletcher, AL Yokoyama, S Scott, KL Garraway, LA Song, JS Granter, SR Turley, SJ Fisher, DE Novina, CD AF Levy, Carmit Khaled, Mehdi Iliopoulos, Dimitrios Janas, Maja M. Schubert, Steffen Pinner, Sophie Chen, Po-Hao Li, Shuqiang Fletcher, Anne L. Yokoyama, Satoru Scott, Kenneth L. Garraway, Levi A. Song, Jun S. Granter, Scott R. Turley, Shannon J. Fisher, David E. Novina, Carl D. TI Intronic miR-211 Assumes the Tumor Suppressive Function of Its Host Gene in Melanoma SO MOLECULAR CELL LA English DT Article ID BREAST-CANCER; MALIGNANT-MELANOMA; MASTER REGULATOR; IN-VIVO; EXPRESSION; MICRORNAS; METASTASIS; CELLS; MITF; PROGNOSIS AB When it escapes early detection, malignant melanoma becomes a highly lethal and treatment-refractory cancer. Melastatin is greatly downregulated in metastatic melanomas and is widely believed to function as a melanoma tumor suppressor. Here we report that tumor suppressive activity is not mediated by melastatin but instead by a microRNA (miR-211) hosted within an intron of melastatin. Increasing expression of miR-211 but not melastatin reduced migration and invasion of malignant and highly invasive human melanomas characterized by low levels of melastatin and miR-211. An unbiased network analysis of melanoma-expressed genes filtered for their roles in metastasis identified three central node genes: IGF2R, TGFBR2, and NFAT5. Expression of these genes was reduced by miR-211, and knockdown of each gene phenocopied the effects of increased miR-211 on melanoma invasiveness. These data implicate miR-211 as a suppressor of melanoma invasion whose expression is silenced or selected against via suppression of the entire melastatin locus during human melanoma progression. C1 [Levy, Carmit; Khaled, Mehdi; Yokoyama, Satoru; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Khaled, Mehdi; Janas, Maja M.; Schubert, Steffen; Pinner, Sophie; Chen, Po-Hao; Li, Shuqiang; Fletcher, Anne L.; Turley, Shannon J.; Novina, Carl D.] Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Boston, MA 02115 USA. [Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Granter, Scott R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Song, Jun S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Khaled, Mehdi; Janas, Maja M.; Schubert, Steffen; Chen, Po-Hao; Li, Shuqiang; Garraway, Levi A.; Novina, Carl D.] Broad Inst Harvard, Cambridge, MA 02141 USA. [Khaled, Mehdi; Janas, Maja M.; Schubert, Steffen; Chen, Po-Hao; Li, Shuqiang; Garraway, Levi A.; Novina, Carl D.] MIT, Cambridge, MA 02141 USA. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. EM dfisher3@partners.org; carl_novina@dfci.harvard.edu RI khaled, mehdi/C-4854-2012; Acton, Sophie/G-9784-2012 OI Acton, Sophie/0000-0003-2704-716X FU National Institutes of Health (NIH) [AR043369]; Melanoma Research Alliance; Adelson Medical Research Foundation; US-Israel Binational Science Foundation; Doris Duke Medical Foundation; American Cancer Society; NRSA [NIH/NCI T32 CA070083] FX We would like to gratefully acknowledge Dr. Meenhard Herlyn for supplying several melanoma short-term cultures for these studies. We also wish to thank Dr. Andrew Kung and Dr. Hans Wildund for insightful discussions. This work was funded by National Institutes of Health (NIH) grant AR043369 (D.E.F.), the Melanoma Research Alliance (D.E.F), the Adelson Medical Research Foundation (D.E.F.), The US-Israel Binational Science Foundation (D.E.F.), the Doris Duke Medical Foundation (D.E.F.), the Doris Duke Medical Foundation (C.D.N.), and by American Cancer Society (C.D.N.). S.L. was supported by NRSA Fellowship (NIH/NCI T32 CA070083). NR 28 TC 118 Z9 121 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC 10 PY 2010 VL 40 IS 5 BP 841 EP 849 DI 10.1016/j.molcel.2010.11.020 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 695XL UT WOS:000285405800017 PM 21109473 ER PT J AU Kovacs, DM Gersbacher, MT Kim, DY AF Kovacs, Dora M. Gersbacher, Manuel T. Kim, Doo Yeon TI Alzheimer's secretases regulate voltage-gated sodium channels SO NEUROSCIENCE LETTERS LA English DT Review DE Alzheimer's disease; BACE1; beta-Secretase; Presenilin; gamma-Secretase; Voltage-gated sodium channel; Sodium channel beta 2-subnit ID AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE; NEURONAL-ACTIVITY; NERVOUS-SYSTEM; CELL-ADHESION; IN-VIVO; MOLECULAR-MECHANISMS; SYNAPTIC PLASTICITY; GAMMA-SECRETASE; UP-REGULATION AB BACE1 and presenilin (PS)/gamma-secretase are primary proteolytic enzymes responsible for the generation of pathogenic amyloid beta-peptides (A beta) in Alzheimer's disease. We and others have found that beta-subunits of the voltage-gated sodium channel (Na(v)beta s) also undergo sequential proteolytic cleavages mediated by BACE1 and PS/gamma-secretase. In a follow-up study, we reported that elevated BACE1 activity regulates total and surface expression of voltage-gated sodium channels (Na(v)1 channels) and thereby modulates sodium currents in neuronal cells and mouse brains. In this review, we focus on the molecular mechanism of how BACE1 and PS/gamma-secretase regulate Na(v)1 channels in neuronal cells. We will also discuss potential physiological and pathological roles of BACE1- and PS/gamma-secretase-mediated processing of Na(v)beta s in relation to Na(v)1 channel function. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Kovacs, Dora M.; Gersbacher, Manuel T.; Kim, Doo Yeon] Harvard Univ, Massachusetts Gen Hosp, Neurobiol Dis Lab,Sch Med, Genet & Aging Res Unit,MassGen Inst Neurodegenera, Charlestown, MA 02129 USA. RP Kim, DY (reprint author), Harvard Univ, Massachusetts Gen Hosp, Neurobiol Dis Lab,Sch Med, Genet & Aging Res Unit,MassGen Inst Neurodegenera, Charlestown, MA 02129 USA. EM dkim@helix.mgh.harvard.edu FU NIH/NIA; Cure Alzheimer's Fund FX This work is supported by grants from the NIH/NIA to D.M.K. and D.Y.K. and from the Cure Alzheimer's Fund to D.M.K. NR 74 TC 13 Z9 14 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 10 PY 2010 VL 486 IS 2 SI SI BP 68 EP 72 DI 10.1016/j.neulet.2010.08.048 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 681HR UT WOS:000284302500004 PM 20817076 ER PT J AU Fiehn, O Garvey, WT Newman, JW Lok, KH Hoppel, CL Adams, SH AF Fiehn, Oliver Garvey, W. Timothy Newman, John W. Lok, Kerry H. Hoppel, Charles L. Adams, Sean H. TI Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women SO PLOS ONE LA English DT Article ID BODY PROTEIN-METABOLISM; REGISTRY PROJECT SUGAR; FATTY-ACID-METABOLISM; DIET-INDUCED OBESITY; MUSCLE LIPID-CONTENT; INSULIN-RESISTANCE; SKELETAL-MUSCLE; WHOLE-BODY; LEUCINE METABOLISM; MELLITUS AB Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = -0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is "anaplerotic stress" emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery. C1 [Fiehn, Oliver] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Garvey, W. Timothy; Lok, Kerry H.] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Garvey, W. Timothy; Lok, Kerry H.] Birmingham VA Med Ctr, Birmingham, AL USA. [Newman, John W.; Adams, Sean H.] Univ Calif Davis, Obes & Metab Res Unit, USDA, Agr Res Serv,Western Human Nutr Res Ctr, Davis, CA 95616 USA. [Newman, John W.; Adams, Sean H.] Univ Calif Davis, Dept Nutr, Davis, CA 95616 USA. [Hoppel, Charles L.] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. RP Fiehn, O (reprint author), Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. EM sean.h.adams@ars.usda.gov FU USDA-ARS [5306-51530-016-00D]; NIH-NIDDK [R01DK078328-01]; NIH [DK-038764, DK-083562, P01 HL-055782]; Department of Veterans Affairs; UAB Center for Clinical and Translational Science [UL1 RR025777]; UAB Nutrition and Obesity Research Center [P30-DK56336]; UAB Diabetes Research and Training Center [P60 DK079626] FX Work was funded in part by the following: intramural USDA-ARS Project 5306-51530-016-00D and NIH-NIDDK R01DK078328-01 (to S.H.A.); NIH grants DK-038764, DK-083562, and P01 HL-055782 and the Merit Review program of the Department of Veterans Affairs (W.T.G.). The authors also acknowledge support from the research core facilities of the UAB Center for Clinical and Translational Science (UL1 RR025777), the UAB Nutrition and Obesity Research Center (P30-DK56336), and the UAB Diabetes Research and Training Center (P60 DK079626). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 132 Z9 132 U1 0 U2 24 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 10 PY 2010 VL 5 IS 12 AR e15234 DI 10.1371/journal.pone.0015234 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 692UU UT WOS:000285181400022 PM 21170321 ER PT J AU Keire, DA Whitelegge, JP Souda, P Faull, KF Bassilian, S Reidelberger, RD Haver, AC Reeve, JR AF Keire, David A. Whitelegge, Julian P. Souda, Puneet Faull, Kym F. Bassilian, Sara Reidelberger, Roger D. Haver, Alvin C. Reeve, Joseph R., Jr. TI PYY(1-36) is the major form of PYY in rat distal small intestine: Quantification using high-resolution mass spectrometry SO REGULATORY PEPTIDES LA English DT Article DE Intestinal mucosa; PYY(3-36); Gly-extended; Gastrointestinal peptides ID INHIBITS FOOD-INTAKE; PEPTIDE-YY PYY; GUT HORMONE; BODY-WEIGHT; STRUCTURAL CHARACTERIZATION; PANCREATIC-SECRETION; INTRAVENOUS-INFUSION; ACID-SECRETION; OBESE RATS; PYY(3-36) AB We measured molecular forms of PYY in the distal half of rat small intestine using a new method for tissue extraction, three sequential reverse phase chromatography steps, and PYY radioimmunoassay and mass spectrometry to measure their levels. The extraction method called RAPID, developed to minimize artifactual degradation of PYY during tissue extraction and sample preparation, uses Reduced temperature, Acidified buffer, Peptidase inhibitors, Isotopically enriched mass spectrometry standards, and Dilution to inhibit and monitor endogenous peptide degradation during tissue processing. Synthetic peptides [PYY(1-36)-NH(2), PYY (3-36)-NH(2), PYY(1-36)-Gly-OH, and PYY(3-36)-Gly-OH] selectively enriched with (13)C(3)-alanine were added as internal standards to the extraction buffer. By collecting mass spectra rather than multiple-reaction-monitoring (MRM) profiles, we simultaneously screen for any PYY forms that were present in the immunoreactive fractions. PYY(1-36)-NH(2), PYY(3-36)-NH(2), PYY(1-36)-Gly-OH, and PYY(3-36)-Gly-OH were identified and quantified at 64.3+/-4.5, 6.1+/-0.9, 0.9+/-0.1, and <0.3 pmol/g of tissue, respectively (n=3). Thus, we found that in rat distal small intestine proPYY is processed to PYY(1-36)-NH(2) with little conversion to PYY(3-36)-NH(2). These data suggest that production of PYY(3-36)-NH(2) (a form with greater potency than PYY(1-36)-NH(2) for inhibition of feeding and gastric emptying) occurs after the peptide leaves its cell of synthesis by enzymatic action in the circulation. (C) 2010 Elsevier B.V. All rights reserved. C1 [Reeve, Joseph R., Jr.] Greater Los Angeles Vet Hlth Care Syst, CURE Digest Dis Res Ctr, VA GLAHS, Los Angeles, CA 90073 USA. [Keire, David A.; Bassilian, Sara; Reeve, Joseph R., Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Los Angeles, CA 90024 USA. [Whitelegge, Julian P.; Souda, Puneet; Faull, Kym F.] Univ Calif Los Angeles, David Geffen Sch Med, Pasarow Mass Spectrometry Lab, NPI Semel Inst, Los Angeles, CA 90024 USA. [Reidelberger, Roger D.; Haver, Alvin C.] Nebraska Western Iowa Hlth Care Syst, Dept Vet Affairs, Res Serv, Omaha, NE 68105 USA. [Reidelberger, Roger D.] Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA. RP Reeve, JR (reprint author), Greater Los Angeles Vet Hlth Care Syst, CURE Digest Dis Res Ctr, VA GLAHS, Rm 120,Bld 115, Los Angeles, CA 90073 USA. EM jreeve@mednet.ucla.edu FU National Institutes of Health [DK-73152, DK 33850, DK 56805]; Veterans Administration Research Service; NIH Center [DK41301]; Peptidomic, Radioimmunoassay, Proteomic Cores FX Supported by National Institutes of Health grants DK-73152 (to R.R.), DK 33850, and DK 56805 (to J.R.R.), by the Veterans Administration Research Service, and by the NIH Center grant DK41301 (to J.R.R.). Support from the Peptidomic, Radioimmunoassay, Proteomic Cores is gratefully acknowledged. NR 39 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD DEC 10 PY 2010 VL 165 IS 2-3 BP 151 EP 157 DI 10.1016/j.regpep.2010.06.006 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 707PW UT WOS:000286299500005 PM 20615437 ER PT J AU Pereyra, FP Jia, XM McLaren, PJ Telenti, A de Bakker, PIW Walker, BD Ripke, S Brumme, CJ Pulit, SL Carrington, M Kadie, CM Carlson, JM Heckerman, D Graham, RR Plenge, RM Deeks, SG Gianniny, L Crawford, G Sullivan, J Gonzalez, E Davies, L Camargo, A Moore, JM Beattie, N Gupta, S Crenshaw, A Burtt, NP Guiducci, C Gupta, N Carrington, M Gao, XJ Qi, Y Yuki, Y Piechocka-Trocha, A Cutrell, E Rosenberg, R Moss, KL Lemay, P O'Leary, J Schaefer, T Verma, P Toth, I Block, B Baker, B Rothchild, A Lian, J Proudfoot, J Alvino, DML Vine, S Addo, MM Allen, TM Altfeld, M Henn, MR Le Gall, S Streeck, H Haas, DW Kuritzkes, DR Robbins, GK Shafer, RW Gulick, RM Shikuma, CM Haubrich, R Riddler, S Sax, PE Daar, ES Ribaudo, HJ Agan, B Agarwal, S Ahern, RL Allen, BL Altidor, S Altschuler, EL Ambardar, S Anastos, K Anderson, B Anderson, V Andrady, U Antoniskis, D Bangsberg, D Barbaro, D Barrie, W Bartczak, J Barton, S Basden, P Basgoz, N Bazner, S Bellos, NC Benson, AM Berger, J Bernard, NF Bernard, AM Birch, C Bodner, SJ Bolan, RK Boudreaux, ET Bradley, M Braun, JF Brndjar, JE Brown, SJ Brown, K Brown, ST Burack, J Bush, LM Cafaro, V Campbell, O Campbell, J Carlson, RH Carmichael, JK Casey, KK Cavacuiti, C Celestin, G Chambers, ST Chez, N Chirch, LM Cimoch, PJ Cohen, D Cohn, LE Conway, B Cooper, DA Cornelson, B Cox, DT Cristofano, MV Cuchural, G Czartoski, JL Dahman, JM Daly, JS Davis, BT Davis, K Davod, SM Deeks, SG DeJesus, E Dietz, CA Dunham, E Dunn, ME Ellerin, TB Eron, JJ Fangman, JJW Farel, CE Ferlazzo, H Fidler, S Fleenor-Ford, A Frankel, R Freedberg, KA French, NK Fuchs, JD Fuller, JD Gaberman, J Gallant, JE Gandhi, RT Garcia, E Garmon, D Gathe, JC Gaultier, CR Gebre, W Gilman, FD Gilson, I Goepfert, PA Gottlieb, MS Goulston, C Groger, RK Gurley, TD Haber, S Hardwicke, R Hardy, WD Harrigan, PR Hawkins, TN Heath, S Hecht, FM Henry, WK Hladek, M Hoffman, RP Horton, JM Hsu, RK Huhn, GD Hunt, P Hupert, MJ Illeman, ML Jaeger, H Jellinger, RM John, M Johnson, JA Johnson, KL Johnson, H Johnson, K Joly, J Jordan, WC Kauffman, CA Khanlou, H Killian, RK Kim, AY Kim, DD Kinder, CA Kirchner, JT Kogelman, L Kojic, EM Korthuis, T Kurisu, W Kwon, DS LaMar, M Lampiris, H Lanzafame, M Lederman, MM Lee, DM Lee, JML Lee, MJ Lee, ETY Lemoine, J Levy, JA Llibre, JM Liguori, MA Little, SJ Liu, AY Lopez, AJ Loutfy, MR Loy, D Mohammed, DY Man, A Mansour, MK Marconi, VC Markowitz, M Marques, R Martin, JN Martin, HL Mayer, KH McElrath, MJ McGhee, TA McGovern, BH McGowan, K McIntyre, D Mcleod, GX Menezes, P Mesa, G Metroka, CE Meyer-Olson, D Miller, AO Montgomery, K Mounzer, KC Nagami, EH Nagin, I Nahass, RG Nelson, MO Nielsen, C Norene, DL O'Connor, DH Ojikutu, BO Okulicz, J Oladehin, OO Oldfield, EC Olender, SA Ostrowski, M Owen, WF Pae, E Parsonnet, J Pavlatos, AM Perlmutter, AM Pierce, MN Pincus, JM Pisani, L Price, LJ Proia, L Prokesch, RC Pujet, HC Ramgopal, M Rathod, A Rausch, M Ravishankar, J Rhame, FS Richards, CS Richman, DD Robbins, GK Rodes, B Rodriguez, M Rose, RC Rosenberg, ES Rosenthal, D Ross, PE Rubin, DS Rumbaugh, E Saenz, L Salvaggio, MR Sanchez, WC Sanjana, VM Santiago, S Schmidt, W Schuitemaker, H Sestak, PM Shalit, P Shay, W Shirvani, VN Silebi, VI Sizemore, JM Skolnik, PR Sokol-Anderson, M Sosman, JM Stabile, P Stapleton, JT Starrett, S Stein, F Stellbrink, HJ Sterman, FL Stone, VE Stone, DR Tambussi, G Taplitz, RA Tedaldi, EM Telenti, A Theisen, W Torres, R Tosiello, L Tremblay, C Tribble, MA Trinh, PD Tsao, A Ueda, P Vaccaro, A Valadas, E Vanig, TJ Vecino, I Vega, VM Veikley, W Wade, BH Walworth, C Wanidworanun, C Ward, DJ Warner, DA Weber, RD Webster, D Weis, S Wheeler, DA White, DJ Wilkins, E Winston, A Wlodaver, CG van't Wout, A Wright, DP Yang, OO Yurdin, DL Zabukovic, BW Zachary, KC Zeeman, B Zhao, M AF Pereyra, Florencia Jia, Xiaoming McLaren, Paul J. Telenti, Amalio de Bakker, Paul I. W. Walker, Bruce D. Ripke, Stephan Brumme, Chanson J. Pulit, Sara L. Carrington, Mary Kadie, Carl M. Carlson, Jonathan M. Heckerman, David Graham, Robert R. Plenge, Robert M. Deeks, Steven G. Gianniny, Lauren Crawford, Gabriel Sullivan, Jordan Gonzalez, Elena Davies, Leela Camargo, Amy Moore, Jamie M. Beattie, Nicole Gupta, Supriya Crenshaw, Andrew Burtt, Noel P. Guiducci, Candace Gupta, Namrata Carrington, Mary Gao, Xiaojiang Qi, Ying Yuki, Yuko Piechocka-Trocha, Alicja Cutrell, Emily Rosenberg, Rachel Moss, Kristin L. Lemay, Paul O'Leary, Jessica Schaefer, Todd Verma, Pranshu Toth, Ildiko Block, Brian Baker, Brett Rothchild, Alissa Lian, Jeffrey Proudfoot, Jacqueline Alvino, Donna Marie L. Vine, Seanna Addo, Marylyn M. Allen, Todd M. Altfeld, Marcus Henn, Matthew R. Le Gall, Sylvie Streeck, Hendrik Haas, David W. Kuritzkes, Daniel R. Robbins, Gregory K. Shafer, Robert W. Gulick, Roy M. Shikuma, Cecilia M. Haubrich, Richard Riddler, Sharon Sax, Paul E. Daar, Eric S. Ribaudo, Heather J. Agan, Brian Agarwal, Shanu Ahern, Richard L. Allen, Brady L. Altidor, Sherly Altschuler, Eric L. Ambardar, Sujata Anastos, Kathryn Anderson, Ben Anderson, Val Andrady, Ushan Antoniskis, Diana Bangsberg, David Barbaro, Daniel Barrie, William Bartczak, J. Barton, Simon Basden, Patricia Basgoz, Nesli Bazner, Suzane Bellos, Nicholaos C. Benson, Anne M. Berger, Judith Bernard, Nicole F. Bernard, Annette M. Birch, Christopher Bodner, Stanley J. Bolan, Robert K. Boudreaux, Emilie T. Bradley, Meg Braun, James F. Brndjar, Jon E. Brown, Stephen J. Brown, Katherine Brown, Sheldon T. Burack, Jedidiah Bush, Larry M. Cafaro, Virginia Campbell, Omobolaji Campbell, John Carlson, Robert H. Carmichael, J. Kevin Casey, Kathleen K. Cavacuiti, Chris Celestin, Gregory Chambers, Steven T. Chez, Nancy Chirch, Lisa M. Cimoch, Paul J. Cohen, Daniel Cohn, Lillian E. Conway, Brian Cooper, David A. Cornelson, Brian Cox, David T. Cristofano, Michael V. Cuchural, George, Jr. Czartoski, Julie L. Dahman, Joseph M. Daly, Jennifer S. Davis, Benjamin T. Davis, Kristine Davod, Sheila M. Deeks, Steven G. DeJesus, Edwin Dietz, Craig A. Dunham, Eleanor Dunn, Michael E. Ellerin, Todd B. Eron, Joseph J. Fangman, John J. W. Farel, Claire E. Ferlazzo, Helen Fidler, Sarah Fleenor-Ford, Anita Frankel, Renee Freedberg, Kenneth A. French, Neel K. Fuchs, Jonathan D. Fuller, Jon D. Gaberman, Jonna Gallant, Joel E. Gandhi, Rajesh T. Garcia, Efrain Garmon, Donald Gathe, Joseph C., Jr. Gaultier, Cyril R. Gebre, Wondwoosen Gilman, Frank D. Gilson, Ian Goepfert, Paul A. Gottlieb, Michael S. Goulston, Claudia Groger, Richard K. Gurley, T. Douglas Haber, Stuart Hardwicke, Robin Hardy, W. David Harrigan, P. Richard Hawkins, Trevor N. Heath, Sonya Hecht, Frederick M. Henry, W. Keith Hladek, Melissa Hoffman, Robert P. Horton, James M. Hsu, Ricky K. Huhn, Gregory D. Hunt, Peter Hupert, Mark J. Illeman, Mark L. Jaeger, Hans Jellinger, Robert M. John, Mina Johnson, Jennifer A. Johnson, Kristin L. Johnson, Heather Johnson, Kay Joly, Jennifer Jordan, Wilbert C. Kauffman, Carol A. Khanlou, Homayoon Killian, Robert K. Kim, Arthur Y. Kim, David D. Kinder, Clifford A. Kirchner, Jeffrey T. Kogelman, Laura Kojic, Erna Milunka Korthuis, Todd Kurisu, Wayne Kwon, Douglas S. LaMar, Melissa Lampiris, Harry Lanzafame, Massimiliano Lederman, Michael M. Lee, David M. Lee, Jean M. L. Lee, Marah J. Lee, Edward T. Y. Lemoine, Janice Levy, Jay A. Llibre, Josep M. Liguori, Michael A. Little, Susan J. Liu, Anne Y. Lopez, Alvaro J. Loutfy, Mono R. Loy, Dawn Mohammed, Debbie Y. Man, Alan Mansour, Michael K. Marconi, Vincent C. Markowitz, Martin Marques, Rui Martin, Jeffrey N. Martin, Harold L., Jr. Mayer, Kenneth Hugh McElrath, M. Juliana McGhee, Theresa A. McGovern, Barbara H. McGowan, Katherine McIntyre, Dawn Mcleod, Gavin X. Menezes, Prema Mesa, Greg Metroka, Craig E. Meyer-Olson, Dirk Miller, Andy O. Montgomery, Kate Mounzer, Karam C. Nagami, Ellen H. Nagin, Iris Nahass, Ronald G. Nelson, Margret O. Nielsen, Craig Norene, David L. O'Connor, David H. Ojikutu, Bisola O. Okulicz, Jason Oladehin, Olakunle O. Oldfield, Edward C., III Olender, Susan A. Ostrowski, Mario Owen, William F., Jr. Pae, Eunice Parsonnet, Jeffrey Pavlatos, Andrew M. Perlmutter, Aaron M. Pierce, Michael N. Pincus, Jonathan M. Pisani, Leandro Price, Lawrence Jay Proia, Laurie Prokesch, Richard C. Pujet, Heather Calderon Ramgopal, Moti Rathod, Almas Rausch, Michael Ravishankar, J. Rhame, Frank S. Richards, Constance Shamuyarira Richman, Douglas D. Robbins, Gregory K. Rodes, Berta Rodriguez, Milagros Rose, Richard C., III Rosenberg, Eric S. Rosenthal, Daniel Ross, Polly E. Rubin, David S. Rumbaugh, Elease Saenz, Luis Salvaggio, Michelle R. Sanchez, William C. Sanjana, Veeraf M. Santiago, Steven Schmidt, Wolfgang Schuitemaker, Hanneke Sestak, Philip M. Shalit, Peter Shay, William Shirvani, Vivian N. Silebi, Vanessa I. Sizemore, James M., Jr. Skolnik, Paul R. Sokol-Anderson, Marcia Sosman, James M. Stabile, Paul Stapleton, Jack T. Starrett, Sheree Stein, Francine Stellbrink, Hans-Jurgen Sterman, F. Lisa Stone, Valerie E. Stone, David R. Tambussi, Giuseppe Taplitz, Randy A. Tedaldi, Ellen M. Telenti, Amalio Theisen, William Torres, Richard Tosiello, Lorraine Tremblay, Cecile Tribble, Marc A. Trinh, Phuong D. Tsao, Alice Ueda, Peggy Vaccaro, Anthony Valadas, Emilia Vanig, Thanes J. Vecino, Isabel Vega, Vilma M. Veikley, Wenoah Wade, Barbara H. Walworth, Charles Wanidworanun, Chingchai Ward, Douglas J. Warner, Daniel A. Weber, Robert D. Webster, Duncan Weis, Steve Wheeler, David A. White, David J. Wilkins, Ed Winston, Alan Wlodaver, Clifford G. van't Wout, Angelique Wright, David P. Yang, Otto O. Yurdin, David L. Zabukovic, Brandon W. Zachary, Kimon C. Zeeman, Beth Zhao, Meng CA Int HIV Controllers Study TI The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation SO SCIENCE LA English DT Article ID DISEASE PROGRESSION; SURFACE EXPRESSION; INFECTION; AIDS; ALLELES; MHC; RESTRICTION; ASSOCIATION; THERAPY; ABSENCE AB Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection. C1 [Pereyra, Florencia; Walker, Bruce D.; Brumme, Chanson J.; Carrington, Mary; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Le Gall, Sylvie; Streeck, Hendrik; Bazner, Suzane; Birch, Christopher; Bradley, Meg; Kwon, Douglas S.; Nagami, Ellen H.; Pae, Eunice; Rathod, Almas; Tsao, Alice; Ueda, Peggy; Zeeman, Beth] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Regon Inst, Boston, MA USA. [Pereyra, Florencia; Kuritzkes, Daniel R.; Sax, Paul E.; Farel, Claire E.; Johnson, Jennifer A.; Liu, Anne Y.; McGowan, Katherine; Theisen, William] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Infect Dis, Boston, MA 02115 USA. [Jia, Xiaoming] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [McLaren, Paul J.; de Bakker, Paul I. W.; Ripke, Stephan; Pulit, Sara L.; Plenge, Robert M.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noel P.; Guiducci, Candace; Gupta, Namrata; Henn, Matthew R.] Harvard & MIT, Broad Inst, Cambridge, MA USA. [McLaren, Paul J.; de Bakker, Paul I. W.; Pulit, Sara L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. [Telenti, Amalio] Univ Lausanne, Inst Microbiol, Lausanne, Switzerland. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Div Biomed Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Ripke, Stephan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Dept Med, Boston, MA USA. [Gao, Xiaojiang; Qi, Ying; Yuki, Yuko] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick, Frederick, MD 21701 USA. [Kadie, Carl M.] Microsoft Res, Redmond, WA USA. [Carlson, Jonathan M.; Heckerman, David] Microsoft Res, Los Angeles, CA USA. [Graham, Robert R.] Genentech Inc, San Francisco, CA 94080 USA. [Plenge, Robert M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Deeks, Steven G.; Hecht, Frederick M.; Hunt, Peter; Lampiris, Harry; Levy, Jay A.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Haas, David W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Shafer, Robert W.] Stanford Univ, Palo Alto, CA 94304 USA. [Gulick, Roy M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Shikuma, Cecilia M.] Univ Hawaii, John A Burns Sch Med, Hawaii Ctr AIDS, Honolulu, HI 96822 USA. [Haubrich, Richard; Little, Susan J.; Richman, Douglas D.; Taplitz, Randy A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Riddler, Sharon] Univ Pittsburgh, Pittsburgh, PA USA. [Daar, Eric S.; Hardy, W. David; Yang, Otto O.] Univ Calif Los Angeles, Los Angeles, CA USA. [Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Agan, Brian] Uniformed Serv Univ Hlth Sci, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Agarwal, Shanu] Summa Hlth Syst, Akron, OH USA. [Allen, Brady L.; Lee, David M.] Uptown Phys Grp, Dallas, TX USA. [Altidor, Sherly; Metroka, Craig E.] St Lukes Roosevelt Hosp, New York, NY 10025 USA. [Altschuler, Eric L.; Mohammed, Debbie Y.] Univ Med & Dent New Jersey, New Jersey Med Sch, Univ Hosp, Newark, NJ 07103 USA. [Anastos, Kathryn] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Anderson, Ben] St Leonards Med Ctr, St Leonards, NSW, Australia. 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[Kirchner, Jeffrey T.] Lancaster Gen Hosp, Lancaster, PA USA. [Kogelman, Laura; McGovern, Barbara H.] Tufts Med Ctr, Boston, MA USA. [Kojic, Erna Milunka] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Korthuis, Todd] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Lanzafame, Massimiliano] GB Rossi Hosp, Verona, Italy. [Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Lee, Marah J.] LifeWay, Ft Lauderdale, FL USA. [Lee, Edward T. Y.] St Claire Med Associate, Toronto, ON, Canada. [Lemoine, Janice] Greater Lawrence Family Hlth Ctr, Lawrence, MA USA. [Llibre, Josep M.] Hosp Badalona Germans Trias & Pujol, Barcelona, Spain. [Lopez, Alvaro J.] Infect Dis Consultants, Tucker, GA USA. [Loutfy, Mono R.; Ostrowski, Mario] Univ Toronto, Toronto, ON, Canada. [Loy, Dawn; Prokesch, Richard C.; Vega, Vilma M.] Infect Dis Associates, Sarasota, FL USA. [Marconi, Vincent C.] Emory Univ, Sch Med, Atlanta, GA USA. [Markowitz, Martin] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Martin, Harold L., Jr.] Pk Nicollet Clin, St Louis, MN USA. [McGhee, Theresa A.] Absolute Care, Atlanta, GA USA. [Mcleod, Gavin X.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Mesa, Greg] Highland Med Associates, Hendersonville, NC USA. [Meyer-Olson, Dirk] Hannover Med Sch, Abt Klin Immunol, D-30623 Hannover, Germany. [Miller, Andy O.] Hosp Special Surg, New York, NY 10021 USA. [Mounzer, Karam C.] Philadelphia FIGHT, Philadelphia, PA USA. [Nagin, Iris] Lower E Side Serv Ctr, New York, NY USA. [Nielsen, Craig] Univ Colorado, Aurora, CO USA. [Norene, David L.] Sutter Med Grp, Sacramento, CA USA. [O'Connor, David H.; Sosman, James M.] Univ Wisconsin, Madison, WI USA. [Okulicz, Jason] Brooke Army Med Ctr, San Antonio, TX USA. [Oldfield, Edward C., III] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Olender, Susan A.] Columbia Univ, Med Ctr, New York, NY USA. [Owen, William F., Jr.] CA Pacific Med Ctr, San Francisco, CA USA. [Parsonnet, Jeffrey] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Pavlatos, Andrew M.] St Joseph Hosp, Chicago, IL USA. [Pincus, Jonathan M.] Codman Sq Hlth Ctr, Dorchester, MA USA. [Pisani, Leandro; Rodriguez, Milagros; Saenz, Luis; Santiago, Steven] CARE Resource, Miami, FL USA. [Price, Lawrence Jay] Castro Mission Hlth Ctr, San Francisco, CA USA. [Proia, Laurie] Rush Med Coll, Chicago, IL 60612 USA. [Pujet, Heather Calderon] Boulder Community Hosp, Boulder, CO USA. [Ramgopal, Moti] Midway Immunol & Res Ctr, Ft Pierce, FL USA. [Rausch, Michael] Aerztezentrum Nollendorfpl, Berlin, Germany. [Ravishankar, J.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Rhame, Frank S.] Clin 42, Minneapolis, MN USA. [Richards, Constance Shamuyarira] King Edward Mem Hosp, Paget, Bermuda. [Rodes, Berta] Hosp Carlos III, Fdn Invest Biomed, Madrid, Spain. [Rose, Richard C., III] Summit Med Grp, Knoxville, TN USA. [Rosenthal, Daniel] Med Consultants S Florida, Coral Springs, FL USA. [Ross, Polly E.] Western N Carolina Community Hlth Serv, Asheville, NC USA. [Rubin, David S.] New York Hosp, Queens Med Ctr, Flushing, NY USA. [Salvaggio, Michelle R.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Sanchez, William C.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Sanjana, Veeraf M.] Village Care Hlth Ctr, New York, NY USA. [Schuitemaker, Hanneke; van't Wout, Angelique] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Sestak, Philip M.] St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. [Shalit, Peter] Swedish Med Ctr, Seattle, WA USA. [Shirvani, Vivian N.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Silebi, Vanessa I.] Mercy Hosp, Miami, FL USA. [Sizemore, James M., Jr.] Univ Tennessee, Chattanooga, TN USA. [Sokol-Anderson, Marcia] St Louis Univ, St Louis, MO 63103 USA. [Stabile, Paul] William F Ryan Community Hlth Ctr, New York, NY USA. [Stapleton, Jack T.] Univ Iowa, Iowa City, IA USA. [Starrett, Sheree] Rivington House & Village Care, New York, NY USA. [Stellbrink, Hans-Jurgen] Infekt Med Ctr Hamburg, Hamburg, Germany. [Sterman, F. Lisa] Calif Pacific Med Ctr, San Francisco, CA USA. [Stone, David R.] Lemuel Shattuck Hosp, Boston, MA USA. [Tambussi, Giuseppe] Fdn San Raffaele Del Monte Tabor, Milan, Italy. [Tedaldi, Ellen M.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Torres, Richard] Yale Univ, Sch Med, Bridgeport, CT USA. [Tosiello, Lorraine] Jersey City Med Ctr, Jersey City, NJ USA. [Tremblay, Cecile] Univ Montreal, Montreal, PQ, Canada. [Tribble, Marc A.] Baylor Univ, Med Ctr, Dallas, TX USA. [Trinh, Phuong D.] Montgomery Infect Dis Associates, Silver Spring, MD USA. [Vaccaro, Anthony] Northwestern Univ, Chicago, IL 60611 USA. [Valadas, Emilia] Hosp Santa Maria, Fac Med Lisboa, Lisbon, Portugal. [Vanig, Thanes J.] Spectrum Med Grp, Phoenix, AZ USA. [Vecino, Isabel; Weis, Steve] Univ N Texas, Hlth Sci Ctr, Ft Worth, TX USA. [Wade, Barbara H.] Infect Dis Associates NW Florida, Pensacola, FL USA. [Ward, Douglas J.] Dupont Circle Phys Grp, Washington, DC USA. [Weber, Robert D.] Infect Dis Specialists, Colorado Springs, CO USA. [Webster, Duncan] St Johns Hosp, St John, NB, Canada. [Wheeler, David A.] Clin Alliance Res & Educ Infect Dis, Annandale, VA USA. [White, David J.] Birmingham Heartlands Hosp, Birmingham B9 5ST, W Midlands, England. [Wilkins, Ed] N Manchester Grp Hosp, Manchester, Lancs, England. [Wright, David P.] Cent Texas Clin Res, Austin, TX USA. [Yurdin, David L.] Primary Hlth Care, Des Moines, IA USA. [Zabukovic, Brandon W.] Mem Neighborhood Hlth Ctr Cent Clin, South Bend, IN USA. [Zhao, Meng] United Hlth Serv Hosp, Binghamton, NY USA. [Pierce, Michael N.] All Med & Rehabil New York, Bronx, NY USA. RP Walker, BD (reprint author), Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Regon Inst, Boston, MA USA. EM pdebakker@rics.bwh.harvard.edu; bwalker@partners.org RI Robbins, Gregory/F-7988-2011; de Bakker, Paul/B-8730-2009; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; Marconi, Vincent/N-3210-2014; OI de Bakker, Paul/0000-0001-7735-7858; Marconi, Vincent/0000-0001-8409-4689; Valadas, Emilia/0000-0001-5213-1473; Brumme, Chanson/0000-0003-2722-5288 FU Mark and Lisa Schwartz Foundation; Bill and Melinda Gates Foundation; Harvard University Center for AIDS Research [P-30-AI060354]; University of California San Francisco (UCSF) Center for AIDS Research [P-30 AI27763]; UCSF Clinical and Translational Science Institute [UL1 RR024131]; Center for AIDS Research Network of Integrated Clinical Systems [R24 AI067039]; NIH [AI28568, AI030914, AI087145, K24AI069994, AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI069465, AI069511]; Swiss National Science Foundation (SNF) [33CSC0-108787, 310000-110012]; NIH/National Institute of Mental Health [MH085520]; National Cancer Institute/NIH [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This work was made possible through a generous donation from the Mark and Lisa Schwartz Foundation and a subsequent award from the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation. This work was also supported in part by the Harvard University Center for AIDS Research (grant P-30-AI060354); University of California San Francisco (UCSF) Center for AIDS Research (grant P-30 AI27763); UCSF Clinical and Translational Science Institute (grant UL1 RR024131); Center for AIDS Research Network of Integrated Clinical Systems (grant R24 AI067039); and NIH grants AI28568 and AI030914 (B. D. W.); AI087145 and K24AI069994 (S. G. D.); AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI28568, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI68634, AI069502, AI069419, AI068636, and RR024975 (AIDS Clinical Trials Group); and AI077505 and MH071205 (D. W. H.). The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation (SNF grants 33CSC0-108787 and 310000-110012). S. Ripke acknowledges support from NIH/National Institute of Mental Health (grant MH085520). This project has been funded in whole or in part with funds from National Cancer Institute/NIH (grant HHSN261200800001E to M. Carrington). The content of this publication does not necessarily reflect the views or policies of the U. S. Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the U. S. government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 31 TC 469 Z9 473 U1 5 U2 87 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 10 PY 2010 VL 330 IS 6010 BP 1551 EP 1557 DI 10.1126/science.1195271 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 692LE UT WOS:000285153500069 ER PT J AU Fu, YY Zhou, J Li, HB Cao, FL Su, YH Fan, SJ Li, YH Wang, SY Li, LM Gilbert, GE Shi, JL AF Fu, Yueyue Zhou, Jin Li, Huibo Cao, Fenglin Su, Yanhua Fan, Shengjin Li, Yinghua Wang, Shuye Li, Limin Gilbert, Gary E. Shi, Jialan TI Daunorubicin induces procoagulant activity of cultured endothelial cells through phosphatidylserine exposure and microparticles release SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Daunorubicin; endothelial cells; phosphatidylserine; microparticles; lactadherin ID TISSUE FACTOR; ANNEXIN-V; PHOSPHOLIPID-BINDING; LEUKEMIA-CELLS; LACTADHERIN; BLOOD; THROMBOSIS; COAGULATION; HEMOSTASIS; ACTIVATION AB Administration of various chemotherapeutic agents is associated with an increased risk of thrombotic events. Although vascular endothelium plays a predominant role in blood coagulation and fibrinolysis, the effect of cytotoxic drugs on the procoagulant activity (PCA) of endothelial cells has not been well evaluated. Our study aims to investigate the possibility that daunorubicin, a chemotherapeutic agent, exerts prothrombotic effect on endothelial cells. We tested the impact of daunorubicin on phosphatidylserine (PS) exposure, endothelial microparticles (EMPs) release and consequent PCA. Human umbilical vein endothelial cells (HUVECs) were treated with daunorubicin (0.1, 0.2, 0.5, 1, 2 mu M) for 24 hours. PCA of HUVECs was measured using clotting time and purified coagulation complex assays. Counts and PCA of EMPs were evaluated by flow cytometry and clotting time assay, respectively. Lactadherin was used as a novel probe for detection of PS exposure and EMPs release. We found that daunorubicin dose-dependently increased the PS exposure and consequent PCA of HUVECs. Moreover, daunorubicin treatment also enhanced the release of EMPs which were highly procoagulant. This increment was especially significant at 0.2 mu M of daunorubicin or more. Blockade of PS with lactadherin inhibited over 90% of HUVECs and EMPs PCA. However, anti-TF antibody had no significant inhibition effect. Our results demonstrate that daunorubicin treatment enhanced PCA of HUVECs through PS exposure and shedding of procoagulant EMPs. Lactadherin acts as an efficient anticoagulant in this process. C1 [Fu, Yueyue; Zhou, Jin; Li, Huibo; Cao, Fenglin; Su, Yanhua; Fan, Shengjin; Li, Yinghua; Wang, Shuye; Li, Limin; Shi, Jialan] Harbin Med Coll, Affiliated Hosp 1, Dept Hematol, Harbin 150001, Peoples R China. [Gilbert, Gary E.; Shi, Jialan] Brigham & Womens Hosp, Dept Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Gilbert, Gary E.; Shi, Jialan] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Shi, JL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, VA Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM jinzhouh85@163.com; wangshuye@126.com; jialan_shi@hms.harvard.edu FU National Natural Science Foundation of China [30871227]; National Traditional Chinese Medicine Bureau [0607LP15]; International Cooperation Foundation [WH05C01]; Scientific Foundation of Heilongjiang Province [GB08C401-02]; Health Department Foundation of Heilongjiang Province [2009-548, 2009-549] FX This work was supported by the National Natural Science Foundation of China (30871227), the National Traditional Chinese Medicine Bureau (0607LP15), the International Cooperation Foundation (WH05C01), the Scientific Foundation of Heilongjiang Province (GB08C401-02), and the Health Department Foundation of Heilongjiang Province (2009-548, 2009-549). NR 39 TC 23 Z9 24 U1 0 U2 4 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD DEC 10 PY 2010 VL 104 IS 6 BP 1235 EP 1241 DI 10.1160/TH10-02-0102 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 695MJ UT WOS:000285374300021 PM 20886178 ER PT J AU Fornaro, M Iovieno, N Clementi, N Boscaro, M Paggi, F Balercia, G Fava, M Papakostas, GI AF Fornaro, Michele Iovieno, Nadia Clementi, Nicoletta Boscaro, Marco Paggi, Francesca Balercia, Giancarlo Fava, Maurizio Papakostas, George I. TI Diagnosis of co-morbid axis-I psychiatric disorders among women with newly diagnosed, untreated endocrine disorders SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE Major depressive disorder (MDD); axis-I psychiatric disorders; endocrine disorders; co-morbidity; newly diagnosed; screening ID PANIC DISORDER; DEPRESSION; HYPERTHYROIDISM; PREVALENCE; ANXIETY; METAANALYSIS; SYMPTOMS; DISEASE; ADULTS; RISK AB Objectives. To determine the prevalence of major depressive disorder (MDD) and other selected axis-I disorders among women with newly diagnosed, untreated endocrine disorders. Methods. Two hundred and eighteen consecutive women, aged 18-65, with newly diagnosed, untreated endocrine disorders were referred for potential diagnosis of co-morbid axis-I disorders with the use of the Structured Clinical Interview for Axis I-Patient Edition (SCID-P). The SCID-P was re-administered after 12 weeks. Results. At baseline, 64 (29.3%) women met criteria for at least one axis-I disorder. Women who were diagnosed with hyperthyroidism were more likely to meet criteria for generalized anxiety disorder and panic disorder than women without hyperthyroidism. Nine of 154 (5.8 %) women who did not meet criteria for an axis-I disorder at baseline met criteria for at least one axis-I disorder during follow-up. Among them, the presence of diabetes mellitus was statistically correlated with a higher probability of developing major depressive disorder at follow-up. Conclusions. Although preliminary, our findings are consistent with previous studies and suggest an increased prevalence of MDD and other axis-I disorders among women with newly diagnosed endocrine disorders, providing further evidence suggesting that women with endocrine abnormalities may be at increased risk of depression and/or anxiety disorders. C1 [Fornaro, Michele] Univ Genoa, Dept Neurosci, Sect Psychiat, Genoa, Italy. [Fornaro, Michele; Iovieno, Nadia; Fava, Maurizio; Papakostas, George I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. [Iovieno, Nadia] Univ Pisa, Dept Psychiat, Pisa, Italy. [Clementi, Nicoletta] Univ Bristol, Psychopharmacol Unit, Bristol, Avon, England. [Boscaro, Marco; Paggi, Francesca; Balercia, Giancarlo] Polytech Univ Marche, Sch Med, Umberto I Hosp, Dept Internal Med & Appl Biotechnol, Ancona, Italy. RP Fornaro, M (reprint author), Univ Genoa, Dept Neurosci, Sect Psychiat, Largo Rosanna Benzi 16, Genoa, Italy. EM Dott.Fornaro@gmail.com RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; BOSCARO, MARCO/0000-0003-2596-1652; Fornaro, Michele/0000-0002-9647-0853 NR 35 TC 7 Z9 8 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD DEC 10 PY 2010 VL 11 IS 8 BP 991 EP 996 DI 10.3109/15622975.2010.491126 PG 6 WC Psychiatry SC Psychiatry GA 680WM UT WOS:000284268200009 PM 20569197 ER PT J AU Wingard, JR Carter, SL Walsh, TJ Kurtzberg, J Small, TN Baden, LR Gersten, ID Mendizabal, AM Leather, HL Confer, DL Maziarz, RT Stadtmauer, EA Bolanos-Meade, J Brown, J DiPersio, JF Boeckh, M Marr, KA AF Wingard, John R. Carter, Shelly L. Walsh, Thomas J. Kurtzberg, Joanne Small, Trudy N. Baden, Lindsey R. Gersten, Iris D. Mendizabal, Adam M. Leather, Helen L. Confer, Dennis L. Maziarz, Richard T. Stadtmauer, Edward A. Bolanos-Meade, Javier Brown, Janice DiPersio, John F. Boeckh, Michael Marr, Kieren A. CA Blood & Marrow Transplant Clinical TI Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; STEM-CELL; ASPERGILLOSIS; PROPHYLAXIS; RECIPIENTS; POSACONAZOLE; GALACTOMANNAN; SURVEILLANCE; ITRACONAZOLE; MULTICENTER AB Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and over-all survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803. (Blood. 2010;116(24):5111-5118) C1 [Wingard, John R.] Univ Florida, Coll Med, Div Hematol Oncol, Gainesville, FL 32610 USA. [Carter, Shelly L.; Gersten, Iris D.; Mendizabal, Adam M.] EMMES Corp, Rockville, MD USA. [Walsh, Thomas J.] NCI, Bethesda, MD 20892 USA. [Kurtzberg, Joanne] Duke Univ, Durham, NC USA. [Small, Trudy N.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Baden, Lindsey R.] Dana Farber Partners Canc Inst, Boston, MA USA. [Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Stadtmauer, Edward A.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Bolanos-Meade, Javier; Marr, Kieren A.] Johns Hopkins Univ, Baltimore, MD USA. [Brown, Janice] Stanford Univ, Palo Alto, CA 94304 USA. [DiPersio, John F.] Washington Univ, St Louis, MO USA. [Boeckh, Michael; Marr, Kieren A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Wingard, JR (reprint author), Univ Florida, Coll Med, Div Hematol Oncol, 1600 SW Archer Rd,POB 100278, Gainesville, FL 32610 USA. EM wingajr@medicine.ufl.edu FU National Institutes of Health (NIH) [U01-8L069294]; NIH-NHLBI-NCI; Pfizer; Astellas; Merck; Basilea; Novartis; Vestagen; Schering-Plough FX We are also grateful to Pfizer for an unrestricted educational grant. This work was supported by a National Institutes of Health (NIH) grant (U01-8L069294).; Conflict-of-interest disclosure: J.R.W., J.K., L.R.B., J.B., E.A.S., J.B-M., M.B., S.L.C., and D.L.C. have received research funding from NIH-NHLBI-NCI. J.R.W. has received consultancy fees, honoraria, presentation fees, and travel reimbursement from Pfizer and Astellas; consultancy fees, honoraria, and travel reimbursement from Merck; and has served on data-monitoring boards for Basilea and Merck. K.A.M. has received research funding from Merck, consultancy fees from Basilea and Novartis, and has served on boards for Astellas, Merck, and Pfizer. T.J.W. has received research funding from Vestagen. T.N.S. has received honoraria from Pfizer, and a family member is employed by Pfizer. H.L.L. has served on speakers' bureaus and received honoraria from Pfizer, Merck, and Schering-Plough. R.T.M. has served on speakers' bureaus for Schering-Plough. M.B. has received research funding and honoraria from Pfizer and has a patent pending with Pfizer. I.D.G., A.M.M., and J.F.D declare no competing financial interests. NR 32 TC 165 Z9 172 U1 1 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 9 PY 2010 VL 116 IS 24 BP 5111 EP 5118 DI 10.1182/blood-2010-02-268151 PG 8 WC Hematology SC Hematology GA 692GL UT WOS:000285141200008 PM 20826719 ER PT J AU Ko, M Huang, Y Jankowska, AM Pape, UJ Tahiliani, M Bandukwala, HS An, J Lamperti, ED Koh, KP Ganetzky, R Liu, XS Aravind, L Agarwal, S Maciejewski, JP Rao, A AF Ko, Myunggon Huang, Yun Jankowska, Anna M. Pape, Utz J. Tahiliani, Mamta Bandukwala, Hozefa S. An, Jungeun Lamperti, Edward D. Koh, Kian Peng Ganetzky, Rebecca Liu, X. Shirley Aravind, L. Agarwal, Suneet Maciejewski, Jaroslaw P. Rao, Anjana TI Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 SO NATURE LA English DT Article ID DNA METHYLATION; MUTATIONS; MALIGNANCIES; THERAPY; COMMON; HYPOMETHYLATION; MYELOFIBROSIS; EPIGENETICS; CONVERSION; NEOPLASMS AB TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA(1,2). The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies(3). Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML)(4-12). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. C1 [Ko, Myunggon; Huang, Yun; Pape, Utz J.; Tahiliani, Mamta; Bandukwala, Hozefa S.; An, Jungeun; Lamperti, Edward D.; Koh, Kian Peng; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. [Ko, Myunggon; Huang, Yun; Pape, Utz J.; Tahiliani, Mamta; Bandukwala, Hozefa S.; An, Jungeun; Lamperti, Edward D.; Koh, Kian Peng; Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Jankowska, Anna M.; Ganetzky, Rebecca; Maciejewski, Jaroslaw P.] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44195 USA. [Jankowska, Anna M.; Ganetzky, Rebecca; Maciejewski, Jaroslaw P.] Cleveland Clin, Dept Hematol Oncol & Blood Disorders, Cleveland, OH 44195 USA. [Pape, Utz J.; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Pape, Utz J.; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Agarwal, Suneet] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Agarwal, Suneet] Harvard Stem Cell Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Rao, A (reprint author), La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. EM maciejj@ccf.org; arao@idi.harvard.edu OI Huang, Yun/0000-0001-5950-9168 FU NIH [R01 AI44432, RC1 DA028422, K24 HL077522, R01 HL098522, R01 HG4069]; Aplastic Anemia MDS Foundation; Bob Duggan Memorial Research Fund; Harvard Catalyst; Harvard Clinical and Translational Science Center (NIH) [1 UL1 RR 025758-02]; GlaxoSmithKline-Immune Disease Institute (GSK-IDI) Alliance; Leukemia and Lymphoma Society of America FX This work was supported by NIH grants R01 AI44432 and RC1 DA028422 (to A.R.), NIH grants K24 HL077522 and R01 HL098522, an Established Investigator award from the Aplastic Anemia & MDS Foundation, and an award from the Bob Duggan Memorial Research Fund (to J.P.M), NIH grant R01 HG4069 (to X.S.L.) and a pilot grant from Harvard Catalyst, The Harvard Clinical and Translational Science Center (NIH Grant #1 UL1 RR 025758-02, to S.A.). Y.H. was supported by postdoctoral fellowships from the GlaxoSmithKline-Immune Disease Institute (GSK-IDI) Alliance and the Leukemia and Lymphoma Society of America. H.S.B. is supported by a postdoctoral fellowship from the GSK-IDI Alliance. NR 26 TC 583 Z9 604 U1 10 U2 112 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 9 PY 2010 VL 468 IS 7325 BP 839 EP 843 DI 10.1038/nature09586 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 691PQ UT WOS:000285093700049 PM 21057493 ER PT J AU Binder, WD Traum, AZ Makar, RS Colvin, RB AF Binder, William D. Traum, Avram Z. Makar, Robert S. Colvin, Robert B. TI Case 37-2010: A 16-Year-Old Girl with Confusion, Anemia, and Thrombocytopenia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HEMOLYTIC-UREMIC SYNDROME; VON-WILLEBRAND-FACTOR; FACTOR-CLEAVING PROTEASE; THROMBOTIC MICROANGIOPATHIES; NEUROLOGIC MANIFESTATIONS; CLINICAL-OUTCOMES; PLASMA-EXCHANGE; PURPURA; ADAMTS13 C1 [Binder, William D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Traum, Avram Z.] Massachusetts Gen Hosp, Pediat Nephrol Serv, Boston, MA 02114 USA. [Makar, Robert S.] Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Binder, William D.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Traum, Avram Z.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Makar, Robert S.; Colvin, Robert B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Binder, WD (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. NR 38 TC 4 Z9 6 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 9 PY 2010 VL 363 IS 24 BP 2352 EP 2361 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 691PA UT WOS:000285092100012 PM 21142538 ER PT J AU Savgan-Gurol, E Bredella, M Russell, M Mendes, N Klibanski, A Misra, M AF Savgan-Gurol, Eray Bredella, Miriam Russell, Melissa Mendes, Nara Klibanski, Anne Misra, Madhusmita TI Waist to hip ratio and trunk to extremity fat (DXA) are better surrogates for IMCL and for visceral fat respectively than for subcutaneous fat in adolescent girls SO NUTRITION & METABOLISM LA English DT Article ID X-RAY ABSORPTIOMETRY; CARDIOVASCULAR RISK-FACTORS; ABDOMINAL ADIPOSE-TISSUE; INSULIN SENSITIVITY; SKELETAL-MUSCLE; OBESE CHILDREN; TOTAL-BODY; ACCUMULATION; CIRCUMFERENCE; SPECTROSCOPY AB Background: Increased visceral adipose tissue (VAT) and intramyocellular lipids (IMCL) are associated with increased metabolic risk. Clinical and DXA body composition measures that are associated with VAT are generally even more strongly associated with subcutaneous adipose tissue (SAT) reflecting general adiposity, and thus are not specific for VAT. Measures more strongly associated with VAT than SAT (thus more specific for VAT), and predictors of IMCL have not been reported. Subjects/Methods: We studied 30 girls 12-18 years; 15 obese, 15 normal-weight. The following were assessed: (1) anthropometric measures: waist circumference at the umbilicus and iliac crest (WC-UC and WC-IC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), (2) DXA measures: total fat, percent body fat (PBF), percent trunk fat (PTF), trunk-to-extremity fat ratio (TEFR), (3) MRI and 1H-MRS: VAT and SAT (L4-L5), soleus-IMCL. Results: Group as a whole: WC, trunk fat and PBF were more strongly associated with SAT than VAT; none were specific for VAT. In contrast, PTF and TEFR were more significantly associated with VAT (r = 0.83 and 0.81 respectively, p < 0.0001 for both) than SAT (r = 0.77 and 0.75, p < 0.0001 for both). Strongest associations of S-IMCL were with WHR (r = 0.66, p = 0.0004). Subgroup analysis: In obese girls, WHR and WHtR were more strongly correlated with VAT (r = 0.62 and 0.82, p = 0.04 and 0.001) than SAT (r = 0.41 and 0.73, p not significant and 0.007), and for DXA measures, PTF and TEFR were more significantly associated with VAT (r = 0.70 and 0.72, p = 0.007 and 0.006) than SAT (r = 0.52 and 0.53, p = 0.07 and 0.06). In controls, PTF and TEFR were more strongly correlated with VAT (r = 0.79, p = 0.0004 for both) than SAT (r = 0.71 and 0.72, p = 0.003 for both). WHR was associated with IMCL in obese girls (r = 0.78, p = 0.008), but not controls. Conclusion: Overall, WHR (anthropometry), and PTF and TEFR (DXA) are good surrogates for IMCL and for visceral fat respectively in adolescent girls. C1 [Savgan-Gurol, Eray; Russell, Melissa; Mendes, Nara; Klibanski, Anne; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Savgan-Gurol, Eray; Bredella, Miriam; Russell, Melissa; Mendes, Nara; Klibanski, Anne; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Savgan-Gurol, Eray; Russell, Melissa; Misra, Madhusmita] Mass Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Bredella, Miriam] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/E-4682-2013; Mendes Estella, Nara/A-1469-2015 FU [1 UL1 RR025758-01]; [5P30DK4620-15] FX The work was supported in part by grants 1 UL1 RR025758-01 and 5P30DK4620-15. The authors have no conflicts of interest to disclose. We would like to thank the skilled nursing staff of the CRC of Massachusetts General Hospital for the care provided to our subjects at the CRC. We would also like to thank our study volunteers, without whose participation this study would not have been possible. NR 27 TC 23 Z9 24 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD DEC 9 PY 2010 VL 7 AR 86 DI 10.1186/1743-7075-7-86 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 704SL UT WOS:000286072600001 PM 21143876 ER PT J AU McFall, M Saxon, AJ Malte, CA Chow, B Bailey, S Baker, DG Beckham, JC Boardman, KD Carmody, TP Joseph, AM Smith, MW Shih, MC Lu, Y Holodniy, M Lavori, PW AF McFall, Miles Saxon, Andrew J. Malte, Carol A. Chow, Bruce Bailey, Sara Baker, Dewleen G. Beckham, Jean C. Boardman, Kathy D. Carmody, Timothy P. Joseph, Anne M. Smith, Mark W. Shih, Mei-Chiung Lu, Ying Holodniy, Mark Lavori, Philip W. CA CSP 519 Study Team TI Integrating Tobacco Cessation Into Mental Health Care for Posttraumatic Stress Disorder A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SMOKING-CESSATION; MAJOR DEPRESSION; CLINICAL-TRIALS; PSYCHIATRIC-DISORDERS; NICOTINE DEPENDENCE; SMOKERS; VETERANS; PREVALENCE; SYMPTOMS; INTERVENTIONS AB Context Most smokers with mental illness do not receive tobacco cessation treatment. Objective To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates. Design, Setting, and Patients A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009. Intervention Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment. Main Outcome Measures Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status. Results Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P=.004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P<.001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P<.001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P=.03), whose scores did not change over time. Conclusion Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence. C1 [McFall, Miles; Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [McFall, Miles; Saxon, Andrew J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Malte, Carol A.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Washington, DC USA. [Chow, Bruce; Shih, Mei-Chiung; Lu, Ying; Holodniy, Mark] Vet Affairs Palo Alto Hlth Care Syst, Vet Affairs Cooperat Studies Program, Palo Alto, CA USA. [Bailey, Sara] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Bailey, Sara] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Baker, Dewleen G.] Vet Affairs Healthcare Syst, Vet Affairs Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. [Baker, Dewleen G.] Univ Calif San Diego, San Diego, CA 92103 USA. [Beckham, Jean C.] Duke Univ, Med Ctr, Durham Vet Affairs Med Ctr, Vet Affairs Midatlantic Reg Mental Illness Res Ed, Durham, NC USA. [Beckham, Jean C.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Boardman, Kathy D.] Clin Res Pharm Coordinating Ctr, Vet Affairs Cooperat Studies Program, Albuquerque, NM USA. [Carmody, Timothy P.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Carmody, Timothy P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Joseph, Anne M.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Smith, Mark W.] Dept Vet Affairs, Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Shih, Mei-Chiung; Lu, Ying; Lavori, Philip W.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA. RP McFall, M (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way,S-116 MHC, Seattle, WA 98108 USA. EM miles.mcfall@va.gov RI Smith, Mark/G-1522-2012 OI Smith, Mark/0000-0002-4582-9088 FU US Department of Veterans Affairs [CSP 519] FX This work was supported by the US Department of Veterans Affairs Cooperative Studies Program (CSP 519). NR 47 TC 101 Z9 101 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 8 PY 2010 VL 304 IS 22 BP 2485 EP 2493 DI 10.1001/jama.2010.1769 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 691AS UT WOS:000285053300022 PM 21139110 ER PT J AU Foland-Ross, LC Altshuler, LL Bookheimer, SY Lieberman, MD Townsend, J Penfold, C Moody, T Ahlf, K Shen, JK Madsen, SK Rasser, PE Toga, AW Thompson, PM AF Foland-Ross, Lara C. Altshuler, Lori L. Bookheimer, Susan Y. Lieberman, Matthew D. Townsend, Jennifer Penfold, Conor Moody, Teena Ahlf, Kyle Shen, Jim K. Madsen, Sarah K. Rasser, Paul E. Toga, Arthur W. Thompson, Paul M. TI Amygdala Reactivity in Healthy Adults Is Correlated with Prefrontal Cortical Thickness SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FEAR EXTINCTION; IN-VIVO; CORTEX; EMOTION; SCHIZOPHRENIA; MODULATION; NEURONS; HUMANS; MEMORY; HIPPOCAMPUS AB Recent evidence suggests that putting feelings into words activates the prefrontal cortex (PFC) and suppresses the response of the amygdala, potentially helping to alleviate emotional distress. To further elucidate the relationship between brain structure and function in these regions, structural and functional magnetic resonance imaging (MRI) data were collected from a sample of 20 healthy human subjects. Structural MRI data were processed using cortical pattern-matching algorithms to produce spatially normalized maps of cortical thickness. During functional scanning, subjects cognitively assessed an emotional target face by choosing one of two linguistic labels (label emotion condition) or matched geometric forms (control condition). Manually prescribed regions of interest for the left amygdala were used to extract percentage signal change in this region occurring during the contrast of label emotion versus match forms. A correlation analysis between left amygdala activation and cortical thickness was then performed along each point of the cortical surface, resulting in a color-coded r value at each cortical point. Correlation analyses revealed that gray matter thickness in left ventromedial PFC was inversely correlated with task-related activation in the amygdala. These data add support to a general role of the ventromedial PFC in regulating activity of the amygdala. C1 [Thompson, Paul M.] Univ Calif Los Angeles, Lab Neuro Imaging, Dept Neurol, UCLA Sch Med, Los Angeles, CA 90095 USA. [Altshuler, Lori L.; Bookheimer, Susan Y.; Townsend, Jennifer; Penfold, Conor; Moody, Teena; Ahlf, Kyle; Shen, Jim K.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Lieberman, Matthew D.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Altshuler, Lori L.] W Los Angeles Healthcare Ctr, VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA. [Rasser, Paul E.] Schizophrenia Res Inst, Sydney, NSW 2010, Australia. [Rasser, Paul E.] Univ Newcastle, Prior Ctr Brain & Mental Hlth Res, Callaghan, NSW 2308, Australia. RP Thompson, PM (reprint author), Univ Calif Los Angeles, Lab Neuro Imaging, Dept Neurol, UCLA Sch Med, Neurosci Res Bldg 225E,635 Charles Young Dr, Los Angeles, CA 90095 USA. EM thompson@loni.ucla.edu FU National Institute of Mental Health [F31MH078556, K24 MH001848, R21 MH075944, MH01848]; National Institute of Biomedical Imaging and Bioengineering [EB01651]; National Center for Research Resources (NCRR), National Institutes of Health (NIH) [RR12169, RR13642, RR00865]; National Association for Research on Schizophrenia and Affective Disorders; Brain Mapping Medical Research Organization; Brain Mapping Support Foundation; Pierson-Lovelace Foundation; Ahmanson Foundation; Northern Piedmont Community Foundation; Tamkin Foundation; Jennifer Jones-Simon Foundation; Capital Group Companies Charitable Foundation; Robson Family; Northstar Fund FX This study was supported by grants from the National Institute of Mental Health (F31MH078556 to L.C.F.R. and K24 MH001848, R21 MH075944, and MH01848 to L.L.A.), the National Institute of Biomedical Imaging and Bioengineering (EB01651 to P.M.T.), and the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) (RR12169, RR13642, and RR00865). This study was also supported by the National Association for Research on Schizophrenia and Affective Disorders, the Brain Mapping Medical Research Organization, the Brain Mapping Support Foundation, the Pierson-Lovelace Foundation, the Ahmanson Foundation, the William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, the Tamkin Foundation, the Jennifer Jones-Simon Foundation, the Capital Group Companies Charitable Foundation, the Robson Family, and the Northstar Fund. We thank Dr. Katherine L. Narr for methodological consultations. NR 41 TC 21 Z9 22 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 8 PY 2010 VL 30 IS 49 BP 16673 EP 16678 DI 10.1523/JNEUROSCI.4578-09.2010 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 691NW UT WOS:000285089100028 PM 21148006 ER PT J AU Lyddon, R Cuppen, E Haroutunian, V Siever, LJ Dracheva, S AF Lyddon, Rebecca Cuppen, Edwin Haroutunian, Vahram Siever, Larry J. Dracheva, Stella TI No link of serotonin 2C receptor editing to serotonin transporter genotype SO NEUROREPORT LA English DT Article DE 5-HTTLPR polymorphism; serotonin 2C receptor editing serotonin transporter; serotonin transporter knockout rats ID PRE-MESSENGER-RNA; PREFRONTAL CORTEX; SUICIDE; NEUROBIOLOGY; POLYMORPHISM; EXPRESSION; REGION; BRAIN AB RNA editing is a post-transcriptional process, which has the potential to alter the function of encoded proteins. In particular, serotonin 2C receptor (5-HT2cR) mRNA editing can produce 24 protein isoforms of varying functionality. Rodent studies have shown that 5-HT2cR editing is dynamically modulated in response to environmental challenges. Basal extracellular serotonin, which is strongly influenced by serotonin transporter (SERT), was proposed as a potential trigger for this modulation; however, the data remain inconclusive. Here, 5-HT2cR editing is evaluated in SERT mutant versus wild-type rats, and in humans with different SERT genotypes. Our findings argue against the hypothesis that 5-HT2cR editing efficiency is regulated by extracellular serotonin levels. NeuroReport 21:1080-1084 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Haroutunian, Vahram; Siever, Larry J.; Dracheva, Stella] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Lyddon, Rebecca; Haroutunian, Vahram; Siever, Larry J.; Dracheva, Stella] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Cuppen, Edwin] Univ Med Ctr Utrecht, Hubrecht Inst, KNAW, Ct Utrecht, Netherlands. [Cuppen, Edwin] Univ Med Ctr Utrecht, Dept Med Genet, Ct Utrecht, Netherlands. RP Dracheva, S (reprint author), Bronx VA Med Ctr, Psychiat Res 4F-02,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Stella.Dracheva@mssm.edu RI Cuppen, Edwin/F-5696-2011; Cuppen, Edwin/H-2389-2016 OI Cuppen, Edwin/0000-0002-0400-9542; Cuppen, Edwin/0000-0002-0400-9542 FU Department of Veterans Affairs Office of Research and Development; VISN3 Mental Illness Research and Education Clinical Center; VA; American Foundation for Suicide Prevention FX Postmortem brain tissue was donated by The Stanley Medical Research Institute (8401 Connecticut Avenue, Suite 200, Chevy Chase, MD 20815, USA) courtesy of Drs Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. Support: This material is based on the work supported by Department of Veterans Affairs Office of Research and Development and VISN3 Mental Illness Research and Education Clinical Center (S. D., V. H., L. J. S.), by a VA Merit award (S. D.), and by a grant from the American Foundation for Suicide Prevention (S. D.). NR 24 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD DEC 8 PY 2010 VL 21 IS 17 BP 1080 EP 1084 DI 10.1097/WNR.0b013e32834052f0 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 674LM UT WOS:000283745400004 PM 20948451 ER PT J AU Yang, Y Huang, JH Toth, I Lichterfeld, M Yu, XG AF Yang, Yue Huang, Jinghe Toth, Ildiko Lichterfeld, Mathias Yu, Xu G. TI Mutational Escape in HIV-1 CTL Epitopes Leads to Increased Binding to Inhibitory Myelomonocytic MHC Class I Receptors SO PLOS ONE LA English DT Article ID T-LYMPHOCYTE ESCAPE; DENDRITIC CELLS; INFECTION; RESPONSES AB Escape mutations in HIV-1 cytotoxic T cell (CTL) epitopes can abrogate recognition by the TCR of HIV-1-specific CD8+ T cells, but may also change interactions with alternative MHC class I receptors. Here, we show that mutational escape in three HLA-A11-, B8- and B7- restricted immunodominant HIV-1 CTL epitopes consistently enhances binding of the respective peptide/MHC class I complex to Immunoglobulin-like transcript 4 (ILT4), an inhibitory myelomonocytic MHC class I receptor expressed on monocytes and dendritic cells. In contrast, mutational escape in an alternative immunodominant HLA-B57-restricted CTL epitope did not affect ILT4-mediated recognition by myelomonocytic cells. This suggests that in addition to abrogating recognition by HIV-1-specific CD8 T cells, mutational escape in some, but not all CTL epitopes may mediate important immunoregulatory effects by increasing binding properties to ILT4, and augmenting ILT4-mediated inhibitory effects of professional antigen-presenting cells. C1 [Yang, Yue; Huang, Jinghe; Toth, Ildiko; Yu, Xu G.] Harvard & MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Yang, Y (reprint author), Harvard & MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. EM xyu@partners.org RI Huang, Jinghe/O-1986-2015 FU National Institutes of Health [R01 AI078799, P01 AI074415]; Doris Duke Charitable Foundation FX This study was supported by the National Institutes of Health (R01 AI078799 and P01 AI074415 to XGY) and the Doris Duke Charitable Foundation (Clinical Scientist Development Award to XGY and ML). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 4 Z9 4 U1 2 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 8 PY 2010 VL 5 IS 12 AR e15084 DI 10.1371/journal.pone.0015084 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 691MJ UT WOS:000285084100018 PM 21170342 ER PT J AU Guan, R Dai, H Harrison, SC Kirchhausen, T AF Guan, Rong Dai, Han Harrison, Stephen C. Kirchhausen, Tomas TI Structure of the PTEN-like Region of Auxilin, a Detector of Clathrin-Coated Vesicle Budding (Vol 18, 1191, 2010) SO STRUCTURE LA English DT Correction C1 [Guan, Rong; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Dai, Han; Harrison, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Jack & Eileen Connors Struct Biol Lab, Boston, MA 02115 USA. [Harrison, Stephen C.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Guan, Rong; Kirchhausen, Tomas] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Guan, Rong; Kirchhausen, Tomas] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM kirchhausen@crystal.harvard.edu NR 1 TC 0 Z9 0 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 8 PY 2010 VL 18 IS 12 BP 1688 EP 1688 DI 10.1016/j.str.2010.11.007 PG 1 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 693JT UT WOS:000285221100016 ER PT J AU Weyman, AE AF Weyman, Arthur E. TI The Year in Echocardiography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE contrast; echocardiography; imaging; stress ID CARDIAC RESYNCHRONIZATION THERAPY; FUNCTIONAL MITRAL REGURGITATION; INTRACARDIAC FILLING PRESSURE; SYSTOLIC HEART-FAILURE; LEFT ATRIAL PRESSURE; EXERCISE ECHOCARDIOGRAPHY; DOPPLER-ECHOCARDIOGRAPHY; STRESS ECHOCARDIOGRAPHY; DECOMPENSATED PATIENTS; VENTRICULAR-FUNCTION C1 Massachusetts Gen Hosp, Cardiac Unit, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Weyman, AE (reprint author), Massachusetts Gen Hosp, Cardiac Unit, Cardiac Ultrasound Lab, 55 Fruit St,VBK 508,VBK-508, Boston, MA 02114 USA. EM aweyman@partners.org NR 35 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 7 PY 2010 VL 56 IS 24 BP 2033 EP 2044 DI 10.1016/j.jacc.2010.07.029 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 688BD UT WOS:000284822500009 PM 21126643 ER PT J AU Joukov, V De Nicolo, A Rodriguez, A Walter, JC Livingston, DM AF Joukov, Vladimir De Nicolo, Arcangela Rodriguez, Alison Walter, Johannes C. Livingston, David M. TI Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aurora kinase; microtubule-organizing center; protein recruitment ID XENOPUS EGG EXTRACTS; FUNCTION IN-VITRO; MITOTIC-SPINDLE; A KINASE; HUMAN-CELLS; TPX2; RAN; SPD-2; COMMUNICATION; MICROTUBULES AB Centrosomes are primary microtubule (MT)-organizing centers (MTOCs). During mitosis, they dramatically increase their size and MT-nucleating activity and participate in spindle assembly from spindle poles. These events require the serine/threonine kinase, Aurora A (AurA), and the centrosomal protein of 192 kDa (Cep192)/spindle defective 2 (Spd-2), but the underlying mechanism remains unclear. We have found that Cep192, unlike targeting protein for Xklp2 (TPX2), a known MT-localizing AurA activator, is an AurA cofactor in centrosome-driven spindle assembly. Cep192, through a direct interaction, targets AurA to mitotic centrosomes where the locally accumulating AurA forms homodimers or oligomers. The dimerization of endogenous AurA, in the presence of bound Cep192, triggers potent kinase activation that, in turn, drives MT assembly. Depletion of Cep192 or specific interference with AurA-Cep192 binding did not prevent AurA oligomerization on MTs but abrogated AurA recruitment to centrosomes and its activation by either sperm nuclei or anti-AurA antibody (alpha AurA)-induced dimerization. In these settings, MT assembly by both centrosomes and alpha AurA-coated beads was also abolished or severely compromised. Hence, Cep192 activates AurA by a mechanism different from that previously described for TPX2. The Cep192-mediated mechanism maximizes AurA activity at centrosomes and appears essential for the function of these organelles as MTOCs. C1 [Joukov, Vladimir; De Nicolo, Arcangela; Rodriguez, Alison; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Joukov, Vladimir; De Nicolo, Arcangela; Livingston, David M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Walter, Johannes C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Joukov, V (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM vladimir_joukov@dfci.harvard.edu; david_livingston@dfci.harvard.edu FU Department of Defense [W81XWH-04-1-0524]; Susan G. Komen for the Cure [PDF0601163]; National Institute of Health [GM62267, GM80676]; Leukemia Lymphoma Scholar Award; National Cancer Institute; Novartis Institute for Biomedical Research FX We thank C. D. Hu (Purdue University, West Lafayette, IN), M. Dasso (National Institutes of Health, Bethesda), A. C. Groen (Harvard Medical School, Boston), and R. L. Davis (Harvard Medical School, Boston) for generous gifts of reagents; S. Gygi and R. Tomaino for mass spectrometry analysis; L. Cameron for the assistance with microscopy; M. A. Cohn for helpful advice; and R. Bayliss for comments on the manuscript. This work was supported by the Department of Defense Breast Cancer Research Program Award W81XWH-04-1-0524 (to V.J.); Susan G. Komen for the Cure Award PDF0601163 (to A.D.N.); National Institute of Health Grants GM62267 and GM80676 and a Leukemia Lymphoma Scholar Award (to J.C.W.); and grants from the National Cancer Institute (to D. M. L.). D. M. L. is a grantee of and consultant to the Novartis Institute for Biomedical Research. NR 40 TC 43 Z9 43 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 7 PY 2010 VL 107 IS 49 BP 21022 EP 21027 DI 10.1073/pnas.1014664107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 690ZY UT WOS:000285050800034 PM 21097701 ER PT J AU Choi, WI Syrkina, O Kwon, KY Quinn, DA Hales, CA AF Choi, Won-Il Syrkina, Olga Kwon, Kun Young Quinn, Deborah A. Hales, Charles A. TI JNK activation is responsible for mucus overproduction in smoke inhalation injury SO RESPIRATORY RESEARCH LA English DT Article ID N-TERMINAL KINASE; MUCIN GENES; EXPRESSION; BURN; NIGHTCLUB; ALPHA; SHEEP; FIRE; BETA AB Background: Increased mucus secretion is one of the important characteristics of the response to smoke inhalation injuries. We hypothesized that gel-forming mucins may contribute to the increased mucus production in a smoke inhalation injury. We investigated the role of c-Jun N-terminal kinase (JNK) in modulating smoke-induced mucus secretion. Methods: We intubated mice and exposed them to smoke from burning cotton for 15 min. Their lungs were then isolated 4 and 24 h after inhalation injury. Three groups of mice were subjected to the smoke inhalation injury: (1) wild-type (WT) mice, (2) mice lacking JNK1 (JNK1-/- mice), and (3) WT mice administered a JNK inhibitor. The JNK inhibitor (SP 600125) was injected into the mice 1 h after injury. Results: Smoke exposure caused an increase in the production of mucus in the airway epithelium of the mice along with an increase in MUC5AC gene and protein expression, while the expression of MUC5B was not increased compared with control. We found increased MUC5AC protein expression in the airway epithelium of the WT mice groups both 4 and 24 h after smoke inhalation injury. However, overproduction of mucus and increased MUC5AC protein expression induced by smoke inhalation was suppressed in the JNK inhibitor-treated mice and the JNK1 knockout mice. Smoke exposure did not alter the expression of MUC1 and MUC4 proteins in all 3 groups compared with control. Conclusion: An increase in epithelial MUC5AC protein expression is associated with the overproduction of mucus in smoke inhalation injury, and that its expression is related on JNK1 signaling. C1 [Choi, Won-Il; Syrkina, Olga; Quinn, Deborah A.; Hales, Charles A.] Massachusettes Gen Hosp, Pulm Crit Care Unit, Dept Med, Boston, MA 02114 USA. [Choi, Won-Il; Syrkina, Olga; Quinn, Deborah A.; Hales, Charles A.] Harvard Univ, Sch Med, Boston, MA USA. [Choi, Won-Il] Keimyung Univ, Dept Internal Med, Dongsan Hosp, Sch Med, Taegu, South Korea. [Choi, Won-Il; Syrkina, Olga; Hales, Charles A.] Shriners Burn Hosp, Boston, MA USA. [Kwon, Kun Young] Keimyung Univ, Sch Med, Dept Pathol, Dongsan Hosp, Taegu, South Korea. RP Hales, CA (reprint author), Massachusettes Gen Hosp, Pulm Crit Care Unit, Dept Med, Boston, MA 02114 USA. EM chales@partners.org FU Shriners Hospital, Boston [8620]; Susannah Wood foundation FX This study was supported by funds from Shriners Hospital, Boston #8620 and Susannah Wood foundation (CAH). NR 23 TC 12 Z9 12 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD DEC 7 PY 2010 VL 11 AR 172 DI 10.1186/1465-9921-11-172 PG 8 WC Respiratory System SC Respiratory System GA 702CU UT WOS:000285873000001 PM 21134294 ER PT J AU Boucher, J Macotela, Y Bezy, O Mori, MA Kriauciunas, K Kahn, CR AF Boucher, Jeremie Macotela, Yazmin Bezy, Olivier Mori, Marcelo A. Kriauciunas, Kristina Kahn, C. Ronald TI A Kinase-Independent Role for Unoccupied Insulin and IGF-1 Receptors in the Control of Apoptosis SO SCIENCE SIGNALING LA English DT Article ID GROWTH-FACTOR-I; CELL-DEATH; SIGNALING PATHWAYS; EMBRYONIC-DEVELOPMENT; DOWN-REGULATION; BETA-ARRESTINS; CYTOCHROME-C; IAP PROTEINS; INHIBITION; SURVIVAL AB Insulin and insulin-like growth factor 1 (IGF-1) act as antiapoptotic hormones. We found that, unexpectedly, double-knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively) were resistant to apoptosis induced through either the intrinsic or the extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the proapoptotic protein Bax and increases in abundance of the antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily posttranscriptional mechanisms. Restoration of IR or IGF1R to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the IR also restored susceptibility to apoptosis. Thus, IR and IGF1R have bidirectional roles in the control of cell survival and can be viewed as dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded IR and IGF1R, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death. C1 [Kahn, C. Ronald] Harvard Univ, Sch Med, Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU NIH [DK31036]; Joslin Diabetes Center's Diabetes and Endocrinology Research Center [P30DK036836] FX We thank the Joslin Flow Cytometry Core and the Genomics Core facilities supported by Joslin Diabetes Center's Diabetes and Endocrinology Research Center (grant P30DK036836). Funding: This work was supported by funding from NIH grant DK31036. Author contributions: J.B. designed and performed the experiments, analyzed the data, and wrote the paper. Y.M., O.B., M. A. M., and K. K. designed and performed the experiments. C. R. K. designed the experiments, analyzed the data, and wrote the paper. NR 47 TC 39 Z9 41 U1 0 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD DEC 7 PY 2010 VL 3 IS 151 AR ra87 DI 10.1126/scisignal.2001173 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 690ZS UT WOS:000285050100001 PM 21139139 ER PT J AU Shrikhande, GV Scali, ST da Silva, CG Damrauer, SM Csizmadia, E Putheti, P Matthey, M Arjoon, R Patel, R Siracuse, JJ Maccariello, ER Andersen, ND Monahan, T Peterson, C Essayagh, S Studer, P Guedes, RP Kocher, O Usheva, A Veves, A Kaczmarek, E Ferran, C AF Shrikhande, Gautam V. Scali, Salvatore T. da Silva, Cleide G. Damrauer, Scott M. Csizmadia, Eva Putheti, Prabhakar Matthey, Michaela Arjoon, Roy Patel, Rakesh Siracuse, Jeffrey J. Maccariello, Elizabeth R. Andersen, Nicholas D. Monahan, Thomas Peterson, Clayton Essayagh, Sanah Studer, Peter Guedes, Renata Padilha Kocher, Olivier Usheva, Anny Veves, Aristidis Kaczmarek, Elzbieta Ferran, Christiane TI O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice SO PLOS ONE LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; ENDOTHELIAL-CELL ACTIVATION; NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE-CELLS; GLYCEMIC CONTROL; FACTOR-ALPHA; NUCLEOCYTOPLASMIC GLYCOSYLATION; HEXOSAMINE PATHWAY; GLUCOSE-TRANSPORT AB Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-kappa B inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKC beta II, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKC beta II, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes. C1 [Shrikhande, Gautam V.; Scali, Salvatore T.; da Silva, Cleide G.; Damrauer, Scott M.; Csizmadia, Eva; Matthey, Michaela; Arjoon, Roy; Patel, Rakesh; Siracuse, Jeffrey J.; Maccariello, Elizabeth R.; Andersen, Nicholas D.; Monahan, Thomas; Peterson, Clayton; Essayagh, Sanah; Studer, Peter; Guedes, Renata Padilha; Kaczmarek, Elzbieta; Ferran, Christiane] Harvard Univ, Sch Med, Dept Surg, Div Vasc Surg, Boston, MA 02115 USA. [Shrikhande, Gautam V.; Scali, Salvatore T.; da Silva, Cleide G.; Damrauer, Scott M.; Csizmadia, Eva; Matthey, Michaela; Arjoon, Roy; Patel, Rakesh; Siracuse, Jeffrey J.; Maccariello, Elizabeth R.; Andersen, Nicholas D.; Monahan, Thomas; Peterson, Clayton; Essayagh, Sanah; Studer, Peter; Guedes, Renata Padilha; Kaczmarek, Elzbieta; Ferran, Christiane] Harvard Univ, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Sch Med,Dept Med, Boston, MA 02215 USA. [Putheti, Prabhakar; Ferran, Christiane] Harvard Univ, Beth Israel Deaconess Med Ctr, Transplant Inst, Sch Med,Dept Med, Boston, MA 02215 USA. [Kocher, Olivier] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol, Sch Med,Dept Med, Boston, MA 02215 USA. [Usheva, Anny] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Endocrinol, Sch Med,Dept Med, Boston, MA 02215 USA. [Veves, Aristidis] Harvard Univ, Sch Med, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA USA. [Veves, Aristidis] Harvard Univ, Beth Israel Deaconess Med Ctr, Microcirculat Lab, Sch Med,Dept Med, Boston, MA 02215 USA. [Ferran, Christiane] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Nephrol, Sch Med,Dept Med, Boston, MA 02215 USA. RP Shrikhande, GV (reprint author), Columbia Univ, Med Ctr, Div Vasc Surg, New York, NY 10027 USA. EM cferran@bidmc.harvard.edu FU National Institutes of Health (NIH) [HL080130, RO1 DK063275, HL057791, HL075678, HL062458, HL07734]; Juvenile Diabetes Research Foundation [1-2007-567]; American Diabetes Association; Swiss National foundation FX This research was supported by National Institutes of Health (NIH) Research Project Grant Program (R01) grants HL080130, RO1 DK063275, and HL057791; Juvenile Diabetes Research Foundation grant 1-2007-567 to CF; NIH R01 grant HL075678; an American Diabetes Association clinical research grant to AV; and NIH RO1 grant HL062458 to AU. GVS, STS, SMD, VIP, JSJ, CP and MDF are recipients of a fellowship award from the NIH T32 fellowship grant HL07734. PS is the recipient of a fellowship grant from the Swiss National foundation. RPG is the recipient of a research fellowship grant from the CNPQ, Brasil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 24 Z9 24 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 6 PY 2010 VL 5 IS 12 AR e14240 DI 10.1371/journal.pone.0014240 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 690IB UT WOS:000284995300012 PM 21151899 ER PT J AU Edmonds, TG Ding, HT Yuan, X Wei, Q Smith, KS Conway, JA Wieczorek, L Brown, B Polonis, V West, JT Montefiori, DC Kappes, JC Ochsenbauer, C AF Edmonds, Tara G. Ding, Haitao Yuan, Xing Wei, Qing Smith, Kendra S. Conway, Joan A. Wieczorek, Lindsay Brown, Bruce Polonis, Victoria West, John T. Montefiori, David C. Kappes, John C. Ochsenbauer, Christina TI Replication competent molecular clones of HIV-1 expressing Renilla luciferase facilitate the analysis of antibody inhibition in PBMC SO VIROLOGY LA English DT Article DE HIV-1; Neutralizing antibody; PBMC assay; HIV reporter virus; Vaccine assessment; Assay standardization; HIV neutralization; Luciferase; Envelope glycoprotein ID IMMUNODEFICIENCY-VIRUS TYPE-1; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; IN-VITRO; ENVELOPE GLYCOPROTEIN; VIRION INCORPORATION; DRUG SUSCEPTIBILITY; CHIMERIC VIRUS; TARGET-CELLS; ENV CLONES AB Effective vaccine development for human immunodeficiency virus type 1 (HIV-1) will require assays that ascertain the capacity of vaccine immunogens to elicit neutralizing antibodies (NAb) to diverse HIV-1 strains. To facilitate NAb assessment in peripheral blood mononuclear cell (PBMC)-based assays, we developed an assay-adaptable platform based on a Renilla luciferase (LucR) expressing HIV-1 proviral backbone. LucR was inserted into pNL4-3 DNA, preserving all viral open reading frames. The proviral genome was engineered to facilitate expression of diverse HIV-1 env sequences, allowing analysis in an isogenic background. The resulting Env-IMC-LucR viruses are infectious, and LucR is stably expressed over multiple replications in PBMC. HIV-1 neutralization, targeting TZM-bl cells, was highly correlative comparing virus (LucR) and cell (firefly luciferase) readouts. In PBMC, NAb activity can be analyzed either within a single or multiple cycles of replication. These results represent advancement toward a standardizable PBMC-based neutralization assay for assessing HIV-1 vaccine immunogen efficacy. (C) 2010 Elsevier Inc. All rights reserved. C1 [Ding, Haitao; Wei, Qing; Smith, Kendra S.; Conway, Joan A.; Kappes, John C.; Ochsenbauer, Christina] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Edmonds, Tara G.; Kappes, John C.] Univ Alabama Birmingham, Dept Mol & Cellular Pathol, Birmingham, AL 35294 USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL 35233 USA. [Yuan, Xing; Montefiori, David C.] Duke Univ, Med Ctr, Durham, NC 27710 USA. [West, John T.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. [Wieczorek, Lindsay; Brown, Bruce] Henry M Jackson Fdn, Rockville, MD 20850 USA. [Wieczorek, Lindsay; Brown, Bruce; Polonis, Victoria] Walter Reed Army Inst Res, US Mil HIV Res Program MHRP, Rockville, MD 20850 USA. RP Ochsenbauer, C (reprint author), Univ Alabama Birmingham, Dept Med, 701 19th St S,LHRB 613, Birmingham, AL 35294 USA. EM edmondst@uab.edu; Haitao.Ding@ccc.uab.edu; qingwei@uab.edu; ceasmi@uab.edu; conwayj@uab.edu; lwieczorek@hivresearch.org; bbrown@hivresearch.org; vpolonis@hivresearch.org; john-west@ouhsc.edu; monte@duke.edu; John.Kappes@ccc.uab.edu; ochsenba@uab.edu FU NIH Center for HIV/AIDS Vaccine Immunology (CHAVI) [UO1-AI067854]; Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery (CAVD)/Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC) [38619]; UAB Center for AIDS Research [P30-AI-27767]; UAB Mucosal HIV and Immunobiology Center [R24 DK-64400]; Department of Veterans Affairs Medical Center, Research Services; NIH [AI007439]; Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, WA FX This work was supported by the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI), UO1-AI067854; the Bill & Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery (CAVD)/Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC), grant number 38619; facilities of the Virology and Genetic Sequencing cores of the UAB Center for AIDS Research (P30-AI-27767); and the Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center (R24 DK-64400). Research was also supported by a Merit Review Award (JCK), from the Department of Veterans Affairs Medical Center, Research Services. TGE is supported by NIH training grant AI007439. We would like to acknowledge the expertise and support we obtained from the Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, WA. NR 69 TC 98 Z9 98 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 0042-6822 J9 VIROLOGY JI Virology PD DEC 5 PY 2010 VL 408 IS 1 BP 1 EP 13 DI 10.1016/j.viro1.2010.08.028 PG 13 WC Virology SC Virology GA 677DY UT WOS:000283970500001 PM 20863545 ER PT J AU Cherry, A Daley, GQ AF Cherry, Anne Daley, George Q. TI Another Horse in the Meta-Stable State of Pluripotency SO CELL STEM CELL LA English DT Editorial Material ID EMBRYONIC STEM-CELLS; SUBPOPULATIONS AB Reports of heterogeneity within embryonic stem cell lines suggest that pluripotent stem cells captured in culture may be less homogeneous than previously assumed. In a recent issue of Cell, Scholer and colleagues (Han et al., 2010) demonstrate the existence of a dynamic subpopulation of epiblast stem cells that shows features of earlier pluripotent cells. C1 [Cherry, Anne; Daley, George Q.] Childrens Hosp, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, Manton Ctr Orphan Dis Res,Howard Hughes Med Inst, Boston, MA 02115 USA. [Cherry, Anne; Daley, George Q.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Hematol, Boston, MA 02115 USA. [Cherry, Anne; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, Manton Ctr Orphan Dis Res,Howard Hughes Med Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu RI Cherry, Anne/E-7333-2011 NR 9 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD DEC 3 PY 2010 VL 7 IS 6 BP 641 EP 642 DI 10.1016/j.stem.2010.11.020 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 697SU UT WOS:000285537700002 PM 21112555 ER PT J AU Bauer, LK Huffman, JC AF Bauer, Leah K. Huffman, Jeff C. TI Is low cholesterol associated with depression in cardiac patients? SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter DE Depression; Cholesterol; Lipid-lowering; Cardiovascular disease ID DISEASE C1 [Bauer, Leah K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bauer, LK (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St, Boston, MA 02114 USA. EM lbauer@partners.org NR 7 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 3 PY 2010 VL 145 IS 3 BP 537 EP 539 DI 10.1016/j.ijcard.2010.04.070 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 692EU UT WOS:000285136200054 PM 20483180 ER PT J AU Richardson, PG AF Richardson, Paul G. TI Improving the therapeutic index in myeloma SO BLOOD LA English DT Editorial Material ID MULTIPLE-MYELOMA; PERIPHERAL NEUROPATHY; BORTEZOMIB C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 2 PY 2010 VL 116 IS 23 BP 4733 EP 4734 DI 10.1182/blood-2010-10-306373 PG 2 WC Hematology SC Hematology GA 688UU UT WOS:000284880200003 PM 21127178 ER PT J AU Chauhan, D Singh, AV Aujay, M Kirk, CJ Bandi, M Ciccarelli, B Raje, N Richardson, P Anderson, KC AF Chauhan, Dharminder Singh, Ajita V. Aujay, Monette Kirk, Christopher J. Bandi, Madhavi Ciccarelli, Bryan Raje, Noopur Richardson, Paul Anderson, Kenneth C. TI A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma SO BLOOD LA English DT Article ID NF-KAPPA-B; BONE-MARROW; POLY(ADP-RIBOSE) POLYMERASE; IRREVERSIBLE INHIBITOR; ANTITUMOR-ACTIVITY; DRUG-RESISTANCE; CELL-GROWTH; BORTEZOMIB; APOPTOSIS; ANGIOGENESIS AB Bortezomib therapy has proven successful for the treatment of relapsed, relapsed/refractory, and newly diagnosed multiple myeloma (MM). At present, bortezomib is available as an intravenous injection, and its prolonged treatment is associated with toxicity and development of drug resistance. Here we show that the novel proteasome inhibitor ONX 0912, a tripeptide epoxyketone, inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies. The anti-MM activity of ONX-0912 is associated with activation of caspase-8, caspase-9, caspase-3, and poly(ADP) ribose polymerase, as well as inhibition of migration of MM cells and angiogenesis. ONX 0912, like bortezomib, predominantly inhibits chymotrypsin-like activity of the proteasome and is distinct from bortezomib in its chemical structure. Importantly, ONX 0912 is orally bioactive. In animal tumor model studies, ONX 0912 significantly reduced tumor progression and prolonged survival. Immununostaining of MM tumors from ONX 0912-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Finally, ONX 0912 enhances anti-MM activity of bortezomib, lenalidomide dexamethasone, or pan-histone deacetylase inhibitor. Taken together, our study provides the rationale for clinical protocols evaluating ONX 0912, either alone or in combination, to improve patient outcome in MM. (Blood. 2010;116(23):4906-4915) C1 [Chauhan, Dharminder; Singh, Ajita V.; Bandi, Madhavi; Ciccarelli, Bryan; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Jerome Lipper Myeloma Ctr,Dept Med Oncol, Boston, MA 02115 USA. [Chauhan, Dharminder; Singh, Ajita V.; Bandi, Madhavi; Ciccarelli, Bryan; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, LeBow Inst Myeloma Therapeut, Sch Med, Boston, MA 02115 USA. [Aujay, Monette; Kirk, Christopher J.] Onyx Pharmaceut, Emeryville, CA USA. RP Chauhan, D (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Jerome Lipper Myeloma Ctr,Dept Med Oncol, Mayer Bldg Rm 561,44 Binney St, Boston, MA 02115 USA. EM Dharminder_Chauhan@dfci.harvard.edu FU National Institutes of Health [SPORE-P50100707, PO1-CA078378, RO1CA050947] FX This work was supported by National Institutes of Health grants SPORE-P50100707, PO1-CA078378, and RO1CA050947. K. C. A. is an American Cancer Society Clinical Research Professor. NR 53 TC 98 Z9 99 U1 0 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 2 PY 2010 VL 116 IS 23 BP 4906 EP 4915 DI 10.1182/blood-2010-04-276626 PG 10 WC Hematology SC Hematology GA 688UU UT WOS:000284880200028 PM 20805366 ER PT J AU Parkin, B Erba, H Ouillette, P Roulston, D Purkayastha, A Karp, J Talpaz, M Kujawski, L Shakhan, S Li, C Shedden, K Malek, SN AF Parkin, Brian Erba, Harry Ouillette, Peter Roulston, Diane Purkayastha, Anjali Karp, Judith Talpaz, Moshe Kujawski, Lisa Shakhan, Sajid Li, Cheng Shedden, Kerby Malek, Sami N. TI Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; THERAPY-RELATED MYELODYSPLASIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; NUCLEOTIDE POLYMORPHISM ANALYSIS; ACUTE LYMPHOBLASTIC-LEUKEMIA; DE-NOVO AML; UNIPARENTAL DISOMY; COMPLEX KARYOTYPE; PROGNOSTIC IMPACT; POOR-PROGNOSIS AB Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotype-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of cytogenetic analysis is the inability to detect genomic abnormalities less than 5 Mb in size, and it is currently unclear whether overcoming this limitation with high-resolution genomic single-nucleotide polymorphism (SNP) array analysis would be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the conventional karyotype-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. In this study, we analyzed flow cytometer-sorted, AML blast-derived, and paired, buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and loss of heterozygosity using Affymetrix SNP 6.0 arrays, and we correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Using multivariate analyses, we found that having >= 2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age-and karyotype-based risk. Finally, we identified an independent negative prognostic impact of p53 mutations, or p53 mutations and 17p-loss of heterozygosity combined on survival in AML. (Blood. 2010;116(23):4958-4967) C1 [Parkin, Brian; Erba, Harry; Ouillette, Peter; Talpaz, Moshe; Kujawski, Lisa; Shakhan, Sajid; Malek, Sami N.] Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Roulston, Diane; Purkayastha, Anjali] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Karp, Judith] Johns Hopkins Canc Ctr, Dept Oncol, Boston, MA USA. [Li, Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Cheng] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shedden, Kerby] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. RP Malek, SN (reprint author), Univ Michigan, Dept Internal Med, Div Hematol & Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM smalek@med.umich.edu FU National Institutes of Health [1R01 CA136537-01]; Leukemia & Lymphoma Society of America; National Institutes of Health through the University of Michigan's Cancer Center [5 P30 CA46592] FX This work was supported by the National Institutes of Health through 1R01 CA136537-01 (to S. M.) and the Translational Research Program of the Leukemia & Lymphoma Society of America (to S. M.). This research was supported in part by the National Institutes of Health through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592). NR 49 TC 38 Z9 38 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 2 PY 2010 VL 116 IS 23 BP 4958 EP 4967 DI 10.1182/blood-2010-01-266999 PG 10 WC Hematology SC Hematology GA 688UU UT WOS:000284880200034 PM 20729466 ER PT J AU Zhu, JQ Zhu, JH Negri, A Provasi, D Filizola, M Coller, BS Springer, TA AF Zhu, Jieqing Zhu, Jianghai Negri, Ana Provasi, Davide Filizola, Marta Coller, Barry S. Springer, Timothy A. TI Closed headpiece of integrin alpha(IIb)beta(3) and its complex with an alpha(IIb)beta(3)-specific antagonist that does not induce opening SO BLOOD LA English DT Article ID EPTIFIBATIDE-INDUCED THROMBOCYTOPENIA; MURINE MONOCLONAL-ANTIBODY; GLYCOPROTEIN-IIB-IIIA; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GPIIB/IIIA ANTAGONISTS; EXTRACELLULAR SEGMENT; CELL-ADHESION; FIBRINOGEN; LIGAND AB The platelet integrin alpha(IIb)beta(3) is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the alpha(IIb)beta(3) headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the alpha(IIb)beta(3) headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the alpha(IIb) subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, alpha(IIb) Y190 and alpha(IIb) D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce alpha(IIb)beta(3) to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism. (Blood. 2010;116(23):5050-5059) C1 [Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A.] Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Negri, Ana; Provasi, Davide; Filizola, Marta] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY USA. [Coller, Barry S.] Rockefeller Univ, Lab Blood & Vasc Biol, New York, NY 10021 USA. RP Springer, TA (reprint author), Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Zhu, Jianghai/B-7339-2014 FU National Institutes of Health [HL19278, HL46875, ULRR024143]; Stony Brook University FX This work was supported in part by grants from the National Institutes of Health (HL19278, HL46875, and ULRR024143) and Stony Brook University. Computational resources were obtained from NSF TeraGrid (MRAC MCB080077). NR 45 TC 45 Z9 45 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 2 PY 2010 VL 116 IS 23 BP 5050 EP 5059 DI 10.1182/blood-2010-04-281154 PG 10 WC Hematology SC Hematology GA 688UU UT WOS:000284880200044 PM 20679525 ER PT J AU Gurumurthy, S Xie, SZ Alagesan, B Kim, J Yusuf, RZ Saez, B Tzatsos, A Ozsolak, F Milos, P Ferrari, F Park, PJ Shirihai, OS Scadden, DT Bardeesy, N AF Gurumurthy, Sushma Xie, Stephanie Z. Alagesan, Brinda Kim, Judith Yusuf, Rushdia Z. Saez, Borja Tzatsos, Alexandros Ozsolak, Fatih Milos, Patrice Ferrari, Francesco Park, Peter J. Shirihai, Orian S. Scadden, David T. Bardeesy, Nabeel TI The Lkb1 metabolic sensor maintains haematopoietic stem cell survival SO NATURE LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; GLUCOSE-HOMEOSTASIS; TUMOR SUPPRESSION; IN-VIVO; PATHWAY; KINASE; MICE; APOPTOSIS; SYSTEM; ENERGY AB Haematopoietic stem cells (HSCs) can convert between growth states that have marked differences in bioenergetic needs. Although often quiescent in adults, these cells become proliferative upon physiological demand. Balancing HSC energetics in response to nutrient availability and growth state is poorly understood, yet essential for the dynamism of the haematopoietic system. Here we show that the Lkb1 tumour suppressor is critical for the maintenance of energy homeostasis in haematopoietic cells. Lkb1 inactivation in adult mice causes loss of HSC quiescence followed by rapid depletion of all haematopoietic subpopulations. Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP. The haematopoietic effects are largely independent of Lkb1 regulation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling. Instead, these data define a central role for Lkb1 in restricting HSC entry into cell cycle and in broadly maintaining energy homeostasis in haematopoietic cells through a novel metabolic checkpoint. C1 [Gurumurthy, Sushma; Xie, Stephanie Z.; Alagesan, Brinda; Kim, Judith; Yusuf, Rushdia Z.; Saez, Borja; Tzatsos, Alexandros; Scadden, David T.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Gurumurthy, Sushma; Xie, Stephanie Z.; Alagesan, Brinda; Kim, Judith; Yusuf, Rushdia Z.; Saez, Borja; Tzatsos, Alexandros; Scadden, David T.; Bardeesy, Nabeel] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Gurumurthy, Sushma; Xie, Stephanie Z.; Alagesan, Brinda; Kim, Judith; Yusuf, Rushdia Z.; Saez, Borja; Tzatsos, Alexandros; Scadden, David T.; Bardeesy, Nabeel] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Xie, Stephanie Z.; Yusuf, Rushdia Z.; Saez, Borja; Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Xie, Stephanie Z.; Yusuf, Rushdia Z.; Saez, Borja; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02115 USA. [Ozsolak, Fatih; Milos, Patrice] Hel BioSci Corp, Cambridge, MA 02139 USA. [Ferrari, Francesco; Park, Peter J.] Childrens Hosp, Ctr Biomed Informat, Boston, MA 02115 USA. [Ferrari, Francesco; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Ferrari, Francesco; Park, Peter J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Shirihai, Orian S.] Boston Univ, Med Ctr, Mitochondria ARC, Evans Res Ctr,Dept Med, Boston, MA 02118 USA. RP Bardeesy, N (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM Scadden.David@MGH.Harvard.edu; Bardeesy.Nabeel@MGH.Harvard.edu RI Ferrari, Francesco/H-5007-2012 OI Ferrari, Francesco/0000-0002-9811-3753 FU NIH [U01 CA141576-01, DK050234]; Ellison Medical Foundation; Massachusetts Biotechnology Research Council FX We would like to thank the Harvard Stem Cell Institute Flow Cytometry Core and D. Brown and the MGH Electron Microscope Imaging Core for expertise and advice. V. Levy and M. Leisa provided technical assistance in the SeaHorse measurements. D. Van Buren provided advice and assistance in pilot experiments. We thank A. Camacho for mouse colony assistance. We would also like to thank A. Kimmelman, R. Mostoslavsky, M. Vander Heiden, L. Ellisen, W. Kim and M. Ivan for discussions and critical review of the manuscript. We are grateful to S. Morrison and R. DePinho for sharing unpublished data. N.B. would like to acknowledge support from NIH U01 CA141576-01. D.T.S would like to acknowledge support from NIH DK050234 and Ellison Medical Foundation. S.G. was supported by a Massachusetts Biotechnology Research Council Tosteson Fellowship. S.Z.X. was supported by an NIH Ruth L. Kirschstein National Research Service Award. NR 35 TC 172 Z9 184 U1 2 U2 29 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 2 PY 2010 VL 468 IS 7324 BP 659 EP U75 DI 10.1038/nature09572 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 688GB UT WOS:000284836700033 PM 21124451 ER PT J AU Gan, BY Hu, JA Jiang, S Liu, YC Sahin, E Zhuang, L Fletcher-Sananikone, E Colla, S Wang, YA Chin, L DePinho, RA AF Gan, Boyi Hu, Jian Jiang, Shan Liu, Yingchun Sahin, Erguen Zhuang, Li Fletcher-Sananikone, Eliot Colla, Simona Wang, Y. Alan Chin, Lynda DePinho, Ronald A. TI Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells SO NATURE LA English DT Article ID MITOCHONDRIAL BIOGENESIS; ENERGY; RESISTANCE; PATHWAY; BIOLOGY; STRESS; KINASE; FOXOS AB The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases(1-3). Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis. C1 [Gan, Boyi; Hu, Jian; Jiang, Shan; Liu, Yingchun; Sahin, Erguen; Zhuang, Li; Fletcher-Sananikone, Eliot; Colla, Simona; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Gan, Boyi; Hu, Jian; Jiang, Shan; Liu, Yingchun; Sahin, Erguen; Zhuang, Li; Fletcher-Sananikone, Eliot; Colla, Simona; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gan, Boyi; Hu, Jian; Jiang, Shan; Liu, Yingchun; Sahin, Erguen; Zhuang, Li; Fletcher-Sananikone, Eliot; Colla, Simona; Wang, Y. Alan; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu OI Colla, Simona/0000-0001-6583-8910 FU DOD [TS093049]; Multiple Myeloma Research Foundation; Robert A. and Renee E. Belfer Foundation; [U01CA141508]; [R21CA135057] FX We are grateful to A. Berns for providing the Rosa26-creERt2 mouse strain. We are also grateful to S. Zhou for assistance in the animal facility and C. Lim for assistance with genotyping. We thank S. Lazo-Kallanian, J. Daley and P. Schow for assistance with flow cytometry. We also thank N. Bardeesy and S. Morrison for communicating unpublished information; A. Stegh for comments on apoptosis; and D. Nakada for western blotting protocol from sorted HSCs. This research was supported by U01CA141508 (R.A.D. and L.C.), R21CA135057 (R.A.D. and B.G.) and DOD TSCRP Career Transition Award (TS093049) (B.G.). B.G. and J.H. are the Research Fellows of the Leukemia and Lymphoma Society. Y.A.W. is supported by Multiple Myeloma Research Foundation. R.A.D. was supported by an American Cancer Society Research Professorship and the Robert A. and Renee E. Belfer Foundation. NR 24 TC 168 Z9 180 U1 2 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 2 PY 2010 VL 468 IS 7324 BP 701 EP U125 DI 10.1038/nature09595 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 688GB UT WOS:000284836700042 PM 21124456 ER PT J AU Bazari, H AF Bazari, Hasan TI BECOMING A PHYSICIAN Gratitude, Memories, and Meaning in Medicine SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Massachusetts Gen Hosp, Internal Med Residency Program, Boston, MA 02114 USA. RP Bazari, H (reprint author), Massachusetts Gen Hosp, Internal Med Residency Program, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2187 EP 2189 DI 10.1056/NEJMp1001594 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900004 PM 21121831 ER PT J AU Musunuru, K Pirruccello, JP Do, R Peloso, GM Guiducci, C Sougnez, C Garimella, KV Fisher, S Abreu, J Barry, AJ Fennell, T Banks, E Ambrogio, L Cibulskis, K Kernytsky, A Gonzalez, E Rudzicz, N Engert, JC DePristo, MA Daly, MJ Cohen, JC Hobbs, HH Altshuler, D Schonfeld, G Gabriel, SB Yue, P Kathiresan, S AF Musunuru, Kiran Pirruccello, James P. Do, Ron Peloso, Gina M. Guiducci, Candace Sougnez, Carrie Garimella, Kiran V. Fisher, Sheila Abreu, Justin Barry, Andrew J. Fennell, Tim Banks, Eric Ambrogio, Lauren Cibulskis, Kristian Kernytsky, Andrew Gonzalez, Elena Rudzicz, Nicholas Engert, James C. DePristo, Mark A. Daly, Mark J. Cohen, Jonathan C. Hobbs, Helen H. Altshuler, David Schonfeld, Gustav Gabriel, Stacey B. Yue, Pin Kathiresan, Sekar TI Exome Sequencing, ANGPTL3 Mutations, and Familial Combined Hypolipidemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; APO-B GENE; APOLIPOPROTEIN-B; FATTY LIVER; CAUCASIAN FAMILIES; HYPOBETALIPOPROTEINEMIA; METABOLISM; LIPASE; INHIBITION; CAPTURE AB We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. C1 [Musunuru, Kiran; Pirruccello, James P.; Do, Ron; Daly, Mark J.; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran; Pirruccello, James P.; Do, Ron; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Musunuru, Kiran; Daly, Mark J.; Altshuler, David; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Peloso, Gina M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Musunuru, Kiran; Pirruccello, James P.; Do, Ron; Guiducci, Candace; Sougnez, Carrie; Garimella, Kiran V.; Fisher, Sheila; Abreu, Justin; Barry, Andrew J.; Fennell, Tim; Banks, Eric; Ambrogio, Lauren; Cibulskis, Kristian; Kernytsky, Andrew; Gonzalez, Elena; DePristo, Mark A.; Daly, Mark J.; Altshuler, David; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Musunuru, Kiran; Pirruccello, James P.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Do, Ron; Rudzicz, Nicholas; Engert, James C.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Peloso, Gina M.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cohen, Jonathan C.; Hobbs, Helen H.] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. [Cohen, Jonathan C.; Hobbs, Helen H.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Schonfeld, Gustav; Yue, Pin] Washington Univ, Sch Med, St Louis, MO USA. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-252, Boston, MA 02114 USA. EM skathiresan@partners.org RI Altshuler, David/A-4476-2009 OI Altshuler, David/0000-0002-7250-4107 FU National Human Genome Research Institute of the National Institutes of Health (NIH) [U54 HG003067]; National Heart, Lung, and Blood Institute (NHLBI) of the NIH [RC1 HL099793, RC1 HL099634, RC2 HL101864, K99 HL098364, R01 HL082896]; Donovan Family Foundation; Sarnoff Cardiovascular Research Foundation; Canadian Institutes of Health Research; National Human Genome Research Institute FX Supported by grants from the National Human Genome Research Institute of the National Institutes of Health (NIH) (Medical Sequencing Program grant U54 HG003067, to the Broad Institute for exome sequencing), the National Heart, Lung, and Blood Institute (NHLBI) of the NIH (RC1 HL099793, RC1 HL099634, and RC2 HL101864, to Dr. Kathiresan; K99 HL098364, to Dr. Musunuru; and R01 HL082896, to Drs. Cohen and Hobbs for analysis of ANGPTL3 in the Dallas Heart Study), the Donovan Family Foundation (to Dr. Kathiresan), the Sarnoff Cardiovascular Research Foundation (a research fellowship, to Mr. Pirruccello), and the Canadian Institutes of Health Research (a Canada Graduate Doctoral Scholarship, to Mr. Do).; Funded by the National Human Genome Research Institute and others NR 22 TC 215 Z9 234 U1 0 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2220 EP 2227 DI 10.1056/NEJMoa1002926 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900009 PM 20942659 ER PT J AU Sankaran, VG Nathan, DG AF Sankaran, Vijay G. Nathan, David G. TI Reversing the Hemoglobin Switch. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID FETAL-HEMOGLOBIN; BCL11A; EXPRESSION C1 [Sankaran, Vijay G.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Sankaran, VG (reprint author), Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 5 TC 23 Z9 23 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2258 EP 2260 DI 10.1056/NEJMcibr1010767 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900016 PM 21121839 ER PT J AU Flaherty, KT Chapman, PB AF Flaherty, Keith T. Chapman, Paul B. TI Inhibition of Mutated BRAF in Melanoma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MUTATIONS; NRAS C1 [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Chapman, Paul B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM kflaherty@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2261 EP 2262 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900018 ER PT J AU Hodi, FS O'Day, SJ Urba, WJ AF Hodi, F. Stephen O'Day, Steven J. Urba, Walter J. TI Diarrhea from Ipilimumab in Melanoma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [O'Day, Steven J.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Urba, Walter J.] Earle A Chiles Res Inst, Portland, OR USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2262 EP 2263 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900020 ER PT J AU Temel, JS Greer, JA Pirl, WF AF Temel, Jennifer S. Greer, Joseph A. Pirl, William F. TI Early Palliative Care in Non-Small-Cell Lung Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Temel, Jennifer S.; Greer, Joseph A.; Pirl, William F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jtemel@partners.org NR 4 TC 0 Z9 0 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 2 PY 2010 VL 363 IS 23 BP 2264 EP 2265 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 688EP UT WOS:000284832900025 ER PT J AU Chu-Shore, J Westover, MB Bianchi, MT AF Chu-Shore, Jesse Westover, M. Brandon Bianchi, Matt T. TI Power Law versus Exponential State Transition Dynamics: Application to Sleep-Wake Architecture SO PLOS ONE LA English DT Article ID PATTERNS; VARIABILITY; PHYSIOLOGY; DISEASE; CYCLE; MODEL AB Background: Despite the common experience that interrupted sleep has a negative impact on waking function, the features of human sleep-wake architecture that best distinguish sleep continuity versus fragmentation remain elusive. In this regard, there is growing interest in characterizing sleep architecture using models of the temporal dynamics of sleep-wake stage transitions. In humans and other mammals, the state transitions defining sleep and wake bout durations have been described with exponential and power law models, respectively. However, sleep-wake stage distributions are often complex, and distinguishing between exponential and power law processes is not always straightforward. Although mono-exponential distributions are distinct from power law distributions, multi-exponential distributions may in fact resemble power laws by appearing linear on a log-log plot. Methodology/Principal Findings: To characterize the parameters that may allow these distributions to mimic one another, we systematically fitted multi-exponential-generated distributions with a power law model, and power law-generated distributions with multi-exponential models. We used the Kolmogorov-Smirnov method to investigate goodness of fit for the "incorrect" model over a range of parameters. The "zone of mimicry" of parameters that increased the risk of mistakenly accepting power law fitting resembled empiric time constants obtained in human sleep and wake bout distributions. Conclusions/Significance: Recognizing this uncertainty in model distinction impacts interpretation of transition dynamics (self-organizing versus probabilistic), and the generation of predictive models for clinical classification of normal and pathological sleep architecture. C1 [Chu-Shore, Jesse] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. [Westover, M. Brandon] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. [Bianchi, Matt T.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. RP Chu-Shore, J (reprint author), Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. EM thebianchi@gmail.com FU Neurology Department, Massachusetts General Hospital; Harvard/MIT Health Sciences and Technology - Beth Israel Deaconess Medical Center; Pfizer, Inc; Merck Co. FX Dr. Bianchi receives funding from the Neurology Department, Massachusetts General Hospital, and the Clinical Investigator Training Program: Harvard/MIT Health Sciences and Technology - Beth Israel Deaconess Medical Center, in collaboration with Pfizer, Inc. and Merck & Co. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 21 Z9 21 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 2 PY 2010 VL 5 IS 12 AR e14204 DI 10.1371/journal.pone.0014204 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 688QY UT WOS:000284868000018 PM 21151998 ER PT J AU Lonial, S Anderson, KC Fonseca, R Love, N AF Lonial, Sagar Anderson, Kenneth C. Fonseca, Rafael Love, Neil TI Up-Front Management of Multiple Myeloma SO ONCOLOGY-NEW YORK LA English DT Article ID PREDNISONE PLUS THALIDOMIDE; RANDOMIZED CONTROLLED-TRIAL; ELDERLY-PATIENTS; COMBINATION CHEMOTHERAPY; ORAL MELPHALAN; PHASE-III; DEXAMETHASONE; BORTEZOMIB AB The management of multiple myeloma (MM) has undergone rapid change with the recent emergence of several effective novel agents that have added complexity to individualized treatment decision-making. This paper reviews the initial management of 276 patients with MM diagnosed and treated by 43 US-based community oncologists since January 1, 2008. The case survey data obtained are evaluated within the broad context of published findings from major phase III randomized trials and as such reveal potential education gaps and implications for oncology CME. Overall, the results reveal that most patients were symptomatic at diagnosis and were risk-stratified by fluorescene in situ hybridization (FISH) and/or cytogenetics. When analyzed by age, the overall symptomatology and biomarker-defined risk profiles appeared similar in the three age groups studied (<65, 65-74, >= 75 years). Moreover, the short-term clinical benefits and toxicity associated with the induction regimens described did not vary by age group, and the physician-reported response rates broadly corresponded to those documented in the literature for the respective treatments employed. The findings also illustrate that both proteasome inhibitors and immunomomodulataory agents are widely utilized for patients who are and are not eligible for transplant, suggesting that the rapid development of newer management strategies in MM is being effectively translated into community-based patient care. C1 [Lonial, Sagar] Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Fonseca, Rafael] Mayo Clin Arizona, Mayo Clin Canc Ctr, Scottsdale, AZ USA. [Love, Neil] Res To Practice, Miami, FL USA. RP Lonial, S (reprint author), Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD DEC PY 2010 VL 24 IS 12 SU 5 BP 8 EP 14 PG 7 WC Oncology SC Oncology GA 800PL UT WOS:000293375300002 ER PT J AU Niquet, J Lopez-Meraz, ML Wasterlain, CG AF Niquet, Jerome Lopez-Meraz, Maria-Leonor Wasterlain, Claude G. TI Programmed necrosis after status epilepticus SO EPILEPSIA LA English DT Article DE Apoptosis; Caspase; Epilepsy; Excitotoxicity; Maturation; Mitochondria; Seizures AB P>Recent data suggest that neuronal necrosis plays a prominent role in neuronal injury following status epilepticus (SE), even in the immature brain. We review the evidence that SE-induced neuronal necrosis is an active form of death involving caspases and mitochondrial death factors. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AC, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books). C1 [Niquet, Jerome] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. VA Greater Angeles Hlth Care Syst, Los Angeles, CA USA. RP Niquet, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM jniquet@ucla.edu NR 3 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD DEC PY 2010 VL 51 SU 5 BP 36 EP 36 DI 10.1111/j.1528-1167.2010.02822.x PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 695QV UT WOS:000285388600031 ER PT J AU Houser, CR Zhang, NH Peng, ZC AF Houser, Carolyn R. Zhang, Nianhui Peng, Zechun TI Alterations in the distribution of GABA(A) receptorsin epilepsy SO EPILEPSIA LA English DT Article DE Interneurons; Subcellular location; GABA(A) receptor subunits; Plasticity; Seizures; Synapse; Tonic inhibition ID TEMPORAL-LOBE EPILEPSY; MOUSE MODEL; EXPRESSION; SUBUNIT AB P>Alterations in the distribution of GABA(A) receptors are likely to play pivotal roles in epilepsy. Current findings indicate that such changes are more complex than general increases or decreases in specific subunits and can involve differential changes in principal cells and interneurons, altered localization at synapses, and altered subunit partnerships. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books). C1 [Houser, Carolyn R.; Zhang, Nianhui; Peng, Zechun] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Houser, Carolyn R.] W Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Houser, CR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. EM houser@mednet.ucla.edu NR 4 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD DEC PY 2010 VL 51 SU 5 BP 47 EP 47 DI 10.1111/j.1528-1167.2010.02833.x PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 695QV UT WOS:000285388600042 ER PT J AU Tanaka, M DeLorey, TM Delgado-Escueta, AV Olsen, RW AF Tanaka, Miyabi DeLorey, Timothy M. Delgado-Escueta, Antonio V. Olsen, Richard W. TI GABRB3, epilepsy, and neurodevelopment SO EPILEPSIA LA English DT Article DE Angelman syndrome; Autism spectrum disorder; beta 3 subunit of GABA(A) receptor; Childhood absence epilepsy; Embryonic brain; Rett syndrome; Seizures AB P>GABRB3 is important to neurodevelopment, and appears to be influenced by non-Mendelian and epigenetic mechanisms. GABRB3 abnormalities have been implicated in a variety of neurodevelopmental conditions presenting epilepsy phenotypes, including childhood absence epilepsy, Angelman syndrome, and autism. Gabrb3 disruption in mice also results in seizure phenotypes, ataxia, and sensory and learning disorders. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books). C1 [Olsen, Richard W.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Tanaka, Miyabi; Delgado-Escueta, Antonio V.] VA GLAHS W Los Angeles, Los Angeles, CA USA. [DeLorey, Timothy M.] Mol Res Inst, Palo Alto, CA 94304 USA. RP Olsen, RW (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Room CHS 23-120,650 Young Dr S, Los Angeles, CA 90095 USA. EM rolsen@mednet.ucla.edu FU NIH [NS35985, MH65393] FX NIH grants NS35985 and MH65393. NR 4 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD DEC PY 2010 VL 51 SU 5 BP 77 EP 77 DI 10.1111/j.1528-1167.2010.02863.x PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 695QV UT WOS:000285388600072 ER PT J AU Walker, LJ Kang, YH Smith, MO Oo, Y Lauer, G Barnes, E Adams, DH Klenerman, P AF Walker, L. J. Kang, Y. -H. Smith, M. O. Oo, Y. Lauer, G. Barnes, E. Adams, D. H. Klenerman, P. TI Novel functions, phenotype and homing of Human CD8aa cells SO IMMUNOLOGY LA English DT Meeting Abstract CT Annual Congress of the British-Society-for-Immunology CY DEC 06-10, 2010 CL Liverpool, ENGLAND SP British Soc Immunol C1 [Walker, L. J.; Kang, Y. -H.; Smith, M. O.; Barnes, E.; Klenerman, P.] Univ Oxford, Oxford, England. [Oo, Y.; Adams, D. H.] Univ Birmingham, Liver Res Ctr, Birmingham, W Midlands, England. [Lauer, G.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD DEC PY 2010 VL 131 SU 1 BP 38 EP 38 PG 1 WC Immunology SC Immunology GA 689XL UT WOS:000284964100095 ER PT J AU Lodato, S Meleski, AM Molyneaux, BJ Arlotta, P AF Lodato, S. Meleski, A. M. Molyneaux, B. J. Arlotta, P. TI Molecular signals governing early development of corticospinal motor neurons by Fezf2 SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Meeting Abstract CT 18th Biennial Meeting of the International-Society-for-Developmental-Neuroscience CY JUN 06-09, 2010 CL Estoril, PORTUGAL SP Int Soc Dev Neurosci DE Corticospinal motor neurons; Transcription factors; Cortical development C1 [Lodato, S.; Meleski, A. M.; Molyneaux, B. J.] Harvard Univ, Cambridge, MA 02138 USA. [Arlotta, P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD DEC PY 2010 VL 28 IS 8 SI SI BP 670 EP 670 DI 10.1016/j.ijdevneu.2010.07.085 PG 1 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 689YS UT WOS:000284967600082 ER PT J AU Gangadhar, TC Nandi, S Rolle, C Ramirez, E Surati, M Kanteti, R Sattler, M Husain, AN Salgia, R AF Gangadhar, T. C. Nandi, S. Rolle, C. Ramirez, E. Surati, M. Kanteti, R. Sattler, M. Husain, A. N. Salgia, R. TI CXCR4 as a Therapeutic Target in Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Gangadhar, T. C.; Nandi, S.; Rolle, C.; Ramirez, E.; Surati, M.; Kanteti, R.; Husain, A. N.; Salgia, R.] Univ Chicago, Chicago, IL 60637 USA. [Sattler, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2010 VL 5 IS 12 SU 7 BP S542 EP S542 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 690HQ UT WOS:000284994100109 ER PT J AU Sequist, LV Waltman, B Dias-Santagata, D Gettinger, S Fidias, P Shaw, AT Lanuti, M Iafrate, AJ Mino-Kenudson, M Engelman, JA AF Sequist, L. V. Waltman, B. Dias-Santagata, D. Gettinger, S. Fidias, P. Shaw, A. T. Lanuti, M. Iafrate, A. J. Mino-Kenudson, M. Engelman, J. A. TI Small Cell Lung Cancer Harboring EGER Mutations: Phenotype and Genotype Changes Observed With Acquired EGFR TKI Resistance in EGER-Mutant NSCLC SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Sequist, L. V.; Fidias, P.; Shaw, A. T.; Lanuti, M.; Engelman, J. A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Waltman, B.] Harvard Univ, Sch Med, Boston, MA USA. [Dias-Santagata, D.; Iafrate, A. J.; Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gettinger, S.] Yale Univ, Sch Med, New Haven, CT USA. [Gettinger, S.] Yale Univ, Ctr Canc, New Haven, CT USA. NR 0 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 DEC PY 2010 VL 5 IS 12 SU 7 BP S501 EP S501 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 690HQ UT WOS:000284994100003 ER PT J AU Von Pawel, J Akerley, W Brugger, W Ferrari, D Garmey, E Gerber, D Orlov, S Ramlau, R Sequist, L Schiller, J AF Von Pawel, J. Akerley, W. Brugger, W. Ferrari, D. Garmey, E. Gerber, D. Orlov, S. Ramlau, R. Sequist, L. Schiller, J. TI Microscopic Vascular Invasion and its Relationship With T Size-based Categories in Early Stage Non-small Cell Lung Cancer: Did the 2009 TNM Staging System Miss Something? SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Von Pawel, J.] Asklepios Klinikum Gauting, Munich, Germany. [Akerley, W.] Univ Utah, Huntsman Canc Inst, Huntsman Canc Inst Intermt Canc Care Program, Salt Lake City, UT USA. [Ferrari, D.; Garmey, E.] Ar Qule Inc, Woburn, MA USA. [Gerber, D.; Schiller, J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Brugger, W.] Schwarzwald Baar Clin, Schwenningen, Germany. [Orlov, S.] St Petersburg Pavlov State Med Univ, St Petersburg, Russia. [Sequist, L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ramlau, R.] Wielkopolskie Centrum Chorob Pluc & Gruzlicy, Poznan, Poland. 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 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2010 VL 5 IS 12 SU 7 BP S501 EP S502 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 690HQ UT WOS:000284994100004 ER PT J AU Von Pawel, J Akerley, W Brugger, W Ferrari, D Garmey, E Gerber, D Orlov, S Ramlau, R Sequist, L Schiller, J AF Von Pawel, J. Akerley, W. Brugger, W. Ferrari, D. Garmey, E. Gerber, D. Orlov, S. Ramlau, R. Sequist, L. Schiller, J. TI Final Results from Arq 197-209: A Global Randomized Placebo-controlled Phase 2 Clinical Trial of Erlotinib Plus ARQ 197 Versus Erlotinib Plus Placebo in Previously Treated EGER-inhibitor Naive Patients With Advanced Non-small Cell Lung Cancer (NSCLC) SO JOURNAL OF THORACIC ONCOLOGY LA English DT Meeting Abstract C1 [Von Pawel, J.] Asklepios Klinikum Gauting, Munich, Germany. [Akerley, W.] Univ Utah, Huntsman Canc Inst, Huntsman Canc Inst Canc Care Program, Salt Lake City, UT USA. [Brugger, W.] Schwarzwald Baar Clin, Schwenningen, Germany. [Ferrari, D.; Garmey, E.] Ar Qule Inc, Woburn, MA USA. [Gerber, D.; Schiller, J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Orlov, S.] St Petersburg Pavlov State Med Univ, St Petersburg, Russia. [Ramlau, R.] Wielkopolskie Centrum Chorob Pluc & Gruzlicy, Poznan, Poland. [Sequist, L.] Massachusetts Gen Hosp, Boston, MA 02114 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 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD DEC PY 2010 VL 5 IS 12 SU 7 BP S501 EP S501 PG 1 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 690HQ UT WOS:000284994100002 ER PT J AU Sloan, DM Sandt, AR AF Sloan, Denise M. Sandt, Arthur R. TI Depressed mood and emotional responding (vol 84, pg 368, 2010) SO BIOLOGICAL PSYCHOLOGY LA English DT Correction C1 [Sloan, Denise M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Sloan, Denise M.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Sandt, Arthur R.] Temple Univ, Philadelphia, PA 19122 USA. RP Sloan, DM (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. EM dsloan@bu.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD DEC PY 2010 VL 85 IS 3 BP 522 EP 522 DI 10.1016/j.biopsycho.2010.09.001 PG 1 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 728TG UT WOS:000287896800062 ER PT J AU Fehringer, EV Mikuls, TR Michaud, KD Henderson, WG O'Dell, JR AF Fehringer, Edward V. Mikuls, Ted R. Michaud, Kaleb D. Henderson, William G. O'Dell, James R. TI Shoulder Arthroplasties have Fewer Complications than Hip or Knee Arthroplasties in US Veterans (vol 468, pg 717, 2010) SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Correction C1 [Fehringer, Edward V.] Univ Nebraska, Med Ctr, Dept Orthopaed Surg & Rehabil, Nebraska Med Ctr 981080, Omaha, NE 68198 USA. [Fehringer, Edward V.; Mikuls, Ted R.; Michaud, Kaleb D.; O'Dell, James R.] Nebraska Arthrit Outcome Res Ctr NAORC, Omaha, NE USA. [Henderson, William G.] Univ Colorado Hlth Outcomes Program UCD, AMC, Denver, CO USA. [Henderson, William G.] Denver VA Med Ctr, Denver, CO USA. RP Fehringer, EV (reprint author), Univ Nebraska, Med Ctr, Dept Orthopaed Surg & Rehabil, Nebraska Med Ctr 981080, 600 S 42nd St, Omaha, NE 68198 USA. EM evfehringer@unmc.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD DEC PY 2010 VL 468 IS 12 BP 3428 EP 3428 DI 10.1007/s11999-010-1593-0 PG 1 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 735TJ UT WOS:000288440700043 ER PT J AU Hsu, YH Chen, X Gupta, M Karasik, D Meigs, J Cupples, LA Kiel, DP AF Hsu, Yi-Hsiang Chen, Xing Gupta, Mayetri Karasik, David Meigs, James Cupples, L. Adrienne Kiel, Douglas P. TI A Powerful Multi-Phenotype Approach on GenomeWide Association Studies (GWAS) to Identify Novel Pleiotropic Genes that Affected Multiple Quantitative Traits SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-12, 2010 CL Boston, MA SP Int Genet Epidemiol Soc C1 [Hsu, Yi-Hsiang; Karasik, David; Kiel, Douglas P.] Harvard Univ, Sch Med, Boston, MA USA. [Hsu, Yi-Hsiang; Karasik, David; Kiel, Douglas P.] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Chen, Xing] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Gupta, Mayetri; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Meigs, James] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2010 VL 34 IS 8 MA 21 BP 922 EP 923 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 686TR UT WOS:000284719100034 ER PT J AU Kim, S Tsuang, D Wijsman, E AF Kim, Sulgi Tsuang, Debby Wijsman, Ellen TI Batch Effects with Illumina 1M Onmi-Quad Chip in CNV Detection SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-12, 2010 CL Boston, MA SP Int Genet Epidemiol Soc C1 [Kim, Sulgi; Wijsman, Ellen] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Tsuang, Debby] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2010 VL 34 IS 8 MA 41 BP 928 EP 928 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 686TR UT WOS:000284719100054 ER PT J AU Konig, IR Erdmann, J Thompson, JR Preuss, M Absher, D Assimes, TL Blankenberg, S Boerwinkle, E Chen, L Cupples, A Hall, AS Halperin, E Hengstenberg, C Holm, H Laaksonen, R Li, MY Marz, W McPherson, R Musunuru, K Nelson, CP Burnett, MS Epstein, SE O'Donnell, CJ Quertermous, T Rader, DJ Roberts, R Schillert, A Stewart, AF Thorleifsson, G Thorsteinsdottir, U Voight, BF Wells, GA Ziegler, A Kathiresan, S Reilly, MP Samani, NJ Schunkert, H AF Konig, Inke R. Erdmann, Jeanette Thompson, John R. Preuss, Michael Absher, Devin Assimes, Themistocles L. Blankenberg, Stefan Boerwinkle, Eric Chen, Li Cupples, Adrienne Hall, Alistair S. Halperin, Eran Hengstenberg, Christian Holm, Hilma Laaksonen, Reijo Li, Mingyao Marz, Winfried McPherson, Ruth Musunuru, Kiran Nelson, Christopher P. Burnett, Mary S. Epstein, Stephen E. O'Donnell, Christopher J. Quertermous, Thomas Rader, Daniel J. Roberts, Robert Schillert, Arne Stewart, Alexandre F. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Voight, Benjamin F. Wells, George A. Ziegler, Andreas Kathiresan, Sekar Reilly, Muredach P. Samani, Nilesh J. Schunkert, Heribert TI Genetics of Coronary Artery Disease: Results from the CARDIOGRAM Meta-analysis SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-12, 2010 CL Boston, MA SP Int Genet Epidemiol Soc C1 [Konig, Inke R.; Preuss, Michael; Schillert, Arne; Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Thompson, John R.; Nelson, Christopher P.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Absher, Devin] Hudson Alpha Inst, Huntsville, AL USA. [Assimes, Themistocles L.; Quertermous, Thomas] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Blankenberg, Stefan] Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Univ Med, Mainz, Germany. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Chen, Li; McPherson, Ruth; Roberts, Robert; Stewart, Alexandre F.; Wells, George A.] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Cupples, Adrienne] Boston Univ, Dept Biostat & Epidemiol, Boston, MA 02215 USA. [Hall, Alistair S.] Univ Leeds, LIGHT Res Inst, Fac Med & Hlth, Leeds, W Yorkshire, England. [Halperin, Eran] Tel Aviv Univ, Blavatnik Sch Comp Sci, Tel Aviv, Israel. [Halperin, Eran] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, Tel Aviv, Israel. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Holm, Hilma; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur] deCODE Genet, IS-101 Reykjavik, Iceland. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, Tampere, Finland. [Marz, Winfried] Synlab Ctr Lab Diagnost Heidelberg, Heidelberg, Germany. [Musunuru, Kiran; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Burnett, Mary S.; Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, MedStar Res Inst, Washington, DC 20010 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen, Div Cardiol, Boston, MA USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. RI Laaksonen, Reijo/D-6323-2014 NR 0 TC 0 Z9 0 U1 0 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 DEC PY 2010 VL 34 IS 8 MA 132 BP 953 EP 953 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 686TR UT WOS:000284719100142 ER PT J AU Chang, SC Pauls, DL Lange, C Lasky-Su, J Daly, M Santangelo, SL AF Chang, Shun-Chiao Pauls, David L. Lange, Christoph Lasky-Su, Jessica Daly, Mark Santangelo, Susan L. TI Male-Specific Risk Alleles of Autism Spectrum Disorders in a Genome-wide Association Analysis SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-12, 2010 CL Boston, MA SP Int Genet Epidemiol Soc C1 [Chang, Shun-Chiao; Lange, Christoph] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Pauls, David L.; Daly, Mark; Santangelo, Susan L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Cambridge, MA 02138 USA. [Lasky-Su, Jessica] Brigham & Womens Hosp, Channing Labs, Boston, MA 02115 USA. [Lasky-Su, Jessica] Harvard Univ, Sch Med, Cambridge, MA 02138 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 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2010 VL 34 IS 8 MA 178 BP 966 EP 966 PG 1 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 686TR UT WOS:000284719100186 ER PT J AU Tranah, GJ Manini, TM Lohman, KK Nalls, MA Kritchevsky, S Newman, AB Harris, TB 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. Biffi, Alessandro Cummings, Steven R. Liu, Yongmei TI Mitochondrial DNA Variation in Human Metabolic Rate, Energy Expenditure and Mortality: The Health, Aging and Body Composition Study SO GENETIC EPIDEMIOLOGY LA English DT Meeting Abstract CT 19th Annual Meeting of the International-Genetic-Epidemiology-Society CY OCT 10-12, 2010 CL Boston, MA SP Int Genet Epidemiol Soc C1 [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. [Lohman, Kurt K.] Wake Forest Univ, Dept Biostat Sci, Sch Med, Winston Salem, NC 27109 USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Kritchevsky, Stephen; Liu, Yongmei] Wake Forest Univ, Sticht Ctr Aging, Sch Med, Winston Salem, NC 27109 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 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. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 2 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 DEC PY 2010 VL 34 IS 8 MA 199 BP 972 EP 973 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 686TR UT WOS:000284719100206 ER PT J AU Lee, IS Spector, M AF Lee, In-Seop Spector, Myron TI Fu-Zhai Cui's vision and leadership SO BIOMEDICAL MATERIALS LA English DT Editorial Material C1 [Lee, In-Seop] Yonsei Univ, Seoul 120749, South Korea. [Spector, Myron] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Cambridge, MA 02138 USA. RP Lee, IS (reprint author), Yonsei Univ, Seoul 120749, South Korea. NR 0 TC 0 Z9 0 U1 2 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1748-6041 J9 BIOMED MATER JI Biomed. Mater. PD DEC PY 2010 VL 5 IS 6 AR 060201 DI 10.1088/1748-6041/5/6/060201 PG 2 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 703ZO UT WOS:000286020800001 ER PT J AU Adams, M Schmidt, U Stelfox, H Bittner, E AF Adams, M. Schmidt, Ulrich Stelfox, H. Bittner, Edward TI EXAMINATION OF EMERGENCY AIRWAY SERVICE PATTERNS IN A LARGE ACADEMIC MEDICAL CENTER SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Adams, M.; Schmidt, Ulrich; Bittner, Edward] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Stelfox, H.] Univ Calgary, Calgary, AB T2N 1N4, Canada. 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 112 BP U30 EP U30 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800107 ER PT J AU Bazick, H Chang, D Mahadevappa, K Gibbons, F Christopher, K AF Bazick, Heidi Chang, Domingo Mahadevappa, Karthik Gibbons, Fiona Christopher, Kenneth TI RED CELL DISTRIBUTION WIDTH AND MORTALITY IN CRITICAL ILLNESS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Bazick, Heidi; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chang, Domingo; Mahadevappa, Karthik; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 543 BP U169 EP U169 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801031 ER PT J AU Beier, K Eppanapally, S Bazick, H Chang, D Mahadevappa, K Gibbons, F Christopher, K AF Beier, Kevin Eppanapally, Sabitha Bazick, Heidi Chang, Domingo Mahadevappa, Karthik Gibbons, Fiona Christopher, Kenneth TI BUN IS PREDICTIVE OF BLOOD CULTURE POSITIVITY AND MORTALITY IN CRITICALLY ILL PATIENTS INDEPENDENT OF 'NORMAL' CREATININE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Beier, Kevin] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Eppanapally, Sabitha; Chang, Domingo; Mahadevappa, Karthik; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bazick, Heidi; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 526 BP U164 EP U164 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801013 ER PT J AU Bittner, E Driscoll, W Hess, D Schmidt, U AF Bittner, Edward Driscoll, Wilhelm Hess, Dean Schmidt, Ulrich TI TRENDS IN VENTILATION STRATEGY IN THE OPERATING ROOM: ANALYSIS OF A LARGE DATA SET SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Bittner, Edward; Driscoll, Wilhelm; Hess, Dean; Schmidt, Ulrich] Massachusetts Gen Hosp, Boston, MA 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 634 BP U195 EP U195 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801118 ER PT J AU Braun, A Chang, D Mahadevappa, K Gibbons, F Giovannucci, E Liu, Y Christopher, K AF Braun, Andrea Chang, Domingo Mahadevappa, Karthik Gibbons, Fiona Giovannucci, Edward Liu, Yan Christopher, Kenneth TI ASSOCIATION OF LOW SERUM 25-HYDROXYVITAMIN D LEVELS AND MORTALITY IN THE CRITICALLY ILL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Braun, Andrea; Chang, Domingo; Mahadevappa, Karthik; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Giovannucci, Edward; Liu, Yan] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 33 BP U11 EP U11 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800034 ER PT J AU Byrnes, C Cummings, B Stathopoulos, W Noviski, N Gordon, J AF Byrnes, Chelsie Cummings, Brian Stathopoulos, Wayne Noviski, Natan Gordon, James TI OBJECTIVELY EVALUATING PEDIATRIC RESIDENT PERFORMANCE USING CLOSED MALPRACTICE CLAIMS IN A SIMULATOR BASED TESTING ENVIRONMENT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Byrnes, Chelsie; Cummings, Brian; Stathopoulos, Wayne; Noviski, Natan; Gordon, James] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 494 BP U138 EP U138 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800468 ER PT J AU Cummings, B Yager, P Riley, J Carew, A Noviski, N AF Cummings, Brian Yager, Phoebe Riley, JoAnne Carew, Anita Noviski, Natan TI IMPACT OF HOSPITAL-BASED PEDIATRIC TRANSPORT TEAM CLOSURE ON TRANSPORTS AND TRANSPORT REQUESTS TO A PEDIATRIC INTENSIVE CARE UNIT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Cummings, Brian; Yager, Phoebe; Riley, JoAnne; Carew, Anita; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 121 BP U32 EP U32 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800117 ER PT J AU Durall, A Wolfe, J AF Durall, Amy Wolfe, Joanne TI CLINICIAN PERSPECTIVES ON THE DO NOT RESUSCITATE ORDER AT A CHILDREN'S HOSPITAL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Durall, Amy; Wolfe, Joanne] Childrens Hosp, Boston, MA 02115 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 722 BP U221 EP U221 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801203 ER PT J AU Elmer, J Pallin, D Liu, S Pearson, C Chang, Y Greenberg, S Rosand, J Goldstein, J AF Elmer, Jonathan Pallin, Daniel Liu, Shan Pearson, Catherine Chang, Yuchiao Greenberg, Steven Rosand, Jonathan Goldstein, Joshua TI PROLONGED EMERGENCY DEPARTMENT LENGTH OF STAY DOES NOT INCREASE RESOURCE UTILIZATION IN PATIENTS WITH INTRACEREBRAL HEMORRHAGE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Elmer, Jonathan; Liu, Shan; Pearson, Catherine; Chang, Yuchiao; Greenberg, Steven; Rosand, Jonathan; Goldstein, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Elmer, Jonathan; Pallin, Daniel] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pallin, Daniel] Childrens Hosp Boston, Boston, MA USA. RI Pallin, Daniel/H-6382-2013 OI Pallin, Daniel/0000-0002-8517-9702 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 337 BP U93 EP U93 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800314 ER PT J AU Fisher, D Thorne, G Bilodeau, ML Fagan, S AF Fisher, Daniel Thorne, Grace Bilodeau, Mary-Liz Fagan, Shawn TI BRONCHOALVEOLAR LAVAGE AS A SCREENING TOOL FOR PULMONARY INFECTIONS IN BURN PATIENTS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Fisher, Daniel; Thorne, Grace; Bilodeau, Mary-Liz; Fagan, Shawn] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 698 BP U215 EP U215 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801180 ER PT J AU Johnson, D Bittner, E Schmidt, U Pino, R AF Johnson, Daniel Bittner, Edward Schmidt, Ulrich Pino, Richard TI DELAY IN TRANSFER FROM THE SURGICAL ICU: INCIDENCE, CAUSES AND FINANCIAL IMPACT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 114 BP U30 EP U30 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800108 ER PT J AU Karvellas, C Farhat, M Sajjad, I Mogensen, S Bagshaw, S AF Karvellas, Constantine Farhat, Maha Sajjad, Imran Mogensen, Simon Bagshaw, Sean TI TIMING OF INITIATION OF RENAL REPLACEMENT THERAPY IN ACUTE KIDNEY INJURY: A META-ANALYSIS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Karvellas, Constantine] Univ Alberta, Edmonton, AB T6G 2M7, Canada. [Farhat, Maha] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sajjad, Imran] Harvard Univ, Cambridge, MA 02138 USA. [Mogensen, Simon] Hvidovre Univ Hosp, Hvidovre, Denmark. [Bagshaw, Sean] Univ Alberta Hosp, Div Crit Care Med, Edmonton, AB, Canada. 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 385 BP U107 EP U107 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800361 ER PT J AU Keles, E Zhang, J Koppula, R Chung, J Whalen, M AF Keles, Eyup Zhang, Jimmy Koppula, Rajani Chung, Joon Whalen, Michael TI EFFICACY OF POLOXAMER P188 COMPARED TO P407 AND POLYETHYLENE GLYCOL AFTER TRAUMATIC BRAIN INJURY IN MICE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Keles, Eyup; Zhang, Jimmy; Koppula, Rajani; Chung, Joon; Whalen, Michael] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 149 BP U42 EP U42 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800141 ER PT J AU Kumar, A Goldfarb, J Bittner, E AF Kumar, Asheesh Goldfarb, Jeremy Bittner, Edward TI A CASE OF SEVERE DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS) SYNDROME COMPLICATING AIRWAY MANAGEMENT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Kumar, Asheesh; Goldfarb, Jeremy; Bittner, Edward] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 935 BP U281 EP U281 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801401 ER PT J AU Lipnick, M Braun, A Bazick, H Chang, D Cheung, TW Gibbons, F Christopher, K AF Lipnick, Michael Braun, Andrea Bazick, Heidi Chang, Domingo Cheung, Ting-Wai Gibbons, Fiona Christopher, Kenneth TI CHANGE IN ANION GAP AND MORTALITY IN CRITICALLY ILL PATIENTS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Lipnick, Michael; Braun, Andrea; Chang, Domingo; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bazick, Heidi; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cheung, Ting-Wai] Schulich Sch Med & Dent, London, ON, Canada. 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 676 BP U208 EP U208 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801158 ER PT J AU Srinivasan, R Wiener-Kronish, J Flori, H AF Srinivasan, Ramya Wiener-Kronish, Jeanine Flori, Heidi TI RELIABILITY OF 3 DIFFERENT CULTURE DIAGNOSTICS FOR IDENTIFICATION OF THE MICROBIAL ETIOLOGY OF PEDIATRIC VAP SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Wiener-Kronish, Jeanine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Flori, Heidi] Childrens Hosp Oakland, Oakland, CA USA. [Srinivasan, Ramya] UCSF, San Francisco, CA 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 822 BP U248 EP U248 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801289 ER PT J AU Sulemanji, D Bao, FP Jiang, YD Kacmarek, R AF Sulemanji, Demet Bao, Fangping Jiang, Yandong Kacmarek, Robert TI UNIDIRECTIONAL BREATHING PATTERN IMPROVES THE BREATHING EFFICIENCY IN COPD PATIENTS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Sulemanji, Demet; Bao, Fangping; Jiang, Yandong; Kacmarek, Robert] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 825 BP U249 EP U249 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801294 ER PT J AU Sulemanji, D Marchese, A Wysocki, M Kacmarek, R AF Sulemanji, Demet Marchese, Andrew Wysocki, Marc Kacmarek, Robert TI ADAPTIVE SUPPORT VENTILATION WITH AND WITHOUT END-TIDAL CO2 CLOSED LOOP CONTROL VS. CONVENTIONAL VENTILATION SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Sulemanji, Demet; Marchese, Andrew; Kacmarek, Robert] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 832 BP U251 EP U251 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801300 ER PT J AU Yager, P Lok, J Gordon, J Beauchamp, K French, B Parker, L English, P Simon, R Stathopoulos, W Noviski, N AF Yager, Phoebe Lok, Josephine Gordon, James Beauchamp, Kathryn French, Brian Parker, Lois English, Patricia Simon, Robert Stathopoulos, Wayne Noviski, Natan TI MEDICAL AND TEAM TRAINING IN A PEDIATRIC INTENSIVE CARE UNIT THROUGH A MULTIDISCIPLINARY, IN SITU SIMULATION PROGRAM SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Yager, Phoebe; Lok, Josephine; Gordon, James; Beauchamp, Kathryn; French, Brian; Parker, Lois; English, Patricia; Simon, Robert; Stathopoulos, Wayne; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 511 BP U160 EP U160 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520801004 ER PT J AU Yager, P Whalen, M Cummings, B Noviski, N AF Yager, Phoebe Whalen, Michael Cummings, Brian Noviski, Natan TI USE OF TELEMEDICINE TO PROVIDE ENHANCED COMMUNICATION BETWEEN AT-HOME ATTENDINGS AND BEDSIDE PERSONNEL IN A PEDIATRIC INTENSIVE CARE UNIT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Yager, Phoebe; Whalen, Michael; Cummings, Brian; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 105 BP U28 EP U28 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800101 ER PT J AU Zager, S Mendu, M Chang, D Bazick, H Gibbons, F Christopher, K AF Zager, Sam Mendu, Mallika Chang, Domingo Bazick, Heidi Gibbons, Fiona Christopher, Kenneth TI RELATIONSHIP BETWEEN NEIGHBORHOOD POVERTY RATE AND MORTALITY IN THE CRITICALLY ILL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 40th Critical Care Congress CY JAN 15-19, 2011 CL San Diego, CA SP Soc Crit Care Med C1 [Zager, Sam] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Mendu, Mallika; Chang, Domingo; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bazick, Heidi; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2010 VL 38 IS 12 SU S MA 9 BP U5 EP U5 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 684BA UT WOS:000284520800010 ER PT J AU Musunuru, K AF Musunuru, Kiran TI SORTI: deciphering the biological and genetic link between cholesterol and coronary heart disease SO CLINICAL LIPIDOLOGY LA English DT Editorial Material DE cardiovascular disease; genetics; genomics; lipids ID GENOME-WIDE ASSOCIATION; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; SEQUENCE VARIANTS; BLOOD-LIPIDS; LDL RECEPTOR; LOCI; POPULATION; MUTATIONS; RISK AB "While the traditional approaches for the identification of disease-causing rare DNA mutations have identified several genes that influence both lipid traits and [coronary heart disease] risk, [genome-wide association studies] appear to have localized as many new genes, including SORTI, which are linked to both phenotypes." C1 [Musunuru, Kiran] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran] Harvard Univ, Sch Med, Boston, MA USA. [Musunuru, Kiran] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Musunuru, K (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM kmusunuru@partners.org NR 25 TC 0 Z9 0 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-4299 J9 CLIN LIPIDOL JI Clin. Lipidol. PD DEC PY 2010 VL 5 IS 6 BP 765 EP 768 DI 10.2217/CLP.10.63 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 710BC UT WOS:000286484700001 ER PT J AU Ginde, AA Rao, M Simon, EL Edwards, JM Gardner, A Rogers, J Lopez, E Camargo, CA Piazza, G Rosenau, A Schneider, S Jouriles, N AF Ginde, Adit A. Rao, Mitesh Simon, Erin L. Edwards, J. Matthew Gardner, Angela Rogers, John Lopez, Edwin Camargo, Carlos A., Jr. Piazza, Gina Rosenau, Alex Schneider, Sandra Jouriles, Nicholas TI Regionalization of Emergency Care Future Directions and Research: Workforce Issues SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID ON-CALL COVERAGE; NURSE-PRACTITIONERS; MEDICINE RESIDENCY; IMPACT; SHORTAGE; QUALITY; DEPARTMENTS; MANAGEMENT; PHYSICIANS; SURGEON AB The provision of emergency care in the United States, regionalized or not, depends on an adequate workforce. Adequate must be defined both qualitatively and quantitatively. There is currently a shortage of emergency care providers, one that will exist for the foreseeable future. This article discusses what is known about the current emergency medicine (EM) and non-EM workforce, future trends, and research opportunities. ACADEMIC EMERGENCY MEDICINE 2010; 17:1286-1296 (C) 2010 by the Society for Academic Emergency Medicine. C1 [Simon, Erin L.; Jouriles, Nicholas] Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Emergency Med, Akron Gen Med Ctr, Akron, OH USA. [Rao, Mitesh] Yale Univ, Dept Emergency Med, New Haven, CT USA. [Ginde, Adit A.] Univ Colorado, Dept Emergency Med, Aurora, CO USA. [Edwards, J. Matthew] Univ Penn, Dept Emergency Med, Philadelphia, PA 19104 USA. [Gardner, Angela] Univ Texas SW, Dept Emergency Med, Dallas, TX USA. [Rogers, John] Coliseum Northside Hosp, Dept Emergency Med, Macon, GA USA. [Lopez, Edwin] Loma Linda Univ, Dept Emergency Med, Los Angeles, CA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Piazza, Gina] Med Coll Georgia, Dept Emergency Med, Augusta, GA 30912 USA. [Rosenau, Alex] Lehigh Valley Healthcare Network, Dept Emergency Med, Allentown, PA USA. [Schneider, Sandra] Univ Rochester, Dept Emergency Med, Rochester, NY USA. RP Jouriles, N (reprint author), Northeastern Ohio Univ Coll Med & Pharm, Coll Med, Dept Emergency Med, Akron Gen Med Ctr, Akron, OH USA. EM njouriles@gmail.com RI Siry, Bonnie/D-7189-2017 NR 53 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2010 VL 17 IS 12 BP 1286 EP 1296 DI 10.1111/j.1553-2712.2010.00938.x PG 11 WC Emergency Medicine SC Emergency Medicine GA 688KL UT WOS:000284848100006 PM 21122010 ER PT J AU Muelleman, RL Sullivan, AF Espinola, JA Ginde, AA Wadman, MC Camargo, CA AF Muelleman, Robert L. Sullivan, Ashley F. Espinola, Janice A. Ginde, Adit A. Wadman, Michael C. Camargo, Carlos A., Jr. TI Distribution of Emergency Departments According to Annual Visit Volume and Urban-Rural Status: Implications for Access and Staffing SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID MEDICINE; CARE; US; PHYSICIANS; WORKFORCE; IMPACT AB Objectives: Ongoing efforts to improve access to emergency care and emergency department (ED) staffing would benefit from a better understanding of the distribution of EDs in the United States by size and location. This article describes the distribution of U.S. ED visit volumes according to ED urban versus rural status. Methods: The authors used the 2007 National Emergency Department Inventories (NEDI)-USA database to identify all nonfederal U.S. hospitals with EDs and their annual ED visit volumes. One of twelve 2003 Urban Influence Codes was applied to each ED location based on its county. These categories were collapsed into urban counties and three types of rural counties: adjacent to urban, large nonadjacent, and small nonadjacent. The number of emergency physicians (EPs) needed to staff the higher-volume rural EDs was estimated. Results: Of the 4,874 U.S. EDs in 2007, 58% were in urban counties and 42% in rural counties. Among the 2,038 rural EDs, 56% were adjacent to urban, 15% were large nonadjacent, and 29% were small nonadjacent. Of the 1,503 lower-volume (< 10,000 visit) EDs, 21% were in urban counties. Of the 3,371 higher-volume (>= 10,000 visit) EDs, 25% were in rural counties. Of the 857 higher-volume rural EDs, 66% were adjacent to urban, 22% were large nonadjacent, and 12% were small nonadjacent. The authors estimate that approximately 5,600 EPs are needed to staff these higher-volume rural EDs. Conclusions: There are many lower-volume EDs in urban areas and higher-volume EDs in rural areas. Most higher-volume rural EDs are in rural areas adjacent to urban counties. These data challenge popular assumptions regarding ED visit volumes, locations, and staffing needs. ACADEMIC EMERGENCY MEDICINE 2010; 17:1390-1397 (C) 2010 by the Society for Academic Emergency Medicine. C1 [Muelleman, Robert L.; Wadman, Michael C.] Univ Nebraska Med Ctr, Dept Emergency Med, Omaha, NE USA. [Sullivan, Ashley F.; Espinola, Janice A.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ginde, Adit A.] Univ Colorado Denver, Sch Med, Aurora, CO USA. RP Muelleman, RL (reprint author), Univ Nebraska Med Ctr, Dept Emergency Med, Omaha, NE USA. EM rmuellem@unmc.edu RI Siry, Bonnie/D-7189-2017 NR 26 TC 13 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2010 VL 17 IS 12 BP 1390 EP 1397 DI 10.1111/j.1553-2712.2010.00924.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 688KL UT WOS:000284848100021 PM 21122024 ER PT J AU Ahmadi, N Nabavi, V Yang, E Hajsadeghi, F Lakis, M Flores, F Zeb, I Bevinal, M Ebrahimi, R Budoff, M AF Ahmadi, Naser Nabavi, Vahid Yang, Eric Hajsadeghi, Fereshteh Lakis, Mustapha Flores, Ferdinand Zeb, Irfan Bevinal, Manzoor Ebrahimi, Ramin Budoff, Matthew TI Increased Epicardial, Pericardial, and Subcutaneous Adipose Tissue Is Associated with the Presence and Severity of Coronary Artery Calcium SO ACADEMIC RADIOLOGY LA English DT Article DE Epicardial adipose tissue; pericardial adipose tissue; total thoracic adipose tissue; subcutaneous adipose tissue; coronary artery calcium; coronary artery disease; risk factor ID VISCERAL ABDOMINAL FAT; CARDIOVASCULAR-DISEASE; HEART-DISEASE; COMPUTED-TOMOGRAPHY; RISK-FACTORS; MACROPHAGES; OBESITY; ATHEROSCLEROSIS; CALCIFICATION; ACCUMULATION AB Rationale and Objectives: Epicardial adipose tissue (EAT), pericardial adipose tissue (PAT), and subcutaneous adipose tissue (SAT) are mediators of metabolic risk and may be involved in the pathogenesis of coronary artery disease. The aim of this study was to investigate the association of visceral and subcutaneous fat depots with the presence and severity of coronary artery calcium (CAC) in asymptomatic individuals. Materials and Methods: One hundred eleven consecutive subjects underwent CAC assessment, and their Framingham risk scores were measured. EAT, total thoracic adipose tissue, and SAT volumes were measured from slice level 15 mm above to 30 mm below the ostium of the left main coronary artery. PAT was calculated as thoracic adipose tissue - EAT. SAT was defined as the volume of fat depot anterior to the sternum and posterior to the vertebra. CAC was defined as 0, 1 to 100, 101 to 400, or >= 400. Relative risk regression analysis was used to assess the association between fat depots and CAC. Results: There were modest correlations between EAT (r = 0.58), PAT (r = 0.47), SAT (r = 0.34), and CAC (P < .01). EAT, PAT, and SAT increased proportionally with the severity of CAC in both genders (P < .05). After adjustment for cardiovascular risk factors and body mass index, the relative risks for each standard deviation increase in EAT, PAT, and SAT were 3.3 (95% confidence interval, 1.9-5.6), 2.7 (95% confidence interval, 1.6-3.9), and 2.6 (95% confidence interval, 1.5-4.4) for CAC >= 100 compared to CAC 0, respectively (P < .05). The area under the receiver-operating characteristic curve to predict CAC >= 100 was higher in each fat depot compared to Framingham risk score, and addition of fat depots to Framingham risk score provided maximum prognostication value to detect CAC >= 100. Conclusions: Increased EAT, PAT, and SAT are associated with the severity of CAC independent of risk factors. C1 [Ahmadi, Naser; Nabavi, Vahid; Yang, Eric; Hajsadeghi, Fereshteh; Lakis, Mustapha; Flores, Ferdinand; Zeb, Irfan; Bevinal, Manzoor; Budoff, Matthew] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Ebrahimi, Ramin] Univ Calif Los Angeles, Sch Med, Greater Los Angeles VA Med Ctr, Los Angeles, CA USA. RP Ahmadi, N (reprint author), Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. EM nahmadi@labiomed.org OI Yang, Eric/0000-0003-4889-7454 NR 33 TC 28 Z9 29 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD DEC PY 2010 VL 17 IS 12 BP 1518 EP 1524 DI 10.1016/j.acra.2010.08.017 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 684ML UT WOS:000284553900009 PM 20947390 ER PT J AU Fayaz, HC Jupiter, JB AF Fayaz, H. C. Jupiter, J. B. TI Monteggia Fractures in Adults SO ACTA CHIRURGIAE ORTHOPAEDICAE ET TRAUMATOLOGIAE CECHOSLOVACA LA English DT Review ID DIAPHYSEAL FOREARM FRACTURES; RADIAL HEAD; LESION; DISLOCATIONS; ELBOW; ULNA AB Over the past fifty years, treatment outcomes of traumatic injuries in the upper limb have improved with the advent of better implants. However, the Monteggia fracture is often still associated with various complications, poor functional outcomes and a relatively high rate of revision surgeries. Rigid anatomic fixation of ulnar fracture is paramount. Open relocation of the radial head and soft tissue procedures are redundant. Monteggia fractures are challenging to treat. Critical analysis with respect to the high rate of complications and unsatisfactory functional outcomes is required. The type of fracture and associated injuries such as coronoid fracture and radial head fracture appear to influence the outcome in most cases. Negative prognostic factors such as prolonged immobilization, associated coronoid and radial head fractures must be minimized and treated appropriately. Prior to surgery the patient should be informed regarding the possible risk of residual functional limitations and the potential need for further revision surgeries. C1 [Fayaz, H. C.; Jupiter, J. B.] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Orthopaed Surg Harvard Med Sch, Boston, MA 02114 USA. RP Fayaz, HC (reprint author), Harvard Univ, Sch Med, Orthopaed Hand Serv, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. EM hfayaz@partners.org NR 30 TC 3 Z9 3 U1 0 U2 2 PU GALEN SRO PI PRAGUE 5 PA NA BELIDLE 34, PRAGUE 5, 150 00, CZECH REPUBLIC SN 0001-5415 J9 ACTA CHIR ORTHOP TR JI Acta Chir. Orthop. Traumatol. Cechoslov. PD DEC PY 2010 VL 77 IS 6 BP 457 EP 462 PG 6 WC Orthopedics SC Orthopedics GA 704US UT WOS:000286081700003 PM 21223824 ER PT J AU Bitton, A Raw, M Richards, A McNeill, A Rigotti, NA AF Bitton, Asaf Raw, Martin Richards, Ann McNeill, Ann Rigotti, Nancy A. TI A comparison of four international surveys of tobacco dependence treatment provision: implications for monitoring the Framework Convention on Tobacco Control SO ADDICTION LA English DT Article DE Global; surveys; tobacco dependence treatment AB Aims Article 14 of the Framework Convention on Tobacco Control (FCTC) requires countries to implement systems to provide tobacco dependence treatment. We report on global efforts to monitor the implementation of Article 14, and compare the surveys used in this effort. Design Cross-sectional comparison of agreement (concordance and discordance) among the four main surveys used to monitor tobacco dependence treatment provision. Setting Four global surveys of tobacco treatment provision. Participants The four surveys were Raw et al. (2009), the Framework Convention Alliance (FCA) Monitor, World Health Organization (WHO) MPOWER survey and the FCTC Party Reports. Measurements Concordance as measured by percentage providing the same answers, as well as kappa statistic of inter-rater agreement. Findings The four surveys used to monitor Article 14 implementation vary widely in countries sampled, questions asked, respondent characteristics and survey design. The four surveys generally show a moderate to high concordance (kappa > 0.60) with each other across most survey pairs and most domains, except for the MPOWER and FCTC Party governmental surveys (63% overall concordance, kappa = 0.26). This concordance was lower than any other survey pair examined. Government respondents to the WHO MPOWER and FCTC Party Report surveys provided answers to the same question domains with relatively poorer concordance than those from surveys of non-governmental or mixed governmental/non-governmental sources. Conclusions Current surveys of tobacco dependence treatment provision are in general agreement with each other except for the two official government surveys that rely on governmental respondents. We believe that this points to the continued need for independent non-governmental monitoring of FCTC protocol implementation. C1 [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, Boston, MA 02114 USA. [Bitton, Asaf] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Bitton, Asaf] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Raw, Martin; McNeill, Ann] Univ Nottingham, Div Epidemiol & Publ Hlth, UK Ctr Tobacco Control Studies, Nottingham NG7 2RD, England. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Div Gen Med, 50 Staniford St,Room 914, Boston, MA 02114 USA. EM nrigotti@partners.org FU Pfizer; Free and Clear; Health Resources and Services Administration of the United States Department of Health and Human Services [T32HP10251]; Mid-Career Mentoring Award [K24-HL04440-05]; Association for the Treatment of Tobacco Use and Dependence FX A.B., A.R. and A.M. have no competing interests. M. R. has, in the last 5 years, had conference expenses reimbursed, been paid an honorarium for a talk and received freelance fees from Pfizer, but has accepted no support from pharmaceutical companies in the last 2 years. N.R. has received consulting fees from Free and Clear (ending February 2009) and from Pfizer (ending July 2008). She has been site Principle Investigator for research grants to her institution from manufacturers of investigational and/or marketed smoking cessation products.; Asaf Bitton is supported by grant number T32HP10251 from the Health Resources and Services Administration of the United States Department of Health and Human Services to support the Harvard Medical School Fellowship in General Medicine and Primary Care. Nancy Rigotti's work was supported by a Mid-Career Mentoring Award (#K24-HL04440-05). The study contents are solely the responsibility of the authors and do not necessarily represent the official views of the United States Department of Health and Human Services. Ann Richards was supported in part by a grant from the Association for the Treatment of Tobacco Use and Dependence. NR 12 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD DEC PY 2010 VL 105 IS 12 BP 2184 EP 2191 DI 10.1111/j.1360-0443.2010.03060.x PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 676VK UT WOS:000283946600025 PM 20735369 ER PT J AU Liong, M Shao, H Haun, JB Lee, H Weissleder, R AF Liong, Monty Shao, Huilin Haun, Jered B. Lee, Hakho Weissleder, Ralph TI Carboxymethylated Polyvinyl Alcohol Stabilizes Doped Ferrofluids for Biological Applications SO ADVANCED MATERIALS LA English DT Article ID IRON-OXIDE; MAGNETIC NANOPARTICLES; QUANTUM DOTS; AMPHIPHILIC POLYMERS; NANOCRYSTALS; CANCER; CONTRAST; CELLS; SIZE; MEDIA AB Highly magnetic MnFe2O4 nanocrystals (NCs) are coated with non-cross-linked carboxymethyl polyvinyl alcohol to produce conjugates that are highly stable under varying temperatures, pH, and ionic strengths. The polymer-coated NCs exhibit low nonspecific cell binding. They are also amenable to chemical linking with biomolecules, allowing for the efficient labeling of surface receptors on targeted cancer cells in vitro. C1 [Liong, Monty; Shao, Huilin; Haun, Jered B.; Lee, Hakho; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Liong, Monty; Shao, Huilin; Haun, Jered B.; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Lee, H (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM hlee@mgh.harvard.edu; rweissleder@mgh.harvard.edu FU NIH [2RO1EB004626, U01-HL080731, U54-CA119349, T32-CA79443] FX We thank T.-J. Yoon, M. Fernandez-Suarez, R. Mazitschek, and T. Reiner for their helpful experimental suggestions; S. Earley, V. Cortez-Retamozo, A. Newton and V. Pruzinsky for their assistance in cell culture and flow cytometry; I. Bagyadev for help in confocal microscopy; N. Sergeyev for providing cross-linked dextran-coated iron oxide nanoparticles; Y. Fisher-Jeffes for reviewing the manuscript. This work was supported in part by NIH Grants 2RO1EB004626, U01-HL080731, U54-CA119349 and T32-CA79443. NR 39 TC 35 Z9 36 U1 1 U2 34 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD DEC 1 PY 2010 VL 22 IS 45 BP 5168 EP + DI 10.1002/adma.201002219 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 695TV UT WOS:000285396400020 PM 20859943 ER PT J AU Hartzell, TL Sangji, NF Hertl, MC AF Hartzell, Tristan L. Sangji, Naveen F. Hertl, Mary C. TI Ischemia of Postmastectomy Skin After Infiltration of Local Anesthetic with Epinephrine: A Case Report and Review of the Literature SO AESTHETIC PLASTIC SURGERY LA English DT Review DE Nipple-areola; Skin necrosis; Epinephrine; Breast reconstruction; Mastectomy ID AMBULATORY PHLEBECTOMY; COMPLICATION; ADRENALINE AB The goals of this study were to review the literature regarding the use of local anesthetic with epinephrine and to report an observation of prolonged ischemia and necrosis in postmastectomy skin. A PubMed literature review was performed and the patient's medical record was reviewed. Prior skin necrosis with epinephrine use in acral areas was often due to physician or manufacturing overdose. Many large studies have confirmed subsequently epinephrine's safety in acral areas. There are reports of prolonged ischemia in the dermatology literature when used in areas with impaired venous and lymphatic drainage. Our case report suggests that the impaired clearance mechanisms in postmastectomy skin with an underlying implant can lead to ischemia when using local anesthetic with epinephrine. The addition of epinephrine to local anesthetic increases the duration of analgesia and provides for a relatively bloodless operating field. In the past many surgeons were reluctant to use it because of concerns about arterial vasospasm and tissue necrosis. However, perceptions have recently changed as large reviews have documented its safe use in acral areas. Based on our review of the literature and this case, epinephrine use may not be appropriate in patients with compromised venous and lymphatic drainage. C1 [Hartzell, Tristan L.] Brigham & Womens Hosp, Div Plast Surg, Dept Surg, Boston, MA 02115 USA. [Sangji, Naveen F.] Harvard Univ, Div Plast Surg, Dept Surg, Sch Med, Boston, MA 02115 USA. [Hertl, Mary C.] Massachusetts Gen Hosp, Div Plast Surg, Dept Surg, Boston, MA 02114 USA. RP Hartzell, TL (reprint author), Brigham & Womens Hosp, Div Plast Surg, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM thartzell@partners.org NR 12 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-216X J9 AESTHET PLAST SURG JI Aesthet. Plast. Surg. PD DEC PY 2010 VL 34 IS 6 BP 782 EP 784 DI 10.1007/s00266-010-9528-4 PG 3 WC Surgery SC Surgery GA 687HS UT WOS:000284770200017 PM 20464394 ER PT J AU Gong, B Chen, F Pan, Y Arrieta-Cruz, I Yoshida, Y Haroutunian, V Pasinetti, GM AF Gong, Bing Chen, Fei Pan, Yong Arrieta-Cruz, Isabel Yoshida, Yukiko Haroutunian, Vahram Pasinetti, Giulio M. TI SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function SO AGING CELL LA English DT Article DE Alzheimer's disease; BACE1; Fbx2; synaptic function ID BETA-SECRETASE ACTIVITY; UBIQUITIN-PROTEASOME SYSTEM; MOUSE MODEL; TRANSCRIPTIONAL COACTIVATOR; MITOCHONDRIAL BIOGENESIS; PRECURSOR PROTEIN; MEMORY DEFICITS; TRANSGENIC MICE; LIGASE; PGC-1-ALPHA AB P>BACE1 (beta-secretase) plays a central role in the beta-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCFFbx2-E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and beta-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced beta-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPAR gamma coactivator-1 alpha (PGC-1 alpha) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC-1 alpha was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing beta-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD. C1 [Gong, Bing; Chen, Fei; Pan, Yong; Arrieta-Cruz, Isabel; Haroutunian, Vahram; Pasinetti, Giulio M.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Yoshida, Yukiko] Tokyo Metropolitan Inst Med Sci, Lab Frontier Sci, Tokyo 113, Japan. [Haroutunian, Vahram; Pasinetti, Giulio M.] James J Peters VA Med Ctr, Geriatr Res & Clin Ctr, Bronx, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1230, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU NIH [NS-15076]; Columbia ADRC [AG-008702]; US National Institutes of Health; Alzheimer's Association [IIRG-07-59856, IIRG-08-89354] FX We gratefully thank Dr M. Shelanski and Dr O. Arancio (Columbia University) for generously supporting the reported preliminary feasibility studies (NIH grant NS-15076 and the Columbia ADRC AG-008702); W. Zhao and S. Yemul for key contributions to the qRT-PCR experiments and for the human brain sample collection; J. Wang and L. Ho for helpful comments on this manuscript; and H. Fivecoat and I. Orozco for assistance in preparing this manuscript. The studies described here were supported in part from a grant from the Veterans Administration by the US National Institutes of Health grants and by grants from Alzheimer's Association to (IIRG-07-59856) G. M. P and (IIRG-08-89354) to B. NR 51 TC 41 Z9 42 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD DEC PY 2010 VL 9 IS 6 BP 1018 EP 1031 DI 10.1111/j.1474-9726.2010.00632.x PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 678KB UT WOS:000284071400010 PM 20854419 ER PT J AU Niikura, Y Niikura, T Wang, N Satirapod, C Tilly, JL AF Niikura, Yuichi Niikura, Teruko Wang, Ning Satirapod, Chonthicha Tilly, Jonathan L. TI Systemic signals in aged males exert potent rejuvenating effects on the ovarian follicle reserve in mammalian females SO AGING-US LA English DT Article DE aging; germ cell; oogenesis; oocyte; ovary; stem cell; parabiosis ID GERMLINE STEM-CELLS; RETINOIC ACID; MEIOTIC INITIATION; MEIOSIS; OOCYTES; ENVIRONMENT; OOGENESIS; STRA8 AB Through the use of parabiosis in mice, aging-related deterioration of skeletal muscle and liver has been linked to a loss of systemic factors that support adult stem or progenitor cell activity. Since aging-related ovarian failure has recently been attributed, at least in part, to a loss of de-novo oocyte-containing follicle formation associated with declining oogonial stem cell activity, herein we tested in mice if aging-related changes in systemic factors influence the size of the ovarian follicle reserve. Ovaries of young (2-month-old) females parabiotically joined with young females for 5 weeks possess comparable numbers of healthy and degenerative (atretic) oocyte-containing follicles in their ovaries as those detected in non-parabiotic young females. Joining of young females with young males significantly increases follicle atresia without a net change healthy follicle numbers. Surprisingly, young females joined with aged (24-month-old) males exhibit a significant increase in the number of primordial follicles comprising the ovarian reserve, and this occurs without changes in follicle growth activation or atresia. Blood of aged males also induces ovarian expression of the germ cell-specific meiosis gene, Stimulated by retinoic acid gene 8 (Stra8), in ovaries of female parabionts, further supporting the conclusion that the observed changes in the follicle reserve of females joined with aged males reflect increased oocyte formation. Thus, factors in male blood exert dramatic effects on ovarian follicle dynamics, and aging males possess a beneficial systemic factor that significantly expands the ovarian follicle reserve in females through enhanced oogenesis. C1 [Niikura, Yuichi; Niikura, Teruko; Wang, Ning; Satirapod, Chonthicha; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol,Vincent Ctr Reprod, Boston, MA 02114 USA. RP Tilly, JL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Dept Obstet & Gynecol,Vincent Ctr Reprod, Boston, MA 02114 USA. EM jtilly@partners.org FU NIH [R37-AG012279]; Henry and Vivian Rosenberg Philanthropic Fund; Sea Breeze Foundation; Vincent Memorial Research Funds FX We thank A. Wagers for teaching us how to perform parabiosis in mice. This work was supported by NIH MERIT Award R37-AG012279, the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation, and Vincent Memorial Research Funds. NR 28 TC 19 Z9 19 U1 0 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD DEC PY 2010 VL 2 IS 12 BP 999 EP 1003 PG 5 WC Cell Biology SC Cell Biology GA 705PI UT WOS:000286148000017 PM 21212462 ER PT J AU Hahn, JA Bwana, MB Javors, MA Martin, JN Emenyonu, NI Bangsberg, DR AF Hahn, Judith A. Bwana, Mwebesa B. Javors, Martin A. Martin, Jeffrey N. Emenyonu, Nneka I. Bangsberg, David R. TI Biomarker Testing to Estimate Under-Reported Heavy Alcohol Consumption by Persons with HIV Initiating ART in Uganda SO AIDS AND BEHAVIOR LA English DT Article DE Carbohydrate-deficient transferrin; Biological markers; Alcohol drinking; HIV; Antiretroviral therapy; Uganda ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; METAANALYSIS; HPLC; CDT AB Alcohol affects the transmission and treatment of HIV, yet may be under-reported in resource-limited settings We compared self-reported alcohol consumption with levels of plasma carbohydrate-deficient transferin (%CDT), a biomarker of heavy alcohol consumption in persons initiating antiretroviral therapy in Uganda Almost seven percent (6 7%) of persons reporting abstaining and 10% reporting consuming 1-40 drinks in the prior month tested positive for %CDT, and actual under-report may be higher due to low sensitivity of %CDT These results suggest likely under-report in those reporting abstaining and current drinking Improved identification of heavy alcohol consumption is needed for research and clinical purposes C1 [Hahn, Judith A.; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bwana, Mwebesa B.; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Javors, Martin A.] Univ Texas Hlth Sci Ctr, San Antonio, TX USA. [Emenyonu, Nneka I.; Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hahn, JA (reprint author), Univ Calif San Francisco, Box 0811, San Francisco, CA 94143 USA. FU NIMH NIH HHS [K24 MH087227, R01 MH054907, R01 MH54907] NR 12 TC 12 Z9 12 U1 0 U2 2 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 DEC PY 2010 VL 14 IS 6 BP 1265 EP 1268 DI 10.1007/s10461-010-9768-y PG 4 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 679CX UT WOS:000284138100005 PM 20697796 ER PT J AU Haberer, JE Kiwanuka, J Nansera, D Wilson, IB Bangsberg, DR AF Haberer, Jessica E. Kiwanuka, Julius Nansera, Denis Wilson, Ira B. Bangsberg, David R. TI Challenges in Using Mobile Phones for Collection of Antiretroviral Therapy Adherence Data in a Resource-Limited Setting SO AIDS AND BEHAVIOR LA English DT Article DE mHealth; Mobile phones; Adherence data collection; Resource-limited settings ID INTERACTIVE VOICE RESPONSE; BEHAVIOR-CHANGE; HEALTH-CARE; HIV; TECHNOLOGY; INTERVENTION; METAANALYSIS; COUNTRIES; TIME AB Frequent antiretroviral therapy adherence monitoring could detect incomplete adherence before viral rebound develops and thus potentially prevent treatment failure Mobile phone technologies make frequent, brief adherence interviews possible in resource-limited settings however, feasibility and acceptability are unknown Interactive voice response (IVR) and short message service (SMS) text messaging were used to collect adherence data from 19 caregivers of HIV-infected children in Uganda IVR calls or SMS quantifying missed doses were sent in the local language once weekly for 3-4 weeks Qualitative interviews were conducted to assess participant impressions of the technologies Participant interest and participation rates were high, however, weekly completion rates for adherence queries were low (0-33%), most commonly due to misunderstanding of personal identification numbers Despite near ubiquity of mobile phone technology in resource-limited settings individual level collection of healthcare data presents challenges Further research is needed for effective training and incentive methods C1 [Haberer, Jessica E.; Bangsberg, David R.] Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. [Haberer, Jessica E.] Massachusetts Gen Hosp, Dept Gen Internal Med, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.] MIT, Ragon Inst, Massachusetts Gen Hosp, Charlestown, MA USA. [Kiwanuka, Julius; Nansera, Denis] Mbarara Univ Sci & Technol, Dept Pediat, Kampala, Uganda. [Wilson, Ira B.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Fac Med, Kampala, Uganda. [Haberer, Jessica E.; Bangsberg, David R.] Harvard Univ, Charlestown, MA USA. RP Haberer, JE (reprint author), Harvard Initiat Global Hlth, 104 Mt Auburn St,3rd Floor, Cambridge, MA 02138 USA. RI Wilson, Ira/F-9190-2016 OI Wilson, Ira/0000-0002-0246-738X FU NIMH NIH HHS [K23 MH087228, K24 MH087227, K24 MH092242, R01 MH054907, R21 MH083306, R21 MH083306-01, R21MH083306] NR 33 TC 48 Z9 50 U1 1 U2 18 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 DEC PY 2010 VL 14 IS 6 BP 1294 EP 1301 DI 10.1007/s10461-010-9720-1 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 679CX UT WOS:000284138100009 PM 20532605 ER PT J AU Haberer, JE Kahane, J Kigozi, I Emenyonu, N Hunt, P Martin, J Bangsberg, DR AF Haberer, Jessica E. Kahane, Josh Kigozi, Isaac Emenyonu, Nneka Hunt, Peter Martin, Jeffrey Bangsberg, David R. TI Real-Time Adherence Monitoring for HIV Antiretroviral Therapy SO AIDS AND BEHAVIOR LA English DT Article DE Real-time adherence monitoring; Wireless technology; Antiretroviral therapy ID INFORMATION-TECHNOLOGY; USER ACCEPTANCE; INTERVENTIONS; RESISTANCE; VIREMIA AB Current adherence assessments typically detect missed doses long after they occur Real-time, wireless monitoring strategies for antiretroviral therapy may provide novel opportunities to proactively prevent virologic rebound and treatment failure Wisepill a wireless pill container that transmits a cellular signal when opened, was pilot tested in ten Ugandan individuals for 6 months Adherence levels measured by Wisepill, unannounced pill counts, and self-report were compared with each other prior standard electronic monitoring, and HIV RNA Wisepill data was initially limited by battery life and signal transmission interruptions Following device improvements, continuous data was achieved with median (interquartile range) adherence levels of 93% (87-97%) by Wisepill 100% (99-100%) by unannounced pill count, 100% (100-100%) by self-report, and 92% (79-98%) by prior standard electronic monitoring Four individuals developed transient, low-level viremia After overcoming technical challenges, real-time adherence monitoring is feasible for resource-limited settings and may detect suboptimal adherence prior to viral rebound C1 [Haberer, Jessica E.; Kahane, Josh; Emenyonu, Nneka; Bangsberg, David R.] Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. [Haberer, Jessica E.; Emenyonu, Nneka; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA USA. [Kigozi, Isaac; Emenyonu, Nneka; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Hunt, Peter; Martin, Jeffrey] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Haberer, Jessica E.; Bangsberg, David R.] Harvard Univ, Charlestown, MA USA. RP Haberer, JE (reprint author), Harvard Initiat Global Hlth, 104 Mt Auburn St,3rd Floor, Cambridge, MA 02138 USA. FU NIMH NIH HHS [K23 MH087228-02, R01 MH054907, R01 MH054907-16, K23 MH087228, K24 MH087227]; PHS HHS [K-23 087228, K-24 087227, R0-1 54907] NR 27 TC 71 Z9 72 U1 0 U2 2 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 DEC PY 2010 VL 14 IS 6 BP 1340 EP 1346 DI 10.1007/s10461-010-9799-4 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 679CX UT WOS:000284138100014 PM 20809380 ER PT J AU Venkatesh, KK Srikrishnan, AK Mayer, KH Kumarasamy, N Raminani, S Thamburaj, E Prasad, L Triche, EW Solomon, S Safren, SA AF Venkatesh, Kartik K. Srikrishnan, A. K. Mayer, Kenneth H. Kumarasamy, N. Raminani, Sudha Thamburaj, E. Prasad, Lakshmi Triche, Elizabeth W. Solomon, Suniti Safren, Steven A. TI Predictors of Nonadherence to Highly Active Antiretroviral Therapy Among HIV-Infected South Indians in Clinical Care: Implications for Developing Adherence Interventions in Resource-Limited Settings SO AIDS PATIENT CARE AND STDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MEDICATION ADHERENCE; PREVENTION INTERVENTIONS; HIV-1-INFECTED PATIENTS; POSITIVE PATIENTS; SEXUAL-BEHAVIOR; RURAL UGANDA; ALCOHOL-USE; TRANSMISSION; RISK AB In light of the increasing availability of generic highly active antiretroviral therapy (HAART) in India, further data are needed to examine variables associated with HAART nonadherence among HIV-infected Indians in clinical care. We conducted a cross-sectional analysis of 198 HIV-infected South Indian men and women between January and April 2008 receiving first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. Nonadherence was defined as taking less than 95% of HAART doses in the last 1 month, and was examined using multivariable logistic regression models. Half of the participants reported less than 95% adherence to HAART, and 50% had been on HAART for more than 24 months. The median CD4 cell count was 435 cells per microliter. An increased odds of nonadherence was found for participants with current CD4 cell counts greater than 500 cells per microliter (adjusted odds ratio [AOR]: 2.22 [95% confidence interval {CI}: 1.04-4.75]; p = 0.038), who were on HAART for more than 24 months (AOR: 3.07 [95% CI: 1.35-7.01]; p = 0.007), who reported alcohol use (AOR: 5.68 [95% CI: 2.10-15.32]; p - 0.001), who had low general health perceptions (AOR: 3.58 [95% CI: 1.20-10.66]; p - 0.021), and who had high distress (AOR: 3.32 [95% CI: 1.19-9.26]; p - 0.022). This study documents several modifiable risk factors for nonadherence in a clinic population of HIV-infected Indians with substantial HAART experience. Further targeted culturally specific interventions are needed that address barriers to optimal adherence. C1 [Mayer, Kenneth H.] Brown Univ, Dept Med, Div Infect Dis, Miriam Hosp,Alpert Med Sch, Providence, RI 02906 USA. [Venkatesh, Kartik K.; Mayer, Kenneth H.; Thamburaj, E.; Triche, Elizabeth W.] Brown Univ, Alpert Med Sch, Dept Community Hlth, Providence, RI 02912 USA. [Srikrishnan, A. K.; Kumarasamy, N.; Thamburaj, E.; Prasad, Lakshmi; Solomon, Suniti] YR Gaitonde Ctr AIDS Res & Educ YRG CARE, Chennai, Tamil Nadu, India. [Mayer, Kenneth H.; Raminani, Sudha; Safren, Steven A.] Fenway Community Hlth, Boston, MA USA. [Safren, Steven A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Mayer, KH (reprint author), Brown Univ, Dept Med, Div Infect Dis, Miriam Hosp,Alpert Med Sch, 164 Summit Ave, Providence, RI 02906 USA. EM Kenneth_Mayer@brown.ed RI Triche, Elizabeth/I-4986-2014 FU Brown/Tufts/Lifespan Center for AIDS Research (CFAR) [P30AI042853]; National Institute of Mental Health (NIMH) [F30 MH079738-01A2]; Brown University, Fogarty International Center at the National Institutes of Health (NIH) [D43TW00237] FX Support provided by: Brown/Tufts/Lifespan Center for AIDS Research (CFAR) (grant no. P30AI042853) (K.H.M., S.A.S.), F-30 M.D./Ph.D. National Institute of Mental Health (NIMH) Ruth Kirschtein National Research Service Award (NRSA) (grant no. F30 MH079738-01A2) (K.K.V.), and Brown University's AIDS International Research and Training Program of the Fogarty International Center at the National Institutes of Health (NIH) (grant no. D43TW00237) (K.H.M.). NR 50 TC 25 Z9 25 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD DEC PY 2010 VL 24 IS 12 BP 795 EP 803 DI 10.1089/apc.2010.0153 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 690ZO UT WOS:000285049700008 PM 21091232 ER PT J AU Gazdzinski, S Durazzo, TC Mon, A Meyerhoff, DJ AF Gazdzinski, Stefan Durazzo, Timothy C. Mon, Anderson Meyerhoff, Dieter J. TI Body Mass Index Is Associated With Brain Metabolite Levels in Alcohol Dependence-A Multimodal Magnetic Resonance Study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol Dependence; Body Mass Index; Obesity; Magnetic Resonance Spectroscopy; Brain Imaging ID CHRONIC CIGARETTE-SMOKING; NATIONAL EPIDEMIOLOGIC SURVEY; GROWTH-FACTOR RESISTANCE; PROTON MR SPECTROSCOPY; SHORT-TERM RECOVERY; DSM-IV ALCOHOL; USE DISORDERS; INSULIN-RESISTANCE; ABDOMINAL OBESITY; FAMILY-HISTORY AB Background: Recent studies demonstrated that alcohol dependence and excessive alcohol consumption are associated with increased rates of obesity. In healthy light-drinkers, we and others have observed associations between elevated body mass index (BMI) and reductions in brain volumes, lower concentrations of N-acetyl-aspartate (NAA, marker of neuronal viability) and choline-containing compounds (Cho, involved in membrane turnover), and lower glucose utilization, particularly in frontal lobe-a brain region that is particularly vulnerable to the effects of alcohol dependence. Here, we evaluated whether BMI in alcohol-dependent individuals was independently associated with regional measures of brain structure, metabolite concentrations, and neocortical blood flow. Methods: As part of a study on the effects of alcohol dependence on neurobiology, we analyzed retrospectively data from 54 alcohol-dependent males, abstinent from alcohol for about 1 month and with BMI between 20 and 37 kg/m(2) by structural MRI, perfusion MRI (blood flow), and proton magnetic resonance spectroscopic imaging. Results: After correction for age, smoking status, and various measures of alcohol consumption, higher BMI was associated with lower concentrations of NAA, Cho, creatine and phosphocreatine (Cr, involved in high energy metabolism), and myo-inositol (m-Ino, a putative marker of astrocytes) primarily in the frontal lobe, in subcortical nuclei, and cerebellar vermis (p < 0.004). Regional brain volumes and perfusion were not significantly related to BMI. Furthermore, comorbid conditions, clinical laboratory measures, and nutritional assessments were not significant predictors of these MR-based measures. Conclusions: The results suggest that BMI, independent of age, alcohol consumption, and common comorbidities, is related to regional NAA, Cho, Cr, and m-Ino concentrations in this cohort of alcohol-dependent individuals. Additionally, as some common comorbid conditions in alcohol dependence such as cigarette smoking are associated with BMI, their associations with regional brain metabolite levels in alcohol-dependent individuals may also be influenced by BMI. C1 [Gazdzinski, Stefan] Jagiellonian Univ, Marian Smoluchowski Inst Phys, PL-30059 Krakow, Poland. [Gazdzinski, Stefan; Durazzo, Timothy C.; Mon, Anderson; Meyerhoff, Dieter J.] San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Durazzo, Timothy C.; Mon, Anderson; Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA USA. RP Gazdzinski, S (reprint author), Jagiellonian Univ, Marian Smoluchowski Inst Phys, Ul Reymonta 4, PL-30059 Krakow, Poland. EM Stefan.Gazdzinski@uj.edu.pl FU [AA10788]; [DA025202]; [DA24136]; [JU-WRBW-8/IF/2010] FX This project was supported by AA10788 (DJM) and partly by DA025202 (DJM), DA24136 (TCD), and JU-WRBW-8/IF/2010 (SG). This material is the result of work supported with resources and the use of facilities at the Radiology Research Service of the Veterans Administration Medical Center in San Francisco. We thank Mr J. O'Hara, and Drs G. Matson, and A. Ebel for technical support. We also extend our gratitude to Mary Rebecca Young and Bill Clift of the Veterans Administration Substance Abuse Day Hospital and Dr. David Pating, Karen Moise and their colleagues at the Kaiser Permanente Chemical Dependency Recovery Program in San Francisco for their valuable assistance in recruiting participants. Finally, we thank our participants who made this research possible. NR 67 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD DEC PY 2010 VL 34 IS 12 BP 2089 EP 2096 DI 10.1111/j.1530-0277.2010.01305.x PG 8 WC Substance Abuse SC Substance Abuse GA 682AB UT WOS:000284366100014 PM 21087290 ER PT J AU Javed, U Deedwania, PC Bhatt, DL Cannon, CP Dai, D Hernandez, AF Peterson, ED Fonarow, GC AF Javed, Usman Deedwania, Prakash C. Bhatt, Deepak L. Cannon, Christopher P. Dai, David Hernandez, Adrian F. Peterson, Eric D. Fonarow, Gregg C. TI Use of intensive lipid-lowering therapy in patients hospitalized with acute coronary syndrome: An analysis of 65,396 hospitalizations from 344 hospitals participating in Get With The Guidelines (GWTG) SO AMERICAN HEART JOURNAL LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; TO-Z TRIAL; UNSTABLE ANGINA; RAT HEARTS; SIMVASTATIN; ASSOCIATION; MORTALITY; EFFICACY; CRUSADE; STATINS AB Objectives The study aimed to analyze the use of intensive lipid-lowering therapy (LLT) at discharge in a broad population of patients hospitalized with acute coronary syndrome (ACS). Background Early and intensive statin therapy in ACS was shown to reduce cardiovascular morbidity and mortality. Utilization and predictors of LLT among hospitalized ACS patients are not known. Methods The GWTG database was analyzed for ACS-related hospitalizations from 2005 to 2009. The use of LLT (defined as dose of statin or combination therapy likely to produce >50% reductions in low-density lipoprotein [LDL]) and less intensive LLT at discharge was assessed. Baseline characteristics and temporal trends in LLT were compared in these 2 treatment groups. Results Of 65,396 patients receiving LLT, only 25,036 (38.3%) were treated with an LLT regimen. Mean total cholesterol, LDL, and triglycerides were significantly higher in the LLT group. Even among those with LDL >130 mg/dL, 50% or less received LLT. Predictors of LLT at discharge included LLT before admission, hyperlipidemia, prior coronary artery disease, increasing body mass index, and in-hospital percutaneous coronary intervention. Although there was some temporal improvement in the rate of LLT from 2005 to 2007, a decline in use of LLT was noted in 2008 and 2009. This was attributed to a sharp reduction in use of ezetimibe in combination with statin, without corresponding increases in intensive statin monotherapy. Conclusions In a large cohort of patients admitted with ACS, most of the eligible patients were not discharged on LLT. These data suggest the need for better implementation of guideline-recommended intensive statin therapy in patients with ACS. (Am Heart J 2010;160:1130-1136.e3.) C1 [Javed, Usman; Deedwania, Prakash C.] Univ Calif San Francisco, San Francisco Fresno Med Educ Program, Fresno, CA USA. [Bhatt, Deepak L.; Cannon, Christopher P.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.; Cannon, Christopher P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Dai, David; Hernandez, Adrian F.; Peterson, Eric D.] Duke Univ, Med Ctr, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Deedwania, PC (reprint author), UCSF Program Fresno, Cardiol Sect, 2615 E Clinton Ave 111, Fresno, CA 93703 USA. EM deed1@sbcglobal.net RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU Astra Zeneca; Bristol-Myers Squibb; Eisai; Ethicon; Heartscape; Sanofi Aventis; Medicines Company; Bristol Myers Squibb; Accumetrics; AstraZeneca; Bristol-Myers Squibb/Sanofi; Glaxo Smith Kline Intekrin Therapeutics; Novartis; Takeda; Johnson and Johnson; Merck FX Dr Bhatt: research grants from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis and the Medicines Company. Dr Deedwania: consultant/advisory board of AstraZeneca and Pfizer. Dr Peterson: research funding from Bristol Myers Squibb, Sanofi Aventis partnership. Dr Cannon: research grants from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, Glaxo Smith Kline Intekrin Therapeutics, Novartis, Takeda, clinical advisor and equity in Automedics Medical Systems. Dr Hernandez: research grant from Johnson and Johnson, Merck, and honorarium from AstraZeneca and Medtronic. Dr Fonarow: consultant/advisory board to Merck Schering Plough and honorarium from Abbott, AstraZeneca, Merck Schering Plough, and Pfizer. Other authors have no disclosures. NR 27 TC 19 Z9 20 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2010 VL 160 IS 6 BP 1130 EP U172 DI 10.1016/j.ahj.2010.08.041 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 692WW UT WOS:000285187600025 PM 21146668 ER PT J AU Uthamalingam, S Kandala, J Daley, M Patvardhan, E Capodilupo, R Moore, SA Januzzi, JL AF Uthamalingam, Shanmugam Kandala, Jagdesh Daley, Marilyn Patvardhan, Eshan Capodilupo, Robert Moore, Stephanie A. Januzzi, James L., Jr. TI Serum albumin and mortality in acutely decompensated heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID TUMOR-NECROSIS-FACTOR; IDIOPATHIC DILATED CARDIOMYOPATHY; TRANSCAPILLARY ESCAPE RATE; NUTRITIONAL INTAKE; CARDIAC CACHEXIA; FACTOR RECEPTORS; ELDERLY-PATIENTS; RISK; SURVIVAL AB Background Although hypoalbuminemia has been associated with decreased survival in chronic systolic heart failure (HF), its role for prognosticating outcomes in those with acutely decompensated heart failure (ADHF) has not been established. Methods and Results 438 consecutive patients with ADHF (mean age 75 +/- 13 years, mean left ventricular ejection fraction 41% +/- 20%) admitted to a large community hospital were studied. The mean serum albumin level for the group was 3.4 g/dL; quintile analysis demonstrated an inflection of risk for death below this value. Patients with hypoalbuminemia (defined as a serum albumin <3.4 g/dL; N = 236, 54% overall) were more likely to have prior HF, more severe HF symptoms, more likely to be edematous, and had more prevalent prognostically meaningful laboratory abnormalities, such as a higher frequency of renal dysfunction and elevated B-type natriuretic peptide. Independent associations between anemia, hyponatremia, lack of therapy with vasodilators at presentation, prior history of obstructive airways disease, severe tricuspid regurgitation, low serum cholesterol, and the presence of a pleural effusion on chest radiography were found with reduced serum albumin; interestingly, body mass index was not predictive of albumin levels. In Cox proportional hazards analysis, hypoalbuminemia predicted 1-year mortality (hazard ratio [HR](adjusted) = 2.05, 95% CI 1.10-3.81, P = .001). Reduced serum albumin concentrations were prognostic across a wide range of body mass index but had highest HR in obese patients (HR(adjusted) = 4.39 [95% CI = 1.66 to 11.60], P = .003). As well, hypoalbuminemia was mainly predictive of outcomes among those with systolic HF (HR(adjusted) = 5.00, 95% CI = 2.17-11.5, P < .001). Conclusion Hypoalbuminemia is common among patients with ADHF and is independently associated with increased one year mortality in patients admitted with ADHF. (Am Heart J 2010;160:1149-55.) C1 [Uthamalingam, Shanmugam; Moore, Stephanie A.; Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Uthamalingam, Shanmugam; Kandala, Jagdesh; Daley, Marilyn; Capodilupo, Robert] Catholic Med Ctr, Dept Med, Div Cardiol, New England Heart Inst, Manchester, NH USA. [Patvardhan, Eshan] Tufts Med Ctr, Div Cardiol, Boston, MA USA. RP Januzzi, JL (reprint author), 32 Fruit St,Yawkey 5984, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU Balson scholar award FX Dr. Januzzi is supported in part by the Balson scholar award. The authors acknowledge the invaluable assistance of Cynthia David, MLS MPS. NR 27 TC 46 Z9 46 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2010 VL 160 IS 6 BP 1149 EP 1155 DI 10.1016/j.ahj.2010.09.004 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 692WW UT WOS:000285187600028 PM 21146671 ER PT J AU Miller, SC Lima, JC Mitchell, SL AF Miller, Susan C. Lima, Julie C. Mitchell, Susan L. TI Hospice Care for Persons With Dementia: The Growth of Access in US Nursing Homes SO AMERICAN JOURNAL OF ALZHEIMERS DISEASE AND OTHER DEMENTIAS LA English DT Article DE dementia; nursing home; hospice; length of stay; death ID MINIMUM DATA SET; VISIT VOLUME; END; RESIDENTS; LIFE; MDS; ENROLLMENT; VALIDATION; MANAGEMENT; SURVIVAL AB Background/Rationale: Persons with dementia often die in nursing homes (NHs); however, concerns exist about their low use of Medicare hospice. Methods: For 1999 through 2006 in all US states and DC we merged NH resident assessment data with Medicare claims and enrollment data to identify NH decedents with dementia and hospice use. We studied two groups, those with advanced dementia and those with mild-to-moderately severe dementia. Results: Across study years, 22.2% of all NH decedents had mild-to-moderately severe dementia and 19.6% had advanced dementia. In 1999, 14.5% of decedents with advanced and 13.2% with mild-to-moderately severe dementia accessed hospice, increasing to 42.5% and 37.9% respectively in 2006. Between 1999 and 2006, mean days of hospice stays increased from 46 to 118 for advanced dementia and from 39 to 79 for mild-to-moderately severe dementia. These mean length of stay differences resulted from a relatively lower proportion of short hospice stays (<= 7 days) together with higher proportions of longer stays (>= 181 days) among advanced versus mild-to-moderately severe dementia decedents. Hospice access and lengths of stay among US states varied widely. Conclusions: Over 40% of US NH decedents have mild-to-moderately severe or advanced dementia. For these NH decedents, access to and duration of Medicare hospice has increased. However, there is considerable variation in hospice use across US states. C1 [Miller, Susan C.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Miller, Susan C.; Lima, Julie C.] Brown Univ, Ctr Gerontol & Hlth Care Res, Providence, RI 02912 USA. [Mitchell, Susan L.] Deaconess Med Ctr, Inst Aging Res, Boston, MA USA. [Mitchell, Susan L.] Deaconess Med Ctr, Dept Med, Boston, MA USA. RP Miller, SC (reprint author), 121 S Main St,Room 618, Providence, RI 02912 USA. EM Susan_Miller@brown.edu RI Miller, Susan/J-5450-2014 OI Miller, Susan/0000-0003-2008-6385 FU Alzheimer's Association [IIRG-08-91343]; National Institute on Aging [1P01AG027296] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: Alzheimer's Association (IIRG-08-91343); and by the National Institute on Aging (1P01AG027296). NR 42 TC 11 Z9 11 U1 2 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1533-3175 J9 AM J ALZHEIMERS DIS JI Am. J. Alzheimers Dis. Other Dement. PD DEC PY 2010 VL 25 IS 8 BP 666 EP 673 DI 10.1177/1533317510385809 PG 8 WC Geriatrics & Gerontology; Clinical Neurology SC Geriatrics & Gerontology; Neurosciences & Neurology GA 689WM UT WOS:000284961600007 PM 21131673 ER PT J AU Wenger, NK Mischke, JM Schroeder, R Schroeder, K Collins, P Grady, D Kornitzer, M Mosca, L Barrett-Connor, E AF Wenger, Nanette K. Mischke, Jennifer M. Schroeder, Rolf Schroeder, Klaus Collins, Peter Grady, Deborah Kornitzer, Marcel Mosca, Lori Barrett-Connor, Elizabeth TI Electrocardiograms of Menopausal Women With Coronary Heart Disease or at Increased Risk for Its Occurrence SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID POSTMENOPAUSAL WOMEN; RALOXIFENE; EVENTS AB Little is known about electrocardiographic (ECG) characteristics of menopausal women with or at increased risk of coronary heart disease (CHD). Data from 10,101 participants in the Raloxifene Use for The Heart (RUTH) trial were used to correlate baseline ECG abnormalities with clinical characteristics. Baseline characteristics that were statistically significantly associated (p <= 0.05) with ECG findings in univariate analyses were used to derive multivariate model selection. Of 59% normal electrocardiograms, 50% were from women with CHD and 69% from women at increased risk of CHD. In the women with CHD, 59% reported a previous myocardial infarction (MI); 43% had a normal electrocardiogram, and 49% had a definite ECG Q-wave MI. Women in the increased-risk group had not reported a previous MI, yet 11% had a definite ECG Q-wave MI. Of women reporting hypertension, 35% had ECG evidence of left ventricular hypertrophy, but 58% did not have an abnormal electrocardiogram. Significantly more women with diabetes in the increased-risk and documented CHD cohorts had abnormal electrocardiograms (p <0.01 for the 2 cohorts). Percent abnormal electrocardiograms increased with increasing age (55 to 64, 65 to 74, and >= 75 years, p <0.01) in all cohorts. Angina and coronary artery bypass graft surgery, but not percutaneous coronary intervention, predicted an abnormal electrocardiogram. In conclusion, there were high percentages of normal electrocardiograms in the increased-risk and documented CHD groups of RUTH participants, with substantial discrepancy between MI history and ECG MI documentation, and increasing age was the predominant correlate with an abnormal electrocardiogram in all 3 cohorts. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:1580-1587) C1 [Wenger, Nanette K.] Emory Univ, Sch Med, Dept Med Cardiol, Atlanta, GA 30322 USA. [Mischke, Jennifer M.] i3 Statprobe, Eden Prairie, MN USA. [Schroeder, Rolf] Charite, D-13353 Berlin, Germany. [Schroeder, Klaus] Univ Giessen, Giessen, Germany. [Collins, Peter] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Collins, Peter] Royal Brompton Hosp, London SW3 6LY, England. [Grady, Deborah] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Grady, Deborah] San Francisco VA Med Ctr, San Francisco, CA USA. [Kornitzer, Marcel] Free Univ Brussels, Dept Epidemiol & Hlth Promot, Sch Publ Hlth, Brussels, Belgium. [Mosca, Lori] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. RP Wenger, NK (reprint author), Emory Univ, Sch Med, Dept Med Cardiol, Atlanta, GA 30322 USA. EM nwenger@emory.edu FU Eli Lilly and Company, Indianapolis, Indiana FX The Raloxifene Use for The Heart (RUTH) study was funded by Eli Lilly and Company, Indianapolis, Indiana. NR 7 TC 3 Z9 3 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2010 VL 106 IS 11 BP 1580 EP 1587 DI 10.1016/j.amjcard.2010.07.032 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 692AX UT WOS:000285125000009 PM 21094358 ER PT J AU Fung, TT Hu, FB Wu, KN Chiuve, SE Fuchs, CS Giovannucci, E AF Fung, Teresa T. Hu, Frank B. Wu, Kana Chiuve, Stephanie E. Fuchs, Charles S. Giovannucci, Edward TI The Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and colorectal cancer SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NIH-AARP DIET; CORONARY-HEART-DISEASE; IGF-BINDING-PROTEINS; GROWTH-FACTOR-I; PROSPECTIVE COHORT; C-PEPTIDE; RISK; WOMEN; METAANALYSIS; INSULIN AB Background Although the Mediterranean diet has been studied for cancer mortality and the Dietary Approaches to Stop Hypertension (DASH) diet shares similarities with the Mediterranean diet few studies have specifically examined these 2 diets and incident colorectal cancer Objective The objective was to prospectively assess the association between the Alternate Mediterranean Diet (aMed) and the DASH style diet scores and risk of colorectal cancer in middle aged men and women Design A total of 87 256 women and 45 490 men (age 30-55 y for women and 40-75 y for men at baseline) without a history of cancer were followed for <= 26 y The aMed and DASH scores were calculated for each participant by using dietary information that was assessed <= 7 times during follow up Relative risks (RRs) for colorectal cancer were computed with adjustment for potential confounders Results We documented 1432 cases of incident colorectal cancer among women and 1032 cases in men Comparing top with bottom quintiles of the DASH score the pooled RR for total colorectal cancer was 080 (95% CI 0 70 0 91 P for trend = 0 0001) The corresponding RR for DASH score and colon cancer was 081 (95% CI 0 69 0 95 P for trend = 0 002) There was a suggestion of an inverse association with rectal cancer with a pooled RR-of 0 73 (95% CI 0 55 0 98 P for trend = 0 31) when comparing top with bottom quintiles of DASH score No association was observed with aMed score Conclusion Adherence to the DASH diet (which involves higher intakes of whole grains fruit and vegetables moderate amounts of low fat dairy and lower amounts of red or processed meats desserts and sweetened beverages) was associated with a lower risk of colorectal cancer Am J Clin Nutr 2010 92 1429-35 C1 [Fung, Teresa T.] Simmons Coll, Dept Nutr, Boston, MA 02115 USA. [Fung, Teresa T.; Hu, Frank B.; Wu, Kana; Chiuve, Stephanie E.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hu, Frank B.; Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Chiuve, Stephanie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Fung, TT (reprint author), Simmons Coll, Dept Nutr, 300 Fenway, Boston, MA 02115 USA. FU National Institutes of Health [CA98859, CA87969, HL60712] FX Supported by the National Institutes of Health (grant nos CA98859 CA87969 and HL60712) NR 29 TC 69 Z9 71 U1 5 U2 23 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 2010 VL 92 IS 6 BP 1429 EP 1435 DI 10.3945/ajcn.2010.29242 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 690HM UT WOS:000284993600021 PM 21097651 ER PT J AU Genega, EM Ghebremichael, M Najarian, R Fu, YN Wang, YH Argani, P Grisanzio, C Signoretti, S AF Genega, Elizabeth M. Ghebremichael, Musie Najarian, Robert Fu, Yineng Wang, Yihong Argani, Pedram Grisanzio, Chiara Signoretti, Sabina TI Carbonic Anhydrase IX Expression in Renal Neoplasms Correlation With Tumor Type and Grade SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Carbonic anhydrase IX; Renal cell carcinoma; Clear cell renal cell carcinoma ID CLEAR-CELL CARCINOMA; DIFFERENTIAL-DIAGNOSIS; EPITHELIAL NEOPLASMS; INDEPENDENT PREDICTOR; CANCER; IDENTIFICATION; KIDNEY; GENE; IMMUNOREACTIVITY; MANAGEMENT AB Carbonic anhydrase IX (CAD), a hypoxia-induced protein, is expressed in some renal tumors. We evaluated its immunohistochemical expression in 317 primary and 42 metastatic renal neoplasms (186 clear cell, 52 papillary, 35 chromophobe, 47 unclassified, and 15 Xp11.2 translocation rend cell carcinomas [RCCs]; 26 oncocytomas; 2 metanephric adenomas,. 1 urothelial carcinoma; 1 mixed epithelial and stromal tumor; and 1 angiomyolipoma); 7 neoplasms were unknown as to whether they were primary or metastatic. We also correlated expression with tumor type and grade. Variable staining was seen in clear cell, papillary, unclassified, and Xp11.2 translocation carcinomas. One chromophobe carcinoma had focal expression. No staining was seen with other tumors. An association was found between high expression and clear cell vs non-clear cell carcinomas with all cases (P < .01) and primary (P < .01) cases. An association between CAIX expression and grade (P < .01) in primary clear cell carcinomas was found. CAIX expression is more common in clear cell RCC than other renal tumor types and is associated with grade. C1 [Grisanzio, Chiara; Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Genega, Elizabeth M.; Najarian, Robert; Fu, Yineng; Wang, Yihong] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Argani, Pedram] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Grisanzio, Chiara; Signoretti, Sabina] Dana Farber Harvard Canc Ctr, Dept Pathol, Boston, MA USA. [Genega, Elizabeth M.; Fu, Yineng; Signoretti, Sabina] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Signoretti, S (reprint author), Brigham & Womens Hosp, Dept Pathol, Thorn 504A,75 Francis St, Boston, MA 02115 USA. FU Dana-Farber/Harvard Cancer Center Kidney SPORE National Cancer Institute (Bethesda, MD) [P50CA101942]; Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientific (IRCCS), Rome, Italy; American-Italian Cancer Foundation FX Supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE National Cancer Institute (Bethesda, MD) grant P50CA101942 and by an award from the Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientific (IRCCS), Rome, Italy (Dr Signoretti).; Dr Grisanzio is the recipient of an American-Italian Cancer Foundation International Postdoctoral Research Fellowship. NR 27 TC 37 Z9 40 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD DEC PY 2010 VL 134 IS 6 BP 873 EP 879 DI 10.1309/AJCPPPR57HNJMSLZ PG 7 WC Pathology SC Pathology GA 682YY UT WOS:000284440100002 PM 21088149 ER PT J AU Park, JK Hur, B Ko, CC Garcia-Godoy, F Kim, HI Kwon, YH AF Park, Jeong-Kil Hur, Bock Ko, Ching-Chang Garcia-Godoy, Franklin Kim, Hyung-Il Kwon, Yong Hoon TI Effect of light-curing units on the thermal expansion of resin nanocomposites SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID COMPOSITE RESINS; POLYMERIZATION; COEFFICIENT; BEHAVIOR AB Purpose: To examine the thermal expansion of resin nanocomposites after light-curing using different light-curing units. Methods: Four different resin nanocomposites and four different light-curing units [quartz-tungsten-halogen (QTH), light emitting diode (LED), laser, and plasma arc] were chosen. Metal dies were filled with resin to make specimens and light-cured. The light intensity and light-curing time of the QTH and LED light-curing units were 1000 mW/cm(2) and 40 seconds, 700 mW/cm(2) and 40 seconds for the laser, and 1600 mW/cm2 and 3 seconds for the plasma arc. The coefficient of thermal expansion (CTE) was evaluated using a thermomechanical analyzer (TMA) at temperatures ranging from 30-80 degrees C. Results: The CTE of the resin nanocomposites tested ranged from 28.5 to 65.8 (x10(-6)/degrees C), depending on the product and type of light-curing unit used. Among the specimens, Grandio showed the lowest CTE. The specimens cured using the plasma arc unit (Apollo 95E) showed the highest CTE. There was a linear correlation between the CTE and filler content (vol%) (R: -0.94 similar to-0.99 depending on the light-curing unit). The results may suggest a careful selection of the light-curing unit because there was more expansion in the specimens cured using the plasma arc unit than those cured by the other units. (Am J Dent 2010;23:331-334). C1 [Kim, Hyung-Il; Kwon, Yong Hoon] Pusan Natl Univ, Dept Dent Mat, Coll Dent, Pusan 602739, South Korea. [Park, Jeong-Kil; Hur, Bock] Pusan Natl Univ, Dept Conservat Dent, Pusan 602739, South Korea. [Kim, Hyung-Il; Kwon, Yong Hoon] Pusan Natl Univ, Med Res Inst, Pusan 602739, South Korea. [Ko, Ching-Chang] Univ N Carolina, Sch Dent, Dept Orthodont, Chapel Hill, NC 27599 USA. [Garcia-Godoy, Franklin] Univ Tennessee, Hlth Sci Ctr, Coll Dent, Memphis, TN USA. [Garcia-Godoy, Franklin] Univ Memphis, Dept Biomed Engn, Memphis, TN 38152 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Kwon, YH (reprint author), Pusan Natl Univ, Dept Dent Mat, Coll Dent, Pusan 602739, South Korea. EM y0k0916@pusan.ac.kr FU Medical Research Institute, Pusan National University, Busan Korea [2006-48] FX This study was supported by Medical Research Institute Grant (2006-48), Pusan National University, Busan Korea. NR 25 TC 3 Z9 5 U1 0 U2 0 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD DEC PY 2010 VL 23 IS 6 BP 331 EP 334 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 712XV UT WOS:000286700500007 PM 21344832 ER PT J AU Mahalingam, M Srivastava, A Hoang, MP AF Mahalingam, Meera Srivastava, Anvita Hoang, Mai P. TI Expression of Stem-Cell Markers (Cytokeratin 15 and Nestin) in Primary Adnexal Neoplasms-Clues to Etiopathogenesis SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Article DE adnexal neoplasm; apocrine; cytokeratin 15; eccrine; nestin ID SWEAT GLAND TUMORS; DISEASE FLUID PROTEIN-15; BROOKE-SPIEGLER-SYNDROME; HAIR-FOLLICLE; MYOEPITHELIAL DIFFERENTIATION; CARCINOEMBRYONIC ANTIGEN; MONOCLONAL-ANTIBODY; EPITHELIAL MARKERS; DERMAL CYLINDROMA; PROGENITOR CELLS AB Background: The overlap in histopathologic features and immunoprofile of eccrine and apocrine neoplasms confounds basic issues relating to lineage of these entities. Methods: We evaluated expression of follicular stem-cell markers, cytokeratin (CK) 15 and nestin, in 78 benign and 23 malignant adnexal neoplasms. Results: CK15 and nestin expression were noted in 39 of 78 (50%) and 36 of 78 (46%) cases in the benign group, respectively (8 cutaneous mixed tumor, 10 hidradenoma papilliferum, 9 apocrine cystadenoma, 11 cylindroma and/or spiradenoma, and 9 poroma/dermal duct tumor). CK15 and nestin expression were noted in 11 of 23 (48%) and 7 of 23 (30%) cases in the malignant group, respectively (6 microcystic adnexal carcinoma, 7 porocarcinoma, and 9 eccrine carcinoma). Except 1, both markers were negative in 4 syringocystadenoma papilliferum, 10 hidradenoma, 1 syringofibroadenoma, 10 syringoma, 1 eccrine adenoma, 8 poroma/dermal duct tumor, 5 eccrine hidrocystoma, and 1 apocrine carcinoma. Conclusions: Given that follicular germinative cells give rise to the folliculosebaceous apocrine unit, expression of CK15 and nestin in the majority of cutaneous mixed tumor, hidradenoma papilliferum, apocrine cystadenoma, and cylindroma/spiradenoma is suggestive of an apocrine origin/differentiation of these neoplasms. Reinforcing this and a novel finding of our study is the preferential expression of nestin in myoepithelial cells of these lesions. C1 [Hoang, Mai P.] Massachusetts Gen Hosp, Dermatopathol Unit, Dept Pathol, Boston, MA 02114 USA. [Hoang, Mai P.] Harvard Univ, Sch Med, Boston, MA USA. [Mahalingam, Meera; Srivastava, Anvita] Boston Univ, Sch Med, Dept Dermatol, Dermatopathol Sect, Boston, MA 02118 USA. RP Hoang, MP (reprint author), Massachusetts Gen Hosp, Dermatopathol Unit, Dept Pathol, 55 Fruit St,Warren 820, Boston, MA 02114 USA. EM mhoang@partners.org OI Mahalingam, Meera/0000-0002-2800-9985 NR 44 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0193-1091 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD DEC PY 2010 VL 32 IS 8 BP 774 EP 779 DI 10.1097/DAD.0b013e3181dafd8c PG 6 WC Dermatology SC Dermatology GA 682DO UT WOS:000284380300005 PM 20700038 ER PT J AU Ko, CW Dominitz, JA Green, P Kreuter, W Baldwin, LM AF Ko, Cynthia W. Dominitz, Jason A. Green, Pam Kreuter, William Baldwin, Laura-Mae TI Utilization and Predictors of Early Repeat Colonoscopy in Medicare Beneficiaries SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID COLORECTAL-CANCER; BOWEL PREPARATION; NATIONAL-SURVEY; CLAIMS DATA; TASK-FORCE; AMERICAN-COLLEGE; SURVEILLANCE; GUIDELINES; PHYSICIAN; ACCURACY AB OBJECTIVES: Early repeat colonoscopy after an index examination may be justifiable, but may also reflect quality issues during the first examination. The aims of this study were to examine the use of second colonoscopy within 1 year of an index colonoscopy, and to examine patient and provider factors associated with use of early repeat colonoscopy. METHODS: We performed a retrospective cohort study using a 20% nationally representative sample of 2003 Medicare claims. Patients aged >= 66 years undergoing colonoscopy were included in this study. We identified the use of second colonoscopy and barium enema within 1 year of the index procedure. We used logistic regression analyses to examine the independent predictors of these procedures. RESULTS: We included 328,167 outpatient colonoscopies. In all, 5% had second colonoscopy and 2.2% had barium enema within 1 year of the index examination. Early repeat colonoscopy was more common if the index examination was performed by a family physician (odds ratio 1.39, 95% confidence interval 1.23-1.56), general surgeon (odds ratio 1.18, 95% confidence interval 1.10-1.27) or internist (odds ratio 1.12, 95% confidence interval 1.02-1.23) compared with a gastroenterologist, or after colonoscopies by an endoscopist in the lower quartiles of colonoscopy volume compared with endoscopists in the highest quartile. Increasing patient age and comorbidity, polyp detection, biopsy, polyp removal, incomplete index examination, and site of service were also significantly associated with early repeat colonoscopy. CONCLUSIONS: Early repeat colonoscopy is not unusual. The association of specialty and colonoscopy volume with early repeat colonoscopy suggests that there are modifiable processes of care or training that may prevent some of these repeat procedures. C1 [Ko, Cynthia W.] Univ Washington, Div Gastroenterol, Dept Med, Seattle, WA 98195 USA. [Dominitz, Jason A.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Green, Pam; Baldwin, Laura-Mae] Univ Washington, Dept Family Med, Seattle, WA 98195 USA. [Kreuter, William] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Ko, CW (reprint author), Univ Washington, Div Gastroenterol, Dept Med, Box 356424, Seattle, WA 98195 USA. EM cwko@u.washington.edu OI Dominitz, Jason/0000-0002-8070-7086 FU American College of Gastroenterology; American Society for Gastrointestinal Endoscopy; VA Puget Sound Health Care System, Seattle, Washington FX This work was funded by the American College of Gastroenterology. J.A.D. was supported by the American Society for Gastrointestinal Endoscopy Endoscopic Research Career Development Award. This material is the result of work supported in part by resources from the VA Puget Sound Health Care System, Seattle, Washington. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or the Department of Veterans Affairs. This study was presented in part at Digestive Disease Week 2010, New Orleans, Louisiana. NR 39 TC 15 Z9 15 U1 2 U2 3 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 DEC PY 2010 VL 105 IS 12 BP 2670 EP 2679 DI 10.1038/ajg.2010.344 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 689PQ UT WOS:000284940900023 PM 20736933 ER PT J AU Kish, TD Chang, MH Fung, HB AF Kish, Troy D. Chang, Mei H. Fung, Horatio B. TI Treatment of Skin and Soft Tissue Infections in the Elderly: A Review SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Review DE skin and soft tissue infection; elderly; community-acquired methicillin-resistant Staphylococcus aureus; diabetic foot infections; infected pressure ulcers; shingles ID RESISTANT STAPHYLOCOCCUS-AUREUS; DIABETIC FOOT INFECTIONS; PLACEBO-CONTROLLED TRIAL; B STREPTOCOCCAL DISEASE; ACUTE HERPES-ZOSTER; METHICILLIN-RESISTANT; COMPLICATED SKIN; DOUBLE-BLIND; POSTHERPETIC NEURALGIA; UNITED-STATES AB Background: Skin and soft tissue infections (SSTIs) have become the second most common type of infection among persons residing in long-term care facilities. Objective: The purpose of this article was to review the latest information on SSTIs among the elderly, including age-related changes, challenges, and treatment strategies in the era of emerging bacterial resistance. Methods: Relevant information was identified through a search of MEDLINE (1970 April 2010), International Pharmaceutical Abstracts (1970 April 2010), and Google Scholar using the terms skin and soft tissue infection, skin and skin structure infection, cellulitis, treatment guidelines, and elderly. Additional publications were found by searching the reference lists of the identified articles. Trials published since 1970 were selected for this review if they prospectively evaluated mostly adults (>= 18 years of age), included >50 patients, and reported diagnostic criteria as well as clinical outcomes in patients treated for simple or complicated SSTIs. Results: Fifty-eight of 664 identified studies were selected and included in this review. A search of the literature did not identify any prospective clinical trials that were conducted exclusively in the elderly. Information on the treatment of SSTIs in the elderly was based solely on clinical studies that were conducted in adults in general. As recommended by the Infectious Diseases Society of America (IDSA) 2008 update, SSTIs should be suspected in elderly patients who have skin lesions and present with a decline in functional status, with or without fever. Patients who present with symptoms of systemic toxicity should be hospitalized for further evaluation. Current challenges in the management of SSTIs include the rapid emergence of community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA), the emergence of macrolide-resistant streptococci within the past decade, and the lack of a reliable algorithm to differentiate potentially life-threatening SSTIs that require aggressive interventions and prompt hospitalization from those that can be managed in an outpatient setting. S aureus was the most common cause of SSTIs, being isolated in 42.8% (5015/11,723) of wounds, followed by streptococci. Common SSTIs in the elderly such as shingles, diabetic foot infections, infected pressure ulcers, and scabies, and their treatment were also discussed. Based on reviews of published trials, treatment of simple SSTIs generally consisted of administration of agents with activity against S aureus and Streptococcus species such as a penicillinase-resistant beta-lactam, a first-generation cephalosporin, or clindamycin. Broadening of the antimicrobial spectrum to include gram-negative and anaerobic organisms should be implemented for complicated SSTIs such as diabetic foot infections and infected pressure ulcers. Local rates of MRSA, CA-MRSA, and macrolide-resistant streptococci should be considered when selecting empiric therapy. Conclusions: A search of the literature did not identify any prospective clinical trials on the treatment of SSTIs in the elderly; therefore, it is recommended to follow treatment based on the current IDSA guidelines. More research and publications are needed to establish proper selection of antimicrobial agents, treatment strategies, and duration of therapy of SSTIs in the elderly population. (Am J Geriatr Pharmacother. 2010;8:485-513) (C) 2010 Elsevier HS Journals, Inc. C1 [Kish, Troy D.; Chang, Mei H.; Fung, Horatio B.] James J Peters Vet Affairs Med Ctr, Serv Pharm, Bronx, NY 10468 USA. RP Fung, HB (reprint author), James J Peters Vet Affairs Med Ctr, Serv Pharm, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Horatio.Fung@va.gov NR 155 TC 12 Z9 12 U1 1 U2 14 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD DEC PY 2010 VL 8 IS 6 BP 485 EP 513 DI 10.1016/j.amjopharm.2010.12.003 PG 29 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 705YG UT WOS:000286176000002 PM 21356502 ER PT J AU Steinman, MA Patil, S Kamat, P Peterson, C Knight, SJ AF Steinman, Michael A. Patil, Sneha Kamat, Priya Peterson, Carolyn Knight, Sara J. TI A Taxonomy of Reasons for Not Prescribing Guideline-Recommended Medications for Patients With Heart Failure SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 13-16, 2009 CL Miami, FL SP Soc Gen Internal Med DE decision making; guideline adherence; heart failure; aged; physician's practice patterns; angiotensin-converting enzyme inhibitors; adrenergic beta-antagonists ID CLINICAL-PRACTICE GUIDELINES; QUALITY-OF-CARE; PHYSICIAN ADHERENCE; EFFECTIVE MANAGEMENT; TREATMENT DECISIONS; PROCESS PERFORMANCE; ELDERLY-PATIENTS; BARRIERS; PROVIDER; SYSTEM AB Background: Performance-measurement systems may work best when they account for the reasons why physicians do not provide guideline-recommended interventions. Objective: This article develops a conceptual framework for understanding the proximate, patient-centered reasons why physicians do not prescribe angiotensin-converting enzyme (ACE) inhibitors or beta-blockers to patients with heart failure and reduced systolic function. Methods: This was a focus group study using a 2-stage design. Academically affiliated clinicians of different specialties and levels of training were recruited by e-mailed invitations sent to clinicians within each target group. To be included, candidates needed to be currently practicing in an ambulatory care setting in which they encountered patients with heart failure. In the first part of each group, participants were asked to describe reasons for not prescribing ACE inhibitors or beta-blockers for patients with heart failure. Next, participants were asked to develop concept maps that organized these reasons into categories and described the relationships between these categories. The concept maps from each group were synthesized to develop a consensus scheme for categorizing reasons for nonprcscribing. Results: There were 31 participants in 7 focus groups; median age was 31 years and 55% (17/31) were women. Two broad themes emerged. First, clinicians hinted at their own attitude-related barriers to prescribing. However, they framed their comments largely in terms of patient-centered reasons for nonprescribing that arose in individual patient encounters. Second, decision making about heart failure drug therapy often involved a complex and overlapping series of considerations. Five categories of reasons for not prescribing ACE inhibitors or beta-blockers emerged: (1) adverse effects of drug therapy; (2) nonadherence to therapeutic and monitoring plan; (3) patients' preferences and beliefs; (4) comanagement and transitions of care; and (5) prioritization and patient benefit. Conclusions: Physicians' reasons for not prescribing guideline-recommended drugs for heart failure are complex but can be organized into a useful taxonomy. This taxonomy may be helpful for performance-measurement and quality-improvement programs that seek to understand reasons for physicians' nonadherence to guidelines. (Am J Geriatr Pharmacother. 2010;8:583-594) (C) 2010 Elsevier HS Journals, Inc. C1 [Steinman, Michael A.; Patil, Sneha; Kamat, Priya; Peterson, Carolyn; Knight, Sara J.] San Francisco VA Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, San Francisco, CA 94121 USA. [Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Kamat, Priya] Northwestern Univ, Dept Psychol, Evanston, IL USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. RP Steinman, MA (reprint author), San Francisco VA Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM mike.steinman@ucsf.edu FU NIA NIH HHS [K23-AG030999, K23 AG030999] NR 37 TC 10 Z9 11 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD DEC PY 2010 VL 8 IS 6 BP 583 EP 594 DI 10.1016/j.amjopharm.2010.11.001 PG 12 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 705YG UT WOS:000286176000007 PM 21356507 ER PT J AU Rubright, J Sankar, P Casarett, DJ Gur, R Xie, SX Karlawish, J AF Rubright, Jonathan Sankar, Pamela Casarett, David J. Gur, Ruben Xie, Sharon X. Karlawish, Jason TI A Memory and Organizational Aid Improves Alzheimer Disease Research Consent Capacity: Results of a Randomized, Controlled Trial SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Alzheimer's disease; informed consent; capacity; research ethics ID INFORMED-CONSENT; COMPETENCE; SCHIZOPHRENIA; DEMENTIA; SAFETY AB Objectives: Early and progressive cognitive impairments of patients with Alzheimer disease (AD) hinder their capacity to provide informed consent. Unfortunately, the limited research on techniques to improve capacity has shown mixed results. Therefore, the authors tested whether a memory and organizational aid improves the performance of patients with AD on measures of capacity and competency to give informed consent. Design, Setting, and Participants: Patients with AD randomly assigned to standard consent or standard plus a memory and organizational aid. Intervention: Memory and organizational aid summarized the content of information mandated under the informed consent disclosure requirements of the Common Rule at a sixth grade reading level. Measurements: Three psychiatrists without access to patient data independently reviewed MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) interview transcripts to judge whether the patient was capable of providing informed consent. The agreement of at least two of the three experts defined a participant as capable of providing informed consent. Secondary outcomes are MacCAT-CR measures of understanding, appreciation and reasoning, and comparison with cognitively normal older adult norms. Results: AD intervention and control groups were similar in terms of age, education, and cognitive status. The intervention group was more likely to be judged competent than control group and had higher scores on MacCAT-CR measure of understanding. The intervention had no effect on the measures of appreciation or reasoning. Conclusions: A consent process that addresses the deficits in memory and attention of a patient with AD can improve capacity to give informed consent for early phase AD research. The results also validate the MacCAT-CR as an instrument to measure capacity, especially the understanding subscale. Trial Registry: ClinicalTrials. Gov # NCT00105612, http://clinicaltrials.gov/show/NCT00105612. (Am J Geriatr Psychiatry 2010; 18: 1124-1132) C1 [Casarett, David J.; Gur, Ruben; Karlawish, Jason] Univ Penn, Inst Aging, Philadelphia, PA 19104 USA. [Sankar, Pamela; Karlawish, Jason] Univ Penn, Dept Med Eth, Philadelphia, PA 19104 USA. [Casarett, David J.; Karlawish, Jason] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Gur, Ruben] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Gur, Ruben] Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Gur, Ruben] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Sankar, Pamela; Casarett, David J.; Karlawish, Jason] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Sankar, Pamela; Casarett, David J.; Karlawish, Jason] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Rubright, Jonathan] Univ Delaware, Delaware Educ Res & Dev Ctr, Sch Educ, Newark, DE USA. [Xie, Sharon X.; Karlawish, Jason] Alzheimers Dis Ctr, Dept Biostat & Epidemiol, New York, NY USA. [Casarett, David J.] Philadelphia Vet Affairs Ctr Hlth Equ Res & Promo, Philadelphia, PA USA. RP Karlawish, J (reprint author), Univ Penn, Inst Aging, 3615 Chestnut St, Philadelphia, PA 19104 USA. EM Jason.Karlawish@uphs.upenn.edu FU NIH [R01-AG020627, P30-AG-10124]; Marian S. Ware Alzheimer Program; National Institute on Aging; Pfizer FX The authors thank the participants and family members who participated in this research. They also thank James Beaver and Bryan James for their assistance in data gathering and analyses. This research funded by NIH R01-AG020627, NIH P30-AG-10124, and the Marian S. Ware Alzheimer Program. Dr. Karlawish is the site principal investigator for a clinical trial sponsored by National Institute on Aging and Pfizer. Other authors report no conflicts of interest. NR 43 TC 15 Z9 16 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD DEC PY 2010 VL 18 IS 12 BP 1124 EP 1132 DI 10.1097/JGP.0b013e3181dd1c3b PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 685CP UT WOS:000284603300008 PM 20808101 ER PT J AU Dawson, LK Hamilton, LA AF Dawson, Leslie K. Hamilton, Leslie A. TI Risk of cancer in patients receiving insulin glargine SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Diabetes mellitus; Insulin glargine; Insulins; Neoplasms; Toxicity ID DIABETES-MELLITUS; COLORECTAL-CANCER; ANALOGS; METAANALYSIS; MALIGNANCIES; RECEPTOR; BINDING; TYPE-2 AB Purpose. The risk of malignancy in patients using insulin glargine was evaluated. Summary. Patients with diabetes mellitus have increased rates of cancers including breast, colon, and pancreatic cancers. Since nondiabetic patients with increased levels of insulin have similar rates of the same cancers, hyperinsulinemia could be key. Normally, insulin produces metabolic effects and insulin-like growth factor-I (IGF-I) produces mitogenic effects. Since the molecules are structurally similar, it is possible for insulin to act like IGF-I, promoting mitogenicity. Concern that insulin may promote the growth of some cancers is heightened with insulin analogues, since changing the structure of human insulin could produce molecules with increased mitogenic potential. In vivo, insulin glargine has been shown to have greater mitogenic potential than human insulin. It is unknown whether this occurs in vitro, because the insulin glargine molecule is transformed once injected. Studies published in 2009 suggest that patients on insulin glargine could be at greater risk for cancer than patients on other antidiabetes therapies, but the trial results are conflicting. In response, the Food and Drug Administration, American Diabetes Association, American Association of Clinical Endocrinologists, and European Association for the Study of Diabetes have formally stated that patients should continue to use insulin glargine until more information is available. Conclusion. Studies on the relationship between insulin glargine and cancer have been inconclusive. C1 [Hamilton, Leslie A.] Auburn Univ, Harrison Sch Pharm, Dept Pharm Practice, Auburn, AL 36849 USA. [Dawson, Leslie K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Hamilton, LA (reprint author), Auburn Univ, Harrison Sch Pharm, Dept Pharm Practice, 1321 Walker Bldg, Auburn, AL 36849 USA. EM lah0010@auburn.edu NR 25 TC 10 Z9 11 U1 1 U2 4 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD DEC 1 PY 2010 VL 67 IS 23 BP 2025 EP 2031 DI 10.2146/ajhp100109 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858BX UT WOS:000297772000012 PM 21098374 ER PT J AU Renella, R AF Renella, Raffaele TI Progress in the congenital dyserythropoietic anemias: juicy but high-hanging fruits? SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID MUTATIONS; GENE; MULTINUCLEARITY; LOCALIZATION; SEARCH C1 [Renella, Raffaele] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [Renella, Raffaele] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Renella, R (reprint author), Childrens Hosp Boston, Div Hematol Oncol, Dana 3,44 Binney St, Boston, MA 02115 USA. EM raffaele.renella@childrens.harvard.edu OI Renella, Raffaele/0000-0002-5041-2308 NR 16 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2010 VL 85 IS 12 BP 913 EP 914 DI 10.1002/ajh.21900 PG 2 WC Hematology SC Hematology GA 692PP UT WOS:000285165300001 PM 21108324 ER PT J AU Roper, N DeAngelo, DJ Kuo, F dal Cin, P Ghobrial, I Aster, JC AF Roper, Nitin DeAngelo, Daniel J. Kuo, Frank dal Cin, Paola Ghobrial, Irene Aster, Jon C. TI An asymptomatic 61-year-old man with BCR-ABL-positive bone marrow following autologous transplantation for multiple myeloma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC GRANULOCYTIC-LEUKEMIA; CHRONIC MYELOCYTIC-LEUKEMIA; PHILADELPHIA-CHROMOSOME; HEALTHY-INDIVIDUALS; FUSION GENES; DISEASE; COEXISTENCE C1 [Kuo, Frank; dal Cin, Paola; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Roper, Nitin; DeAngelo, Daniel J.; Ghobrial, Irene] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Aster, JC (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM jaster@rics.bwh.harvard.edu FU NCI NIH HHS [P01 CA119070, P01 CA119070-04] NR 17 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2010 VL 85 IS 12 BP 944 EP 946 DI 10.1002/ajh.21809 PG 3 WC Hematology SC Hematology GA 692PP UT WOS:000285165300008 PM 20730794 ER PT J AU Khor, B Van Cott, EM AF Khor, Bernard Van Cott, Elizabeth M. TI Laboratory tests for antithrombin deficiency SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID INHERITED THROMBOPHILIA; VENOUS THROMBOSIS; ENDOTHELIAL-CELLS; HEPARAN-SULFATE; PROTEIN-S; AT-III; PLASMA; ASSAY; RISK; COAGULATION AB Hereditary antithrombin deficiency is a hypercoagulable state associated with an increased risk for venous thrombosis. The recommended initial test for antithrombin is an activity (functional) assay. The advantages and disadvantages of the various testing options are presented. The causes of acquired antithrombin deficiency are much more common than hereditary deficiency. Therefore, this article describes the appropriate steps to take when antithrombin activity is low, in order to confirm or exclude a hereditary deficiency. The causes of falsely normal results are also described, including direct thrombin inhibitors. Am. J. Hematol. 85:947-950, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Coagulat Lab, Dept Pathol, Boston, MA 02114 USA. RP Van Cott, EM (reprint author), Massachusetts Gen Hosp, Coagulat Lab, Dept Pathol, Gray Jackson 235,55 Fruit St, Boston, MA 02114 USA. OI Khor, Bernard/0000-0003-4689-5092 NR 42 TC 22 Z9 23 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2010 VL 85 IS 12 BP 947 EP 950 DI 10.1002/ajh.21893 PG 4 WC Hematology SC Hematology GA 692PP UT WOS:000285165300009 PM 21108326 ER PT J AU Singh, H Werner, L DeAngelo, D Ballen, K Amrein, P Wadleigh, M Neuberg, D Fox, E Stone, R Attar, E AF Singh, Harshabad Werner, Lillian DeAngelo, Daniel Ballen, Karen Amrein, Philip Wadleigh, Martha Neuberg, Donna Fox, Edward Stone, Richard Attar, Eyal TI Clinical outcome of patients with acute promyelocytic leukemia and FLT3 mutations SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID TRANS-RETINOIC ACID; CYTOGENETIC CHANGES; ARSENIC TRIOXIDE; GENE; PETHEMA; IMPACT; PROGNOSIS; DIAGNOSIS; PROTOCOL; FEATURES AB Acute promyelocytic leukemia (APL) represents a subset of AML with t(15;17), responsiveness to ATRA, and a favorable prognosis, yet the impact of FLT3ITD mutations over wild-type (wt)FLT3 remains unclear. We retrospectively analyzed the outcome of 26 APL patients treated at our center according to their FLT3 receptor mutation status. We show that APL patients with an ITD mutation (n = 9) have a lower fibrinogen at presentation (103.5 vs. 235 mg/dl, p = 0.04) and a worse disease free survival (DFS) (p = 0.0114) but similar overall survival (OS) compared to patients with a wt FLT3 (n = 13). Our data suggests that APL with FLT3ITD represents a subset of APL patients who have a higher risk of relapse and should be treated with aggressive therapies upfront, possibly by including targeted therapy in the form of FLT3 inhibitors. C1 [Singh, Harshabad; Ballen, Karen; Amrein, Philip; Attar, Eyal] Massachusetts Gen Hosp, Ctr Canc, Hematol & Oncol Unit, Boston, MA 02114 USA. [Werner, Lillian; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [DeAngelo, Daniel; Wadleigh, Martha; Stone, Richard] Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. [Fox, Edward] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02115 USA. [Fox, Edward] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Attar, E (reprint author), Massachusetts Gen Hosp, Ctr Canc, Hematol & Oncol Unit, 100 Blossom St, Boston, MA 02114 USA. EM rstone@partners.org; eattar@partners.org FU NCI NIH HHS [K23 CA118419] NR 22 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2010 VL 85 IS 12 BP 956 EP 957 DI 10.1002/ajh.21867 PG 2 WC Hematology SC Hematology GA 692PP UT WOS:000285165300013 PM 20981678 ER PT J AU Melanson, SEF Stevenson, K Kim, H Antin, JH Court, MH Ho, VT Ritz, J Soiffer, RJ Kuo, FC Longtine, JA Jarolim, P AF Melanson, Stacy E. F. Stevenson, Kristen Kim, Haesook Antin, Joseph H. Court, Michael H. Ho, Vincent T. Ritz, Jerome Soiffer, Robert J. Kuo, Frank C. Longtine, Janina A. Jarolim, Petr TI Allelic variations in CYP2B6 and CYP2C19 and survival of patients receiving cyclophosphamide prior to myeloablative hematopoietic stem cell transplantation SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID DRUG-METABOLIZING-ENZYMES; HUMAN LIVER; GENETIC POLYMORPHISMS; IFOSFAMIDE ACTIVATION; VENOOCCLUSIVE DISEASE; CANCER-PATIENTS; TOXICITY; PHARMACOKINETICS; PHARMACOGENETICS; BIOACTIVATION AB In hematopoietic stem cell transplantation (HSCT), patients receive cyclophosphamide (CPA) conditioning based on body weight, under the assumption that each individual will metabolize the drug with the same efficiency [1-3]. However, up to 20% of patients experience adverse outcomes related to CPA [4-7]. We hypothesized that due to their effects on CPA metabolism certain allelic variations of cytochrome P450 (CYP) 2B6 and 2C19 enzymes would be associated with higher regimen-related toxicity and worse outcomes in patients. We genotyped 359 patients who received allogeneic HSCT with high dose CPA conditioning. We investigated the effect of allelic variants of CYP2B6 and CYP2C19 on toxicity outcomes, nonrelapse mortality (NRM), relapse, progression free survival (PFS) and overall survival (OS). Overall, 65 (18%) patients experienced toxicity. There was no significant difference in toxicity events in patients with allelic variants of CYP2B6 or CYP2C19. However, compared to poor metabolizers, ultrarapid CYP2B6 metabolizers had worse PFS (P = 0.04). In addition, patients homozygous for CYP2C19 *2 allele had significantly worse PFS (P = 0.008) and OS (P = 0.004). Our results suggest that genotyping may help to predict survival in patients receiving high dose CPA, guide patient management and improve outcomes. C1 [Melanson, Stacy E. F.; Kuo, Frank C.; Longtine, Janina A.; Jarolim, Petr] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pathol, Boston, MA 02115 USA. [Stevenson, Kristen; Kim, Haesook; Antin, Joseph H.; Ho, Vincent T.; Ritz, Jerome; Soiffer, Robert J.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Div Hematol Malignancies, Boston, MA 02115 USA. [Court, Michael H.] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. RP Melanson, SEF (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pathol, 75 Francis St,Amory 2, Boston, MA 02115 USA. EM semelanson@partners.org NR 29 TC 11 Z9 11 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2010 VL 85 IS 12 BP 967 EP 971 DI 10.1002/ajh.21889 PG 5 WC Hematology SC Hematology GA 692PP UT WOS:000285165300017 PM 21108329 ER PT J AU Tamura, MK O'Hare, AM McCulloch, CE Johansen, KL AF Tamura, Manjula Kurella O'Hare, Ann M. McCulloch, Charles E. Johansen, Kirsten L. TI Signs and Symptoms Associated With Earlier Dialysis Initiation in Nursing Home Residents SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Dialysis initiation; end-stage renal disease; elderly ID STAGE RENAL-DISEASE; MINIMUM DATA SET; CHRONIC KIDNEY-DISEASE; UNITED-STATES; INCREASED MORTALITY; SURVIVAL; VALIDITY; FAILURE; ADULTS; ESRD AB Background: Factors driving the trend of earlier dialysis initiation for persons with end-stage renal disease are unknown. We wanted to determine the association of the number and type of signs and symptoms with timing of initiation of dialysis in US nursing home residents. Study Design: Observational study. Setting & Participants: We used data from the US Renal Data System linked with the Minimum Data Set, a national registry of nursing home residents. The cohort consisted of 2,402 nursing home residents who initiated dialysis between 1998 and 2000 and had at least 2 recorded clinical assessments in the year before dialysis initiation. Predictors: We evaluated 7 clinical signs and symptoms: dependence in activities of daily living, cognitive function, edema, dyspnea, nutritional problems, vomiting, and body size. Outcomes: Earlier dialysis initiation was defined as estimated glomerular filtration rate >= 15 mL/min/1.73 m(2) at the start of dialysis. Results: Median estimated glomerular filtration rate at the start of dialysis was 9.8 (25th-75th percentile, 7.4-13.4) mL/min/1.73 m(2). After adjustment for age, sex, race, and comorbid conditions, each additional sign or symptom was associated with a higher odds for earlier dialysis initiation (OR, 1.16 per symptom; 95% CI, 1.06-1.28), as was each adversely changing sign or symptom (OR, 1.26 per symptom; 95% CI, 1.16-1.38). The population-attributable risk for earlier dialysis initiation associated with having one or more signs and symptoms of volume overload, cognitive decline, increasing activities of daily living dependence, and weight loss was 31%; volume overload had the largest aggregate population-attributable risk. Limitations: We lacked information about metabolic indications for dialysis initiation. Conclusions: Volume overload, cognitive decline, increasing activities of daily living dependence, and weight loss were associated with earlier dialysis initiation; however, these factors explained less than one-third of cases of earlier dialysis initiation in nursing home residents. Am J Kidney Dis 56: 1117-1126. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Tamura, Manjula Kurella] Stanford Univ, Div Nephrol, Dept Med, Sch Med, Palo Alto, CA 94304 USA. [Tamura, Manjula Kurella] Vet Affairs Palo Alto Hlth Care Syst, Geriatr Res & Educ Clin Ctr, Palo Alto, CA USA. [O'Hare, Ann M.] Univ Washington, Dept Med, Div Nephrol, Seattle, WA 98195 USA. [O'Hare, Ann M.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [McCulloch, Charles E.; Johansen, Kirsten L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA USA. RP Tamura, MK (reprint author), Stanford Univ, Div Nephrol, Dept Med, Sch Med, 780 Welch Rd,Ste 106, Palo Alto, CA 94304 USA. EM mktamura@stanford.edu RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU National Institute of Aging [K23AG028952, K23AG28980]; National Institute of Diabetes and Digestive and Kidney Diseases [N01DK70005]; National Center for Research Resources [KL2RR024130]; Centers for Disease Control and Prevention FX This work was supported by Paul B. Beeson Career Development Award in Aging grants (K23AG028952 to Dr Kurella Tamura and K23AG28980 to Dr O'Hare) from the National Institute of Aging, N01DK70005 from the National Institute of Diabetes and Digestive and Kidney Diseases, KL2RR024130 from the National Center for Research Resources, and a grant from the Centers for Disease Control and Prevention (Dr O'Hare). NR 32 TC 13 Z9 13 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2010 VL 56 IS 6 BP 1117 EP 1126 DI 10.1053/j.ajkd.2010.08.017 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 682KG UT WOS:000284401800016 ER PT J AU Cohen, LJ Rennke, HG Laubach, JP Humphreys, BD AF Cohen, Lisa J. Rennke, Helmut G. Laubach, Jacob P. Humphreys, Benjamin D. TI The Spectrum of Kidney Involvement in Lymphoma: A Case Report and Review of the Literature SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Renal failure; Hodgkin lymphoma; non-Hodgkin lymphoma; nephrotic ID CHANGE NEPHROTIC SYNDROME; NON-HODGKINS-LYMPHOMA; RENAL-FAILURE; MEMBRANOUS NEPHROPATHY; GLOMERULONEPHRITIS; GLOMERULOPATHIES; DISEASE; INFILTRATION; PATHOGENESIS; ASSOCIATION AB Kidney involvement is an under-recognized complication of both Hodgkin and non-Hodgkin lymphoma. The diversity of lymphoma-related renal manifestations makes diagnosis difficult. Although abrupt worsening of kidney function may be the first sign of malignant disease, renal effects can be subtle or even silent. The causes of renal involvement similarly are varied. We discuss a case of non-Hodgkin lymphoma and associated kidney failure from several distinct malignancy-related mechanisms and review the spectrum of lymphoma-related kidney involvement. Am J Kidney Dis 56: 1191-1196. (C) 2010 by the National Kidney Foundation, Inc. C1 [Cohen, Lisa J.; Humphreys, Benjamin D.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [Rennke, Helmut G.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Laubach, Jacob P.; Humphreys, Benjamin D.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cohen, LJ (reprint author), Channing Labs, Rm 570,181 Longwood Ave, Boston, MA 02115 USA. EM lcohen11@partners.org FU National Institutes of Health (NIH) [T32 DK007527, DK073628, DK084316] FX Dr Cohen is supported by National Institutes of Health (NIH) grant T32 DK007527. Dr Humphreys is supported by NIH grants DK073628 and DK084316. NR 30 TC 14 Z9 17 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2010 VL 56 IS 6 BP 1191 EP 1196 DI 10.1053/j.ajkd.2010.07.009 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 682KG UT WOS:000284401800024 PM 20843590 ER PT J AU Ganz, DA Koretz, BK Bail, JK McCreath, HE Wenger, NS Roth, CP Reuben, DB AF Ganz, David A. Koretz, Brandon K. Bail, Julia K. McCreath, Heather E. Wenger, Neil S. Roth, Carol P. Reuben, David B. TI Nurse Practitioner Comanagement for Patients in an Academic Geriatric Practice SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ADULT PRIMARY-CARE; QUALITY-OF-CARE; VULNERABLE ELDERS; URINARY-INCONTINENCE; COLLABORATIVE CARE; HEALTH-CARE; INDICATORS; DEPRESSION; MANAGEMENT AB Objective: To determine whether nurse practitioner (NP) comanagement can improve the quality of care for 5 chronic conditions in an academic geriatrics practice. Study Design and Methods: From September 2006 to September 2007, 18 primary care geriatricians were divided into an intervention group that could refer patients to an NP for comanagement of dementia, depression, falls, heart failure, and/or urinary incontinence, or a control group that indicated which patients would have been referred to the NP for these conditions. The NP used structured visit notes to guide care delivery for the 5 conditions concordant with Assessing Care of Vulnerable Elders-3 (ACOVE-3) quality indicators. We reviewed charts to determine adherence to recommended processes of care. Results: A total of 200 patients (108 intervention, 92 control) were eligible for at least 1 process of care recommended by ACOVE-3 for the 5 conditions. Patients' mean (SD) age was 85 years (7 years), 67% were women, and patients were eligible for a mean (SD) of 6.9 (4.4) processes of care. Intervention patients were eligible for more care processes than controls (7.8 vs 5.9 processes per patient; P = .002). Quality of care was higher for patients in the intervention group compared with the control group (54% vs 34% of care processes completed; P < .001). The adjusted absolute difference between intervention and control groups in care processes completed was 20% (95% confidence interval = 13%, 27%). Conclusion: NP comanagement of 5 chronic conditions was associated with higher quality of care, even in a practice of geriatricians. (Am J Manag Care. 2010; 16(12): e343-e355) C1 [Ganz, David A.; Bail, Julia K.; McCreath, Heather E.; Reuben, David B.] Univ Calif Los Angeles, Div Geratr Med & Gerontol, Los Angeles, CA 90073 USA. [Wenger, Neil S.] Univ Calif Los Angeles, Div Gen Internal Med, Los Angeles, CA 90073 USA. [Ganz, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Hlth Serv Res & Dev Ctr Excellence, Los Angeles, CA USA. [Roth, Carol P.] RAND Corp, Santa Monica, CA USA. RP Ganz, DA (reprint author), Univ Calif Los Angeles, Div Geratr Med & Gerontol, 11301 Wilshire Blvd,Bldg 220,Rm 313 11G, Los Angeles, CA 90073 USA. EM dganz@mednet.ucla.edu FU John A.Hartford Foundation; Donald W. Reynolds Foundation; US Department of Veterans Health Administration; VA Health Services Research & Development (HSR&D) Service through the VA Greater Los Angeles HSR&D Center of Excellence [VA CD2 08-012-01]; VA/Robert Wood Johnson Foundation; National Institute on Aging [5P30AG028748] FX This project was supported by a grant from the John A.Hartford Foundation to Dr Reuben and a supplementary grant from the Donald W. Reynolds Foundation to Dr Koretz. Dr Ganz was supported by the US Department of Veterans Health Administration, VA Health Services Research & Development (HSR&D) Service through the VA Greater Los Angeles HSR&D Center of Excellence (Project #VA CD2 08-012-01), and the VA/Robert Wood Johnson Foundation Physician Faculty Scholars Program. Data collection and analysis were supported in part by the UCLA Claude Pepper Older Americans Independence Center funded by the National Institute on Aging (5P30AG028748). None of the funders played a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 28 TC 13 Z9 13 U1 0 U2 5 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD DEC PY 2010 VL 16 IS 12 BP E343 EP E355 PG 13 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 699SL UT WOS:000285683000002 PM 21291291 ER PT J AU Casamassima, F Hay, AC Benedetti, A Lattanzi, L Cassano, GB Perlis, RH AF Casamassima, Francesco Hay, Aleena C. Benedetti, Alessandra Lattanzi, Lorenzo Cassano, Giovanni B. Perlis, Roy H. TI L-Type Calcium Channels and Psychiatric Disorders: A Brief Review SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE L-type calcium channels; psychiatric disorders; mood disorders; calcium-channel antagonists ID L-TYPE CA2+; BIPOLAR AFFECTIVE-DISORDER; MAJOR DEPRESSIVE DISORDER; GENOME-WIDE ASSOCIATION; BEHAVIORAL DESPAIR TEST; CONDITIONED PLACE PREFERENCES; ETHANOL WITHDRAWAL SYNDROME; CHRONIC MORPHINE TREATMENT; FORCED SWIMMING TEST; EYE-MOVEMENT SLEEP AB Emerging evidence from genome-wide association studies (GWAS) support the association of polymorphisms in the alpha 1C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with bipolar disorder. These studies extend a rich prior literature implicating dysfunction of L-type calcium channels (LTCCs) in the pathophysiology of neuropsychiatric disorders. Moreover, calcium channel blockers reduce Ca(2+) flux by binding to the alpha 1 subunit of the LTCC and are used extensively for treating hypertension, preventing angina, cardiac arrhythmias and stroke. Calcium channel blockers have also been studied clinically in psychiatric conditions such as mood disorders and substance abuse/dependence, yielding conflicting results. In this review, we begin with a summary of LTCC pharmacology. For each category of disorder, this article then provides a review of animal and human data. In particular, we extensively focus on animal models of depression and clinical trials in mood disorders and substance abuse/dependence. Through examining rationale and study design of published clinical trials, we provide some of the possible reasons why we still do not have definitive evidence of efficacy of calcium-channel antagonists for mood disorders. Refinement of genetic results and target phenotypes, enrollment of adequate sample sizes in clinical trials and progress in physiologic and pharmacologic studies to synthesize tissue and isoform specific calcium channel antagonists, are all future challenges of research in this promising field. (C) 2010 Wiley-Liss, Inc. C1 [Casamassima, Francesco; Hay, Aleena C.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Casamassima, Francesco; Perlis, Roy H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Casamassima, Francesco; Perlis, Roy H.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Casamassima, Francesco; Benedetti, Alessandra; Lattanzi, Lorenzo; Cassano, Giovanni B.] Univ Pisa, Div Psychiat, Pisa, Italy. RP Casamassima, F (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM fcasamassima@hotmail.it NR 238 TC 48 Z9 50 U1 1 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC PY 2010 VL 153B IS 8 BP 1373 EP 1390 DI 10.1002/ajmg.b.31122 PG 18 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 685IU UT WOS:000284623200002 PM 20886543 ER PT J AU Talkowski, ME McCann, KL Chen, M McClain, L Bamne, M Wood, J Chowdari, KV Watson, A Prasad, KM Kirov, G Georgieva, L Toncheva, D Mansour, H Lewis, DA Owen, M O'Donovan, M Papasaikas, P Sullivan, P Ruderfer, D Yao, JK Leonard, S Thomas, P Miyajima, F Quinn, J Lopez, AJ Nimgaonkar, VL AF Talkowski, Michael E. McCann, Kathleen L. Chen, Michael McClain, Lora Bamne, Mikhil Wood, Joel Chowdari, Kodavali V. Watson, Annie Prasad, Konasale M. Kirov, George Georgieva, Lyudmilla Toncheva, Draga Mansour, Hader Lewis, David A. Owen, Michael O'Donovan, Michael Papasaikas, Panagiotis Sullivan, Patrick Ruderfer, Douglas Yao, Jeffrey K. Leonard, Sherry Thomas, Pramod Miyajima, Fabio Quinn, John Lopez, A. Javier Nimgaonkar, Vishwajit L. TI Fine-Mapping Reveals Novel Alternative Splicing of the Dopamine Transporter SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE dopamine transporter; schizophrenia; alternative splicing; genetic association ID PRE-MESSENGER-RNA; NAIVE SCHIZOPHRENIC-PATIENTS; MONOAMINE TRANSPORTERS; PARKINSONS-DISEASE; TRANSCRIPTIONAL ACTIVITY; PREFRONTAL CORTEX; BINDING-SITES; HUMAN BRAIN; GENE; ASSOCIATION AB The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neuro-developmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow-up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post-mortem human substantia nigra (SN). As E3b introduces multiple in-frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post-mortem human SN. In mini-gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta-analyses across genome-wide association studies did not support the initial associations and further post-mortem studies did not suggest case-control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. (C) 2010 Wiley-Liss, Inc. C1 [Talkowski, Michael E.; McClain, Lora; Bamne, Mikhil; Wood, Joel; Chowdari, Kodavali V.; Watson, Annie; Prasad, Konasale M.; Mansour, Hader; Lewis, David A.; Yao, Jeffrey K.; Thomas, Pramod; Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Talkowski, Michael E.; Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15213 USA. [McCann, Kathleen L.; Chen, Michael; Papasaikas, Panagiotis; Lopez, A. Javier] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. [Kirov, George; Georgieva, Lyudmilla; Owen, Michael; O'Donovan, Michael] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, MRC Ctr Neuropsychiat Genet & Gen, Cardiff, S Glam, Wales. [Toncheva, Draga] Med Univ, Sofia, Bulgaria. [Sullivan, Patrick] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Ruderfer, Douglas] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ruderfer, Douglas] Broad Inst, Boston, MA USA. [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Leonard, Sherry] Univ Colorado, Dept Psychiat, Denver, CO 80202 USA. [Miyajima, Fabio; Quinn, John] Univ Liverpool, Div Human Anat & Cell Biol, Liverpool L69 3BX, Merseyside, England. [Miyajima, Fabio; Quinn, John] Univ Liverpool, Sch Biomed Sci, Liverpool L69 3BX, Merseyside, England. RP Nimgaonkar, VL (reprint author), Univ Pittsburgh, Sch Med, Dept Psychiat & Human Genet, Room 441,3811 OHara St, Pittsburgh, PA 15213 USA. EM nimga@pitt.edu RI Papasaikas, Panagiotis/J-8581-2015; Ruderfer, Douglas/M-5795-2016; OI Papasaikas, Panagiotis/0000-0002-1640-7636; Prasad, Konasale/0000-0003-0245-1393; Ruderfer, Douglas/0000-0002-2365-386X; McCann, Kathleen/0000-0002-7144-4851; Miyajima, Fabio/0000-0002-1347-4825; O'Donovan, Michael/0000-0001-7073-2379 FU Bristol-Myers Squibb Foundation; Bristol-Myers Squibb; Curridium Ltd; Pfizer; AstraZeneca; Hoffman-Roche; Lilly; Merck; Neurogen; National Institutes of Health [MH56242, MH63480, GM081293]; NSF [0821202]; Pennsylvania Department of Health [4100043365]; NIMH National Research Service Award [F31MH080582]; National Institute of Mental Health [N01 MH90001]; National Center for Research Resources (NCRR) [UL1 RR 024153]; VA Research Career Scientist and Merit Review Awards; NIH Roadmap for Medical Research FX Grant sponsor: Bristol-Myers Squibb Foundation; Grant sponsor: Bristol-Myers Squibb; Grant sponsor: Curridium Ltd; Grant sponsor: Pfizer; Grant sponsor: AstraZeneca; Grant sponsor: Hoffman-Roche; Grant sponsor: Lilly; Grant sponsor: Merck; Grant sponsor: Neurogen; Grant sponsor: National Institutes of Health; Grant numbers: MH56242, MH63480, GM081293; Grant sponsor: NSF; Grant number: 0821202; Grant sponsor: Pennsylvania Department of Health; Grant number: SAP# 4100043365; Grant sponsor: NIMH National Research Service Award; Grant number: F31MH080582; Grant sponsor: National Institute of Mental Health; Grant number: N01 MH90001; Grant sponsor: National Center for Research Resources (NCRR); Grant number: UL1 RR 024153.; This work was supported by National Institutes of Health (grant numbers MH56242, MH63480 to V.L.N., GM081293 to A.J.L.), NSF (grant 0821202 to A.J.L.), VA Research Career Scientist and Merit Review Awards (J.K.Y., S.L.), and Pennsylvania Department of Health (SAP# 4100043365; PI, R. Loeber). M. Talkowski was supported by an NIMH National Research Service Award (F31MH080582). K. McCann was an Undergraduate Research Scholar of the Arnold and Mabel Beckman Foundation. The CATIE project was funded by National Institute of Mental Health (contract N01 MH90001). Funding for the MGS sample was provided by the National Institute of Mental Health and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). We thank Bernie Devlin, PhD for helpful advice and Jeffrey Muller of Applied Biosystems, Inc. for technical support. The data set used for the analyses described in this manuscript were obtained from the GAIN Database (http://view.ncbi.nlm.nih.gov/dbgap-controlled through dbGaP); accession number phs000017.v1.p1. Samples and associated phenotype data for the Linking Genome-Wide Association Study of Schizophrenia were provided by P. Gejman, MD. We thank Pamela Sklar, MD PhD for enabling access to the International Schizophrenia Consortium GWAS data. The project described was supported by grant number UL1 RR 024153 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. NR 79 TC 6 Z9 6 U1 2 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC PY 2010 VL 153B IS 8 BP 1434 EP 1447 DI 10.1002/ajmg.b.31125 PG 14 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 685IU UT WOS:000284623200007 PM 20957647 ER PT J AU Atkins, D Kupersmith, J AF Atkins, David Kupersmith, Joel TI Implementation Research: A Critical Component of Realizing the Benefits of Comparative Effectiveness Research SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Comparative effectiveness; Implementation research; Veterans ID QUALITY IMPROVEMENT; COLLABORATIVE CARE; HEALTH-CARE; INFORMATION-TECHNOLOGY; DEPRESSION; METAANALYSIS; QUERI; ORGANIZATIONS; PREVENTION; SERVICES AB Comparative effectiveness research (CER) holds the promise of improving patient-centered care and increasing value in the healthcare system. Achieving these goals, however, depends on effectively implementing the findings of CER. In this article, we draw on lessons from implementation research and our experience in the Veterans Administration (VA) healthcare system to offer recommendations about what is needed to support implementation of CER. There is no single strategy for successful implementation. Implementation efforts must take into account the nature of the evidence, the type of change being implemented, the clinical context in which the findings are being applied, and the specific barriers and facilitators to implementing new practices. The experience of the VA illustrates the importance of taking a systems approach that aligns numerous elements of the healthcare system-guidelines, decision support, performance measures, financial incentives, coverage and benefits policy, and health information technology-to support implementation:. We illustrate these principles with an example of implementing a new model of evidence-based depression care. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, e38-e45 C1 [Atkins, David] US Dept Vet Affairs, Hlth Serv Res & Dev Program, Off Res & Dev, Washington, DC 20420 USA. RP Atkins, D (reprint author), US Dept Vet Affairs, Hlth Serv Res & Dev Program, Off Res & Dev, 810 Vermont Ave NW 124, Washington, DC 20420 USA. EM David.atkins@va.gov NR 55 TC 14 Z9 15 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E38 EP E45 DI 10.1016/j.amjmed.2010.10.007 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700007 PM 21184866 ER PT J AU Concato, J Lawler, EV Lew, RA Gaziano, JM Aslan, M Huang, GD AF Concato, John Lawler, Elizabeth V. Lew, Robert A. Gaziano, J. Michael Aslan, Mihaela Huang, Grant D. TI Observational Methods in Comparative Effectiveness Research SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Comparative effectiveness research; Epidemiology; Evidence-based medicine; Research methods ID SECONDARY DATA SOURCES; HORMONE REPLACEMENT THERAPY; VITAMIN-E; PROSTATE-CANCER; METHODOLOGICAL ISSUES; MYOCARDIAL-INFARCTION; CONTROLLED-TRIALS; MORTALITY; SUPPLEMENTATION; SCIENCE AB Comparative effectiveness research (CER) may be defined informally as an assessment of available options for treating specific medical conditions in selected groups of patients. In this context, the most prominent features of CER are the various patient populations, medical ailments, and treatment options involved in any particular project. Yet, each research investigation also has a corresponding study design or "architecture," and in patient-oriented research a common distinction used to describe such designs are randomized controlled trials (RCTs) versus observational studies. The purposes of this overview, with regard to CER, are to (1) understand how observational studies can provide accurate results, comparable to RCTs; (2) recognize strategies used in selected newer methods for conducting observational studies; (3) review selected observational studies from the Veterans Health Administration; and (4) appreciate the importance of fundamental methodological principles when conducting or evaluating individual studies. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, e16-e23 C1 [Concato, John] VA Connecticut Healthcare Syst, Clin Epidemiol Res Ctr, West Haven, CT 06516 USA. [Concato, John; Aslan, Mihaela] VA Clin Epidemiol Res Ctr, West Haven, CT USA. [Concato, John; Aslan, Mihaela] Yale Univ, Dept Med, New Haven, CT 06520 USA. [Lawler, Elizabeth V.; Lew, Robert A.; Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Lew, Robert A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Lawler, Elizabeth V.; Gaziano, J. Michael] Harvard Univ, Sch Med, Boston, MA USA. [Huang, Grant D.] US Dept Vet Affairs, VA Cooperat Studies Program Cent Off, Washington, DC USA. RP Concato, J (reprint author), VA Connecticut Healthcare Syst, Clin Epidemiol Res Ctr, 950 Campbell Avenue 151B, West Haven, CT 06516 USA. EM john.concato@yale.edu NR 44 TC 53 Z9 54 U1 0 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E16 EP E23 DI 10.1016/j.amjmed.2010.10.004 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700004 PM 21184862 ER PT J AU D'Avolio, LW Farwell, WR Fiore, LD AF D'Avolio, Leonard W. Farwell, Wildon R. Fiore, Louis D. TI Comparative Effectiveness Research and Medical Informatics SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Comparative effectiveness research; Data collection; Medical informatics ID DECISION-SUPPORT; PATIENT-CARE; HEALTH-CARE; RECORDS; ARCHITECTURE; MANAGEMENT; VIEW AB As is the case for environmental, ecological, astronomical, and other sciences, medical practice and research finds itself in a tsunami of data. This data deluge, due primarily to the introduction of digitalization in routine medical care and medical research, affords the opportunity for improved patient care and scientific discovery. Medical informatics is the subdiscipline of medicine created to make greater use of information in order to improve healthcare. The 4 areas of medical informatics research (information access, structure, analysis, and interaction) are used as a framework to discuss the overlap in information needs of comparative effectiveness research and potential contributions of medical informatics. Examples of progress from the medical informatics literature and the Veterans Affairs Healthcare System are provided. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, e32-e37 C1 [D'Avolio, Leonard W.; Farwell, Wildon R.; Fiore, Louis D.] MAVERIC, VA Boston Healthcare Syst, Boston, MA USA. [D'Avolio, Leonard W.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [D'Avolio, Leonard W.; Farwell, Wildon R.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [D'Avolio, Leonard W.; Farwell, Wildon R.] Harvard Univ, Sch Med, Boston, MA USA. [Fiore, Louis D.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP D'Avolio, LW (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave 151 MAV, Jamaica Pl, MA 02130 USA. EM Leonard.Davolio@va.gov NR 33 TC 20 Z9 20 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E32 EP E37 DI 10.1016/j.amjmed.2010.10.006 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700006 PM 21184865 ER PT J AU Huang, GD Ferguson, RE Peduzzi, PN O'Leary, TJ AF Huang, Grant D. Ferguson, Ryan E. Peduzzi, Peter N. O'Leary, Timothy J. TI Scientific and Organizational Collaboration in Comparative Effectiveness Research: The VA Cooperative Studies Program Model SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Clinical research; Clinical trials; Comparative effectiveness; Veterans ID RANDOMIZED CONTROLLED-TRIAL; PRACTICAL CLINICAL-TRIALS; MEDICAL THERAPY; VETERANS; DESIGN; DISEASE; SURGERY; ANGINA; ETHICS; DEATH AB Comparative effectiveness research (CER) has the ability to improve health and inform patients, clinicians, and decision makers. However, calls for more devoted efforts with regard to CER have been countered by methodological, resource, and translational challenges related to conducting these studies. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) is a clinical research infrastructure that has contributed much evidence to support clinical practice for several decades. Although the CSP does not exclusively focus on CER, it employs strategies that lend themselves toward the planning and execution of studies that seek to compare interventions and/or strategies for treating disease. Consequently, the CSP provides a model for addressing important scientific, structural, and operational factors for clinical research, including large, national and multinational comparative effectiveness studies. Exploration of the difficulties the CSP has encountered can help to elucidate barriers that face CER. This article discusses factors and approaches for collaboratively developing and conducting definitive studies that produce outcomes aimed at influencing clinical practice, lessons that have resulted from such efforts, and ongoing challenges. Future program directions are also presented to highlight areas of emphasis and implications for CER within the VA and nationally. Published by Elsevier Inc. The American Journal of Medicine (2010) 123, e24-e31 C1 [Huang, Grant D.; O'Leary, Timothy J.] US Dept Vet Affairs, Off Res & Dev, Washington, DC 20420 USA. [Huang, Grant D.; O'Leary, Timothy J.] US Dept Vet Affairs, Cooperat Studies Program Cent Off, Washington, DC 20420 USA. [Ferguson, Ryan E.] Massachusetts Vet Epidemiol Res & Informat Ctr, Boston VA Cooperat Studies Program Coordinating C, Boston, MA USA. [Peduzzi, Peter N.] W Haven VA Cooperat Studies Program Coordinating, West Haven, CT USA. [Peduzzi, Peter N.] Yale Univ, Sch Publ Hlth, Div Biostat, New Haven, CT USA. RP Huang, GD (reprint author), US Dept Vet Affairs, Off Res & Dev 12, 810 Vermont Ave NW, Washington, DC 20420 USA. EM grant.huang@va.gov FU Office of Research and Development, of the US Department of Veterans Affairs FX This study was supported by the Cooperative Studies Program, Office of Research and Development, of the US Department of Veterans Affairs. NR 56 TC 3 Z9 3 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E24 EP E31 DI 10.1016/j.amjmed.2010.10.005 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700005 PM 21184863 ER PT J AU Kupersmith, J Ommaya, AK AF Kupersmith, Joel Ommaya, Alexander K. TI The Past, Present, and Future of Comparative Effectiveness Research in the US Department of Veterans Affairs SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Clinical trials; Comparative effectiveness research; Observational research; Veterans affairs ID CLINICAL-PRACTICE; MEDICAL THERAPY; PRIMARY-CARE; HEALTH-CARE; DISEASE; TRIAL; PHYSICIANS; SURGERY; QUALITY; POLICY AB A particular challenge for the healthcare provider and the patient is to choose among competing therapeutic approaches for a particular condition. Often, the relative benefits and risks of potential therapies are not uniformly available from the existing scientific information. Many have pointed to the need for more comparative effectiveness research (CER) to aide in these decisions. The US Department of Veterans Affairs (VA) has a long history of conducting CER. The success of the VA CER program has been facilitated by several important aspects of scientific infrastructure related to (1) research question refinement, (2) study design, planning and coordination, (3) evidence synthesis, and (4) implementation research. In publications that had VA coauthors in 2 major medical journals, 25% of the published studies were classified as CER. The most frequent categories of study were pharmaceutical and behavioral interventions. In the future, the CER enterprise will move toward increased input from clinicians in research topic choice and enhanced consideration of other methodologies besides the randomized controlled trial. (C) 2010 Published by Elsevier Inc. The American Journal of Medicine (2010) 123, e3-e7 C1 [Kupersmith, Joel; Ommaya, Alexander K.] US Dept Vet Affairs, Off Res & Dev, Washington, DC 20420 USA. RP Kupersmith, J (reprint author), US Dept Vet Affairs, Off Res & Dev 12, 810 Vermont Ave NW, Washington, DC 20420 USA. EM Joel.Kupersmith@va.gov NR 39 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E3 EP E7 DI 10.1016/j.amjmed.2010.10.002 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700002 PM 21184864 ER PT J AU Kupersmith, J AF Kupersmith, Joel TI Comparative Effectiveness Research-Objectives, Challenges, and Contributions of the US Department of Veterans Affairs Introduction SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Kupersmith, Joel] US Dept Vet Affairs, Off Res & Dev, Washington, DC 20420 USA. RP Kupersmith, J (reprint author), US Dept Vet Affairs, Off Res & Dev 12, 810 Vermont Ave NW, Washington, DC 20420 USA. EM Joel.Kupersmith@va.gov 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 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E1 EP E2 DI 10.1016/j.amjmed.2010.10.001 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700001 PM 21184861 ER PT J AU Peduzzi, P Kyriakides, T O'Connor, TZ Guarino, P Warren, SR Huang, GD AF Peduzzi, Peter Kyriakides, Tassos O'Connor, Theresa Z. Guarino, Peter Warren, Stuart R. Huang, Grant D. TI Methodological Issues in Comparative Effectiveness Research: Clinical Trials SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Clinical trials; Comparative effectiveness research; Equipoise ID RANDOMIZED-TRIAL; BYPASS-SURGERY; STABLE ANGINA; DESIGN; VETERANS; RATIONALE; THERAPY; DISEASE; COMPLICATIONS; EQUIPOISE AB The US Department of Veterans Affairs (VA) Cooperative Studies Program has been conducting comparative effectiveness clinical trials for nearly 4 decades in many disease areas, including cardiovascular disease/surgery, diabetes mellitus, mental health, neurologic disorders, cancer, infectious diseases, and rheumatoid arthritis. The features that have made this program advantageous for conducting comparative effectiveness clinical trials are described along with methodological considerations for future trials based on lessons learned from its experience conducting these types of studies. Some of the lessons learned involve managing risk factors, clinical equipoise, patient preferences, evolving technology, the use of usual care as a comparator and pharmaceutical issues related to study drug blinding. These issues are not unique to the VA but can play an important role in enabling valid comparisons between treatments that may have differences in delivery or mechanisms of action and could affect the execution and feasibility of conducting a clinical trial with a comparative effectiveness aim. We also outline some future directions for comparative effectiveness clinical trials. (C) 2010 Elsevier Inc. All rights reserved. The American Journal of Medicine (2010) 123, e8-e15 C1 [Peduzzi, Peter] Yale Univ, Sch Publ Hlth, New Haven, CT 06519 USA. [Peduzzi, Peter; Kyriakides, Tassos; O'Connor, Theresa Z.; Guarino, Peter] US Dept Vet Affairs, VA Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Warren, Stuart R.] US Dept Vet Affairs, VA Cooperat Studies Program, Clin Res Pharm Coordinating Ctr, Albuquerque, NM USA. [Huang, Grant D.] US Dept Vet Affairs, VA Cooperat Studies Program Cent Off, Washington, DC USA. RP Peduzzi, P (reprint author), Yale Univ, Sch Publ Hlth, 2 Church St S,Suite 112, New Haven, CT 06519 USA. EM Peter.Peduzzi@Yale.edu FU Department of Veterans Affairs Office of Research and Development FX This study was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. NR 28 TC 5 Z9 5 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2010 VL 123 IS 12 SU 1 BP E8 EP E15 DI 10.1016/j.amjmed.2010.10.003 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 698EQ UT WOS:000285575700003 PM 21184867 ER PT J AU Giani, A Cigada, M Choudhry, N Deiro, AP Oldani, M Pellegrini, M Invernizzi, A Duca, P Miller, JW Staurenghi, G AF Giani, Andrea Cigada, Mario Choudhry, Netan Deiro, Antonio Peroglio Oldani, Marta Pellegrini, Marco Invernizzi, Alessandro Duca, Piergiorgio Miller, Joan W. Staurenghi, Giovanni TI Reproducibility of Retinal Thickness Measurements on Normal and Pathologic Eyes by Different Optical Coherence Tomography Instruments SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID DIABETIC MACULAR EDEMA; TIME-DOMAIN; QUANTITATIVE ASSESSMENT; FOVEAL THICKNESS; REPEATABILITY; HEALTHY; DEGENERATION; DIAGNOSIS; ANALYZER; OCT AB PURPOSE: To compare retinal thickness measurements produced by different time-domain and spectral-domain optical coherence tomography (TD-OCT and SD-OCT) devices when imaging normal and pathologic eyes. DESIGN: Prospective, observational study in an academic institutional setting. METHODS: A total of 110 eyes were imaged by 6 different OCT devices: Stratus and Cirrus (Carl Zeiss Meditec Inc), Spectra lis HRA+OCT (Heidelberg Engineering), RTVue-100 (Optovue Inc), SDOCT Copernicus HR (Optopol Technology S.A.), and 3D OCT-1000 (Topcon Corporation). Eyes were normal or affected by different pathologies of the retina, including exudative and nonexudative age-related macular degeneration, epiretinal membrane, cystoid macular edema, and macular hole. For each instrument we used standard analysis protocols for macular thickness evaluation. Mean retinal thickness values between the instruments in the ETDRS central circular 1000-mu m-diameter areas and in the ETDRS midperipheral circular 3000-mu m-diameter areas were compared. RESULTS: The 6 different devices produced measurements that differ in variance (Bartlett test, P = .006), and mean values (Friedman test, P < .001). Bland-Altman analysis revealed that the limits of agreement for all the comparisons were not acceptable. Regression was calculated and it was elaborated into a conversion table, despite a high standard error for both intercepts and slope conversion values. CONCLUSIONS: This study suggests that retinal thickness measurements obtained with various OCT devices are different beyond clinical practice tolerance, according to Bland-Altman analysis. Furthermore, regression analysis reveals high standard error values. These differences appear to be primarily attributable to the analysis algorithms used to set retinal inner and C1 [Duca, Piergiorgio] Univ Milan, Dept Clin Sci Luigi Sacco, Luigi Sacco Hosp, Unita Satist Med & Biometria, I-20100 Milan, Italy. [Giani, Andrea; Choudhry, Netan; Miller, Joan W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Dept Ophthalmol, Boston, MA USA. [Giani, Andrea; Cigada, Mario; Deiro, Antonio Peroglio; Oldani, Marta; Pellegrini, Marco; Invernizzi, Alessandro; Staurenghi, Giovanni] Univ Milan, Eye Clin Luigi Sacco Hosp, I-20100 Milan, Italy. RP Staurenghi, G (reprint author), Univ Milan, Dept Clin Sci Luigi Sacco, Sacco Hosp, Via GB Grassi 74, I-20100 Milan, Italy. EM giovanni.staurenghi@unimi.it OI Duca, Piergiorgio/0000-0003-4499-8805; Invernizzi, Alessandro/0000-0003-3400-1987 FU Heidelberg Engineering, Heidelberg, Germany; Zeiss Meditec, Dublin, California, USA FX THE AUTHORS INDICATE NO FINANCIAL SUPPORT FOR THIS STUDY. ANDREA GIANI RECEIVED TRAVEL FEES FOR ATTENDING a meeting from Heidelberg Engineering, Heidelberg, Germany. Giovanni Staurenghi received fees for service on an advisory board from Heidelberg Engineering, Heidelberg, Germany, and also received fees for attending a meeting from Zeiss Meditec, Dublin, California, USA. The Massachusetts Eye and Ear Infirmary has an ownership interest in 3 US patents directed to the use of verteporfin. In addition, the Massachusetts Eye and Ear Infirmary has an ownership interest in, certain patent applications directed to the selective destruction of subretinal choroidal neovasculature for the treatment of macular degeneration and other disorders. The Massachusetts Eye and Ear Infirmary receives royalties as a result of these patents and patent applications, and Joan W. Miller receives a share of the same in accordance with the Massachusetts Eye and Ear Infirmary's institutional Patent Policy and Procedures, which includes royalty-sharing provisions. Joan W. Miller is also currently on the Alcon Laboratory Board of Directors and is an ad hoc consultant for Bausch & Lomb and Genentech. Involved in design of the study (A.G., MC., G.S.); conduct of the study (A.G., A.O., M.O., M.P., A.I.); collection and management of the data (A.G., MC.); analysis and interpretation of the data (A.G., MC., P.D.); preparation of the manuscript (A.G., MC., N.C., J.W.M., G.S.); and review and approval of the manuscript (A.G., N.C., J.W.M., G.S.). This study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki and was approved by the Sacco Hospital IRB. At the time of follow-up examination, eligible patients were asked to participate in the study and informed consent for participation in this research was obtained. NR 39 TC 70 Z9 71 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2010 VL 150 IS 6 BP 815 EP 824 DI 10.1016/j.ajo.2010.06.025 PG 10 WC Ophthalmology SC Ophthalmology GA 695KB UT WOS:000285367900008 PM 20965494 ER PT J AU Tanaka, N Huttenhower, C Nosho, K Baba, Y Shima, K Quackenbush, J Haigis, KM Giovannucci, E Fuchs, CS Ogino, S AF Tanaka, Noriko Huttenhower, Curtis Nosho, Katsuhiko Baba, Yoshifumi Shima, Kaori Quackenbush, John Haigis, Kevin M. Giovannucci, Edward Fuchs, Charles S. Ogino, Shuji TI Novel Application of Structural Equation Modeling to Correlation Structure Analysis of CpG Island Methylation in Colorectal Cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LOW CIMP-LOW; DNA METHYLATION; COLON-CANCER; MICROSATELLITE INSTABILITY; BRAF MUTATION; SERRATED POLYPS; FAMILY-HISTORY; PHENOTYPE CIMP; EXPRESSION; KRAS AB The CpG island methylator phenotype (CIMP high CIMP1) is a distinct phenotype associated with micro satellite instability (MSI) and BRAF mutation in colon cancer Recent evidence suggests the presence of KRAS mutation associated CIMP subtype (CIMP low CIMP2) We used cluster analysis principal component analysis (PCA), and structural equation modeling (SEM) a novel strategy to decipher the correlation structure of CpG island hypermethylation Using a database of 861 colon and rectal cancers DNA methylation at 16 CpG islands [CACNA1G CDKN2A (p16/ink4a) CHFR CRABP1 HIC1 IGF2 IGFBP3 MGMT MINT 1, MINT 31 MLH1 NEUROG1 p14 (CDKN2A/arf) RUNX3 SOCS1 and WRN] was quantified by real time PCR Tumors were categorized into three groups Group 1 with wild type KRAS/BRAF (N = 440) Group 2 with mutant KRAS and wild type BRAF (N = 308) and Group 3 with wild type KRAS and mutant BRAF (N = 107) Tumors with mutant KRAS/BRAF (N = 6) were excluded In unsupervised hierarchical clustering analysis all but six markers (CACNA1G IGF2 RUNX3 MGMT MINT 1 and SOCS1) were differentially clustered with CIMP high and CIMP low according to KRAS and BRAF status In SEM the correlation structures between GIMP locus specific CpG island methylation and MSI differed according to KRAS and BRAF status which was consistent with PCA results In conclusion KRAS and BRAF mutations appear to differentially influence correlation structure of CpG island methylation Our novel data suggest two distinct perturbations resulting m differential locus specific propensity of CpG methylation. (Am J Pathol 2010 177 2731-2740 DOI 10 2353/ajpath 2010 100361) C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Ctr Mol Oncol Pathol, Dana Farber Canc Inst,Sch Med,Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tanaka, Noriko; Nosho, Katsuhiko; Baba, Yoshifumi; Shima, Kaori; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Ctr Mol Oncol Pathol, Dana Farber Canc Inst,Sch Med,Dept Med, 44 Binney St,Room JF 215C, Boston, MA 02115 USA. OI Huttenhower, Curtis/0000-0002-1110-0096 FU U S National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, R01 CA151993]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Japan Society for the Promotion of Science; Uehara Memorial Foundation FX Supported by U S National Institutes of Health [P01 CA87969 (S H) P01 CA55075 (W W) P50 CA127003 (C S F) K07 CA122826 (S 0) R01 CA151993 (S O)] the Bennett Family Fund for Targeted Therapies Research and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance K N was supported by a fellowship grant from the Japan Society for the Promotion of Science Y B was supported by a fellowship grant from the Uehara Memorial Foundation NR 67 TC 21 Z9 21 U1 1 U2 3 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 DEC PY 2010 VL 177 IS 6 BP 2731 EP 2740 DI 10.2353/ajpath.2010.100361 PG 10 WC Pathology SC Pathology GA 695KU UT WOS:000285369800009 PM 21037082 ER PT J AU Zhang, ZL Zhong, WW Hinrichs, D Wu, XM Weinberg, A Hall, M Spencer, D Wegmann, K Rosenbaum, JT AF Zhang, Zili Zhong, Wenwei Hinrichs, David Wu, Xiumei Weinberg, Andrew Hall, Mark Spencer, Doran Wegmann, Keith Rosenbaum, James T. TI Activation of OX40 Augments Th17 Cytokine Expression and Antigen-Specific Uveitis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CD4 T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; FACTOR-KAPPA-B; ANTERIOR UVEITIS; CO-STIMULATION; T(H)17 CELLS; IN-VIVO; DIFFERENTIATION; DISEASE; INFLAMMATION AB Uveitis is a major and common cause of visual disability Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder Activated T cells express an inducible costimulatory molecule called OX40 and OX40 in turn promotes the activation and proliferation of these lymphocytes Nevertheless it is unclear whether OX40 plays a vital role m enhancing the effector function of Th17 cells as well as the seventy of uveitis In this study we demonstrated an in crease of OX40 transcription in ovalbumin Induced uveitis whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation Next results from flow cytometry showed that activated Th17 cells expressed OX40 and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro To validate the impact of OX40 in vivo we stimulated ovalbumin specific T cells with the OX40 activating antibody Compared to donor cells without OX40 activation adoptive transfer of OX40 stimulated lymphocytes elicited more severe ocular inflammation Furthermore an interleukin 17 neutralizing antibody attenuated OX40 mediated uveitis In conclusion our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation This study thus enhances our knowledge of costimulatory molecule mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40 (Am J Pathol 2010 177 2912-2920. DOI 10 2353/ajpath 2010 100353) C1 [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA. [Spencer, Doran; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Internal Med & Ophthalmol, Portland, OR 97239 USA. [Hinrichs, David; Wegmann, Keith] Portland VA Med Ctr, Portland, OR USA. [Weinberg, Andrew] Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR USA. RP Rosenbaum, JT (reprint author), Oregon Hlth & Sci Univ, Dept Pediat, 707 Gaines St,Mail Code CDRCP, Portland, OR 97239 USA. FU National Institutes of Health [EY016788, EY013093, EY006484]; CDHNF; Stan and Madelle Rosenfeld Family Trust; William and Mary Bauman Foundation; Research to Prevent Blindness; William C Kuzell Foundation FX Supported by National Institutes of Health grants EY016788 (Z Z) EY013093 (J T R) and EY006484 (J T R) and a CDHNF Young Investigator Award (Z Z) Funds from the Stan and Madelle Rosenfeld Family Trust the William and Mary Bauman Foundation Research to Prevent Blindness and William C Kuzell Foundation also supported this work NR 54 TC 10 Z9 11 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2010 VL 177 IS 6 BP 2912 EP 2920 DI 10.2353/ajpath.2010.100353 PG 9 WC Pathology SC Pathology GA 695KU UT WOS:000285369800025 PM 20952591 ER PT J AU Raheem, O Olufemi, SE Bachinski, LL Vihola, A Sirito, M Hampf, JH Haapasalo, H Li, YP Udd, B Krahe, R AF Raheem, Olayinka Olufemi, Shodimu Emmanuel Bachinski, Linda L. Vihola, Anna Sirito, Mario Hampf, Jeanette Holmlund Haapasalo, Hannu Li, Yi Ping Udd, Bjarne Krahe, Ralf TI Mutant (CCTG)n Expansion Causes Abnormal Expression of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy Type 2 SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ZINC-FINGER PROTEIN; MUSCULAR-DYSTROPHY; BINDING-PROTEIN; REPEAT EXPANSION; TRIPLET REPEAT; DM2 PATIENTS; CTG REPEAT; GENE; MUTATION; TRANSLATION AB The mutation that underlies myotonic dystrophy type 2 (DM2) is a (CCTG)n expansion in intron 1 of zinc finger protein 9 (ZNF9) It has been suggested that ZNF9 is of no consequence for disease pathogenesis We determined the expression levels of ZNF9 during muscle cell differentiation and m DM2 muscle by microarray profiling real tune RT PCR splice variant analysis immunofluorescence and Western blotting Our results show that m differentiating myoblasts, ZNF9 protein was localized primarily to the nucleus whereas m mature muscle fibers it was cytoplasmic and organized in sarcomeric striations at the Z disk In patients with DM2 ZNF9 was abnormally ex pressed First there was an overall reduction m both the mRNA and protein levels Second the subcellular localization of the ZNF9 protein was somewhat less cytoplasmic and more membrane bound Third our splice variant analysis revealed retention of intron 3 m an aberrant isoform and fourth quantitative allele specific expression analysis showed the persistence of intron 1 sequences from the abnormal allele further suggesting that the mutant allele is incompletely spliced Thus the decrease m total expression appears to be due to impaired splicing of the mutant transcript Our data indicate that ZNF9 expression m DM2 patients is altered at multiple levels Although toxic RNA effects likely explain overlapping phenotypic manifestations between DM1 and DM2 abnormal ZNF9 levels in DM2 may account for the differences in DM 1 (Am J Pathol 2010 177 3025-3036 DOI 10 2353/ajpath 2010 100179) C1 [Olufemi, Shodimu Emmanuel; Bachinski, Linda L.; Sirito, Mario; Krahe, Ralf] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. Univ Tampere, Neuromuscular Res Unit, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. [Vihola, Anna; Hampf, Jeanette Holmlund] Univ Helsinki, Folkhalsan Inst Genet, Helsinki, Finland. Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Haapasalo, Hannu] Pirkanmaa Hosp Dist, Ctr Lab Med, Dept Pathol, Tampere, Finland. [Li, Yi Ping] Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Udd, Bjarne] Vaasa Cent Hosp, Dept Neurol, Vaasa, Finland. [Krahe, Ralf] Univ Texas Houston, Grad Sch Biomed Sci, Grad Program Human & Mol Genet, Houston, TX USA. [Krahe, Ralf] Univ Texas Houston, Grad Sch Biomed Sci, Grad Program Genes & Dev, Houston, TX USA. RP Krahe, R (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. FU NIH [R01 AR48171]; Muscular Dystrophy Association USA; Kleberg Foundation; Folkhalsan Research Foundation; Liv&Halsa Foundation; Vasa Central Hospital; Tampere University; German ministry of education and research (BMBF Bonn Germany) FX Supported by grants from NIH (R01 AR48171 to R K) Muscular Dystrophy Association USA and the Kleberg Foundation funding from the Folkhalsan Research Foundation (B U) and grants from the Liv&Halsa Foundation the Vasa Central Hospital District Medical Research funds Tampere University Hospital Medical Research funds; We are grateful to the participating patients for their cooperation The microarray expression profiling study has been accomplished through the active collaboration and sharing of patient samples within the European Neuro muscular Centre consortium on DM2 and Other Myotonic Dystrophies by the following members Josep Gamez Jerry Mendell Guillaume Bassez Bruno Eymard and Tetsuo Ashizawa DM1 patient samples were also provided by Lars Edstrom (Karolinska Institute Stockholm Sweden) We thank Jaana Leppikangas Satu Luhtasela Henna Riikka Koskinen Helena Luque Valerie L Neubauer Tamara J Nixon and Tamer Ahmed for their expert technical assistance and Keith Baggerly for statistical assistance We also thank the Muscle Tissue Culture Collection for providing two of the control myoblast cell lines Muscle Tissue Culture Collection is part of the German network on muscular dystrophies (MD NET service structure Si 01GM0601) funded by the German ministry of education and research (BMBF Bonn Germany) The Muscle Tissue Culture Collection is a partner of EuroBioBank and TREAT NMD NR 36 TC 29 Z9 30 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2010 VL 177 IS 6 BP 3025 EP 3036 DI 10.2353/ajpath.2010.100179 PG 12 WC Pathology SC Pathology GA 695KU UT WOS:000285369800034 PM 20971734 ER PT J AU Qiao, F Atkinson, C Kindy, MS Shunmugavel, A Morgan, BP Song, HB Tomlinson, S AF Qiao, Fei Atkinson, Carl Kindy, Mark S. Shunmugavel, Anandakumar Morgan, B. Paul Song, Hongbin Tomlinson, Stephen TI The Alternative and Terminal Pathways of Complement Mediate Post-Traumatic Spinal Cord Inflammation and Injury SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MEMBRANE ATTACK COMPLEX; ISCHEMIA/REPERFUSION INJURY; ENDOTHELIAL-CELLS; ACTIVATION; MOUSE; MICE; RAT; DEGENERATION; DEFICIENCY; INHIBITOR AB Complement is implicated in the inflammatory response and the secondary neuronal damage that occurs after traumatic spinal cord injury (SCI) Complement can be activated by the classical lectin or alternative pathways all of which share a common terminal pathway that culminates in formation of the cytolytic membrane attack complex (MAC) Here, we investigated the role of the alternative and terminal complement pathways in SCI Mice deficient m the alternative pathway protein factor B (fB) were protected from traumatic SCI in terms of reduced tissue damage and demyelination reduced inflammatory cell infiltrate and improved functional recovery In a clinically relevant paradigm treatment of mice with an anti fB mAb resulted in similarly improved out comes These improvements were associated with de creased C3 and fB deposition On the other hand deficiency of CD59 an inhibitor of the membrane at tack complex resulted in significantly increased injury and unpaired functional recovery compared to wild type mice Increased injury in CD59 deficient mice was associated with increased MAC deposition while levels of C3 and fB were unaffected. These data indicate key roles for the alternative and terminal complement path ways in the pathophysiology of SCI Considering a previous study demonstrating an important role for the classical pathway in promoting SCI it is likely that the alternative pathway plays a critical role in amplifying classical pathway initiated complement activation (Am J Pathol 2010 177 3061-3074 DOI 10 2353/ajpath 2010 100158) C1 [Kindy, Mark S.] Med Univ S Carolina, Dept Microbiol & Immunol Neurosci, Childrens Res Inst, Charleston, SC 29425 USA. [Shunmugavel, Anandakumar] Med Univ S Carolina, Dept Pediat, Childrens Res Inst, Charleston, SC 29425 USA. [Qiao, Fei; Song, Hongbin] Acad Mil Med Sci, Inst Dis Control & Prevent, Beijing, Peoples R China. [Kindy, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Morgan, B. Paul] Cardiff Univ, Dept Med Biochem & Immunol, Cardiff CF4 4XN, S Glam, Wales. RP Tomlinson, S (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Childrens Res Inst, Charleston, SC 29425 USA. RI Song, Hongbin/C-1963-2013 FU Christopher and Dana Reeve Foundation; Veterans Administration; National Institutes of Health (National Institute of Neurological Diseases and Stroke) [NS050452]; Science and Technology Research of China [2008ZXJ09004 050]; 863 Project [2007AA02Z144]; National Natural Science Foundation of China [30801004] FX Supported by a grant from Christopher and Dana Reeve Foundation (S T) the Veterans Administration and National Institutes of Health (National Institute of Neurological Diseases and Stroke NS050452 to M S K) Science and Technology Research of China (2008ZXJ09004 050) 863 Project (2007AA02Z144) and National Natural Science Foundation of China (30801004 to H S) NR 55 TC 19 Z9 21 U1 0 U2 7 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 DEC PY 2010 VL 177 IS 6 BP 3061 EP 3070 DI 10.2353/ajpath.2010.100158 PG 10 WC Pathology SC Pathology GA 695KU UT WOS:000285369800037 PM 20952585 ER PT J AU Iezzoni, LI Rao, SR Kinkel, RP AF Iezzoni, Lisa I. Rao, Sowmya R. Kinkel, R. Philip TI Experiences Acquiring and Using Mobility Aids Among Working-Age Persons with Multiple Sclerosis Living in Communities in the United States SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Multiple Sclerosis; Mobility Aids; Wheelchair; Walker ID ASSISTIVE TECHNOLOGY; DISABILITY; INDIVIDUALS; MSWS-12; MS AB Objective: To examine patterns of mobility aid ownership and use among working-age United States residents with multiple sclerosis. Design: A 30-min telephone survey in mid-2007 with 703 community-dwelling, working-age adults who self-reported having multiple sclerosis; response rate was 73.4%. We identified potential survey respondents using membership lists of the National Multiple Sclerosis Society. All analyses and calculations used sampling weights to produce population estimates. Results: Among working-age persons with multiple sclerosis living in communities nationwide, 60.5% own at least one mobility aid, most commonly manual wheelchairs (38.4%), followed by canes or crutches (35.7%). Despite owning mobility aids, many had not used this equipment in the previous 12 mos, including 4.5% of power wheelchair owners, 13.8% of those with manual wheelchairs, and 9.3% of scooter owners. Among manual wheelchair and scooter users, 25%-30% used this equipment only outside their homes. Many reported needing wheeled mobility aids inside their homes but being unable to move their equipment easily within their homes. Conclusions: Persons with multiple sclerosis own many mobility aids but can confront substantial barriers to their use, especially within homes. Consultations with physiatrists and home evaluations by physical or occupational therapists before purchasing equipment could provide practical suggestions for addressing barriers. C1 [Iezzoni, Lisa I.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Iezzoni, Lisa I.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Kinkel, R. Philip] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Kinkel, R. Philip] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Iezzoni, LI (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Room 901B, Boston, MA 02114 USA. FU National Multiple Sclerosis Society (NMSS) [HC 0079] FX The National Multiple Sclerosis Society (NMSS) supported this research (contract No. HC 0079). NMSS staff provided the database of their membership; however, the investigators conducted and designed the sampling scheme. NMSS staff also commented on early drafts of the questionnaire. Otherwise, the NMSS was not involved in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Nonfinancial interests relating to this work: although Dr. Iezzoni has occasionally spoken and assisted in educational sessions sponsored by NMSS local chapters around the country, she has never accepted payment for any of these activities. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. NR 28 TC 3 Z9 3 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2010 VL 89 IS 12 BP 1010 EP 1023 DI 10.1097/PHM.0b013e3181f70292 PG 14 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 681IZ UT WOS:000284306500007 PM 20881588 ER PT J AU Song, XX Kusakari, Y Xiao, CY Kinsella, SD Rosenberg, MA Scherrer-Crosbie, M Hara, K Rosenzweig, A Matsui, T AF Song, Xiaoxiao Kusakari, Yoichiro Xiao, Chun-Yang Kinsella, Stuart D. Rosenberg, Michael A. Scherrer-Crosbie, Marielle Hara, Kenta Rosenzweig, Anthony Matsui, Takashi TI mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE cardiac hypertrophy; heart failure; inflammation; transgenic mice; mammalian target of rapamycin ID INDUCED VENTRICULAR HYPERTROPHY; HEART-FAILURE; PRESSURE-OVERLOAD; MAMMALIAN TARGET; AKT ACTIVATION; FAILING HEART; UP-REGULATION; EXPRESSION; FIBROSIS; INTERLEUKIN-6 AB Song X, Kusakari Y, Xiao C, Kinsella SD, Rosenberg MA, Scherrer-Crosbie M, Hara K, Rosenzweig A, Matsui T. mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol 299: C1256-C1266, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00338.2010.-Previous studies have suggested that inhibition of the mammalian target of rapamycin (mTOR) by rapamycin suppresses myocardial hypertrophy. However, the role of mTOR in the progression of cardiac dysfunction in pathological hypertrophy has not been fully defined. Interestingly, recent reports indicate that the inflammatory response, which plays an important role in the development of heart failure, is enhanced by rapamycin under certain conditions. Our aim in this study was to determine the influence of mTOR on pathological hypertrophy and to assess whether cardiac mTOR regulates the inflammatory response. We generated transgenic mice with cardiac-specific overexpression of wild-type mTOR (mTOR-Tg). mTOR-Tg mice were protected against cardiac dysfunction following left ventricular pressure overload induced by transverse aortic constriction (TAC) (P < 0.01) and had significantly less interstitial fibrosis compared with littermate controls (WT) at 4 wk post-TAC (P < 0.01). In contrast, TAC caused cardiac dysfunction in WT. At 1 wk post-TAC, the proinflammatory cytokines interleukin (IL)-1 beta and IL-6 were significantly increased in WT mice but not in mTOR-Tg mice. To further characterize the effects of mTOR activation, we exposed HL-1 cardiomyocytes transfected with mTOR to lipopolysaccharide (LPS). mTOR overexpression suppressed LPS-induced secretion of IL-6 (P < 0.001), and the mTOR inhibitors rapamycin and PP242 abolished this inhibitory effect of mTOR. In addition, mTOR overexpression reduced NF-kappa B-regulated transcription in HL-1 cells. These data suggest that mTOR mitigates adverse outcomes of pressure overload and that this cardioprotective effect of mTOR is mediated by regulation of the inflammatory reaction. C1 [Song, Xiaoxiao; Kusakari, Yoichiro; Xiao, Chun-Yang; Kinsella, Stuart D.; Rosenberg, Michael A.; Rosenzweig, Anthony; Matsui, Takashi] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Cardiovasc Inst, Boston, MA 02215 USA. [Song, Xiaoxiao] Zhejiang Univ, Coll Med, Hangzhou 310003, Zhejiang, Peoples R China. [Scherrer-Crosbie, Marielle] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. [Hara, Kenta] Kobe Univ, Kobe, Hyogo 657, Japan. [Matsui, Takashi] Univ Hawaii, Cardiovasc Res Ctr, John A Burns Sch Med, Honolulu, HI 96813 USA. RP Matsui, T (reprint author), Univ Hawaii, Cardiovasc Res Ctr, John A Burns Sch Med, 651 Ilalo St,BSB 311D, Honolulu, HI 96813 USA. EM tmatsui@hawaii.edu FU National Institutes of Health (NIH) [HL-098423, HL-077543]; China Scholarship Council; Leducq Network for Research Excellence FX This work was supported in part by National Institutes of Health (NIH) Grants HL-098423 (to T. Matsui) and HL-077543 (to A. Rosenzweig), a China Scholarship Council grant (to X. Song), a Leducq Network for Research Excellence grant (to A. Rosenzweig), and an NIH Training Grant (to M. A. Rosenberg). NR 59 TC 54 Z9 56 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2010 VL 299 IS 6 BP C1256 EP C1266 DI 10.1152/ajpcell.00338.2010 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 688BC UT WOS:000284822100006 PM 20861467 ER PT J AU Tong, MJ Hernandez, JL Purcell, EK Altschuler, RA Duncan, RK AF Tong, Mingjie Hernandez, Jeannie L. Purcell, Erin K. Altschuler, Richard A. Duncan, R. Keith TI The intrinsic electrophysiological properties of neurons derived from mouse embryonic stem cells overexpressing neurogenin-1 SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE neuronal differentiation; neurogenesis; electrophysiology; basic helix-loop-helix; voltage-gated; ion channel ID ROOT GANGLION NEURONS; SENSORY NEURONS; IN-VITRO; NEURAL STEM; POTASSIUM CHANNELS; PROGENITOR CELLS; FIRING PATTERNS; K+ CURRENT; INNER-EAR; DIFFERENTIATION AB Tong M, Hernandez JL, Purcell EK, Altschuler RA, Duncan RK. The intrinsic electrophysiological properties of neurons derived from mouse embryonic stem cells overexpressing neurogenin-1. Am J Physiol Cell Physiol 299: C1335-C1344, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00207.2010.-A mouse embryonic stem (ES) cell line containing an inducible transgene for the proneural gene Neurog1 has been used to generate glutamatergic neurons at a high efficiency. The present study used in vitro electrophysiology to establish the timeline for acquiring a functional neuronal phenotype in Neurog1-induced cells exhibiting a neuronal morphology. TTX-sensitive action potentials could be evoked from over 80% of the cells after only 4.5 days in vitro (DIV). These cells uniformly showed rapidly adapting responses to current injection, firing one to three action potentials at the onset of the stimulus. In the absence of Neurog1, a limited number of ES cells adopted a neuronal morphology, but these cells displayed slow calcium depolarizations rather than sodium-based spikes. Voltage-gated Na+, K+, and Ca2+ currents were present in nearly all induced cells as early as 4.5 DIV. The voltage-dependent properties of these currents changed little from 4 to 12 DIV with half-activation voltage varying by < 10 mV for any current type throughout the culture period. This study demonstrates that forced expression of proneural genes can induce ES cells to quickly acquire a functional neuronal phenotype with mature electrophysiological properties. Transient overexpression of Neurog1 may be used in neural repair strategies that require the rapid induction of functional neurons from pluripotent stem cells. C1 [Duncan, R. Keith] Univ Michigan, Kresge Hearing Res Inst, Dept Otolaryngol, Ann Arbor, MI 48109 USA. [Tong, Mingjie] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Duncan, RK (reprint author), Univ Michigan, Kresge Hearing Res Inst, Dept Otolaryngol, 1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM rkduncan@umich.edu OI Duncan, Robert/0000-0002-8949-8727 FU National Institutes of Health [T32 DC005356, P30 DC005188] FX This work was supported by grants from the National Institutes of Health (T32 DC005356 and P30 DC005188). NR 48 TC 8 Z9 8 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2010 VL 299 IS 6 BP C1335 EP C1344 DI 10.1152/ajpcell.00207.2010 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 688BC UT WOS:000284822100014 PM 20861468 ER PT J AU Dixon, JA Gaillard, WF Rivers, WT Koval, CN Stroud, RE Mukherjee, R Spinale, FG AF Dixon, Jennifer A. Gaillard, William F., II Rivers, William T. Koval, Christine N. Stroud, Robert E. Mukherjee, Rupak Spinale, Francis G. TI Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE membrane type-I matrix metalloproteinase; matrix metalloproteinases ID TYPE-1 MATRIX-METALLOPROTEINASE; CARDIAC-RESTRICTED OVEREXPRESSION; LEFT-VENTRICULAR FUNCTION; FLUOROGENIC SUBSTRATE; CONVERTING-ENZYME; HEART-FAILURE; ACTIVATION; EXPRESSION; INHIBITION; COLLAGENASE AB Dixon JA, Gaillard WF 2nd, Rivers WT, Koval CN, Stroud RE, Mukherjee R, Spinale FG. Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function. Am J Physiol Heart Circ Physiol 299: H1947-H1958, 2010. First published October 8, 2010; doi:10.1152/ajpheart.00314.2010.-After a myocardial infarction (MI), an episode of ischemia-reperfusion (I/R) can result in a greater impairment of left ventricular (LV) regional function (LVRF) than that caused by an initial I/R episode in the absence of MI. Membrane type-I matrix metalloproteinase (MT1-MMP) proteolytically processes the myocardial matrix and is upregulated in LV failure. This study tested the central hypothesis that a differential induction of MT1-MMP occurs and is related to LVRF after I/R in the context of a previous MI. Pigs with a previous MI [3 wk postligation of the left circumflex artery (LCx)] or no MI were randomized to undergo I/R [60-min/120-min left anterior descending coronary artery (LAD) occlusion] or no I/R as follows: no MI and no I/R (n = 6), no MI and I/R (n = 8), MI and no I/R (n = 8), and MI and I/R (n = 8). Baseline LVRF (regional stroke work, sonomicrometry) was lower in the LAD region in the MI group compared with no MI (103 +/- 12 vs. 188 +/- 26 mmHg.mm, P < 0.05) and remained lower with peak ischemia (35 +/- 8 vs. 88 +/- 17 mmHg.mm, P < 0.05). Using a novel interstitial microdialysis method, MT1-MMP was directly measured and was over threefold higher in the LCx region and over twofold higher in the LAD region in the MI group compared with the no MI group at baseline. MT1-MMP fluorogenic activity was persistently elevated in the LCx region in the MI and I/R group but remained unchanged in the LAD region. In contrast, no changes in MT1-MMP occurred in the LCx region in the no MI and I/R group but increased in the LAD region. MT1-MMP mRNA was increased by over threefold in the MI region in the MI and I/R group. In conclusion, these findings demonstrate that a heterogeneous response in MT1-MMP activity likely contributes to regional dysfunction with I/R and that a subsequent episode of I/R activates a proteolytic cascade within the MI region that may contribute to a continued adverse remodeling process. C1 [Spinale, Francis G.] Med Univ S Carolina, Div Cardiovasc Surg, Strom Thurmond Res Ctr, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Spinale, FG (reprint author), Med Univ S Carolina, Div Cardiovasc Surg, Strom Thurmond Res Ctr, 114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU National Heart, Lung, and Blood Institute [HL-57952, HL-59165, HL-95608, HL-78825]; Veterans Affairs Health Administration FX oThis work was supported by National Heart, Lung, and Blood Institute Grants HL-57952, HL-59165, HL-95608, and HL-78825 and by a Veterans Affairs Health Administration Merit Award. NR 50 TC 8 Z9 8 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2010 VL 299 IS 6 BP H1947 EP H1958 DI 10.1152/ajpheart.00314.2010 PG 12 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 689OC UT WOS:000284936600025 PM 20935147 ER PT J AU Watson, PA Birdsey, N Huggins, GS Svensson, E Heppe, D Knaub, L AF Watson, Peter A. Birdsey, Nicholas Huggins, Gordon S. Svensson, Eric Heppe, Daniel Knaub, Leslie TI Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction in female mice SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE oxidative stress; mitochondria; cyclic nucleotide regulatory element binding-protein; apoptosis ID CONGESTIVE-HEART-FAILURE; QUALITY-OF-LIFE; LEFT-VENTRICULAR DYSFUNCTION; GENDER-DIFFERENCES; CYTOCHROME-C; DILATED CARDIOMYOPATHY; SUPEROXIDE-DISMUTASE; CONTRACTILE FUNCTION; COMPLEX-III; ERR-ALPHA AB Watson PA, Birdsey N, Huggins GS, Svensson E, Heppe D, Knaub L. Cardiac-specific overexpression of dominant-negative CREB leads to increased mortality and mitochondrial dysfunction in female mice. Am J Physiol Heart Circ Physiol 299: H2056-H2068, 2010. First published October 8, 2010; doi: 10.1152/ajpheart.00394.2010.-Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415-2426,1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and estrogen-related receptor-alpha content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and mortality. These results provide further support for the role of the CREB transcription factor in regulating mitochondrial integrity and identify a critical pathway that may contribute to sex differences in heart failure. C1 [Watson, Peter A.; Birdsey, Nicholas; Heppe, Daniel; Knaub, Leslie] Univ Colorado, Hlth Sci Ctr, Sch Med, Denver, CO 80262 USA. [Watson, Peter A.; Birdsey, Nicholas; Knaub, Leslie] Denver Vet Affairs Med Ctr, Denver, CO USA. [Huggins, Gordon S.] Tufts Med Ctr, MCRI Ctr Translat Genom, Mol Cardiol Res Inst, Boston, MA USA. [Svensson, Eric] Univ Chicago, Dept Med, Cardiol Sect, Chicago, IL 60637 USA. RP Watson, PA (reprint author), Univ Colorado Denver, Anschutz Med Campus,Mail Stop 8106,12801 E 17th A, Aurora, CO 80045 USA. EM pete.watson@ucdenver.edu FU Veterans Administration Merit Award FX This work was funded by a Veterans Administration Merit Award (to P. A. Watson). NR 37 TC 11 Z9 11 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2010 VL 299 IS 6 BP H2056 EP H2068 DI 10.1152/ajpheart.00394.2010 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 689OC UT WOS:000284936600036 PM 20935148 ER PT J AU LaFemina, MJ Rokkam, D Chandrasena, A Pan, J Bajaj, A Johnson, M Frank, JA AF LaFemina, Michael J. Rokkam, Deepti Chandrasena, Anita Pan, Jue Bajaj, Anisha Johnson, Meshell Frank, James A. TI Keratinocyte growth factor enhances barrier function without altering claudin expression in primary alveolar epithelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE perijunctional actin; actomyosin ring; acute respiratory distress syndrome; acute lung injury ID INDUCED LUNG INJURY; MESENCHYMAL STEM-CELLS; RESPIRATORY-DISTRESS-SYNDROME; IN-VITRO; II CELLS; CYTOCHALASIN-D; OCCLUDING JUNCTIONS; TIGHT JUNCTIONS; COLI ENDOTOXIN; REPAIR AB LaFemina MJ, Rokkam D, Chandrasena A, Pan J, Bajaj A, Johnson M, Frank JA. Keratinocyte growth factor enhances barrier function without altering claudin expression in primary alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 299: L724-L734, 2010. First published September 10, 2010; doi:10.1152/ajplung.00233.2010.-Keratinocyte growth factor (KGF) has efficacy in several experimental models of lung injury; however, the mechanisms underlying KGF's protective effect remain incompletely understood. This study was undertaken to determine whether KGF augments barrier function in primary rat alveolar epithelial cells grown in culture, specifically whether KGF alters tight junction function via claudin expression. KGF significantly increased alveolar epithelial barrier function in culture as assessed by transepithelial electrical resistance (TER) and paracellular permeability. Fluorescence-activated cell sorting of freshly isolated type 1 (AT1) and type 2 (AT2) cells followed by quantitative real-time RT-PCR revealed that more than 97% of claudin mRNA transcripts in these cells were for claudins-3, -4, and -18. Using cultured AT2 cells, we then examined the effect of KGF on the protein levels of the claudins with the highest mRNA levels: -3, -4, -5, -7, -12, -15, and -18. KGF did not alter the levels of any of the claudins tested, nor of zona occludens-1 (ZO-1) or occludin. Moreover, localization of claudins-3, -4, -18, and ZO-1 was unchanged. KGF did induce a marked increase in the apical perijunctional F-actin ring. Actin depolymerization with cytochalasin D blocked the KGF-mediated increase in TER without significantly changing TER in control cells. Together, these data support a novel mechanism by which KGF enhances alveolar barrier function, modulation of the actin cytoskeleton. In addition, these data demonstrate the complete claudin expression profile for AT1 and AT2 cells and indicate that claudins-3, -4, and -18 are the primary claudins expressed in these cell types. C1 [Frank, James A.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, No Calif Inst Res & Educ, NCIRE VAMC, San Francisco, CA 94121 USA. RP Frank, JA (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, No Calif Inst Res & Educ, NCIRE VAMC, 4150 Clement St,Box 111D, San Francisco, CA 94121 USA. EM james.frank@ucsf.edu FU National Heart, Lung, and Blood Institute [HL-088440] FX This work was supported by National Heart, Lung, and Blood Institute Grant HL-088440. NR 69 TC 31 Z9 33 U1 1 U2 6 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 DEC PY 2010 VL 299 IS 6 BP L724 EP L734 DI 10.1152/ajplung.00233.2010 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 689PW UT WOS:000284941600002 PM 20833776 ER PT J AU Steele, SL Wu, YR Kolb, RJ Gooz, M Haycraft, CJ Keyser, KT Guay-Woodford, L Yao, H Bell, PD AF Steele, Stacy L. Wu, Yongren Kolb, Robert J. Gooz, Monika Haycraft, Courtney J. Keyser, Kent T. Guay-Woodford, Lisa Yao, Hai Bell, P. Darwin TI Telomerase immortalization of principal cells from mouse collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE epithelial; polycystic ID T-ANTIGEN EXPRESSION; REVERSE-TRANSCRIPTASE; HUMAN FIBROBLASTS; EPITHELIAL-CELLS; PROMOTER CONTROL; TRANSGENIC MICE; EARLY REGION; SV40; DIFFERENTIATION; CANCER AB Steele SL, Wu Y, Kolb RJ, Gooz M, Haycraft CJ, Keyser KT, Guay-Woodford L, Yao H, Bell PD. Telomerase immortalization of principal cells from mouse collecting duct. Am J Physiol Renal Physiol 299: F1507-F1514, 2010. First published October 6, 2010; doi: 10.1152/ajprenal.00183.2010.-Recently, the use of overexpression of telomerase reverse transcriptase (TERT) has led to the generation of immortalized human cell lines. However, this cell immortalization approach has not been reported in well-differentiated mouse cells, such as renal epithelial cells. We sought to establish and then characterize a mouse collecting duct cell line, using ectopic expression of mTERT. Isolated primary cortical collecting duct (CCD) cell lines were transduced with mouse (m) TERT, using a lentiviral vector. mTERT-negative cells did not survive blasticidin selection, whereas mTERT-immortalized cells proliferated in selection media for over 40 subpassages. mTERT messenger RNA and telomerase activity was elevated in these cells, compared with an SV40-immortalized cell line. Flow cytometry with Dolichos biflorus agglutinin was used to select the CCD principal cells, and we designated this cell line mTERT-CCD. Cells were well differentiated and exhibited morphological characteristics typically found in renal epithelial cells, such as tight junction formation, microvilli, and primary cilia. Further characterization using standard immunofluorescence revealed abundant expression of aquaporin-2 and the vasopressin type 2 receptor. mTERT-CCD cells exhibited cAMP-stimulated/benzamil-inhibited whole cell currents. Whole cell patch-clamp currents were also enhanced after a 6-day treatment with aldosterone. In conclusion, we have successfully used mTERT to immortalize mouse collecting duct cells that retain the basic in vivo phenotypic characteristics of collecting duct cells. This technique should be valuable in generating cell lines from genetically engineered mouse models. C1 [Steele, Stacy L.; Gooz, Monika; Haycraft, Courtney J.; Bell, P. Darwin] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29403 USA. [Steele, Stacy L.; Gooz, Monika; Haycraft, Courtney J.; Bell, P. Darwin] Med Univ S Carolina, Dept Med, Charleston, SC 29403 USA. [Kolb, Robert J.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29403 USA. [Wu, Yongren; Yao, Hai] Clemson Univ, Clemson MUSC Bioengn, Dept Bioengn, Clemson, SC USA. [Keyser, Kent T.] Univ Alabama Birmingham, Dept Vis Sci, Birmingham, AL USA. [Guay-Woodford, Lisa] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. RP Bell, PD (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, 173 Ashley Ave,210 CRI, Charleston, SC 29403 USA. EM Bellpd@musc.edu FU Veterans Affairs; National Institutes of Health [P30DK074038, R01 DK55534, DK32032, KO1 DK075652]; National Science Foundation [EPS-00903795] FX This project was supported by a Veterans Affairs Merit Grant (P. D. Bell), National Institutes of Health Grants P30DK074038 and R01 DK55534 (L. Guay-Woodford), DK32032 (P. D. Bell), and KO1 DK075652 (R. J. Kolb), and National Science Foundation RII Grant EPS-00903795 (H. Yao). NR 41 TC 5 Z9 5 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2010 VL 299 IS 6 BP F1507 EP F1514 DI 10.1152/ajprenal.00183.2010 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 691MN UT WOS:000285084700031 PM 20926633 ER PT J AU Simon, GE Perlis, RH AF Simon, Gregory E. Perlis, Roy H. TI Personalized Medicine for Depression: Can We Match Patients With Treatments? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID STAR-ASTERISK-D; COGNITIVE-BEHAVIOR THERAPY; SEROTONIN TRANSPORTER POLYMORPHISMS; ANTIDEPRESSANT TREATMENT RESPONSE; RANDOMIZED CONTROLLED-TRIAL; TERM TREATMENT RESPONSE; URINARY MHPG LEVELS; MAJOR DEPRESSION; INTERPERSONAL PSYCHOTHERAPY; GENE POLYMORPHISMS AB Objective: Response to specific depression treatments varies widely among individuals. Understanding and predicting that variation could have great benefits for people living with depression. Method: The authors describe a conceptual model for identifying and evaluating evidence relevant to personalizing treatment for depression. They review evidence related to three specific treatment decisions: choice between antidepressant medication and psychotherapy, selection of a specific antidepressant medication, and selection of a specific psychotherapy. They then discuss potential explanations for negative findings as well as implications for research and clinical practice. Results: Many previous studies have examined general predictors of outcome, but few have examined true moderators (predictors of differential response to alternative treatments). The limited evidence indicates that some specific clinical characteristics may inform the choice between antidepressant medication and psychotherapy and the choice of specific antidepressant medication. Research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the choice between medication and psychotherapy, the selection of specific medication, or the selection of a specific psychotherapy. Conclusions: While individuals vary widely in response to specific depression treatments, the variability remains largely unpredictable. Future research should focus on identifying true moderator effects and should consider how response to treatments varies across episodes. At this time, our inability to match patients with treatments implies that systematic follow-up assessment and adjustment of treatment are more important than initial treatment selection. C1 [Simon, Gregory E.] Grp Hlth Res Inst, Seattle, WA 98101 USA. Massachusetts Gen Hosp, Lab Psychiat Pharmacogenom, Boston, MA 02114 USA. RP Simon, GE (reprint author), Grp Hlth Res Inst, 1730 Minor Ave,1600, Seattle, WA 98101 USA. EM simon.g@ghc.org FU AstraZeneca; Bristol-Myers Squibb; Eli Lilly; Glaxo SmithKline; Proteus Biomedical; Pfizer; Concordant Rater Systems; National Institute of Mental Health [P20MH-068572, R01MH-085930, R01MH-086026] FX Dr. Perlis has served as an advisory board member or received consulting or speaking fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Proteus Biomedical, and Pfizer; he also holds equity and receives royalties from Concordant Rater Systems. Dr. Simon reports no financial relationships with commercial interests.; Supported by National Institute of Mental Health grants P20MH-068572, R01MH-085930, and R01MH-086026. NR 87 TC 102 Z9 103 U1 2 U2 48 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 DEC PY 2010 VL 167 IS 12 BP 1445 EP 1455 DI 10.1176/appi.ajp.2010.09111680 PG 11 WC Psychiatry SC Psychiatry GA 689ON UT WOS:000284937700008 PM 20843873 ER PT J AU Olfson, M Marcus, SC AF Olfson, Mark Marcus, Steven C. TI National Trends in Outpatient Psychotherapy SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; HEALTH PLANS; DEPRESSION; MEDICATIONS; DISORDER; PATTERNS; CARE AB Objective: The authors investigated recent trends in the use of outpatient psychotherapy in the United States. Method: Service use data from two representative surveys of the U.S. general population, the 1998 (N=22,953) and 2007 (N=29,370) Medical Expenditure Panel Surveys, were analyzed, focusing on individuals who made more than one outpatient psychotherapy visit during that calendar year. The authors computed rates of any psychotherapy use; percentages of persons treated for mental health conditions with only psychotherapy, only psychotropic medication, or their combination; the mean number of psychotherapy visits of persons receiving psychotherapy; and psychotherapy expenditures. Results: The percentage of persons using outpatient psychotherapy was 3.37% in 1998 and 3.18% in 2007 (adjusted odds ratio=0.95, 95% CI=0.82-1.09). Among individuals receiving outpatient mental health care, use of only psychotherapy (15.9% and 10.5% in 1998 and 2007, respectively; adjusted odds ratio=0.66, 95% CI=0.48-0.90) as well as psychotherapy and psychotropic medication together (40.0% and 32.1%; adjusted odds ratio= 0.73, 95% CI=0.59-0.90) declined while use of only psychotropic medication increased (44.1% and 57.4%; adjusted odds ratio=1.63, 95% CI=1.32-2.00). Declines occurred in annual psychotherapy visits per psychotherapy patient (mean values, 9.7 and 7.9; adjusted beta=-1.53, p<0.0001), mean expenditure per psychotherapy visit ($122.80 and $94.59; beta=28.21, p<0.0001), and total national psychotherapy expenditures ($10.94 and $7.17 billion; z=2.61, p=0.009). Conclusions: During the decade from 1998 to 2007, the percentage of the general population who used psychotherapy remained stable. Over the same period, however, psychotherapy assumed a less prominent role in outpatient mental health care as a large and increasing proportion of mental health outpatients received psychotropic medication without psychotherapy. C1 [Olfson, Mark] Columbia Univ, Dept Psychiat, New York State Psychiat Inst, Coll Phys & Surg, New York, NY 10032 USA. Univ Penn, Sch Social Practice & Policy, Philadelphia, PA 19104 USA. Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Olfson, M (reprint author), Columbia Univ, Dept Psychiat, New York State Psychiat Inst, Coll Phys & Surg, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@columbia.edu FU Eli Lilly; Bristol-Myers Squibb; McNeil Pharmaceuticals; Agency for Healthcare Research and Quality [U18 HS016097] FX Dr. Olfson has received research grants to Columbia University from Eli Lilly and Bristol-Myers Squibb. Dr. Marcus has received research support from Bristol-Myers Squibb, Eli Lilly, and McNeil Pharmaceuticals.; Supported by grant U18 HS016097 from the Agency for Healthcare Research and Quality. NR 41 TC 101 Z9 101 U1 3 U2 14 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 DEC PY 2010 VL 167 IS 12 BP 1456 EP 1463 DI 10.1176/appi.ajp.2010.10040570 PG 8 WC Psychiatry SC Psychiatry GA 689ON UT WOS:000284937700009 PM 20686187 ER PT J AU Perlis, RH Huang, J Purcell, S Fava, M Rush, AJ Sullivan, PF Hamilton, SP McMahon, FJ Schulze, T Potash, JB Zandi, PP Willour, VL Penninx, BW Boomsma, DI Vogelzangs, N Middeldorp, CM Rietschel, M Nothen, M Cichon, S Gurling, H Bass, N McQuillin, A Hamshere, M Craddock, N Sklar, P Smoller, JW AF Perlis, Roy H. Huang, Jie Purcell, Shaun Fava, Maurizio Rush, A. John Sullivan, Patrick F. Hamilton, Steven P. McMahon, Francis J. Schulze, Thomas Potash, James B. Zandi, Peter P. Willour, Virginia L. Penninx, Brenda W. Boomsma, Dorret I. Vogelzangs, Nicole Middeldorp, Christel M. Rietschel, Marcella Noethen, Markus Cichon, Sven Gurling, Hugh Bass, Nick McQuillin, Andrew Hamshere, Marian Craddock, Nick Sklar, Pamela Smoller, Jordan W. CA Wellcome Trust Case Control Consor TI Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID TREATMENT ENHANCEMENT PROGRAM; BIPOLAR DISORDER; PSYCHIATRIC-DISORDERS; DIAGNOSTIC INTERVIEW; DEPRESSIVE DISORDER; MAJOR DEPRESSION; BINDING-PROTEIN; STEP-BD; GENE; BEHAVIOR AB Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/ Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. C1 Massachusetts Gen Hosp, Dept Psychiat, Depress & Bipolar Clin, Boston, MA 02114 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore. Univ N Carolina, Dept Genet, Chapel Hill, NC USA. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIMH, Genet Basis Mood & Anxiety Disorders Div, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. Vrije Univ Amsterdam, Univ Med Ctr, Dept Psychiat, Amsterdam, Netherlands. Vrije Univ Amsterdam, Univ Med Ctr, Dept Biol Psychol, Amsterdam, Netherlands. Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. Univ Heidelberg, Heidelberg, Germany. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. UCL, Dept Mol Psychiat, Sch Med, London WC1E 6BT, England. Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales. Massachusetts Gen Hosp, Res Programs, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Bipolar Clin, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM rperlis@partners.org RI Gurling, Hugh/A-5029-2010; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; McQuillin, Andrew/C-1623-2008; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; McQuillin, Andrew/0000-0003-1567-2240; Hamilton, Steven/0000-0001-8106-6260; Rush, Augustus/0000-0003-2004-2382; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464; Middeldorp, Christel/0000-0002-6218-0428 FU Eli Lilly; Elan/Eisai; AstraZeneca; Bristol-Myers Squibb; Pfizer; GlaxoSmithKline; Abbott Laboratories; Alkermes; Aspect Medical Systems; Cephalon; Forest Pharmaceuticals; J and J Pharmaceuticals; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis; Organon; Pamlab; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals; Wyeth-Ayerst Laboratories; Bayer AG; Biovail Pharmaceuticals; BrainCells; Compellis; Cypress Pharmaceuticals; Dov Pharmaceuticals; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals; Grunenthal GmbH; Janssen Pharmaceutica; Jazz Pharmaceuticals; Knoll Pharmaceutical; Lundbeck; MedAvante; Neuronetics; Nutrition 21; PharmaStar; Sepracor; Somaxon; Somerset Pharmaceuticals; Boehringer-Ingelheim; Guilford Publications and Healthcare Technology Systems; National Institute of Mental Health [R01MH-086026]; NIMH FX Dr. Perlis has received research support from Eli Lilly and Elan/Eisai; he has received advisory/consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer; he has received speaking fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Pfizer; and he has equity holdings and patents with Concordant Rater Systems. Dr. Fava has received research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, J and J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, and Wyeth-Ayerst Laboratories; he has received advisory/consulting fees from Aspect Medical Systems, AstraZeneca, Bayer AG, Biovail Pharmaceuticals, BrainCells, Bristol-Myers Squibb, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Grunenthal GmbH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J and J Pharmaceuticals, Knoll Pharmaceutical, Lundbeck, MedAvante, Neuronetics, Novartis, Nutrition 21, Organon, Pamlab, Pfizer, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals, Somaxon, Somerset Pharmaceuticals, and Wyeth-Ayerst Laboratories; he has received speaking fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Novartis, Organon, Pfizer, PharmaStar, and Wyeth-Ayerst Laboratories; and he is a share holder with Compellis and MedAvante. Dr. Rush has served as a consultant for AstraZeneca, Bristol-Myers Squibb/Otsuka, Merck, and Otsuka Pharmaceuticals; he has also received royalties from Guilford Publications and Healthcare Technology Systems. Dr. Smoller has served as a consultant to Eli Lilly; he has received honoraria from Hoffman-La Roche, Enterprise Analysis, and MPM Capital; and he has served on an advisory board for Roche Diagnostics Corporation. Dr Sullivan receives unrestricted research funding from Eli Lilly for genetic research in schizophrenia. All other authors report no financial relationships with commercial interests.; Supported by National Institute of Mental Health grant R01MH-086026 (Dr. Perlis). Drs. McMahon and Schulze are supported by the NIMH Intramural Research Program. NR 66 TC 51 Z9 51 U1 2 U2 7 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 DEC PY 2010 VL 167 IS 12 BP 1499 EP 1507 DI 10.1176/appi.ajp.2010.10040541 PG 9 WC Psychiatry SC Psychiatry GA 689ON UT WOS:000284937700014 PM 21041247 ER PT J AU Yeung, A Shyu, I Fisher, L Wu, S Yang, HY Fava, M AF Yeung, Albert Shyu, Irene Fisher, Lauren Wu, Shirley Yang, Huaiyu Fava, Maurizio TI Culturally Sensitive Collaborative Treatment for Depressed Chinese Americans in Primary Care SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MENTAL-HEALTH; MANAGEMENT; TELEPHONE; PREVALENCE; VALIDATION; SERVICES; OUTCOMES; IMPACT AB Objectives We examined the feasibility and effectiveness of using culturally sensitive collaborative treatment (CSCT) to improve recognition engagement and treatment of depressed Chinese Americans in primary care Methods Chinese American patients in a primary care setting (n=4228) were screened for depression The primary study outcome was treatment engagement rate and the secondary outcome was treatment response Results Of the study participants 296 (7%) screened positive for depression 122 (41%) of whom presented for a psychiatric assessment 104 (85%) were confirmed with major depressive disorder and 100 (96%) of these patients were randomized into treatment involving either care management or usual care Patients in the care management and usual care groups did not differ in terms of their outcomes CSCT resulted in a nearly 7 fold increase in treatment rate among depressed patients in primary care Conclusions CSCT is both feasible and effective in improving recognition and treatment engagement of depressed Chinese Americans Care management may have limited effects on depressed patients treated by psychiatrists given that these patients tend to have favorable responses in general (Am J Public Health 2010 100 2397-2402 doi 10 2105/AJPH 2009 184911) C1 [Yeung, Albert; Shyu, Irene; Fisher, Lauren; Wu, Shirley; Yang, Huaiyu; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Yeung, Albert] S Cove Community Hlth Ctr, Boston, MA USA. RP Yeung, A (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 1 Bowdoin Sq 6-F, Boston, MA 02114 USA. FU National Institute of Mental Health [MH67085] FX This project was supported by a grant (MH67085) from the National Institute of Mental Health NR 30 TC 28 Z9 28 U1 2 U2 6 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 DEC PY 2010 VL 100 IS 12 BP 2397 EP 2402 DI 10.2105/AJPH.2009.184911 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 684QB UT WOS:000284563300021 PM 20966373 ER PT J AU Maguen, S Ren, L Bosch, JO Marmar, CR Seal, KH AF Maguen, Shira Ren, Li Bosch, Jeane O. Marmar, Charles R. Seal, Karen H. TI Gender Differences in Mental Health Diagnoses Among Iraq and Afghanistan Veterans Enrolled in Veterans Affairs Health Care SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; GULF-WAR VETERANS; VIETNAM VETERANS; RISK-FACTORS; US MILITARY; SYMPTOMS; WOMEN; PREVALENCE; DEPLOYMENT; COHORT AB Objectives We examined gender differences in sociodemographic military service and mental health characteristics among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans We evaluated associations between these sociodemographic and service characteristics and depression and posttraumatic stress disorder (PTSD) diagnoses Methods In a retrospective cross sectional study we used univariate de scriptive statistics and log binominal regression analyses of Department of Veterans Affairs (VA) administrative data on 329049 OEF and OIF veterans seeking VA health care from April 1 2002 through March 31 2008 Results Female veterans were younger and more likely to be Black and to receive depression diagnoses than were male veterans who were more frequently diagnosed with PTSD and alcohol use disorders Older age was associated with a higher prevalence of PTSD and depression diagnoses among women but not among men Conclusions Consideration of gender differences among OEF and OIF veterans seeking health care at the VA will facilitate more targeted prevention and treatment services for these newly returning veterans (Am J Public Health 2010 100 2450-2456 doi 10 2105/AJPH 2009 166165) C1 [Maguen, Shira] San Francisco VA Med Ctr, PTSD Program, San Francisco, CA 94121 USA. [Maguen, Shira; Marmar, Charles R.; Seal, Karen H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Maguen, S (reprint author), San Francisco VA Med Ctr, PTSD Program, 4150 Clement St,116 P, San Francisco, CA 94121 USA. FU Department of Defense; VA Health Services [W81XWH 08 2 0077, RCD06 042] FX This research was supported by a Department of Defense Concept Award grant and a VA Health Services Research and Development Career Development Award (W81XWH 08 2 0077 RCD06 042) NR 26 TC 94 Z9 94 U1 0 U2 6 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 DEC PY 2010 VL 100 IS 12 BP 2450 EP 2456 DI 10.2105/AJPH.2009.166165 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 684QB UT WOS:000284563300028 PM 20966380 ER PT J AU Knox, KL Pflanz, S Talcott, GW Campise, RL Lavigne, JE Bajorska, A Tu, X Caine, ED AF Knox, Kerry L. Pflanz, Steven Talcott, Gerald W. Campise, Rick L. Lavigne, Jill E. Bajorska, Alina Tu, Xin Caine, Eric D. TI The US Air Force Suicide Prevention Program: Implications for Public Health Policy SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; COMPLETED SUICIDE; RISK; OCCUPATION; VETERANS; PATTERNS; ALCOHOL; LIFE AB Objectives We evaluated the effectiveness of the US Air Force Suicide Prevention Program (AFSPP) in reducing suicide and we measured the extent to which air force installations implemented the program Methods We determined the AFSPP s impact on suicide rates in the air force by applying an intervention regression model to data from 1981 through 2008 providing 16 years of data before the program s 1997 launch and 11 years of data after launch Also we measured implementation of program components at 2 points in time during a 2004 increase in suicide rates and 2 years afterward Results Suicide rates in the air force were significantly lower after the AFSPP was launched than before except during 2004 We also determined that the program was being implemented less rigorously in 2004 Conclusions The AFSPP effectively prevented suicides in the US Air Force The long term effectiveness of this program depends upon extensive implementation and effective monitoring of implementation Suicides can be reduced through a multilayered overlapping approach that encompasses key prevention domains and tracks implementation of program activities (Am J Public Health 2010 100 2457-2463 doi 10 2105/AJPH 2009 159871) C1 [Knox, Kerry L.] US Dept Vet Affairs, Canandaigua VA Med Ctr, VA Ctr Excellence Canandaigua, Canandaigua, NY USA. [Knox, Kerry L.; Lavigne, Jill E.] Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. [Pflanz, Steven] Bolling AFB, Med Operat Squadron 579, Washington, DC USA. [Talcott, Gerald W.] Lackland AFB, Mental Hlth Squadron 59, San Antonio, TX USA. [Campise, Rick L.] Langley AFB, Med Operat Squadron 1, Hampton, VA USA. [Bajorska, Alina] Univ Rochester, Dept Community & Prevent Med, Med Ctr, Rochester, NY 14627 USA. [Tu, Xin] Univ Rochester, Dept Biostat & Computat Biol, Med Ctr, Rochester, NY 14627 USA. [Caine, Eric D.] Univ Rochester, Dept Psychiat, Med Ctr, Rochester, NY 14627 USA. RP Knox, KL (reprint author), US Dept Vet Affairs, Canandaigua VA Med Ctr, VA Ctr Excellence Canandaigua, 400 Ft Hill Ave, Canandaigua, NY USA. FU National Institute of Mental Health [K01 MH055317, R01 MH075017 01A1, P20 MH071897] FX This project was supported by National Institute of Mental Health (grants K01 MH055317 R01 MH075017 01A1 and P20 MH071897) NR 24 TC 29 Z9 32 U1 0 U2 8 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 DEC PY 2010 VL 100 IS 12 BP 2457 EP 2463 DI 10.2105/AJPH.2009.159871 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 684QB UT WOS:000284563300029 PM 20466973 ER PT J AU Morgan, BJ Reichmuth, KJ Peppard, PE Finn, L Barczi, SR Young, T Nieto, FJ AF Morgan, Barbara J. Reichmuth, Kevin J. Peppard, Paul E. Finn, Laurel Barczi, Steven R. Young, Terry Nieto, F. Javier TI Effects of Sleep-disordered Breathing on Cerebrovascular Regulation A Population-based Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sleep apnea syndromes; cerebrovascular circulation; blood flow velocity; hypercapnia; endothelial function ID POSITIVE AIRWAY PRESSURE; INTIMA-MEDIA THICKNESS; ENDOTHELIUM-DEPENDENT VASODILATION; CARBON-DIOXIDE; BLOOD-PRESSURE; APNEA SYNDROME; CARDIOVASCULAR-DISEASE; VENTILATORY RESPONSE; OXIDATIVE STRESS; CAROTID-ARTERY AB Rationale: Cerebrovascular regulation is impaired in patients with moderate to severe obstructive sleep apnea; however, it is unknown whether this impairment exists in individuals with less severe sleep-disordered breathing. Objectives: To test the hypothesis that cerebrovascular responses to hypercapnia are attenuated in a nonclinical population-based cohort. Methods: A rebreathing test that raised end-tidal CO(2) tension by 10mm Hg was performed during wakefulness in 373 participants of the Wisconsin Sleep Cohort. Measurements and Main Results: We measured cerebral flow velocity (transcranial Doppler ultrasound); heart rate (electrocardiogram); blood pressure (photoplethysmograph); ventilation (pneumotachograph); and end-tidal CO(2) (expired gas analysis). Cerebrovascular CO(2) responsiveness was quantified as the slope of the linear relationship between flow velocity and end-tidal CO(2) during rebreathing. Linear regression analysis was performed using cerebrovascular CO(2) responsiveness as the outcome variable. Main independent variables were the apnea-hypopnea index and the mean level of arterial oxygen saturation during sleep. We observed a positive correlation between cerebrovascular CO(2) responsiveness and the mean level of oxygen saturation during sleep that was statistically significant in unadjusted analysis and after adjustment for known confounders and the increase in arterial pressure during rebreathing. Each 5% decrease in Sa(O2) during sleep predicted a decrease in cerebrovascular reactivity of 0.4 +/- 0.2 cm/second/mm Hg P(ET)CO(2). In contrast, the negative correlation between cerebrovascular CO(2) responsiveness and apnea-hypopnea index was statistically significant only in the unadjusted analysis. Conclusions: Hypercapnic vasodilation in the cerebral circulation is blunted in individuals with sleep-disordered breathing. This impairment is correlated with hypoxemia during sleep. C1 [Morgan, Barbara J.] Univ Wisconsin, Dept Orthoped & Rehabil, Madison, WI 53706 USA. [Reichmuth, Kevin J.; Barczi, Steven R.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. [Peppard, Paul E.; Finn, Laurel; Young, Terry; Nieto, F. Javier] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI 53706 USA. Middleton Vet Adm Hosp, Madison, WI USA. RP Morgan, BJ (reprint author), Univ Wisconsin, Dept Orthoped & Rehabil, 1300 Univ Ave,4245 Med Sci Ctr, Madison, WI 53706 USA. EM morgan@ortho.wisc.edu FU National Institutes of Health [R01 HL075035, R01 HL062252, R01 AG14124, T32 HL07654]; National Center for Research Resources, National Institutes of Health [1UL1RR025011]; Office of Research and Development, Clinical Science R&D Service, Department of Veterans Affairs; National Heart, Lung, and Blood Institute; Respironics for statistical consulting FX Supported by National Institutes of Health grants R01 HL075035, R01 HL062252, R01 AG14124, and T32 HL07654 and by 1UL1RR025011 from the Clinical and Translational Science Award Program of the National Center for Research Resources, National Institutes of Health. This work was also supported by the Office of Research and Development, Clinical Science R&D Service, Department of Veterans Affairs.; B.J.M. received $1,001-$5,000 from Respironics in consultancy fees and $50,001-$100,000 from the National Heart, Lung, and Blood Institute in sponsored grants. K.J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.E.P. received more than $100,001 from the National Institutes of Health in sponsored grants as an investigator with salary support on multiple National Institutes of Health awards. L.F. received up to $1,000 from Respironics for statistical consulting. S.R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.J.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 63 TC 20 Z9 22 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 1 PY 2010 VL 182 IS 11 BP 1445 EP 1452 DI 10.1164/rccm.201002-0313OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 690OA UT WOS:000285012900016 PM 20639438 ER PT J AU Shea, BS Brooks, SF Fontaine, BA Chun, J Luster, AD Tager, AM AF Shea, Barry S. Brooks, Sarah F. Fontaine, Benjamin A. Chun, Jerold Luster, Andrew D. Tager, Andrew M. TI Prolonged Exposure to Sphingosine 1-Phosphate Receptor-1 Agonists Exacerbates Vascular Leak, Fibrosis, and Mortality after Lung Injury SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE lung injury; vascular leak; fibrosis; sphingosine 1-phosphate; S1P(1) ID NOVO RENAL-TRANSPLANTATION; INDUCED PULMONARY-FIBROSIS; CIRCULATING MATURE LYMPHOCYTES; RANDOMIZED CONTROLLED-TRIAL; PROTEIN-COUPLED RECEPTOR; ORAL FINGOLIMOD FTY720; PRODUCTION IN-VIVO; GROWTH-FACTOR; MULTIPLE-SCLEROSIS; BARRIER INTEGRITY AB Sphingosine 1-phosphate(S1P) is a key endogenous regulator of the response to lung injury, maintaining endothelial barrier integrity through interaction with one of its receptors, S1P(1). The short-term administration of S1P or S1P(1) receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P(1) agonists bind to and activate S1P(1), several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P(1) after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P(1) agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P(1) agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P-S1P(1) signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P(1) agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P(1) agonists can act as functional antagonists of S1P(1) on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P-S1P(1) pathway may also be an effective therapeutic strategy for fibrotic lung diseases. C1 [Shea, Barry S.; Brooks, Sarah F.; Fontaine, Benjamin A.; Tager, Andrew M.] Harvard Univ, Massachusetts Gen Hosp, Pulm & Crit Care Unit, Ctr Immunol & Inflammatory Dis,Sch Med, Charlestown, MA 02129 USA. [Chun, Jerold] Scripps Res Inst, Dept Mol Biol, Helen L Dorris Inst Neurol & Psychiat Disorders, La Jolla, CA 92037 USA. RP Tager, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Pulm & Crit Care Unit, Ctr Immunol & Inflammatory Dis,Sch Med, 149 13th St,Room 8301, Charlestown, MA 02129 USA. EM amtager@partners.org FU Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis/American Thoracic Society; Nirenberg Center for Advanced Lung Disease; National Institutes of Health [R01-HL095732, T32-HL007874, R01-DA019674, R01-NS048478, R01-DC009505]; American Thoracic Society; Amira Pharmaceuticals; Kasowitz; Benson; Torres; Friedman, LLP; DebioPharm, S.A.; LAM Treatment Alliance; National Heart, Lung and Blood Institute/National Institutes of Health FX This work was supported by a Pulmonary Fibrosis Foundation grant, a Coalition for Pulmonary Fibrosis/American Thoracic Society grant, a Nirenberg Center for Advanced Lung Disease grant, and National Institutes of Health grant R01-HL095732 (A. M. T.), an American Thoracic Society Fellows Career Development Award and National Institutes of Health grant T32-HL007874 (B. S. S.), and National Institutes of Health grants R01-DA019674, NIH R01-NS048478, and NIH R01-DC009505 (J.C.).; J.C. serves on the advisory board for Amira Pharmaceuticals and has received $5,001-$10,000. B. S. S. received sponsored grants from the American Thoracic Society for $10,001-$50,000 and the National Institutes of Health for more than $100,001. A. M. T. serves on an advisory board for Amira Pharmaceuticals and has received $10,001-$50,000, and received lecture fees for less than $1,000. He also received expert witness fees from Kasowitz, Benson, Torres and Friedman, LLP, for $1,001-$5,000, and an industry-sponsored grant from DebioPharm, S.A., for $50,001-$100,000, and has a patent pending for "Lysophosphatidic Acid Receptor Targeting for Lung Disease.'' He has received sponsored research grants from the LAM Treatment Alliance for $5,001-$10,000, the Coalition for Pulmonary Fibrosis/American Thoracic Society and the Pulmonary Fibrosis Foundation, both for $50,001-$100,000, and the National Heart, Lung and Blood Institute/National Institutes of Health and the Nirenberg Center for Advanced Lung Disease, both for more than $100,001. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. NR 80 TC 62 Z9 62 U1 1 U2 3 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 DEC PY 2010 VL 43 IS 6 BP 662 EP 673 DI 10.1165/rcmb.2009-0345OC PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 690OD UT WOS:000285013200005 PM 20081052 ER PT J AU Boland, GWL AF Boland, Giles W. L. TI Adrenal Imaging: Why, When, What, and How? Part 1. Why and When to Image? SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE adenoma; adrenal; characterization; CT; malignancy ID MASS C1 [Boland, Giles W. L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Boland, Giles W. L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Boland, GWL (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White 270, Boston, MA 02114 USA. EM gboland@partners.org NR 3 TC 9 Z9 11 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2010 VL 195 IS 6 BP W377 EP W381 DI 10.2214/AJR.10.4204 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 683IH UT WOS:000284468700001 PM 21098167 ER PT J AU de Leval, L Lim, GSD Waltregny, D Oliva, E AF de Leval, Laurence Lim, Gkeok Stzuan Diana Waltregny, David Oliva, Esther TI Diverse Phenotypic Profile of Uterine Tumors Resembling Ovarian Sex Cord Tumors An Immunohistochemical Study of 12 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE UTROSCT; immunohistochemistry; differentiation; sex cord; epithelial; smooth muscle ID ENDOMETRIAL STROMAL SARCOMA; SMOOTH-MUSCLE DIFFERENTIATION; GRANULOSA-CELL TUMORS; OF-THE-LITERATURE; IMMUNOHISTOCHEMICAL ANALYSIS; MESENCHYMAL TUMORS; ALPHA-INHIBIN; CALRETININ EXPRESSION; MONOCLONAL-ANTIBODY; HUMAN-TISSUES AB Background: Uterine tumors resembling ovarian sex cord tumors (UTROSCTs) are rare neoplasms thought to be of putative endometrial stromal origin and solely composed of sex cord elements. Our study aimed to delineate the immunophenotype of these tumors and to verify whether their morphology reflects true sex cord-like differentiation. Design: Representative paraffin blocks from 12 UTROSCTs were selected after confirmation of the diagnosis. Cords and/or trabeculae were seen in all tumors, whereas tubules, diffuse areas, and a retiform pattern were present in 9, 6, and 2 cases, respectively. Tumors were stained for sex cord (inhibin, calretinin, WT1, and melan-A), epithelial (KL1 and epithelial membrane antigen), and smooth muscle markers (smooth muscle actin, desmin, smooth muscle myosin heavy chain, h-caldesmon, and histone deacetylase-8), CD10, HMB45, S100, and CD117. Intensity and percentage of staining were recorded. Results: Six out of 12 tumors were positive for sex cord markers (inhibin 3 of 12, calretinin 4 of 12, WT1 4 of 12, and melan-A 3 of 11) with 4 tumors coexpressing more than one marker. Half of the UTROSCTs showed positivity for KL1, with 2 tumors coexpressing epithelial membrane antigen. All but one tumor expressed one or more smooth muscle markers, with smooth muscle actin, desmin and histone deacetylase-8 being most commonly expressed. CD10 was positive in 6 of 12 tumors, CD117 in 4 of 12, and S100 in 2 of 11 tumors, whereas HMB45 was negative in 11 tumors tested. Conclusions: UTROSCTs have a diverse immunohistochemical profile often coexpressing sex cord, epithelial, and smooth muscle markers. The expression of smooth muscle markers in these tumors does not imply a smooth muscle origin as endometrial and sex cord stromal tumors are not infrequently positive for these markers. Positivity for sex cord markers supports a true sex cord/steroid phenotype. Although the immunohistochemical profile of these tumors overlaps with that of endometrial stromal tumors with sex cord-like differentiation as well as ovarian sex cord stromal tumors, the origin of UTROSCT remains uncertain. C1 [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [de Leval, Laurence; Waltregny, David] CHU Sart Tilman, Dept Pathol, B-4000 Liege, Belgium. [Lim, Gkeok Stzuan Diana] Natl Univ Healthcare Syst, Dept Pathol, Singapore, Singapore. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM eoliva@partners.org NR 97 TC 12 Z9 12 U1 0 U2 4 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 DEC PY 2010 VL 34 IS 12 BP 1749 EP 1761 DI 10.1097/PAS.0b013e3181f8120c PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 685DN UT WOS:000284607800003 PM 21084963 ER PT J AU Rabito, CA van Tongeren, S Zavorskas, PA Stricker-Krongrad, A Robb, J Haupert, GT AF Rabito, Carlos A. van Tongeren, Susan Zavorskas, Paul A. Stricker-Krongrad, Alain Robb, John Haupert, Garner T., Jr. TI Measurement of glomerular filtration rate in anesthetized and conscious rhesus monkeys (Macaca mulatta) SO AMERICAN JOURNAL OF VETERINARY RESEARCH LA English DT Article ID INJECTION INULIN-CLEARANCE; RENAL PLASMA FLOW; SINGLE-INJECTION; TC-99M DTPA; CREATININE; CHILDREN; DISEASE; GFR AB Objective-To validate a method to assess glomerular filtration rate (GFR) in conscious monkeys via transcutaneous radiation detection after IV injection of technetium Tc 99m pentatate (Tc-99m-DTPA) Animals-4 healthy rhesus monkeys Procedures-On day 1 each monkey was anesthetized lothalamate sodium I 125 (I-125-lothalamate) was administered via continuous rate infusion (0 0037 MBq/min) blood and urine samples were obtained for determination of I-125-lothalamate plasma clearance variables and estimation of GFR One dose of Tc-99m-DTPA (74 MBq/kg IV) was also administered during the I-125-lothalamate plasma clearance test and transcutaneous measurements of technetium 99m-emitted radiation were obtained by use of an ambulatory renal monitor (ARM) applied to a brachium of each monkey Determination of GFR by use of the ARM was repeated on days 8 and 45 in the same monkeys without anesthesia Results-Sensitivity accuracy and precision of the 2 methods were similar By use of the ARM GFR determined by use of the renal rate constant (kappa GFR) was calculated the value obtained on day 1 under anesthesia was similar to values determined via 1251-lothalamate plasma clearance testing on the same day but was 16% to 23% less than that measured on days 8 and 45 in conscious monkeys Conclusions and Clinical Relevance-The ARM method for assessment of GFR was less invasive faster and more convenient than the standard clearance method but yielded comparable results The need to train animals and size restrictions of the device may limit the use of this technique in other nonhuman animals (Am J Vet Res 2010 71 1492-1499) C1 [Rabito, Carlos A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Haupert, Garner T., Jr.] Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. [van Tongeren, Susan] Boehringer Ingelheim Pharmaceut Inc, Dept Toxicol, Ridgefield, CT 06877 USA. [Zavorskas, Paul A.; Stricker-Krongrad, Alain] Charles River Labs, Shrewsbury, MA 01545 USA. [Robb, John] Appropriate Technol Co, Newburyport, MA 01950 USA. RP Rabito, CA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. FU Boehringer Ingelheim FX Dr Rabito holds interest in Cuyo Tech Incorporated Drs Rabito and Haupert receive consulting fees from Boehringer Ingelheim Dr Robb holds Interest in Appropriate Technology Company NR 31 TC 1 Z9 1 U1 0 U2 4 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0002-9645 J9 AM J VET RES JI Am. J. Vet. Res. PD DEC PY 2010 VL 71 IS 12 BP 1492 EP 1499 DI 10.2460/ajvr.71.12.1492 PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 690BD UT WOS:000284974200013 PM 21118002 ER PT J AU Atassi, N Ratai, EM Greenblatt, DJ Pulley, D Zhao, YL Bombardier, J Wallace, S Eckenrode, J Cudkowicz, M Dibernardo, A AF Atassi, Nazem Ratai, Eva-Maria Greenblatt, David J. Pulley, Darlene Zhao, Yanli Bombardier, Jeffery Wallace, Stuart Eckenrode, Joanna Cudkowicz, Merit Dibernardo, Allitia TI A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Creatine; ALS; imaging; pharmacokinetics; biomarkers ID HUNTINGTONS-DISEASE; ALS; TRIAL; THERAPY; RILUZOLE; MUSCLE; BRAIN; MODEL; ONSET; MICE AB Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations. C1 [Atassi, Nazem] Massachusetts Gen Hosp, Neurol Clin Trials Unit, Boston, MA 02129 USA. [Greenblatt, David J.; Zhao, Yanli] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. Tufts Med Ctr, Boston, MA USA. RP Atassi, N (reprint author), Massachusetts Gen Hosp, Neurol Clin Trials Unit, 13th St,Bldg 149,Room 2274, Boston, MA 02129 USA. EM NATASSI@PARTNERS.ORG FU Harvard Center for Neurodegeneration and Repair; ALS Therapy Alliance; MGH Mallinckrodt GCRC through National Institutes of Health FX This study was supported by the Harvard Center for Neurodegeneration and Repair, ALS Therapy Alliance, and MGH Mallinckrodt GCRC program through a National Institutes of Health grant. We thank Avicena Pharmaceuticals for providing the drug. NR 31 TC 16 Z9 17 U1 0 U2 5 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1748-2968 J9 AMYOTROPH LATERAL SC JI Amyotroph. Lateral. Scler. PD DEC PY 2010 VL 11 IS 6 BP 508 EP 513 DI 10.3109/17482961003797130 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 680XH UT WOS:000284270300003 PM 20698808 ER PT J AU Butterly, A Schmidt, U Wiener-Kronish, J AF Butterly, Arielle Schmidt, Ulrich Wiener-Kronish, Jeanine TI Methicillin-resistant Staphylococcus Aureus Colonization, Its Relationship to Nosocomial Infection, and Efficacy of Control Methods SO ANESTHESIOLOGY LA English DT Article ID INTENSIVE-CARE UNITS; SURGICAL SITE INFECTION; NASAL COLONIZATION; DIGESTIVE-TRACT; CARDIAC-SURGERY; SELECTIVE DECONTAMINATION; CEFAZOLIN PROPHYLAXIS; HOSPITAL ADMISSION; HIGH PREVALENCE; RISK-FACTOR C1 [Wiener-Kronish, Jeanine] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Wiener-Kronish, J (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444A, Boston, MA 02114 USA. NR 48 TC 14 Z9 15 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2010 VL 113 IS 6 BP 1453 EP 1459 DI 10.1097/ALN.0b013e3181fcf671 PG 7 WC Anesthesiology SC Anesthesiology GA 687WY UT WOS:000284810200028 PM 21068653 ER PT J AU Boudreaux, ED Moon, S Baumann, BM Camargo, CA O'Hea, E Ziedonis, DM AF Boudreaux, Edwin D. Moon, Simon Baumann, Brigitte M. Camargo, Carlos A., Jr. O'Hea, Erin Ziedonis, Douglas M. TI Intentions to Quit Smoking: Causal Attribution, Perceived Illness Severity, and Event-Related Fear During an Acute Health Event SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Smoking cessation; Causal attribution; Perceived illness severity; Fear; Acute health event; Smoking; Readiness to quit; Stage of change; Affect; Illness severity; Emergency medicine ID EMERGENCY-DEPARTMENT PATIENTS; NICOTINE DEPENDENCE; TEACHABLE MOMENT; CESSATION; CANCER; PERCEPTION; DIAGNOSIS; EMOTIONS; BEHAVIOR; SMOKERS AB Background Experiencing a serious consequence related to one's health behavior may motivate behavior change. Purpose This study sought to examine how causal attribution, perceived illness severity, and fear secondary to an acute health event relate to intentions to quit smoking. Methods Using a cross-sectional survey design, adult emergency department patients who smoked provided demographic data and ratings of nicotine dependence, causal attribution, perceived illness severity, event-related fear, and intentions to quit smoking. Results A linear regression analysis was used to examine the relations between the independent variables and quit intentions. We enrolled 186 participants. After adjusting for nicotine dependence, smoking-related causal attribution and event-related fear were associated with intentions to quit (beta=0.26, p<0.01 and beta=0.21, p<0.01, respectively). Perceived illness severity was correlated with event-related fear (r=0.46, p<0.001) but was not associated with intentions to quit (beta=-0.08, p=0.32). Conclusion While causal attribution and event-related fear were modestly associated with quit intentions, perceived illness severity was not. Longitudinal studies are needed to better explicate the relation between these variables and behavior change milestones. C1 [Boudreaux, Edwin D.] Univ Massachusetts, Dept Emergency Med, Sch Med, Worcester, MA 01655 USA. [Boudreaux, Edwin D.; Ziedonis, Douglas M.] Univ Massachusetts, Dept Psychiat, Sch Med, Worcester, MA 01655 USA. [Moon, Simon] LaSalle Univ, Dept Psychol, Philadelphia, PA USA. [Baumann, Brigitte M.] UMDNJ Robert Wood Johnson Med Sch, Dept Emergency Med, Camden, NJ USA. [Baumann, Brigitte M.] Cooper Univ Hosp, Camden, NJ USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [O'Hea, Erin] Stonehill Coll, Dept Psychol, Easton, MA USA. RP Boudreaux, ED (reprint author), Univ Massachusetts, Dept Emergency Med, Sch Med, 55 Lakeshore Ave, Worcester, MA 01655 USA. EM Edwin.boudreaux@umassmed.edu OI Boudreaux, Edwin/0000-0002-3223-6371 FU NIDA NIH HHS [K23 DA016698, K23 DA16698] NR 26 TC 9 Z9 10 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2010 VL 40 IS 3 BP 350 EP 355 DI 10.1007/s12160-010-9227-z PG 6 WC Psychology, Multidisciplinary SC Psychology GA 717JZ UT WOS:000287041100012 PM 20827518 ER PT J AU Helland, LC Westfall, JM Camargo, CA Rogers, J Ginde, AA AF Helland, Luke C. Westfall, John M. Camargo, Carlos A., Jr. Rogers, John Ginde, Adit A. TI Motivations and Barriers for Recruitment of New Emergency Medicine Residency Graduates to Rural Emergency Departments SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID PHYSICIANS AB Study objective: We sought to understand the motivations and barriers for recruitment of new emergency medicine residency graduates to rural emergency departments (EDs). Methods: We used the American Medical Association Physician Masterfile to identify 2006 to 2008 emergency medicine residency graduates and then surveyed everyone currently practicing in rural EDs and a random sample of those practicing in urban EDs. We asked these emergency physicians about the importance of various factors in their choice of practice location. Results: We received responses from 197 (67%) of 296 eligible emergency physicians in 47 states. The factors most often rated as "somewhat" or "very" important in choice of practice location were lifestyle (98%), access to amenities/recreation (95%), ED volume/acuity (93%), and family/spouse (90%). Access to specialists was the biggest difference between groups (very important=20% for rural versus 44% for urban; Delta 24%; 95% confidence interval -37% to -11%). More rural emergency physicians spent their entire childhood in rural areas than urban emergency physicians. The changes that would have most influenced urban emergency physicians to practice in rural communities were family/spouse connection (92%), higher salary/signing bonus (90%), and increased access to specialists (90%). Of urban emergency physicians who did not participate in a rural rotation during residency, 44% said they would have, if it had been available. Conclusion: Promising strategies for recruiting new emergency medicine residency graduates to rural EDs are emergency medicine residency selection of individuals with a rural upbringing and higher salaries. Increasing the availability of rural rotations during emergency medicine residency also may help to motivate and prepare some new graduates to practice in rural EDs. [Ann Emerg Med. 2010;56:668-673.] C1 [Helland, Luke C.; Ginde, Adit A.] Univ Colorado, Dept Emergency Med, Sch Med, Aurora, CO 80045 USA. [Westfall, John M.] Univ Colorado, Dept Family Med, Sch Med, Aurora, CO 80045 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Rogers, John] Monroe Cty Hosp, Forsyth, GA USA. RP Ginde, AA (reprint author), Univ Colorado, Dept Emergency Med, Denver Sch Med, 12401 E 17th Ave,B-215, Aurora, CO 80045 USA. EM adit.ginde@ucdenver.edu RI Siry, Bonnie/D-7189-2017 FU Emergency Medicine Foundation/Society for Academic Emergency Medicine FX By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. This study was funded by the Emergency Medicine Foundation/Society for Academic Emergency Medicine Medical Student Research Grant. NR 10 TC 6 Z9 6 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2010 VL 56 IS 6 BP 668 EP 673 DI 10.1016/j.annemergmed.2010.06.561 PG 6 WC Emergency Medicine SC Emergency Medicine GA 692AY UT WOS:000285125100015 PM 20875691 ER PT J AU Biffi, A Sonni, A Anderson, CD Kissela, B Jagiella, JM Schmidt, H Jimenez-Conde, J Hansen, BM Fernandez-Cadenas, I Cortellini, L Ayres, A Schwab, K Juchniewicz, K Urbanik, A Rost, NS Viswanathan, A Seifert-Held, T Stoegerer, EM Tomas, M Rabionet, R Estivill, X Brown, DL Silliman, SL Selim, M Worrall, BB Meschia, JF Montaner, J Lindgren, A Roquer, J Schmidt, R Greenberg, SM Slowik, A Broderick, JP Woo, D Rosand, J AF Biffi, Alessandro Sonni, Akshata Anderson, Christopher D. Kissela, Brett Jagiella, Jeremiasz M. Schmidt, Helena Jimenez-Conde, Jordi Hansen, Bjorn M. Fernandez-Cadenas, Israel Cortellini, Lynelle Ayres, Alison Schwab, Kristin Juchniewicz, Karol Urbanik, Andrzej Rost, Natalia S. Viswanathan, Anand Seifert-Held, Thomas Stoegerer, Eva-Maria Tomas, Marta Rabionet, Raquel Estivill, Xavier Brown, Devin L. Silliman, Scott L. Selim, Magdy Worrall, Bradford B. Meschia, James F. Montaner, Joan Lindgren, Arne Roquer, Jaume Schmidt, Reinhold Greenberg, Steven M. Slowik, Agnieszka Broderick, Joseph P. Woo, Daniel Rosand, Jonathan CA Int Stroke Genetics Consortium TI Variants at APOE Influence Risk of Deep and Lobar Intracerebral Hemorrhage SO ANNALS OF NEUROLOGY LA English DT Article ID APOLIPOPROTEIN-E GENOTYPE; CEREBRAL AMYLOID ANGIOPATHY; ALZHEIMERS-DISEASE; E POLYMORPHISM; E EPSILON-4; POPULATION; MICE; ASSOCIATION; STROKE; E3 AB Objective: Prior studies investigating the association between APOE alleles epsilon 2/epsilon 4 and risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes, and did not account for confounding by population stratification or determine which genetic risk model was best applied. Methods: We performed a large-scale genetic association study of 2189 ICH cases and 4041 controls from 7 cohorts, which were analyzed using additive models for epsilon 2 and epsilon 4. Results were subsequently meta-analyzed using a random effects model. A proportion of the individuals (322 cases, 357 controls) had available genome-wide data to adjust for population stratification. Results: Alleles epsilon 2 and epsilon 4 were associated with lobar ICH at genome-wide significance levels (odds ratio [OR] = 1.82, 95% confidence interval [CI] = 1.50-2.23, p = 6.6 x 10(-10); and OR = 2.20, 95%CI = 1.85-2.63, p = 2.4 x 10(-11), respectively). Restriction of analysis to definite/probable cerebral amyloid angiopathy ICH uncovered a stronger effect. Allele epsilon 4 was also associated with increased risk for deep ICH (OR = 1.21, 95% CI = 1.08-1.36, p = 2.6 x 10(-4)). Risk prediction evaluation identified the additive model as best for describing the effect of APOE genotypes. Interpretation: APOE epsilon 2 and epsilon 4 are independent risk factors for lobar ICH, consistent with their known associations with amyloid biology. In addition, we present preliminary findings on a novel association between APOE epsilon 4 and deep ICH. Finally, we demonstrate that an additive model for these APOE variants is superior to other forms of genetic risk modeling previously applied. ANN NEUROL 2010;68:934-943 C1 [Biffi, Alessandro; Sonni, Akshata; Anderson, Christopher D.; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Biffi, Alessandro; Sonni, Akshata; Anderson, Christopher D.; Cortellini, Lynelle; Ayres, Alison; Schwab, Kristin; Rost, Natalia S.; Viswanathan, Anand; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Biffi, Alessandro; Sonni, Akshata; Anderson, Christopher D.; Cortellini, Lynelle; Rost, Natalia S.; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Kissela, Brett; Broderick, Joseph P.; Woo, Daniel] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Jagiella, Jeremiasz M.; Juchniewicz, Karol; Urbanik, Andrzej; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Schmidt, Helena] Med Univ Graz, Inst Mol Biol & Med Biochem, Graz, Austria. [Jimenez-Conde, Jordi; Roquer, Jaume] Univ Autonoma Barcelona, Hosp del Mar, Inst Municipal Invest Med, Neurovasc Res Unit,Dept Neurol, E-08193 Barcelona, Spain. [Jimenez-Conde, Jordi; Roquer, Jaume] Univ Autonoma Barcelona, Hosp del Mar, Inst Municipal Invest Med, Program Inflammat & Cardiovasc Disorders, E-08193 Barcelona, Spain. [Hansen, Bjorn M.; Lindgren, Arne] Lund Univ, Dept Clin Sci Lund Neurol, Lund, Sweden. [Hansen, Bjorn M.; Lindgren, Arne] Skane Univ Hosp, Dept Neurol, Lund, Sweden. [Fernandez-Cadenas, Israel; Montaner, Joan] Univ Autonoma Barcelona, Hosp Vall dHebron, Inst Recerca, Neurovasc Res Lab, E-08193 Barcelona, Spain. [Fernandez-Cadenas, Israel; Montaner, Joan] Univ Autonoma Barcelona, Hosp Vall dHebron, Inst Recerca, Neurovasc Unit, E-08193 Barcelona, Spain. [Seifert-Held, Thomas; Stoegerer, Eva-Maria; Schmidt, Reinhold] Med Univ Graz, Dept Neurol, Graz, Austria. [Tomas, Marta; Rabionet, Raquel; Estivill, Xavier] CIBERESP, Natl Genotyping Ctr CeGen, CRG, Genes & Dis Program, Barcelona, Spain. [Tomas, Marta; Rabionet, Raquel; Estivill, Xavier] UPF, Barcelona, Spain. [Brown, Devin L.] Univ Michigan Hlth Syst, Dept Neurol, Stroke Program, Ann Arbor, MI USA. [Silliman, Scott L.] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL USA. [Selim, Magdy] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. [Worrall, Bradford B.] Univ Virginia Hlth Syst, Dept Neurol & Publ Hlth Sci, Charlottesville, VA USA. [Meschia, James F.] Mayo Clin Jacksonville, Dept Neurol, Jacksonville, FL 32224 USA. RP Rosand, J (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN-6818, Boston, MA 02114 USA. EM jrosand@partners.org RI IBIS, NEUROVASCULAR/O-1855-2015; Roquer, Jaume/D-9483-2011; Estivill, Xavier/E-2957-2012; rabionet, raquel/C-8379-2009; rabionet, raquel/A-7407-2009; Estivill, Xavier/A-3125-2013; JIMENEZ-CONDE, JORDI/C-1941-2012; Montaner, Joan/D-3063-2015 OI Kissela, Brett/0000-0002-9773-4013; Hansen, Bjorn/0000-0001-8661-9063; Brown, Devin/0000-0002-9815-3421; Ayres, Alison/0000-0002-5492-1695; Anderson, Christopher/0000-0002-0053-2002; rabionet, raquel/0000-0001-5006-8140; rabionet, raquel/0000-0001-5006-8140; Estivill, Xavier/0000-0002-0723-2256; FU NIH-NINDS [K23NS042695, R01NS059727, 5R01NS042147, NS36695, NS30678]; Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; University of Michigan General Clinical Research Center [M01 RR000042]; National Center for Research Resources; American Heart Association/Bugher Foundation Centers for Stroke Prevention Research [0775010N]; Greater Cincinnati Foundation; Ministerio de Sanidad y Consumo de Espana, Instituto de Salud Carlos III [PI051737, CM06100067]; Spanish Research Networks "Red HERACLES" [RD06/0009]; Polish Ministry of Education [N N402 083934]; Lund University; Region Skane; Swedish Medical Research Council [K2007-61X-20378-01-3]; Government of Spain [PJ060586]; [EC08/00137] FX This research was supported by grants from NIH-NINDS ((K23NS042695, R01NS059727, 5R01NS042147) J.R., S.M.G.); Deane Institute for Integrative Research in Atrial Fibrillation and Stroke (J.R.); University of Michigan General Clinical Research Center (M01 RR000042, D.L.B); National Center for Research Resources (J.R.); American Heart Association/Bugher Foundation Centers for Stroke Prevention Research (0775010N to A.B. and C.D.A.); NIH-NINDS ((NS36695 Genetic and Environmental Risk Factors for Hemorrhagic Stroke; NS30678 Hemorrhagic and Ischemic Stroke among Blacks and Whites) D.W); Greater Cincinnati Foundation Grant (Cincinnati Control Cohort, D.W.); Ministerio de Sanidad y Consumo de Espana, Instituto de Salud Carlos III ((PI051737 "Registro BASICMAR" Funding for Research in Health; CM06100067 Contract for Research Training for Professionals with Specialty) J.R.J.J.C.); Spanish Research Networks "Red HERACLES" (RD06/0009, J.R.); Polish Ministry of Education (N N402 083934, A.S.); Lund University; Region Skane; Swedish Medical Research Council (K2007-61X-20378-01-3, A.L.); Government of Spain (PJ060586 Geno-tPA project-FIS; EC08/00137 GRECAS project, J.M.). NR 36 TC 98 Z9 98 U1 2 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2010 VL 68 IS 6 BP 934 EP 943 DI 10.1002/ana.22134 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 703DE UT WOS:000285953500021 PM 21061402 ER PT J AU Weintraub, D Sohr, M Potenza, MN Siderowf, AD Stacy, M Voon, V Whetteckey, J Wunderlich, GR Lang, AE AF Weintraub, Daniel Sohr, Mandy Potenza, Marc N. Siderowf, Andrew D. Stacy, Mark Voon, Valerie Whetteckey, Jacqueline Wunderlich, Glen R. Lang, Anthony E. TI Amantadine Use Associated with Impulse Control Disorders in Parkinson Disease in Cross-Sectional Study SO ANNALS OF NEUROLOGY LA English DT Article ID DYSREGULATION AB A recent controlled clinical vial suggested a role for amantadine as a treatment for pathological gambling in patients with Parkinson disease (PD). Analyzing data from a large cross-sectional study of impulse control disorders (ICDs) in PD, amantadine use (n = 728), vs no amantadine use (n = 2,357), was positively associated with a diagnosis of any ICD (17.6% vs 12.4%, p < 0.001) and compulsive gambling specifically (7.4% vs 4.2%, p < 0.001). This amantadine association remained after controlling for covariates of amantadine use, including both dopamine. agonist use and levodopa dosage. Further research, including larger clinical trials, is needed to assess the role of amantadine in the development and treatment of ICDs in PD. ANN NEUROL 2010;68:963-968 C1 [Weintraub, Daniel] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, Daniel; Siderowf, Andrew D.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Sohr, Mandy] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Child Study, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Stacy, Mark] Duke Univ, Med Ctr, Dept Neurol, Durham, NC USA. [Voon, Valerie] Univ Cambridge, Cambridge, England. [Whetteckey, Jacqueline] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. [Wunderlich, Glen R.] Boehringer Ingelheim Canada Ltd, Burlington, ON, Canada. [Lang, Anthony E.] Univ Toronto, Dept Neurol, Toronto, ON, Canada. RP Weintraub, D (reprint author), 3615 Chestnut St,330, Philadelphia, PA 19104 USA. EM daniel.weintraub@uphs.upenn.edu FU Boehringer Ingelheim; Brain Cells; EMD Serono; Novartis; Cvation; Wyeth; Somaxon; Mohegan Sun Casino; National Center for Responsible Gaming; Forest Laboratories pharmaceuticals; Osmotica; Biogen; General Electric; Kyowa; Neurologix; Synosia; Teva; Ceregene; Eisai; Medtronic; Prestwick; Merck Serono; Solvay; Taro FX This study was funded by Boehringer Ingelheim.; Dr. Weintraub has received consulting fees or honoraria or grant support from Boehringer Ingelheim, Brain Cells, EMD Serono, Novartis, Cvation, and Wyeth. Dr. Potenza has received consulting fees or honoraria from Boehringer Ingelheim, has consulted for and has financial interests in Somaxon, has received research support from Mohegan Sun Casino, the National Center for Responsible Gaming and its affiliated institute for Research on Gambling Disorders, and Forest Laboratories pharmaceuticals, and has consulted for law offices and the federal public defender's office in issues related to impulse control disorders. Dr. Siderowf has received consulting fees or honoraria from Boehringer Ingelheim, Merck Serono, and Teva. Dr. Stacy has received consulting fees or honoraria from Allergan, Boehringer Ingelheim, Osmotica, Biogen, General Electric, Kyowa, Neurologix, Novartis, Synosia, and Teva. Dr. Lang has received consulting fees or honoraria from Boehringer Ingelheim, Ceregene, Eisai, Medtronic, Novartis, Prestwick, Merck Serono, Solvay, Taro, and Teva. NR 20 TC 60 Z9 61 U1 0 U2 1 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 DEC PY 2010 VL 68 IS 6 BP 963 EP 968 DI 10.1002/ana.22164 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 703DE UT WOS:000285953500026 PM 21154480 ER PT J AU Mayer, EL Dhakil, S Patel, T Sundaram, S Fabian, C Kozloff, M Qamar, R Volterra, F Parmar, H Samant, M Burstein, HJ AF Mayer, E. L. Dhakil, S. Patel, T. Sundaram, S. Fabian, C. Kozloff, M. Qamar, R. Volterra, F. Parmar, H. Samant, M. Burstein, H. J. TI SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer SO ANNALS OF ONCOLOGY LA English DT Article DE antiangiogenesis; bevacizumab; breast cancer; combination biologics; sunitinib; VEGF ID COMBINATION TARGETED THERAPY; ENDOTHELIAL GROWTH-FACTOR; ANTITUMOR-ACTIVITY; PLUS BEVACIZUMAB; PHASE-I; TRIAL; MALATE AB Methods: Patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. Results: Forty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade >= 3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. Conclusion: Adding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents. C1 [Mayer, E. L.; Burstein, H. J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dhakil, S.] Canc Ctr Kansas, Dept Oncol & Internal Med, Wichita, KS USA. [Patel, T.] Mark H Zangmeister Ctr, Dept Oncol & Internal Med, Columbus, OH USA. [Sundaram, S.] Sharp Healthcare, San Diego, CA USA. [Fabian, C.] Univ Kansas, Med Ctr, Dept Internal Med, Kansas City, KS 66103 USA. [Kozloff, M.] Ingalls Mem Hosp, Dept Oncol, Harvey, IL USA. [Qamar, R.] Oncol Alliance, Glendale, WI USA. [Volterra, F.] Eastchester Canc Care, Dept Med Oncol, Bronx, NY USA. [Parmar, H.] Genentech Inc, Dept Avastin BioOncol, San Francisco, CA 94080 USA. [Samant, M.] Genentech Inc, Dept Biostat, San Francisco, CA 94080 USA. RP Mayer, EL (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM emayer@partners.org RI qamar, raheel/D-4543-2012 FU Genentech, Inc., South San Francisco, CA FX The work was supported by Genentech, Inc., South San Francisco, CA. NR 22 TC 31 Z9 31 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2010 VL 21 IS 12 BP 2370 EP 2376 DI 10.1093/annonc/mdq260 PG 7 WC Oncology SC Oncology GA 685OA UT WOS:000284636800010 PM 20497961 ER PT J AU Stankovic, KM Hennessey, AM Herrmann, B Mankarious, LA AF Stankovic, Konstantina M. Hennessey, Ann Marie Herrmann, Barbara Mankarious, Leila A. TI Cochlear Implantation in Children With Congenital X-Linked Deafness Due to Novel Mutations in POU3F4 Gene SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE cochlear implantation; congenital X-linked deafness; DFN3; POU3F4 ID SENSORINEURAL HEARING-LOSS; MIXED DEAFNESS; MISSENSE MUTATION; TYPE-3 DFN3; INNER-EAR; IDENTIFICATION; PHENOTYPE; DELETION; BRAIN-4; FAMILY AB Objectives: We report novel mutations in the POU3F4 gene resulting in congenital X-linked deafness DFN3, and describe the results of cochlear implantation in 4 boys (3 siblings) followed for an average of 3.5 years. Methods: The diagnosis of DFN3 was made in infant boys on the basis of the radiologic criteria of an underdeveloped modiolus, a wide cochlear fossette, and the presence of all cochlear turns. The POU3F4 gene was sequenced. A standard, transmastoid, facial recess approach was used for cochlear implantation. A lumbar drain was placed before the operation. Results: The identified mutations in the POU3F4 gene were novel (p.R167X in the 3 siblings) or recently reported (p.S310del). A high-flow cerebrospinal fluid leak through the cochleostomy was encountered in each patient and was ultimately controlled. Although the implants functioned properly, the auditory perceptual abilities did not progress past sound detection in the 3 siblings, or past closed-set word identification in the non-sibling, who achieved better speech perception with contralateral amplification. Three boys (2 siblings) show signs of other learning disorders; 1 boy was too young for a complete assessment. Conclusions: Preoperative gene mutation analysis in DFN3 patients who are considering cochlear implantation may help in long-term counseling and in avoidance of postoperative complications. Limited auditory perception and language acquisition may result. Amplification may sometimes be a better alternative than cochlear implantation, despite the severity of the hearing loss. C1 [Stankovic, Konstantina M.; Mankarious, Leila A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Hennessey, Ann Marie; Herrmann, Barbara] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Stankovic, Konstantina M.; Herrmann, Barbara; Mankarious, Leila A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Mankarious, LA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 28 TC 15 Z9 17 U1 0 U2 3 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD DEC PY 2010 VL 119 IS 12 BP 815 EP 822 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA 697CY UT WOS:000285491400005 PM 21250553 ER PT J AU Oates, E Dzintars, K AF Oates, Elizabeth Dzintars, Kathryn TI Interaction Between Enfuvirtide, an Injectable Fusion Inhibitor, and Niacin in an HIV-Infected Patient SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE AIDS; enfuvirtide; HIV; interaction; niacin ID EPIDERMAL LANGERHANS CELLS; NICOTINIC-ACID; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR-DISEASE; PROSTAGLANDIN D-2; RISK-FACTORS; ASSOCIATION; IMPACT AB OBJECTIVE: To report a potential drug-drug interaction between enfuvirtide, an injectable HIV fusion inhibitor, and niacin in an HIV-infected man with dilated cardiomyopathy. CASE SUMMARY: A 47-year-old HIV-infected man with dilated cardiomyopathy and prolonged QT syndrome with an automatic implantable cardiovascular defibrillator device was prescribed subcutaneous enfuvirtide 90 mg twice daily as part of his antiretroviral regimen and oral extended-release niacin 500 mg/day for a high-density lipoprotein level of 8 mg/dL. After 1 week of concomitant therapy, the patient began experiencing extreme redness, edema, and swelling at the injection site that corresponded with the flushing sensation due to niacin. This interfered with his daily activities, leading to self-discontinuation of both agents. As the patient had tolerated enfuvirtide therapy prior to the addition of niacin, we reinitiated enfuvirtide with close follow-up, and the patient has been maintained on this agent since then without consequence. Based on the Horn Drug Interaction Probability Scale, a probable interaction occurred between enfurvirtide and niacin. DISCUSSION: We hypothesize that a drug-drug interaction occurs between enfuvirtide and niacin related to prostaglandin synthesis and mobilization of inflammatory cells, specifically Langerhans cells. A theoretical mechanism for this interaction is that the Langerhans cells in the epidermis function improperly due to the presence of HIV and the attachment of enfuvirtide. When these cells are exposed to nicotinic acid, an exaggerated immune response is produced that may lead to pain, redness, and swelling at the injection site. Prostaglandins, cytokines, and other inflammatory molecules may all have a role in this interaction. CONCLUSIONS: Caution should be used when coadministering enfuvirtide and niacin to HIV-infected patients. C1 [Dzintars, Kathryn] S Texas Vet Healthcare Syst, Immunosuppress & Infect Dis Clin, San Antonio, TX USA. [Oates, Elizabeth] Univ Texas Hlth Sci Ctr San Antonio, Univ Texas, Coll Pharm, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. RP Dzintars, K (reprint author), Avera McKennan Hosp, Sioux Falls, SD USA. EM Kathryn.Dzintars@avera.org NR 19 TC 2 Z9 3 U1 0 U2 1 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD DEC PY 2010 VL 44 IS 12 BP 2014 EP 2017 DI 10.1345/aph.1P346 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 701ES UT WOS:000285797700019 PM 21045170 ER PT J AU Faries, MB Thompson, JF Cochran, A Elashoff, R Glass, EC Mozzillo, N Nieweg, OE Roses, DF Hoekstra, HJ Karakousis, CP Reintgen, DS Coventry, BJ Wang, HJ Morton, DL AF Faries, Mark B. Thompson, John F. Cochran, Alistair Elashoff, Robert Glass, Edwin C. Mozzillo, Nicola Nieweg, Omgo E. Roses, Daniel F. Hoekstra, Harold J. Karakousis, Constantine P. Reintgen, Douglas S. Coventry, Brendon J. Wang, He-Jing Morton, Donald L. CA MSLT Cooperative Grp TI The Impact on Morbidity and Length of Stay of Early Versus Delayed Complete Lymphadenectomy in Melanoma: Results of the Multicenter Selective Lymphadenectomy Trial (I) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; DISSECTION; AXILLARY AB Complete lymph node dissection, the current standard treatment for nodal metastasis in melanoma, carries the risk of significant morbidity. Clinically apparent nodal tumor is likely to impact both preoperative lymphatic function and extent of soft tissue dissection required to clear the basin. We hypothesized that early dissection would be associated with less morbidity than delayed dissection at the time of clinical recurrence. The Multicenter Selective Lymphadenectomy Trial I randomized patients to wide excision of a primary melanoma with or without sentinel lymph node biopsy. Immediate completion lymph node dissection (early CLND) was performed when indicated in the SLN arm, while therapeutic dissection (delayed CLND) was performed at the time of clinical recurrence in the wide excision-alone arm. Acute and chronic morbidities were prospectively monitored. Early CLND was performed in 225 patients, and in the wide excision-alone arm 132 have undergone delayed CLND. The 2 groups were similar for primary tumor features, body mass index, basin location, and demographics except age, which were higher for delayed CLND. The number of nodes evaluated and the number of positive nodes was greater for delayed CLND. There was no significant difference in acute morbidity, but lymphedema was significantly higher in the delayed CLND group (20.4% vs. 12.4%, P = .04). Length of inpatient hospitalization was also longer for delayed CLND. Immediate nodal treatment provides critical prognostic information and a likely therapeutic effect for those patients with nodal involvement. These data show that early CLND is also less likely to result in lymphedema. C1 [Faries, Mark B.; Morton, Donald L.] St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Thompson, John F.] Royal Prince Alfred Hosp, Sydney Melanoma Unit, Camperdown, NSW 2050, Australia. [Cochran, Alistair] Univ Calif Los Angeles, Los Angeles, CA USA. [Elashoff, Robert; Wang, He-Jing] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Glass, Edwin C.] Natl Canc Inst, Naples, Italy. [Mozzillo, Nicola] Netherlands Canc Inst, Amsterdam, Netherlands. [Nieweg, Omgo E.] NYU, Sch Med, New York, NY USA. [Roses, Daniel F.] Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Roses, Daniel F.] Univ Groningen, Groningen, Netherlands. [Hoekstra, Harold J.] Millard Fillmore Hosp, Buffalo, NY USA. [Karakousis, Constantine P.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Karakousis, Constantine P.] Res Inst, Tampa, FL USA. [Reintgen, Douglas S.] Royal Adelaide Hosp, Adelaide, SA 5000, Australia. [Coventry, Brendon J.] Univ Adelaide, Adelaide, SA, Australia. RP Faries, MB (reprint author), St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. EM fariesm@jwci.org FU National Cancer Institute [CA29605] FX Supported by grant CA29605 from the National Cancer Institute. NR 17 TC 83 Z9 84 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2010 VL 17 IS 12 BP 3324 EP 3329 DI 10.1245/s10434-010-1203-0 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 688WB UT WOS:000284884600034 PM 20614193 ER PT J AU Walsh, JE Young, MRI AF Walsh, Jarrett E. Young, M. Rita I. TI Interrelationship Between Protein Phosphatase 1 and TGF-beta in Regulating Motility and Cytoskeletal Architecture of Endothelial Cells SO ANTICANCER RESEARCH LA English DT Article DE Cytoskeleton; paxillin; phosphatase; PP-1; TGF-beta; motility; endothelial cells ID TYROSINE PHOSPHORYLATION; PAXILLIN; KERATINOCYTES; ACTIVATION; MIGRATION AB Motility of endothelial cells is a requirement for the vascularization of solid malignancies. While tumors have been shown to produce a host of angiogenic factors, including TGF-beta, the mechanisms by which such factors regulate endothelial cell motility have not yet been defined. Thus, the role of the serine/threonine phosphatase PP-1 in regulating endothelial cell motility and cytoskeletal architecture was studied. The present study demonstrated that TGF-beta stimulation of motility is dependent on PP-1. Likewise, TGF-beta was shown to up-regulate paxillin expression through a process that was PP-1 dependent. The interplay between PP-1 and TGF-beta was further observed by the induction of cell rounding and the loss of paxillin-actin co precipitations upon PP-1 inhibition and the compensation for these effects by TGF-beta. Studies initiated to determine how PP-1 might regulate motility showed its role in maintaining cytoskeletal organization and its capacity to directly dephosphorylate the focal adhesion scaffolding protein paxillin. These studies suggest that the interplay between TGF-beta and PP-1 regulates the motility of endothelial cells that is critical to the process of angiogenesis. C1 [Walsh, Jarrett E.; Young, M. Rita I.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. [Walsh, Jarrett E.; Young, M. Rita I.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. [Young, M. Rita I.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson VA Med Ctr, Res Serv 151, Charleston, SC 29401 USA. EM rita.young@va.gov FU Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs; National Institutes of Health [R01 DE018168, R01CA128837] FX This study is part of the doctoral dissertation of Jarrett Walsh. The study was supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs and by grants R01 DE018168 and R01CA128837 from the National Institutes of Health to MRIY. NR 14 TC 6 Z9 6 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD DEC PY 2010 VL 30 IS 12 BP 4861 EP 4866 PG 6 WC Oncology SC Oncology GA 717BV UT WOS:000287018100010 PM 21187463 ER PT J AU Craig, WA Andes, DR Stamstad, T AF Craig, W. A. Andes, D. R. Stamstad, T. TI In Vivo Pharmacodynamics of New Lipopeptide MX-2401 SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ANIMAL-MODEL; PHARMACOKINETICS; GLYCOPEPTIDES; PARAMETERS; EFFICACY; VITRO; MICE AB MX-2401 is a novel lipopeptide (amphomycin analog) with a broad-spectrum bactericidal activity against Gram-positive organisms. We used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic/pharmacodynamic (PK/PD) activities of MX-2401. The compound (2.5 to 40 mg/kg of body weight) demonstrated linear PK characterized by an area under the concentration-time curve (AUC) of 228 to 3,265 mu g . h/ml and half-lives of 5.7 to 8.8 h. MICs ranged from 0.25 to 2 mu g/ml. The in vivo postantibiotic effect was prolonged (8.5 h with Staphylococcus aureus and 10.3 to 12.3 with Streptococcus pneumoniae). MX-2401 exhibited dose-dependent in vivo activity against various strains of S. pneumoniae and S. aureus; penicillin and macrolide resistance in the pneumococci and methicillin resistance in the staphylococci had no impact on the antimicrobial activity of the drug. To determine which PK/PD index correlated best with MX-2401 activity, dose fractionation studies over a 72-hour period were performed. The maximum concentration of drug in serum divided by the MIC (C(max)/MIC) correlated best with the efficacy for both S. aureus and S. pneumoniae. Static doses required free-drug C(max)/MIC values of 0.683 to 1.06. Free-drug 72-h AUC/MIC values for the static dose were in the range of 7.49 to 32.3 and were less than expected. The drug showed modest enhancement in activity in the presence of white blood cells (1.7- to 3.4-fold). The potency of the drug in the lung was only marginally lower than in the thigh (1.3- to 1.9-fold). Based on its PK/PD profile, MX-2401 appears to be a promising new lipopeptide agent for treatment of infections by Gram-positive bacteria, including those induced by antibiotic-resistant pathogens. C1 [Craig, W. A.] Univ Wisconsin, Div Infect Dis, Sch Med & Publ Hlth, MFCB,Dept Med,Sect Infect Dis, Madison, WI 53705 USA. [Craig, W. A.; Andes, D. R.; Stamstad, T.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Craig, WA (reprint author), Univ Wisconsin, Div Infect Dis, Sch Med & Publ Hlth, MFCB,Dept Med,Sect Infect Dis, 5th Floor,1685 Highland Ave, Madison, WI 53705 USA. EM wac@medicine.wisc.edu FU Migenex, Inc., Vancouver, Canada FX The study was funded by a research grant from Migenex, Inc., Vancouver, Canada. NR 22 TC 13 Z9 13 U1 0 U2 3 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 DEC PY 2010 VL 54 IS 12 BP 5092 EP 5098 DI 10.1128/AAC.00238-10 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 679JP UT WOS:000284158000020 PM 20855736 ER PT J AU Thaler, NS Bello, DT Randall, C Goldstein, G Mayfield, J Allen, DN AF Thaler, Nicholas S. Bello, Danielle T. Randall, Carol Goldstein, Gerald Mayfield, Joan Allen, Daniel N. TI IQ Profiles Are Associated with Differences in Behavioral Functioning Following Pediatric Traumatic Brain Injury SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE Assessment; Childhood brain insult; Intelligence; Statistical methods ID WECHSLER INTELLIGENCE SCALE; INDEX SCORE PATTERNS; GLASGOW COMA SCALE; WISC-III; EXECUTIVE FUNCTION; PROCESSING SPEED; CLUSTER SUBTYPES; YOUNG-CHILDREN; HEAD-INJURY; PERFORMANCE AB Research suggests that IQ profiles identify subgroups of children with traumatic brain injury (TBI) based on sparing and impairment of cognitive abilities, but little information is available regarding whether these subgroups are differentiated on variables that are important for TBI outcome, such as behavioral functioning. The current study examined behavioral disturbances in 123 children with TBI in association with profiles of intellectual abilities identified using cluster analysis. On the basis of prior research, four clusters were hypothesized. Consistent with the hypothesis, cluster analysis identified four IQ clusters in the current sample. Comparisons among the clusters on behavior variables assessed from the Behavioral Assessment System for Children parent ratings indicated significant differences among the four IQ clusters, with the most impaired cluster exhibiting the severest disturbances. Results of the current study indicate that subgroups of children with TBI can be identified using IQ tests and that these subgroups are stable across different samples, and more importantly are moderately associated with behavioral disturbances that persist during the recovery period. C1 [Allen, Daniel N.] Univ Nevada, Neuropsychol Res Program, Dept Psychol, Las Vegas, NV 89154 USA. [Goldstein, Gerald] VA Pittsburgh Healthcare Syst, MIRECC, Pittsburgh, PA USA. [Mayfield, Joan] Our Childrens House Baylor, Dallas, TX USA. RP Allen, DN (reprint author), Univ Nevada, Neuropsychol Res Program, Dept Psychol, 4505 Maryland Pkwy, Las Vegas, NV 89154 USA. EM daniel.allen@unlv.edu NR 64 TC 14 Z9 14 U1 2 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 EI 1873-5843 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD DEC PY 2010 VL 25 IS 8 BP 781 EP 790 DI 10.1093/arclin/acq073 PG 10 WC Psychology, Clinical; Psychology SC Psychology GA 679KE UT WOS:000284159500008 PM 20876194 ER PT J AU Ettenhofer, ML Foley, J Behdin, N Levine, AJ Castellon, SA Hinkin, CH AF Ettenhofer, Mark L. Foley, Jessica Behdin, Nina Levine, Andrew J. Castellon, Steven A. Hinkin, Charles H. TI Reaction Time Variability in HIV-Positive Individuals SO ARCHIVES OF CLINICAL NEUROPSYCHOLOGY LA English DT Article DE AIDS; Cognitive ability; Medication adherence; Immunological status; Continuous Performance Test; CPT-II ID WITHIN-PERSON VARIABILITY; PERFORMANCE VARIABILITY; COGNITIVE IMPAIRMENT; INTRAINDIVIDUAL VARIABILITY; MEDICATION ADHERENCE; ATTENTION; ADULTS; METAANALYSIS; INDICATOR; HIV/AIDS AB Progression of HIV/AIDS is frequently associated with frontal/subcortical dysfunction and mean reaction time (RT) slowing. Beyond group means, within-subject variability of RT has been found to be particularly sensitive to frontal/subcortical dysfunction in other populations. However, the possible relevance of RT variability to HIV/AIDS patients remains unknown. This study evaluated the relationships between RT variability and indicators such as neurocognitive, behavioral, and immunological status. A total of 46 HIV-positive adults on antiretroviral medication regimens were included in this study. Overall performance of this sample was poorer than normative means on measures of RT latency, RT variability, and traditional neurocognitive domains. Results demonstrated that the measures of RT variability were associated with global cognition, medication adherence rates, and peak immunological dysfunction, above and beyond the effects of RT latency. These preliminary findings suggest that measures of RT variability may provide enhanced sensitivity to neurocognitive disease burden in HIV/AIDS relative to more traditional measures of mean RT or cognitive function. C1 [Ettenhofer, Mark L.; Castellon, Steven A.; Hinkin, Charles H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Foley, Jessica; Castellon, Steven A.; Hinkin, Charles H.] VA Greater Los Angeles Hlth Care Syst, Psychol Serv, Los Angeles, CA USA. [Behdin, Nina] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Levine, Andrew J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Ettenhofer, ML (reprint author), USUHS Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ettenhofer@gmail.com FU National Institutes of Health [R01 DA13799]; National Institutes of Health, Ruth L. Kirschstein National Research Service [T32 MH19535] FX This investigation was supported by National Institutes of Health Grant R01 DA13799, and the National Institutes of Health, Ruth L. Kirschstein National Research Service Award T32 MH19535. NR 34 TC 9 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0887-6177 J9 ARCH CLIN NEUROPSYCH JI Arch. Clin. Neuropsychol. PD DEC PY 2010 VL 25 IS 8 BP 791 EP 798 DI 10.1093/arclin/acq064 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 679KE UT WOS:000284159500009 PM 20798183 ER PT J AU Dellavalle, RP AF Dellavalle, Robert P. TI Counseling Patients to Avoid Indoor Tanning SO ARCHIVES OF DERMATOLOGY LA English DT Editorial Material C1 [Dellavalle, Robert P.] Denver Vet Affairs Med Ctr, Dermatol Serv, Denver, CO 80220 USA. [Dellavalle, Robert P.] Univ Colorado Denver, Dept Dermatol, Aurora, CO USA. [Dellavalle, Robert P.] Colorado Sch Publ Hlth, Aurora, CO USA. RP Dellavalle, RP (reprint author), Denver Vet Affairs Med Ctr, Dermatol Serv, 1055 Clermont St,Box 165, Denver, CO 80220 USA. EM robert.dellavalle@ucdenver.edu RI Dellavalle, Robert/L-2020-2013 OI Dellavalle, Robert/0000-0001-8132-088X NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD DEC PY 2010 VL 146 IS 12 BP 1361 EP 1362 DI 10.1001/archdermatol.2010.354 PG 3 WC Dermatology SC Dermatology GA 696US UT WOS:000285467500005 PM 21173320 ER PT J AU Marcus, SC Olfson, M AF Marcus, Steven C. Olfson, Mark TI National Trends in the Treatment for Depression From 1998 to 2007 SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID PRIMARY-CARE PATIENTS; UNITED-STATES; MAJOR DEPRESSION; ANTIDEPRESSANT MEDICATION; ECONOMIC BURDEN; HEALTH PLANS; NCS-R; SEVERITY; PSYCHOTHERAPY; METAANALYSIS AB Context: The rate of outpatient treatment of depression increased markedly in the United States between 1987 and 1997; it is not known whether this trend has continued. Objective: To assess national trends in the outpatient treatment of depression between 1998 and 2007. Design and Setting: Analysis of service utilization data from 2 nationally representative surveys of the US household population, the 1998 (n=22 953) and 2007 (n=29 370) Medical Expenditure Panel Surveys. Participants: Nationally representative sample of the US household population. Main Outcome Measures: The rate of depression treatment and, among patients who received treatment, the rate of antidepressant medication use, psychotherapy, number of outpatient treatment visits, and expenditures. Results: The rate of outpatient treatment for depression increased from 2.37 per 100 persons in 1998 to 2.88 per 100 persons in 2007 (adjusted odds ratio [AOR], 1.18; 95% confidence interval [CI], 1.03-1.35). The percentage of treated patients who used antidepressants was little changed from 73.8% (1998) to 75.3% (2007) (AOR, 1.14; 95% CI, 0.85-1.51), but the percentage of those receiving psychotherapy declined from 53.6% (1998) to 43.1% (2007) (AOR, 0.71; 95% CI, 0.53-0.95). National expenditures for the outpatient treatment of depression increased from $10.05 billion to $12.45 billion (z=1.73, P=.08). This was primarily driven by an increase in medication expenditures from $4.59 billion (1998) to $6.60 billion (2007) (z=2.88, P=.004), which in turn was related to an increase in Medicare expenditures for depression treatment from $0.52 billion (1998) to $2.25 billion (2007) (z=5.62, P<.001). Conclusions: Rapid increases in depression treatment from 1987 to 1997 were followed by more modest increases during the following decade. Although there was little change in the proportion of patients receiving antidepressants, treatment with psychotherapy has declined. C1 [Olfson, Mark] Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Olfson, M (reprint author), Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. EM mo49@.columbia.edu FU Bristol-Myers Squibb; Eli Lilly Company; Agency for Healthcare Research and Quality [U18-HS016097] FX Dr Olfson has received research grants from Bristol-Myers Squibb and Eli Lilly & Company to Columbia University.; This work was supported by U18-HS016097 from the Agency for Healthcare Research and Quality. NR 57 TC 111 Z9 111 U1 3 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2010 VL 67 IS 12 BP 1265 EP 1273 DI 10.1001/archgenpsychiatry.2010.151 PG 9 WC Psychiatry SC Psychiatry GA 690NO UT WOS:000285011700010 PM 21135326 ER PT J AU Tsai, AC Weiser, SD Petersen, ML Ragland, K Kushel, MB Bangsberg, DR AF Tsai, Alexander C. Weiser, Sheri D. Petersen, Maya L. Ragland, Kathleen Kushel, Margot B. Bangsberg, David R. TI A Marginal Structural Model to Estimate the Causal Effect of Antidepressant Medication Treatment on Viral Suppression Among Homeless and Marginally Housed Persons With HIV SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; MAJOR DEPRESSIVE DISORDER; SEROTONIN REUPTAKE INHIBITORS; HUMAN-IMMUNODEFICIENCY-VIRUS; COMORBIDITY SURVEY REPLICATION; RANDOMIZED CLINICAL-TRIALS; UNITED-STATES; 2ND-GENERATION ANTIDEPRESSANTS; SAN-FRANCISCO; TRICYCLIC ANTIDEPRESSANTS AB Context: Depression strongly predicts nonadherence to human immunodeficiency virus (HIV) antiretroviral therapy, and adherence is essential to maintaining viral suppression. This suggests that pharmacologic treatment of depression may improve virologic outcomes. However, previous longitudinal observational analyses have inadequately adjusted for time-varying confounding by depression severity, which could yield biased estimates of treatment effect. Application of marginal structural modeling to longitudinal observation data can, under certain assumptions, approximate the findings of a randomized controlled trial. Objective: To determine whether antidepressant medication treatment increases the probability of HIV viral suppression. Design: Community-based prospective cohort study with assessments conducted every 3 months. Setting: Community-based research field site in San Francisco, California. Participants: One hundred fifty-eight homeless and marginally housed persons with HIV who met baseline immunologic (CD4+ T-lymphocyte count, <350/mu L) and psychiatric (Beck Depression Inventory II score, >13) inclusion criteria, observed from April 2002 through August 2007. Main Outcome Measures: Probability of achieving viral suppression to less than 50 copies/mL. Secondary outcomes of interest were probability of being on an antiretroviral therapy regimen, 7-day self-reported percentage adherence to antiretroviral therapy, and probability of reporting complete (100%) adherence. Results: Marginal structural models estimated a 2.03 greater odds of achieving viral suppression (95% confidence interval [CI], 1.15-3.58; P=.02) resulting from antidepressant medication treatment. In addition, antidepressant medication use increased the probability of antiretroviral uptake (weighted odds ratio, 3.87; 95% CI, 1.98-7.58; P<.001). Self-reported adherence to antiretroviral therapy increased by 25 percentage points(95% CI, 14-36; P<.001), and the odds of reporting complete adherence nearly doubled (weighted odds ratio, 1.94; 95% CI, 1.20-3.13; P=.006). Conclusions: Antidepressant medication treatment increases viral suppression among persons with HIV. This effect is likely attributable to improved adherence to a continuum of HIV care, including increased uptake and adherence to antiretroviral therapy. C1 [Tsai, Alexander C.] Univ Calif San Francisco, Langley Porter Psychiat Inst, San Francisco, CA 94143 USA. [Weiser, Sheri D.] Univ Calif San Francisco, Div HIV AIDS, San Francisco Gen Hosp, San Francisco, CA 94143 USA. [Ragland, Kathleen; Kushel, Margot B.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco Gen Hosp, San Francisco, CA 94143 USA. [Weiser, Sheri D.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Petersen, Maya L.] Univ Calif Berkeley, Sch Publ Hlth, Div Biostat, Berkeley, CA 94720 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Bangsberg, David R.] Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Bangsberg, David R.] MIT, Phillip T & Susan M Ragon Inst, Massachusetts Gen Hosp, Charlestown, MA USA. [Bangsberg, David R.] Harvard Univ, Charlestown, MA USA. RP Bangsberg, DR (reprint author), Harvard Initiat Global Hlth, 104 Mt Auburn St, Cambridge, MA 02138 USA. EM dbangsberg@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU National Institute of Mental Health (NIMH) [R01 MH-054907, R25 MH-060482, K23 MH-079713-01, K24 MH-087227]; National Institutes of Health/National Center for Research Resources UCSF-Clinical and Translational Science Institute [UL1 RR-024131] FX The REACH study was funded by National Institute of Mental Health (NIMH) grant R01 MH-054907. Members of the research team also received funding from the following sources: NIMH Institutional Training Award R25 MH-060482 (Dr Tsai); National Institutes of Health/National Center for Research Resources UCSF-Clinical and Translational Science Institute grant UL1 RR-024131 (Dr Tsai); NIMH grant K23 MH-079713-01 (Dr Weiser); and NIMH grant K24 MH-087227 (Dr Bangsberg). The HIV RNA kits were donated by Roche Molecular Systems. NR 88 TC 53 Z9 53 U1 4 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2010 VL 67 IS 12 BP 1282 EP 1290 DI 10.1001/archgenpsychiatry.2010.160 PG 9 WC Psychiatry SC Psychiatry GA 690NO UT WOS:000285011700012 PM 21135328 ER PT J AU Saxon, AJ McFall, ME AF Saxon, Andrew J. McFall, Miles E. TI Tobacco Use Data Questioned in Veterans Study SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID POSTTRAUMATIC-STRESS-DISORDER; PREVALENCE; DEMENTIA; SMOKING C1 Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Saxon, AJ (reprint author), Vet Affairs Med Ctr S 116 ATC, Dept Psychiat & Behav Sci, 1660 S Columbian Way, Seattle, WA 98108 USA. EM andrew.saxon@va.gov NR 5 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2010 VL 67 IS 12 BP 1324 EP 1324 DI 10.1001/archgenpsychiatry.2010.166 PG 1 WC Psychiatry SC Psychiatry GA 690NO UT WOS:000285011700017 PM 21135333 ER PT J AU Yaffe, K Vittinghoff, E Lindquist, K Barnes, D Covinsky, KE Neylan, T Kluse, M Marmar, C AF Yaffe, Kristine Vittinghoff, Eric Lindquist, Karla Barnes, Deborah Covinsky, Kenneth E. Neylan, Thomas Kluse, Molly Marmar, Charles TI Tobacco Use Data Questioned in Veterans Study Reply SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID RISK C1 [Yaffe, Kristine; Covinsky, Kenneth E.; Neylan, Thomas; Marmar, Charles] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Yaffe, Kristine; Barnes, Deborah; Neylan, Thomas; Kluse, Molly; Marmar, Charles] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine; Vittinghoff, Eric] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lindquist, Karla; Covinsky, Kenneth E.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. RP Yaffe, K (reprint author), San Francisco VA Med Ctr, 4150 Clement St,Box 181, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu NR 3 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 2010 VL 67 IS 12 BP 1324 EP 1325 DI 10.1001/archgenpsychiatry.2010.167 PG 2 WC Psychiatry SC Psychiatry GA 690NO UT WOS:000285011700018 ER PT J AU Bushnell, CD Zimmer, LO Pan, WQ Olson, DM Zhao, X Meteleva, T Schwamm, L Ovbiagele, B Williams, L LaBresh, KA Peterson, ED AF Bushnell, Cheryl D. Zimmer, Louise O. Pan, Wenqin Olson, DaiWai M. Zhao, Xin Meteleva, Tatiana Schwamm, Lee Ovbiagele, Bruce Williams, Linda LaBresh, Kenneth A. Peterson, Eric D. CA Adherence Evaluation Ischemic Stro TI Persistence With Stroke Prevention Medications 3 Months After Hospitalization SO ARCHIVES OF NEUROLOGY LA English DT Article ID ISCHEMIC-STROKE; MYOCARDIAL-INFARCTION; SECONDARY PREVENTION; HEART-DISEASE; FOLLOW-UP; ADHERENCE; RATES; DISCONTINUATION; ASSOCIATION; INITIATION AB Objective: To measure longitudinal use of stroke prevention medications following stroke hospital discharge. We hypothesized that a combination of patient-, provider-, and system-level factors influence medication-taking behavior. Design: Observational cohort design. Setting: One hundred six US hospitals participating in the American Heart Association Get With The Guidelines Stroke program. Patients: Two thousand eight hundred eighty-eight patients 18 years or older admitted with ischemic stroke or transient ischemic attack. Main Outcome Measure: Regimen persistence, including use of antiplatelet therapies, warfarin, antihypertensive therapies, lipid-lowering therapies, or diabetes medications, from discharge to 3 months. Reasons for nonpersistence were also ascertained. Results: Two thousand five hundred ninety-eight patients (90.0%) were eligible for analysis. At 3 months, 75.5% of subjects continued taking all secondary prevention medications prescribed at discharge. Persistence at 3 months was associated with decreasing number of medication classes prescribed, increasing age, medical history, less severe stroke disability, having insurance, working status, understanding why medications are prescribed and how to refill them, increased quality of life, financial hardship, geographic region, and hospital size. Conclusions: One-quarter of stroke patients reported discontinuing 1 or more of their prescribed regimen of secondary prevention medications within 3 months of hospitalization for an acute stroke. Several modifiable factors associated with regimen persistence were identified and could be targets for improving long-term secondary stroke prevention. C1 [Bushnell, Cheryl D.] Wake Forest Univ Hlth Sci, Dept Neurol, Winston Salem, NC 27157 USA. [Zimmer, Louise O.; Pan, Wenqin; Olson, DaiWai M.; Zhao, Xin; Meteleva, Tatiana; Peterson, Eric D.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [LaBresh, Kenneth A.] Res Triangle Int, Res Triangle Pk, NC USA. [Schwamm, Lee] Harvard Univ, Boston, MA 02115 USA. [Schwamm, Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ovbiagele, Bruce] Univ Calif Los Angeles, David Geffen Sch Med, Stroke Ctr, Los Angeles, CA 90095 USA. [Ovbiagele, Bruce] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Williams, Linda] Indiana Univ Sch Med, Indianapolis, IN USA. [Williams, Linda] Roudebush VA Med Ctr, Indianapolis, IN USA. RP Bushnell, CD (reprint author), Wake Forest Univ Hlth Sci, Dept Neurol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM cbushnel@wfubmc.edu RI LaBresh, Kenneth/A-6995-2017; OI LaBresh, Kenneth/0000-0001-9040-1956; Schwamm, Lee/0000-0003-0592-9145 FU Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; GWTG; Agency for Healthcare Research and Quality [U18HS016964]; Bushnell; Peterson FX Drs Bushnell and Peterson both received research salary support from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership for their roles as co-principal investigators on the AVAIL registry. Dr Schwamm is chair of the national steering committee for GWTG. This research project was supported by unrestricted funds from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership and conducted through collaboration with the GWTG-Stroke program.; The study was conceived and designed by the AVAIL team, researchers at the Duke Clinical Research Institute, the project executive committee, and an American Heart Association representative. The AVAIL analyses were also supported in part by Agency for Healthcare Research and Quality grant U18HS016964.; Obtained funding: Bushnell and Peterson. NR 19 TC 50 Z9 52 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2010 VL 67 IS 12 BP 1456 EP 1463 DI 10.1001/archneuro1.2010.190 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 693HV UT WOS:000285216100006 PM 20697032 ER PT J AU Jun, G Naj, AC Beecham, GW Wang, LS Buros, J Gallins, PJ Buxbaum, JD Ertekin-Taner, N Fallin, D Friedland, R Inzelberg, R Kramer, P Rogaeva, E George-Hyslop, PS Cantwell, LB Dombroski, BA Saykin, AJ Reiman, EM Bennett, DA Morris, JC Lunetta, KL Martin, ER Montine, TJ Goate, AM Blacker, D Tsuang, DW Beekly, D Cupples, LA Hakonarson, H Kukull, W Foroud, TM Haines, J Mayeux, R Farrer, LA Pericak-Vance, MA Schellenberg, GD AF Jun, Gyungah Naj, Adam C. Beecham, Gary W. Wang, Li-San Buros, Jacqueline Gallins, Paul J. Buxbaum, Joseph D. Ertekin-Taner, Nilufer Fallin, Daniele Friedland, Robert Inzelberg, Rivka Kramer, Patricia Rogaeva, Ekaterina George-Hyslop, Peter St. Cantwell, Laura B. Dombroski, Beth A. Saykin, Andrew J. Reiman, Eric M. Bennett, David A. Morris, John C. Lunetta, Kathryn L. Martin, Eden R. Montine, Thomas J. Goate, Alison M. Blacker, Deborah Tsuang, Debby W. Beekly, Duane Cupples, L. Adrienne Hakonarson, Hakon Kukull, Walter Foroud, Tatiana M. Haines, Jonathan Mayeux, Richard Farrer, Lindsay A. Pericak-Vance, Margaret A. Schellenberg, Gerard D. CA Alzheimers Dis Genetics Consortium TI Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes SO ARCHIVES OF NEUROLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; MILD COGNITIVE IMPAIRMENT; AGE-AT-ONSET; IDENTIFIES VARIANTS; MISSENSE MUTATIONS; PARKINSON DISEASE; LINKAGE ANALYSIS; ARAB POPULATION; GENE; FRAMINGHAM AB Objectives: To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design: Association study of AD and CLU, PICALM, CR1, and APOE genotypes. Setting: Academic research institutions in the United States, Canada, and Israel. Participants: Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results: Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CRI (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE 64 was significantly associated with AD (ORs, 1.809.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE 64 allele greatly reduced evidence for association with PICALM but not CRI or CLU. Models with the main SNP effect, presence or absence of APOE 64, and an interaction term showed significant interaction between presence or absence of APOE epsilon 4 and PICALM. Conclusions: We confirm in a completely independent data set that CRI, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE epsilon 4-positive subjects. Thus, APOE and PICALM synergistically interact. C1 [Jun, Gyungah; Buros, Jacqueline; Farrer, Lindsay A.] Boston Univ, Genet Program, Dept Med, Boston, MA 02215 USA. [Jun, Gyungah] Boston Univ, Dept Ophthalmol, Boston, MA 02215 USA. [Jun, Gyungah; Lunetta, Kathryn L.; Cupples, L. Adrienne] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Farrer, Lindsay A.] Boston Univ, Dept Genet & Genom & Epidemiol, Boston, MA 02215 USA. [Blacker, Deborah] Massachusetts Gen Hosp, Dept Psychiat & Epidemiol, Charlestown, MA USA. [Naj, Adam C.; Beecham, Gary W.; Gallins, Paul J.; Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Beecham, Gary W.; Martin, Eden R.; Pericak-Vance, Margaret A.] Univ Miami, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL USA. [Ertekin-Taner, Nilufer] Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. [Ertekin-Taner, Nilufer] Mayo Clin Jacksonville, Dept Neurol, Jacksonville, FL 32224 USA. [Schellenberg, Gerard D.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Mayeux, Richard] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10027 USA. [Mayeux, Richard] Columbia Univ, Taub Inst, New York, NY USA. [Fallin, Daniele] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Friedland, Robert] Univ Louisville, Dept Neurol, Louisville, KY 40292 USA. [Inzelberg, Rivka] Tel Aviv Univ, Chaim Sheba Med Ctr, Dept Neurol, Tel Aviv, Israel. [Inzelberg, Rivka] Tel Aviv Univ, Chaim Sheba Med Ctr, Dept Med, Tel Aviv, Israel. [Kramer, Patricia] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Kramer, Patricia] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. [Rogaeva, Ekaterina; George-Hyslop, Peter St.] Univ Toronto, Dept Med, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [George-Hyslop, Peter St.] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge, England. [Saykin, Andrew J.] Indiana Univ, Dept Radiol & Imaging Sci, Indianapolis, IN 46204 USA. [Saykin, Andrew J.; Foroud, Tatiana M.] Indiana Univ, Dept Med & Mol Genet, Indianapolis, IN 46204 USA. [Reiman, Eric M.] Univ Arizona, Arizona Alzheimers Consortium, Phoenix, AZ USA. [Reiman, Eric M.] Univ Arizona, Neurogenom Div, Translat Genom Res Inst, Phoenix, AZ USA. [Reiman, Eric M.] Univ Arizona, Dept Psychiat, Phoenix, AZ USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Morris, John C.] Washington Univ, Dept Neurol, St Louis, MO USA. [Morris, John C.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Goate, Alison M.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Beekly, Duane; Kukull, Walter] Univ Washington, Natl Alzheimers Coordinating Ctr, Seattle, WA 98195 USA. [Kukull, Walter] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Haines, Jonathan] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Schellenberg, GD (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs, Room 609B,422 Curie Blvd, Philadelphia, PA 19104 USA. EM gerardsc@mail.med.upenn.edu RI Roberson, Erik/A-5718-2009; Morris, John/A-1686-2012; Haines, Jonathan/C-3374-2012; Kowall, Neil/G-6364-2012; Saykin, Andrew/A-1318-2007; Friedland, Robert/A-2834-2010; Tsuang, Debby/L-7234-2016; OI Roberson, Erik/0000-0002-1810-9763; Kowall, Neil/0000-0002-6624-0213; Saykin, Andrew/0000-0002-1376-8532; Friedland, Robert/0000-0001-5721-1843; Tsuang, Debby/0000-0002-4716-1894; Farrer, Lindsay/0000-0001-5533-4225; Kukull, Walter/0000-0001-8761-9014; Buros, Jacqueline/0000-0001-9588-4889; Buxbaum, Joseph/0000-0001-8898-8313 FU Teva Pharmaceuticals; state of Arizona; Kronos Life Sciences; GlaxoSmithKline; AstraZeneca; Avid; Abbott; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation; Genentech; GE Healthcare; Innogenetics; Johnson Johnson; Eli Lilly and Co; Medpace Inc; Merck and Co Inc; Novartis AG; Pfizer Inc; F. Hoffman-La Roche; Schering-Plough; Synarc Inc; Wyeth; US National Institutes of Health (NIH); NIA; NIH-NIA [U01 AG032984, RC2 AG036528, U01 AG016976, P30 AGO 13846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, R01 MH080295, P50 AG008702, P30 AG028377, AG025688, P30 AG10133, P50 AG005146, R01 AG020688, P50 AG016574, P50 AG005138, P30 AG08051, U01 AG16976, M01 RR00096, UL1 RR029893, P30 AGO 13854, P30 AG008017, P30 AGO 10161, P50 AG016582, UL1 RR02777, P30 AG010129, P50 AG016573, P50 AG016575, P50 AG016576, P50 AG016577, P50 AG016570, P50 AG005131, P50 AG023501, P01 AG019724, P30 AG028383, P50 AG008671, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG005681, P01 AG03991]; National Cell Repository for Alzheimer's Disease [U24-AG021886]; ADCs: Banner Alzheimer's Institute [P30 AG019610]; Boston University; Columbia University; Duke University; Emory University; Indiana University; Johns Hopkins University; Massachusetts General Hospital [P50 AG005134]; Mayo Clinic [P50 AG016574]; Mount Sinai School of Medicine; New York University; Northwestern University; Oregon Health and Science University; Rush University; University of Alabama at Birmingham; University of California, Davis; University of California, Irvine; University of California, Los Angeles; University of California, San Diego; University of California, San Francisco; University of Kentucky; University of Michigan; University of Pennsylvania; University of Pittsburgh; University of Southern California; University of Texas Southwestern; University of Washington; Washington University; Alzheimer's Association [IIRG 08-89720]; VA New England Geriatric Research Education and Clinical Center; NIH [U01 AG016976, P30 AG028377, P50 AG005146, P30 AG008017, P30 AG010129, P30 AG028383, P01 AG03991, U24 AG026395, R01 AG026916, P50 AG16574, U01 AG06786, P30 AG10161, R01 AG17917, P30 AG10129, P50 AG05131, P50 AG08671, P50 AG05681, R01 AG031581, U01 AG024904, K01 AG030514]; ADNI [U01 AG024904, RC2 AG036535]; Framingham Heart Study [N01 HC-25195, R01 NS017950, R01 AG08122, R01 AG16495, R01 AG033193, R01 AG031287]; Collaborative Aging and Memory Project [R01 AG019085]; MIRAGE [R01 AG009029]; Wadi Ara study [R01 AG017173]; Multiethnic Genome-wide Association [R01 AG025259]; NIA-NIH [AGO 10491, AG002219, AG005138, AG027944, AG021547, AG019757, R01 AG 027944]; Natural Science Foundation of China [30730057, 30700442]; National Institute of Biomedical Imaging and Bioengineering; Dana Foundation; [R37 AGO 15473] FX Dr Gilman serves on safety monitoring committees for Elan, Pfizer, Janssen, and Allergan pharmaceutical companies and a steering committee for a trial of rasagiline for multiple system atrophy sponsored by Teva Pharmaceuticals. He receives reimbursement only for his time by each of these sponsors. He also consults for Longitude Capital and the Gerson Lehman Group. Dr Reiman has received research grants and contracts from the NIA, state of Arizona, Kronos Life Sciences, GlaxoSmithKline, AstraZeneca, and Avid and has provided consultation and advisory board services to AstraZeneca, Amnestix/Sygnis, Elan, Eli Lilly, and Siemens. Dr Rosenberg is editor of the Archives of Neurology and,obtained an independent review and assessment of the manuscript from outside the editorial office prior to its acceptance. The ADNI is funded through generous contributtons from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly and Co, Medpace Inc, Merck and Co Inc, Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc Inc, and Wyeth.; The ADGC is funded by the US National Institutes of Health (NIH), NIA grants U01 AG032984 and RC2 AG036528 and a grant from a private foundation wishing to remain anonymous. The NIH-NIA also provides financial support to National Alzheimer's Coordinating Center (grant U01 AG016976), National Cell Repository for Alzheimer's Disease (grant U24-AG021886), and the ADCs: Banner Alzheimer's Institute (grant P30 AG019610), Boston University (grants P30 AGO 13846, R01 HG02213, K24 AG027841, U01 AG10483, R01 CA129769, and R01 MH080295), Columbia University (grant P50 AG008702), Duke University (grant P30 AG028377), Emory University (grant AG025688), Indiana University (grant P30 AG10133), Johns Hopkins University (grant P50 AG005146), Massachusetts General Hospital (grant P50 AG005134), Mayo Clinic (grant P50 AG016574), Mount Sinai School of Medicine (grant P50 AG005138), New York University (grants P30 AG08051, U01 AG16976, M01 RR00096, and UL1 RR029893), Northwestern University (grant P30 AGO 13854), Oregon Health and Science University (grant P30 AG008017), Rush University (grant P30 AGO 10161), University of Alabama at Birmingham (grant P50 AG016582 and grant UL1 RR02777 through the University of Alabama at Birmingham Center for Clinical and Translational Science), University of California, Davis (grant P30 AG010129), University of California, Irvine (grants P50 AG016573, P50 AG016574, P50 AG016575, P50 AG016576, and P50 AG016577), University of California, Los Angeles (grant P50 AG016570), University of California, San Diego (grant P50 AG005131), University of California, San Francisco (grants P50 AG023501 and P01 AG019724), University of Kentucky (grant P30 AG028383), University of Michigan (grant P50 AG008671), University of Pennsylvania (grant P30 AG010124), University of Pittsburgh (grant P50 AG005133), University of Southern California (grant P50 AG005142), University of Texas Southwestern (grant P30 AG012300), University of Washington (grant P50 AG005136), and Washington University (grants P50 AG005681 and P01 AG03991). The work completed by Boston University is also supported by Alzheimer's Association grant IIRG 08-89720 and VA New England Geriatric Research Education and Clinical Center. This project was also made possible by the many contributions of individual study data sets, supported in part by NIH. These include the NIA-LOAD Family Study (NIH grant U24 AG026395), Columbia University study (NIH grant R37 AGO 15473), ADNI (grants U01 AG024904 and RC2 AG036535), Framingham Heart Study (grants N01 HC-25195, R01 NS017950, R01 AG08122, R01 AG16495, R01 AG033193, and R01 AG031287), Collaborative Aging and Memory Project (grant R01 AG019085), Johns Hopkins University (grant R01 AG020688), MIRAGE Study (grant R01 AG009029), Wadi Ara study (grant R01 AG017173), and the Multiethnic Genome-wide Association Study (Dr Farrer; grant R01 AG025259). The University of Miami/Vanderbilt University/Mount Sinai School of Medicine work was supported by grants from the NIA-NIH (AGO 10491, AG002219, AG005138, AG027944, AG021547, AG019757, and R01 AG 027944) and from the Alzheimer's Association (IIRG 05-14147). A subset of these participants was ascertained while Dr Pericak-Vance was a faculty member at Duke University.; The study by Oregon Health and Science University was supported by NIA grants R01 AG026916, P30 AG028377, P50 AG005146, P30 AG028383, P50 AG16574, U01 AG06786, P30 AG008017, P30 AG10161, R01 AG17917, P30 AG10129, P50 AG05131, P50 AG08671, P50 AG05681, P01 AG03991, and U01 AG016976 of the NIH and by the Natural Science Foundation of Cina (project numbers 30730057 and 30700442). The Translational Genomics Research Institute is supported by NIH grant R01 AG031581, Kronos Life Sciences, and the state of Arizona.; The ADNI data collection and sharing for this project was funded by NIH grant U01 AG024904 (principal investigator, Michael W. Weiner, MD). The ADNI is funded by the NIA and the National Institute of Biomedical Imaging and Bioengineering, as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514 and the Dana Foundation. NR 51 TC 186 Z9 191 U1 2 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2010 VL 67 IS 12 BP 1473 EP 1484 DI 10.1001/archneuro1.2010.201 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 693HV UT WOS:000285216100008 PM 20697030 ER PT J AU Chen, L Wang, KY Esmaili, DD Xu, GZ AF Chen, Ling Wang, Keyan Esmaili, Daniel D. Xu, Gezhi TI Rhegmatogenous Retinal Detachment Due to Paravascular Linear Retinal Breaks Over Patchy Chorioretinal Atrophy in Pathologic Myopia SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID PARS-PLANA VITRECTOMY; POSTERIOR STAPHYLOMA; HOLES; EYES AB Objective: To characterize posterior paravascular linear retinal breaks over areas of patchy chorioretinal atrophy as a cause of retinal detachment among patients with pathologic myopia. Methods: In this retrospective case series, we evaluated 10 pathologically myopic eyes having rhegmatogenous retinal detachment associated with posterior paravascular linear retinal breaks. Results: Ten eyes with posterior paravascular linear retinal breaks and retinal detachment were identified from January 1, 2008, to July 31, 2009. The retinal breaks were most frequently found along the inferotemporal vascular arcade, followed by the superotemporal arcade. The length of the breaks ranged from 0.25 to 1 disc diameter, and their distance from the optic disc ranged from 1 to 5 disc diameters. These paravascular linear retinal breaks have distinct clinical characteristics, including a strong propensity to occur over areas of patchy chorioretinal atrophy, a linear shape that is oriented parallel to the adjacent retinal vessels, and a tendency to result in progressive retinal detachment. Vitrectomy with gas tamponade was performed in all cases, and retinal reattachment was achieved in 9 cases by a single operation. Conclusions: Paravascular linear retinal breaks over areas of patchy chorioretinal atrophy represent a distinct clinical entity that can result in a special category of retinal detachment among patients with pathologic myopia. These breaks are apt to elude detection before surgery, and a careful search along the posterior vascular arcades during vitrectomy may help to detect these abnormalities. Pars plana vitrectomy with photocoagulation and intraocular tamponade may lead to a resolution of such rhegmatogenous retinal detachments. C1 [Chen, Ling; Wang, Keyan; Xu, Gezhi] Fudan Univ, Eye & Ears Nose & Throat Hosp, Shanghai 200031, Peoples R China. [Chen, Ling; Wang, Keyan; Xu, Gezhi] Fudan Univ, Dept Ophthalmol, Shanghai Med Sch, Shanghai 200031, Peoples R China. [Esmaili, Daniel D.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA USA. [Esmaili, Daniel D.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Xu, GZ (reprint author), Fudan Univ, Eye & Ears Nose & Throat Hosp, Shanghai 200031, Peoples R China. EM xugezhi@sohu.com FU National Basic Research Program of China [2007CB512205]; Pudong New Area Science and Technology Development Fund [PKJ2008-Y02]; 211 Talents Start-up Funding FX This study was supported by grant GZX/No.2007CB512205 from the National Basic Research Program of China, by grant GZX/No.PKJ2008-Y02 from the Pudong New Area Science and Technology Development Fund, and by 211 Talents Start-up Funding (Dr Chen). NR 23 TC 4 Z9 5 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2010 VL 128 IS 12 BP 1551 EP 1554 DI 10.1001/archophthalmol.2010.284 PG 4 WC Ophthalmology SC Ophthalmology GA 693GL UT WOS:000285212500008 PM 21149778 ER PT J AU Guess, SM Butt, AL Neely, SB Wild, RC Chou, AF Chodosh, J AF Guess, Scott M. Butt, Amir L. Neely, Stephen B. Wild, Robert C. Chou, Ann F. Chodosh, James TI Dissemination of Knowledge From Randomized Clinical Trials for Herpes Simplex Virus Keratitis SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID EYE DISEASE; QUALITY C1 [Guess, Scott M.; Chodosh, James] Oklahoma Hlth Sci Ctr, Dean McGee Eye Inst, Dept Ophthalmol, Oklahoma City, OK USA. [Chou, Ann F.] Oklahoma Hlth Sci Ctr, Coll Med, Dept Family & Prevent Med, Oklahoma City, OK USA. [Butt, Amir L.; Neely, Stephen B.; Wild, Robert C.] Oklahoma Hlth Sci Ctr, Dept Biostat & Epidemiol, Coll Publ Hlth, Oklahoma City, OK USA. [Chou, Ann F.] Oklahoma Hlth Sci Ctr, Dept Hlth Adm & Policy, Coll Publ Hlth, Oklahoma City, OK USA. RP Chodosh, J (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu NR 7 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2010 VL 128 IS 12 BP 1624 EP 1625 DI 10.1001/archophthalmol.2010.274 PG 2 WC Ophthalmology SC Ophthalmology GA 693GL UT WOS:000285212500023 PM 21149792 ER PT J AU Jakobiec, FA Stacy, RC Hatton, MP AF Jakobiec, Frederick A. Stacy, Rebecca C. Hatton, Mark P. TI Clinical Characterization and Immunopathologic Features of Sclerosing Dacryoadenitis and Riedel Thyroiditis SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID ORBITAL INVOLVEMENT; MULTIFOCAL FIBROSCLEROSIS; STRUMA; DISEASE C1 [Jakobiec, Frederick A.; Stacy, Rebecca C.] Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalmol Pathol, Boston, MA 02114 USA. [Jakobiec, Frederick A.; Stacy, Rebecca C.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Hatton, Mark P.] Ophthalm Consultants Boston, Boston, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalmol Pathol, 243 Charles St,Ste 321, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 14 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2010 VL 128 IS 12 BP 1626 EP 1628 DI 10.1001/archophthalmol.2010.299 PG 3 WC Ophthalmology SC Ophthalmology GA 693GL UT WOS:000285212500025 PM 21149794 ER PT J AU Auger, M Moriarty, AT Laucirica, R Souers, R Chmara, BA Fatheree, LA Wilbur, DC AF Auger, Manon Moriarty, Ann T. Laucirica, Rodolfo Souers, Rhona Chmara, Beth Anne Fatheree, Lisa A. Wilbur, David C. TI Granulomatous Inflammation-An Underestimated Cause of False-Positive Diagnoses in Lung Fine-Needle Aspirates Observations From the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID LOCALIZED PULMONARY-LESIONS; WEGENERS-GRANULOMATOSIS; CYTOLOGY; BIOPSY; SPECIMENS; NEOPLASMS; PITFALL AB Context.-The false-positive rate for fine-needle aspirates of the lung has been cited as less than 1% for granulomatous inflammation, comprising one of the known causes of false-positive diagnoses. Objective.-To determine the rate of false-positive diagnoses of granulomatous inflammation for lung fine-needle aspirates by assessing the false-positive response rate in the context of the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program. Design.-We performed a retrospective review of 1092 participant responses for lung fine-needle aspirate challenges with the reference diagnosis of specific infections/granulomatous inflammation from 1998 to 2008 from the College of American Pathologists Nongynecologic Cytopathology Interlaboratory Comparison Program. False-positive rates by participant type (pathologist versus cytotechnologist), general diagnosis category, reference diagnosis, and preparation type were analyzed for the pathologists' responses. Results.-Of the 502 general category responses for pathologists, 428 (85.3%) were benign, 55 (11%) were malignant, and 19 (3.8%) were suspicious. There was no difference in the false-positive rate between preparations (P = .76) or participants (P = .39). Of those responses by pathologists that were benign, only 68.7% (292 of 425) were an exact match to granulomatous inflammation. Non-small cell carcinoma, adenocarcinoma, and squamous carcinoma represented 64% of false-positive/suspicious responses, while small cell carcinoma and carcinoid comprised 13%. Conclusion.-In an interlaboratory comparison program, granulomatous inflammation represents an important cause of false-positive/suspicious responses in lung fine-needle aspirates (14.8%) and is much higher than false-positive rates reported historically in clinical studies. These results highlight the importance of granulomatous inflammation as a mimic of carcinoma. (Arch Pathol Lab Med. 2010;134:1793-1796) C1 [Auger, Manon] McGill Univ, Dept Pathol, Ctr Hlth, Montreal, PQ H3A 2B4, Canada. [Moriarty, Ann T.] AmeriPath Indiana, Dept Cytol, Indianapolis, IN USA. [Laucirica, Rodolfo] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Chmara, Beth Anne; Fatheree, Lisa A.] Coll Amer Pathologists, Dept Cytol Surveys, Northfield, IL USA. [Wilbur, David C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Auger, M (reprint author), McGill Univ, Dept Pathol, Ctr Hlth, 3775 Univ St,Room 105, Montreal, PQ H3A 2B4, Canada. EM manon.auger@mcgill.ca NR 20 TC 3 Z9 3 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2010 VL 134 IS 12 BP 1793 EP 1796 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 695QM UT WOS:000285387700013 PM 21128777 ER PT J AU Nakamura, MM Ferris, TG DesRoches, CM Jha, AK AF Nakamura, Mari M. Ferris, Timothy G. DesRoches, Catherine M. Jha, Ashish K. TI Electronic Health Record Adoption by Children's Hospitals in the United States SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PHYSICIAN ORDER ENTRY; ADVERSE DRUG EVENTS; INFORMATION-TECHNOLOGY; SYSTEMS; CARE; QUALITY; PEDIATRICS; SAFETY; IMPACT AB Objective: To assess adoption of electronic health records (EHRs) and clinical functionalities, involvement in health information exchange, and barriers to and facilitators of adoption among children's hospitals in the United States. Design: Survey presented as an information technology supplement to the American Hospital Association's annual member survey. Setting: General acute care children's hospitals in 2008, identified using the membership directory of the National Association of Children's Hospitals and Related Institutions. Participants: Chief information officers or equivalent hospital leaders. Main Exposures: Potential barriers to or facilitators of EHR adoption. Main Outcome Measures: Rates of EHR adoption, determined using expert-formulated definitions based on presence of essential functionalities, and rates of implementation for individual functionalities and participation in health information exchange. Results: Of 155 children's hospitals, 108 (69.7%) responded to the survey. Only 2.8% had a comprehensive EHR, whereas an additional 17.9% had a basic system. Adoption of individual functionalities varied widely; comprehensive implementations of computerized provider order entry for medications and many forms of decision support were reported by fewer than half. In all, 15.7% of hospitals exchanged health information electronically. Hospital characteristics were not associated with EHR adoption or participation in health information exchange. Hospitals identified financing as the most important target for policy strategies. Conclusions: Most children's hospitals lack the minimum functionalities needed for a basic EHR. Ensuring access to adequate financial resources will be critical for inclusion of children's hospitals in efforts to expand EHR use. C1 [Nakamura, Mari M.] Childrens Hosp Boston, Div Infect Dis, Dept Med, Boston, MA 02115 USA. [Nakamura, Mari M.] Childrens Hosp Boston, Informat Serv Dept, Boston, MA 02115 USA. [Ferris, Timothy G.; DesRoches, Catherine M.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Jha, Ashish K.] Vet Affairs Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA USA. RP Nakamura, MM (reprint author), Childrens Hosp Boston, Div Infect Dis, Dept Med, 300 Longwood Ave,Enders 7, Boston, MA 02115 USA. FU UpToDate; Harvard Medical School and Harvard Pilgrim Health Care; Office of the National Coordinator for Health Information Technology in the Department of Health and Human Services; Robert Wood Johnson Foundation FX Dr Jha reports consulting fees from UpToDate and serves on the Scientific Advisory Board for Humedica.; This study was supported in part by a fellowship award from Harvard Medical School and Harvard Pilgrim Health Care and by grants from the Office of the National Coordinator for Health Information Technology in the Department of Health and Human Services and from the Robert Wood Johnson Foundation. NR 27 TC 14 Z9 14 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD DEC PY 2010 VL 164 IS 12 BP 1145 EP 1151 DI 10.1001/archpediatrics.2010.234 PG 7 WC Pediatrics SC Pediatrics GA 690MW UT WOS:000285009900015 PM 21135344 ER PT J AU Seel, RT Sherer, M Whyte, J Katz, DI Giacino, JT Rosenbaum, AM Hammond, FM Kalmar, K Pape, TLB Zafonte, R Biester, RC Kaelin, D Kean, J Zasler, N AF Seel, Ronald T. Sherer, Mark Whyte, John Katz, Douglas I. Giacino, Joseph T. Rosenbaum, Amy M. Hammond, Flora M. Kalmar, Kathleen Pape, Theresa Louise-Bender Zafonte, Ross Biester, Rosette C. Kaelin, Darryl Kean, Jacob Zasler, Nathan TI Assessment Scales for Disorders of Consciousness: Evidence-Based Recommendations for Clinical Practice and Research SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Coma; Consciousness Disorders; Brain injuries; Diagnosis; Outcome assessment; Persistent vegetative state; Practice guidelines as topic; Prognosis; Rehabilitation; Review ID REACTION-LEVEL-SCALE; GLASGOW-COMA-SCALE; PERSISTENT VEGETATIVE STATE; SEVERE HEAD-INJURY; TRAUMATIC BRAIN-INJURY; MINIMALLY RESPONSIVE PATIENTS; SENSORY MODALITY ASSESSMENT; REHABILITATION TECHNIQUE SMART; RECOVERY SCALE; MOTOR RESPONSE AB Report of the American Congress of Rehabilitation Medicine, Brain Injury-Interdisciplinary Special Interest Group, Disorders of Consciousness Task Force: Seel RT, Task Force Chair, Sherer M, Whyte J, Katz DI, Giacino if, Rosenbaum AM, Hammond FM, Kalmar K, Pape TL, Zafonte R, Biester RC, Kaelin D, Kean J, Zasler N. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 2010;91:1795-1813. Objectives: To conduct a systematic review of behavioral assessment scales for disorders of consciousness (DOC); provide evidence-based recommendations for clinical use based on their content validity, reliability, diagnostic validity, and ability to predict functional outcomes; and provide research recommendations on DOC scale development and validation. Data Sources: Articles published through March 31, 2009, using MEDLINE, CINAHL, Psychology and Behavioral Sciences Collection, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Biomedical Reference Collection, and PsycINFO. Thirteen primary terms that defined DOC were paired with 30 secondary terms that defined aspects of measurement. Scale names, abbreviations, and authors were also used as search terms. Task force members identified additional articles by using personal knowledge and examination of references in reviewed articles. Study Selection: Primary criteria included the following: (I) provided reliability, diagnostic validity, and/or prognostic validity data; (2) examined a cohort, case control, or case series sample of persons with DOC who were age older than or equal to 18 years; and (3) assessed in an acute care or rehabilitation setting. Articles were excluded if peer review was not conducted, original data were not reported, or an English language article was not available. The initial search yielded 580 articles. After paired rater review of study abstracts, guideline development was based on 37 articles representing 13 DOC scales. Data Extraction: Rater pairs classified studies addressing diagnostic and prognostic validity by using the American Academy of Neurology 4-tier level of evidence scheme, and reliability by using a task force developed 3-tier evidence scheme. An independent quality review of ratings was conducted, and corrections were made. Data Synthesis: The Coma Recovery Scale-Revised (CRS-R), Sensory Stimulation Assessment Measure (SSAM), Wessex Head Injury Matrix (WHIM), Western Neuro Sensory Stimulation Profile (WNSSP), Sensory Modality Assessment Technique (SMART), Disorders of Consciousness Scale (DOCS), and Coma/Near-Coma Scale (CNC) have acceptable standardized administration and scoring procedures. The CRS-R has excellent content validity and is the only scale to address all Aspen Work-group criteria. The SMART, SSAM, WHIM, and WNSSP demonstrate good content validity, containing items that could distinguish persons who are in a vegetative state, are in a minimally conscious state (MCS), or have emerged from MCS. The Full Outline of UnResponsiveness Score (FOUR), WNSSP, CRS-R, Comprehensive Levels of Consciousness Scale (CLOCS), and Innsbruck Coma Scale (INNS) showed substantial evidence of internal consistency. The FOUR and the CRS-R showed substantial evidence of good interrater reliability. Evidence of diagnostic validity and prognostic validity in brain injury survivor samples had very high levels of potential bias because of methodologic issues such as lack of rater masking. Conclusions: The CRS-R may be used to assess DOC with minor reservations, and the SMART, WNSSP, SSAM, WHIM, and DOCS may be used to assess DOC with moderate reservations. The CNC may be used to assess DOC with major reservations. The FOUR, INNS, Glasgow-Liege Coma Scale, Swedish Reaction Level Scale-1985, Loewenstein Communication Scale, and CLOCS are not recommended at this time for bedside behavioral assessment of DOC because of a lack of content validity, lack of standardization, and/or unproven reliability. C1 [Seel, Ronald T.; Kaelin, Darryl] Shepherd Ctr, Crawford Res Inst, Atlanta, GA 30309 USA. [Seel, Ronald T.; Kaelin, Darryl] Shepherd Ctr, Brain Injury Program, Atlanta, GA 30309 USA. [Sherer, Mark] Univ Texas Med Sch Houston, Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX USA. [Sherer, Mark] Univ Texas Med Sch Houston, TIRR Mem Hermann, Houston, TX USA. [Whyte, John] Moss Rehabil Res Inst, Elkins Pk, PA USA. [Katz, Douglas I.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Katz, Douglas I.] Braintree Rehabil Hosp, Brain Injury Program, Braintree, MA USA. [Rosenbaum, Amy M.] Pk Terrace Care Ctr, Queens, NY USA. [Giacino, Joseph T.; Zafonte, Ross] Harvard Univ, Spaulding Rehabil Hosp, Boston, MA 02115 USA. [Hammond, Flora M.; Kean, Jacob] Indiana Univ Sch Med, Dept Phys Med & Rehabil, Indianapolis, IN USA. [Giacino, Joseph T.; Kalmar, Kathleen] JFK Med Ctr, Ctr Head Injuries, JFK Johnson Rehabil Inst, Edison, NJ USA. [Pape, Theresa Louise-Bender] Northwestern Univ, Feinberg Sch Med, Res Serv, Chicago, IL 60611 USA. [Pape, Theresa Louise-Bender] Northwestern Univ, Feinberg Sch Med, Edward Hines Jr Vet Affairs Hosp, Complex Chron Care Ctr Excellence,Ctr Management, Chicago, IL 60611 USA. [Pape, Theresa Louise-Bender] Northwestern Univ, Feinberg Sch Med, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. [Biester, Rosette C.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Zasler, Nathan] Concuss Care Ctr Virginia, Richmond, VA USA. [Zasler, Nathan] Tree Life Serv, Richmond, VA USA. RP Seel, RT (reprint author), Shepherd Ctr, Crawford Res Inst, 2020 Peachtree Rd, Atlanta, GA 30309 USA. EM ron_seel@shepherd.org OI Pape, Theresa/0000-0001-7738-5963; Kean, Jacob/0000-0002-8577-0586 FU American Congress of Rehabilitation Medicine Clinical Practice Committee; National Institute on Disability and Rehabilitation Research Model Systems Knowledge Translation Center FX Financial and technical support by the American Congress of Rehabilitation Medicine Clinical Practice Committee and the National Institute on Disability and Rehabilitation Research Model Systems Knowledge Translation Center. NR 132 TC 121 Z9 128 U1 2 U2 35 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2010 VL 91 IS 12 BP 1795 EP 1813 DI 10.1016/j.apmr.2010.07.218 PG 19 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 700KY UT WOS:000285738900001 ER PT J AU Niehaus, AF Jackson, J Davies, S AF Niehaus, Ashley F. Jackson, Joan Davies, Stephanie TI Sexual Self-Schemas of Female Child Sexual Abuse Survivors: Relationships with Risky Sexual Behavior and Sexual Assault in Adolescence SO ARCHIVES OF SEXUAL BEHAVIOR LA English DT Article DE Child sexual abuse; Sexual self-schema; Sexual risk; Adolescent sexual assault ID WOMEN; REVICTIMIZATION; ADJUSTMENT; IMPACT; PSYCHOPATHOLOGY; AROUSABILITY; PERCEPTIONS; INVENTORY; HISTORY; SCALE AB Childhood sexual trauma has been demonstrated to increase survivors' risk for engaging in unrestricted sexual behaviors and experiencing adolescent sexual assault. The current study used the sexual self-schema construct to examine cognitive representations of sexuality that might drive these behavioral patterns. In Study 1 (N = 774), we attempted to improve the content validity of the Sexual Self Schema Scale for child sexual abuse (CSA) survivors, introducing a fourth sexual self-schema factor titled the "immoral/irresponsible" factor. In Study 2 (N = 1150), the potential differences in sexual self-views, as assessed by the four sexual self-schema factors, between CSA survivors and non-victims were explored. In addition, Study 2 evaluated how these sexual self-schema differences may contribute to participation in unrestricted sexual behaviors and risk for sexual assault in adolescence. Results indicated that a history of CSA impacted the way women viewed themselves as a sexual person on each of the four factors. CSA survivors were found to view themselves as more open and possessing more immoral/irresponsible cognitions about sexuality as compared to women who did not have a CSA history. In addition, the CSA survivors endorsed less embarrassment and passionate/romantic views of their sexual selves. The interaction of CSA severity and the sexual self-schemas explained variance in adolescent sexual assault experiences above and beyond the severity of CSA history and participation in risky sexual behaviors. The findings suggest that sexual self-views may serve to moderate the relationship between CSA and adolescent sexual assault. Implications of these findings and directions for future research are discussed. C1 [Niehaus, Ashley F.] Boston VA Healthcare Syst, Psychol Serv 116B, Boston, MA 02130 USA. [Jackson, Joan] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. RP Niehaus, AF (reprint author), Boston VA Healthcare Syst, Psychol Serv 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM ashley.niehaus@va.gov NR 46 TC 9 Z9 9 U1 2 U2 17 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0004-0002 J9 ARCH SEX BEHAV JI Arch. Sex. Behav. PD DEC PY 2010 VL 39 IS 6 BP 1359 EP 1374 DI 10.1007/s10508-010-9600-9 PG 16 WC Psychology, Clinical; Social Sciences, Interdisciplinary SC Psychology; Social Sciences - Other Topics GA 676SS UT WOS:000283939500022 PM 20229148 ER PT J AU Cherayil, BJ AF Cherayil, Bobby J. TI Iron and Immunity: Immunological Consequences of Iron Deficiency and Overload SO ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS LA English DT Review DE Iron; Metabolism; Macrophage; Inflammation; Lymphocyte ID REGULATORY HORMONE HEPCIDIN; TOLL-LIKE RECEPTORS; HEREDITARY HEMOCHROMATOSIS; KAPPA-B; CONGENITAL ATRANSFERRINEMIA; TRANSCRIPTION FACTORS; TRANSFERRIN RECEPTOR; INNATE IMMUNITY; DIETARY IRON; IN-VIVO AB The influence of iron on immune function has been long appreciated. However, the molecular basis for this interaction is less well understood. Recently, there have been several important advances that have shed light on the mechanisms that regulate mammalian iron metabolism. The new insights provide a conceptual framework for understanding and manipulating the cross-talk between iron homeostasis and the immune system. This article will review what is currently known about how disturbances of iron metabolism can affect immunity and how activation of the immune system can lead to alterations in iron balance. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat,Mucosal Immunol Lab, Boston, MA 02129 USA. RP Cherayil, BJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat,Mucosal Immunol Lab, Bldg 114,16th St, Boston, MA 02129 USA. EM cherayil@helix.mgh.harvard.edu FU National Institutes of Health [R56 AI089700]; Broad Medical Research Program [IBD-0253]; Crohn's and Colitis Foundation of America FX Work in the author's laboratory is supported by grants from the National Institutes of Health (R56 AI089700), the Broad Medical Research Program (IBD-0253) and the Crohn's and Colitis Foundation of America. NR 93 TC 23 Z9 26 U1 1 U2 17 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 0004-069X J9 ARCH IMMUNOL THER EX JI Arch. Immunol. Ther. Exp. PD DEC PY 2010 VL 58 IS 6 BP 407 EP 415 DI 10.1007/s00005-010-0095-9 PG 9 WC Immunology SC Immunology GA 666TR UT WOS:000283144000003 PM 20878249 ER PT J AU Wan, JB Huang, LL Rong, R Tan, R Wang, JD Kang, JX AF Wan, Jian-Bo Huang, Li-Li Rong, Rong Tan, Rui Wang, Jingdong Kang, Jing X. TI Endogenously Decreasing Tissue n-6/n-3 Fatty Acid Ratio Reduces Atherosclerotic Lesions in Apolipoprotein E-Deficient Mice by Inhibiting Systemic and Vascular Inflammation SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; fat-1 transgenic mice; n-3 fatty acids; n-6/n-3 fatty acid ratio; inflammation ID FAT-1 TRANSGENIC MICE; E KNOCKOUT MICE; FISH-OIL; CARDIOVASCULAR-DISEASE; ENDOTHELIAL ADHESION; LIPID MEDIATORS; OMEGA-3-FATTY-ACIDS; ATHEROGENESIS; EXPRESSION; RISK AB Objective-To use the fat-1 transgenic mouse model to determine the role of tissue n-6/n-3 fatty acid ratio in atherosclerotic plaque formation. Although it has been suggested that a low ratio of n-6/n-3 polyunsaturated fatty acids (PUFAs) is more desirable in reducing the risk of atherosclerotic cardiovascular disease, the role of tissue n-6/n-3 fatty acid ratio in atherosclerosis has not been sufficiently tested in a well-controlled experimental system. The fat-1 transgenic mouse model, expressing an n-3 fatty acid desaturase, is capable of producing n-3 PUFAs from n-6 PUFAs and thereby has a ratio of n-6/n-3 fatty acids close to 1:1 in tissues and organs. Methods and Results-To generate apolipoprotein E-deficient plus fat-1 transgenic mice (apoE(-/-)/fat-1), we crossed heterozygous fat-1 mice with apoE(-/-) mice. After 14 weeks of a Western-type diet rich in n-6 PUFAs, the apoE(-/-)/fat-1 mice showed a lower ratio of n-6/n-3 fatty acids than the apoE(-/-) mice in all organs and tissues tested. The aortic lesion area in apoE(-/-)/fat-1 mice was significantly reduced when compared with that of apoE(-/-) littermates (7.14 +/- 0.54% versus 13.49 +/- 1.61%). There were no differences in plasma cholesterol or high-and low-density lipoprotein levels between the 2 groups, except for a higher triglyceride level in the apoE(-/-)/fat-1 mice. A significant reduction of interleukin 6 and prostaglandin E-2 in both plasma and aorta culture medium was observed in apoE(-/-)/fat-1 mice. RT-PCR analysis also indicated that the expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, interleukin 6, and cyclooxygenase-2 was lower in the aortas and the circulating monocytes from apoE(-/-)/fat-1 mice. In addition, the expression of nuclear factor kappa B/p65 in the aorta and the recruitment of macrophages into atherosclerotic plaques were reduced in apoE(-/-)/fat-1 mice, compared with apoE(-/-) mice. Conclusion-To our knowledge, this is the first study to provide direct evidence for the role of tissue n-6/n-3 ratio in atherosclerosis using the fat-1 transgenic mouse model. Our findings demonstrate that a decreased n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apoE(-/-) mice. This protective effect may be attributed to the antiinflammatory properties of n-3 fatty acids, rather than their lipid-lowering effect. (Arterioscler Thromb Vasc Biol. 2010;30:2487-2494.) C1 [Wan, Jian-Bo; Huang, Li-Li; Rong, Rong; Tan, Rui; Wang, Jingdong; Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. [Huang, Li-Li] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Obstet & Gynecol, Guangzhou 510275, Guangdong, Peoples R China. RP Kang, JX (reprint author), Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, 149 13th St,Room 4433, Charlestown, MA 02129 USA. EM jxkang@partners.org RI Wan, Jian-Bo/D-8368-2014 OI Wan, Jian-Bo/0000-0002-6750-2617 FU E-fund Education Foundation, Guangzhou, China FX This study is partly supported by the E-fund Education Foundation, Guangzhou, China. NR 46 TC 49 Z9 52 U1 2 U2 12 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 DEC PY 2010 VL 30 IS 12 BP 2487 EP U282 DI 10.1161/ATVBAHA.110.210054 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 681JU UT WOS:000284309000034 PM 20705919 ER PT J AU Hoofnagle, AN Wu, MY Gosmanova, AK Becker, JO Wijsman, EM Brunzell, JD Kahn, SE Knopp, RH Lyons, TJ Heinecke, JW AF Hoofnagle, Andrew N. Wu, Mingyuan Gosmanova, Albina K. Becker, Jessica O. Wijsman, Ellen M. Brunzell, John D. Kahn, Steven E. Knopp, Robert H. Lyons, Timothy J. Heinecke, Jay W. TI Low Clusterin Levels in High-Density Lipoprotein Associate With Insulin Resistance, Obesity, and Dyslipoproteinemia SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE high-density lipoprotein; atherosclerosis; apolipoprotein J; clusterin; intra-abdominal fat; insulin resistance; obesity ID CORONARY-HEART-DISEASE; TANDEM MASS-SPECTROMETRY; APOLIPOPROTEIN-A-II; METABOLIC SYNDROME; ANTIINFLAMMATORY PROPERTIES; CARDIOVASCULAR-DISEASE; HDL METABOLISM; LDL RECEPTOR; ATHEROSCLEROSIS; COMPLEMENT AB Objective-To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. Methods and Results-Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean insulin-sensitive, lean insulin-resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low-density lipoprotein. Conclusion-Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDL's cardioprotective properties. (Arterioscler Thromb Vasc Biol. 2010;30:2528-2534.) C1 [Hoofnagle, Andrew N.; Becker, Jessica O.] Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. [Hoofnagle, Andrew N.; Wijsman, Ellen M.; Brunzell, John D.; Kahn, Steven E.; Knopp, Robert H.; Heinecke, Jay W.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Hoofnagle, Andrew N.; Heinecke, Jay W.] Univ Washington, Sch Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Wu, Mingyuan; Gosmanova, Albina K.; Lyons, Timothy J.] Univ Oklahoma, Hlth Sci Ctr, Harold Hamm Oklahoma Diabet Ctr, Oklahoma City, OK USA. [Wu, Mingyuan; Gosmanova, Albina K.; Lyons, Timothy J.] Univ Oklahoma, Hlth Sci Ctr, Sect Endocrinol & Diabet, Oklahoma City, OK USA. [Wijsman, Ellen M.] Univ Washington, Sch Med, Dept Biostat, Seattle, WA 98195 USA. [Kahn, Steven E.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Hoofnagle, AN (reprint author), Univ Washington, Sch Med, Dept Lab Med, Seattle, WA 98195 USA. EM ahoof@u.washington.edu OI Wijsman, Ellen/0000-0002-2725-6669; Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [DK002456, HL030086, HL086798]; Clinical Nutrition Research Unit (University of Washington) [DK035816]; Diabetes and Endocrinology Research Center (University of Washington) [DK017047]; Clinical Mass Spectrometry Facility (University of Washington); Proteome Resource (University of Washington); General Clinical Research Center (University of Oklahoma Health Sciences Center); US Department of Veterans Affairs FX This study was supported by grants DK002456, HL030086, and HL086798 from the National Institutes of Health; grant DK035816 from the Clinical Nutrition Research Unit (University of Washington); grant DK017047 from the Diabetes and Endocrinology Research Center (University of Washington); the Clinical Mass Spectrometry Facility (University of Washington); the Proteome Resource (University of Washington); the General Clinical Research Center (University of Oklahoma Health Sciences Center); and the US Department of Veterans Affairs. NR 45 TC 39 Z9 40 U1 0 U2 3 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 DEC PY 2010 VL 30 IS 12 BP 2528 EP U374 DI 10.1161/ATVBAHA.110.212894 PG 16 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 681JU UT WOS:000284309000039 PM 20847305 ER PT J AU Mahr, AD Edberg, JC Stone, JH Hoffman, GS St Clair, EW Specks, U Dellaripa, PF Seo, P Spiera, RF Rouhani, FN Brantly, ML Merkel, PA AF Mahr, Alfred D. Edberg, Jeffrey C. Stone, John H. Hoffman, Gary S. St Clair, E. William Specks, Ulrich Dellaripa, Paul F. Seo, Philip Spiera, Robert F. Rouhani, Farshid N. Brantly, Mark L. Merkel, Peter A. CA Wegeners Granulomatosis Genetic TI Alpha(1)-Antitrypsin Deficiency-Related Alleles Z and S and the Risk of Wegener's Granulomatosis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; POSITIVE SYSTEMIC VASCULITIS; ALPHA-1-ANTITRYPSIN DEFICIENCY; PIZ ALLELE; ANCA; EPIDEMIOLOGY AB Objective. Deficiency of alpha(1)-antitrypsin (alpha(1)AT) may be a determinant of susceptibility to Wegener's granulomatosis (WG). Several previous, mainly small, case-control studies have shown that 5-27% of patients with WG carried the alpha(1)AT deficiency Z allele. It is not clear whether the S allele, the other major alpha(1)AT deficiency variant, is associated with WG. This study investigated the relationship of the alpha(1)AT deficiency Z and S alleles with the risk of developing WG in a large cohort. Methods. We studied the distribution of the alpha(1)AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods. Results. Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98-2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33-infinity). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying >= 1 Z or >= 1 S allele. Conclusion. Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between alpha(1)AT deficiency and susceptibility to WG. C1 [Merkel, Peter A.] Boston Univ, Sch Med, Vasculitis Ctr, Boston, MA 02118 USA. [Edberg, Jeffrey C.] Univ Alabama Birmingham, Birmingham, AL USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [St Clair, E. William] Duke Univ, Med Ctr, Durham, NC USA. [Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Dellaripa, Paul F.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Spiera, Robert F.] Hosp Special Surg, New York, NY 10021 USA. [Rouhani, Farshid N.; Brantly, Mark L.] Univ Florida, Gainesville, FL USA. RP Merkel, PA (reprint author), Boston Univ, Sch Med, Vasculitis Ctr, E5,72 E Concord St, Boston, MA 02118 USA. EM pmerkel@bu.edu FU NIH/National Center for Research Resources [U54-RR-019497]; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases [P60-AR-047785, R01-AR-047799, K24-AR-02224]; Societe Nationale Francaise de Medicine Interne; NIH/National Heart, Lung, and Blood Institute [K24-HL-004456] FX Supported by the Vasculitis Clinical Research Consortium (funded by NIH/National Center for Research Resources grant U54-RR-019497) and NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases grants P60-AR-047785 and R01-AR-047799. Dr. Mahr's work was supported in part by a grant from the Societe Nationale Francaise de Medicine Interne. Dr. Brantly is recipient of an NIH/National Heart, Lung, and Blood Institute Mid-Career Development Award in Clinical Investigation (K24-HL-004456) and is the Alpha-1 Foundation Research Professor at the University of Florida. Dr. Merkel is recipient of an NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Mid-Career Development Award in Clinical Investigation (K24-AR-02224). NR 27 TC 37 Z9 38 U1 0 U2 1 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 DEC PY 2010 VL 62 IS 12 BP 3760 EP 3767 DI 10.1002/art.27742 PG 8 WC Rheumatology SC Rheumatology GA 693FO UT WOS:000285210200029 PM 20827781 ER PT J AU Suri, P Morgenroth, DC Kwoh, CK Bean, JF Kalichman, L Hunter, DJ AF Suri, Pradeep Morgenroth, David C. Kwoh, C. Kent Bean, Jonathan F. Kalichman, Leonid Hunter, David J. TI Low Back Pain and Other Musculoskeletal Pain Comorbidities in Individuals With Symptomatic Osteoarthritis of the Knee: Data From the Osteoarthritis Initiative SO ARTHRITIS CARE & RESEARCH LA English DT Article ID OLDER-ADULTS; RHEUMATOID-ARTHRITIS; DISABILITY; IMPACT; EPIDEMIOLOGY; OUTCOMES; HEALTH; INDEX; REPLACEMENT; RELIABILITY AB Objective. To examine the association of concurrent low back pain (LBP), and other musculoskeletal pain comorbidity, with knee pain severity in symptomatic knee osteoarthritis (OA). Methods. Individuals from the Progression Cohort of the Osteoarthritis Initiative (n = 1,389, ages 45-79 years) with symptomatic tibiofemoral knee OA were studied. Participants identified pain in the low back, neck, shoulder, elbow, wrist, hand, hip, knee, ankle, or foot. The primary outcome was the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) applied to the more symptomatic knee. We examined WOMAC pain score in persons with and without LBP, before and after adjusting for other musculoskeletal symptoms. Results. Of the participants, 57.4% reported LBP. The mean +/- SD WOMAC pain score (possible range 0-20) was 6.5 +/- 4.1 in participants with and 5.2 +/- 3.4 in participants without LBP (P < 0.0001). In multivariate analyses, LBP was significantly associated with increased WOMAC knee pain score (beta [SE] = 1.00 [0.21], P < 0.0001). However, pain in all other individual musculoskeletal locations demonstrated similar associations with knee pain score. In models including all pain locations simultaneously, only LBP (beta [SE] = 0.65 [0.21], P = 0.002), ipsilateral elbow pain (beta [SE] = 0.98 [0.40], P = 0.02), and ipsilateral foot pain (beta [SE] = 1.03 [0.45], P = 0.02) were significantly associated with knee pain score. Having >1 pain location was associated with greater WOMAC knee pain; this relationship was strongest for individuals having 4 (beta [SE] = 1.83 [0.42], P < 0.0001) or >= 5 pain locations (beta [SE] = 1.86 [0.36], P < 0.0001). Conclusion. LBP, foot pain, and elbow pain are significantly associated with WOMAC knee pain score, as are a higher total number of pain locations. This may have implications for clinical trial planning. C1 [Suri, Pradeep; Bean, Jonathan F.] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA USA. [Suri, Pradeep] VA Boston Healthcare Syst, Boston, MA USA. [Morgenroth, David C.] Univ Washington, Med Ctr, VA Puget Sound Healthcare Syst, Seattle, WA 98195 USA. [Kwoh, C. Kent] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kalichman, Leonid] Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. [Hunter, David J.] Univ Sydney, No Clin Sch, Sydney, NSW 2006, Australia. RP Suri, P (reprint author), New England Baptist Hosp, Div Res, 125 Parker Hill Ave, Boston, MA 02130 USA. EM psuri@caregroup.harvard.edu RI Hunter, David/A-4622-2010; Bean, Jonathan/F-5798-2017; OI Hunter, David/0000-0003-3197-752X; Bean, Jonathan/0000-0001-8385-8210; Morgenroth, David/0000-0002-0226-7775; Kalichman, Leonid/0000-0003-2987-4396 FU Osteoarthritis Initiative (OAI); Merck Research Laboratories; Novartis Pharmaceuticals Corporation; GlaxoSmithKline; Pfizer; Rehabilitation Medicine Scientist Training Program; NIH [K2-HD01097]; Australian Research Council; NIH, a branch of the Department of Health and Human Services [N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262] FX Private funding partners of the Osteoarthritis Initiative (OAI) include Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer. Private sector funding for the OAT is managed by the Foundation for the NIH. This manuscript has received the approval of the OAI Publications Committee based on a review of its scientific content and data interpretation. The private funding partners listed above had no role in the design, data collection, data analysis, or writing of this manuscript. The publication of this article was not contingent on the approval of Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer.; Dr. Suri and Morgenroth's work was supported by Rehabilitation Medicine Scientist Training Program and the NIH (grant K2-HD01097), Dr. Hunter's work was supported by an Australian Research Council Future Fellowship. The Osteoarthritis Initiative is supported by the NIH, a branch of the Department of Health and Human Services (contracts N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, and N01-AR-2-2262), and by Merck Research Laboratories, Novartis Pharmaceuticals Corporation, GlaxoSmithKline, and Pfizer NR 34 TC 29 Z9 29 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2010 VL 62 IS 12 BP 1715 EP 1723 DI 10.1002/acr.20324 PG 9 WC Rheumatology SC Rheumatology GA 694VL UT WOS:000285327000006 PM 20799265 ER PT J AU Lee, BL Stone, JH Gimbel, D Khosroshahi, A AF Lee, Brittany L. Stone, John H. Gimbel, Devon Khosroshahi, Arezou TI A 44-Year-Old Woman With Cutaneous Bullae and Extensive Skin Necrosis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; MIDLINE DESTRUCTIVE LESIONS; ANTIPHOSPHOLIPID SYNDROME; COCAINE ABUSE; INDUCED VASCULITIS; CIRCULATING AUTOANTIBODIES; CLASSIFICATION CRITERIA; POLYARTERITIS-NODOSA; LEVAMISOLE; DISEASE C1 [Stone, John H.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, 55 Fruit St Yawkey 2C, Boston, MA 02114 USA. EM jhstone@partners.org NR 41 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2010 VL 62 IS 12 BP 1805 EP 1811 DI 10.1002/acr.20240 PG 7 WC Rheumatology SC Rheumatology GA 694VL UT WOS:000285327000017 PM 20506546 ER PT J AU Oh, B Butow, P Mullan, B Beale, P Pavlakis, N Rosenthal, D Clarke, S AF Oh, Byeongsang Butow, Phyllis Mullan, Barbara Beale, Philip Pavlakis, Nick Rosenthal, David Clarke, Stephen TI The use and perceived benefits resulting from the use of complementary and alternative medicine by cancer patients in Australia SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Article DE cancer; complementary and alternative medicine; efficacy; safety ID BREAST-CANCER; PROSTATE-CANCER; THERAPY USE; WOMEN; CAM; COMMUNICATION; PREVALENCE AB Aim: The use of complementary and alternative medicine (CAM) by cancer patients is growing. However, few studies have examined the perceived benefits and adverse effects resulting from the use of CAM by cancer patients. The aim of this study was to evaluate CAM use by cancer patients and to explore their perceptions of the benefit, safety and efficacy of CAM in general. Methods: Oncologists from three university teaching hospitals screened patients for eligibility. Eligible patients (N = 1323) were mailed a letter of invitation with a questionnaire between January and May 2008. Results: Overall 381 questionnaires were returned, showing that 65% of cancer patients used at least one form of CAM. Patients considered taking biological CAM before, during and after chemotherapy. Up to 90% of CAM users believed that CAM provided potential health benefits and less than 3% reported adverse effects experienced from the use of CAM. Most respondents (80%) believed CAM can provide health benefits even when efficacy has not been proven. Most patients (90%) believed that doctors should consider learning about CAM to provide appropriate advice to their cancer patients, and most (83%) indicated they would be happier to accept CAM if it was offered by the hospital. Conclusion: A substantial portion of Australian cancer patients use CAM. Given the limited data on efficacy and safety for most CAM, it may be reasonable to offer CAM within the hospital environment so its use can be monitored and patients can receive more evidence-based care. C1 [Oh, Byeongsang; Beale, Philip; Pavlakis, Nick; Clarke, Stephen] Univ Sydney, Dept Med, Sydney, NSW 2006, Australia. [Oh, Byeongsang; Butow, Phyllis; Mullan, Barbara] Univ Sydney, Ctr Med Psychol & Evidence Based Decis Making, Sydney, NSW 2006, Australia. [Oh, Byeongsang; Beale, Philip; Clarke, Stephen] Concord Hosp, Sydney Canc Ctr, Sydney, NSW, Australia. [Pavlakis, Nick] Royal N Shore Hosp, Dept Med Oncol, Sydney, NSW, Australia. [Rosenthal, David] Dana Faber Canc Inst, Boston, MA USA. [Rosenthal, David] Harvard Univ, Sch Med, Boston, MA USA. RP Oh, B (reprint author), Univ Sydney, Concord Repatriat Gen Hosp, Dept Med, Concord, NSW 2139, Australia. EM byeong.oh@sydney.edu.au OI Mullan, Barbara/0000-0002-0177-8899 FU University of Sydney FX This research was supported by the University of Sydney Cancer Research Fund and carried out at the University teaching hospitals (Royal Prince Alfred Hospital, Concord Hospital and Royal North Shore Hospital). The authors wish to acknowledge the contribution of the research assistant, Emily Kothe, who provided data entry, and especially to thank the participants who made this study possible. NR 32 TC 23 Z9 23 U1 2 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-7555 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD DEC PY 2010 VL 6 IS 4 BP 342 EP 349 DI 10.1111/j.1743-7563.2010.01329.x PG 8 WC Oncology SC Oncology GA 687IF UT WOS:000284771500014 PM 21114784 ER PT J AU Ta, NN Li, YC Schuyler, CA Lopes-Virella, MF Huang, Y AF Ta, Nga N. Li, Yanchun Schuyler, Corinne A. Lopes-Virella, Maria F. Huang, Yan TI DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes SO ATHEROSCLEROSIS LA English DT Article DE Dipeptidyl peptidase-4; CD26; Mitogen-activated protein kinase; Matrix metalloproteinase; Atherosclerosis ID DIPEPTIDYL-PEPTIDASE-IV; PROTEIN-KINASE; CYTOKINE PRODUCTION; DNA-SYNTHESIS; CANCER CELLS; DP-IV; PATHWAY; TOLERABILITY; MACROPHAGE; PROFILES AB Dipeptidyl peptidase-4 (DPP-4)/CD26, a cell surface glycoprotein, is expressed by a variety of cells including T cells, B cells, NK cells, and macrophages. Although it has been shown that DPP-4/CD26 is involved in T cell activation, its role in biological functions in macrophages has not been well investigated. In this study, we used alogliptin, a specific inhibitor of DPP 4/CD26, to study the effect of DPP-4/CD26 on the activation of the extracellular signal-regulated kinase (ERK) that plays a critical role in the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs) in U937 histiocytes. Results showed that 1 nM of alogliptin inhibited ERK phosphorylation induced by lipopolysaccharide (LPS), a ligand for toll-like receptor (TLR) 4, by 91%. Furthermore, results showed that alogliptin inhibited LPS-stimulated MMP-1 expression in a concentration-dependent manner and 1 nM of alogliptin inhibited MMP-1 expression by 60%. To confirm the involvement of the ERK pathway in MMP-1 expression by U937 cells, we showed that PD98059, a specific inhibitor for the ERK pathway, blocked LPS-stimulated MMP-1 expression. In addition to MMP-1, our study showed that alogliptin also inhibited MMP-9, -12 and -15, but had no effect on TIMP-1 and -2 expression. Taken together, this study showed for the first time that the inhibition of DPP-4/CD26 by alogliptin suppressed TLR4-mediated ERK activation and ERK-dependent MMP expression by U937 cells, suggesting that DPP-4/CD26 may play an important role in macrophage-mediated inflammation response and tissue remodeling. Published by Elsevier Ireland Ltd. C1 [Ta, Nga N.; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Schuyler, Corinne A.; Lopes-Virella, Maria F.; Huang, Yan] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Huang, Y (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU Takeda Pharmaceuticals North America, Inc.; Department of Veterans Affairs; NIH [DE016353] FX This work was supported by a pre-clinical grant from Takeda Pharmaceuticals North America, Inc., a Merit Review Grant from Department of Veterans Affairs and NIH grant DE016353 (to Y.H.). NR 33 TC 45 Z9 52 U1 2 U2 16 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 DEC PY 2010 VL 213 IS 2 BP 429 EP 435 DI 10.1016/j.atherosclerosis.2010.08.064 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 688RM UT WOS:000284869700015 PM 20843518 ER PT J AU Zhang, MH Na, B Schiller, N Whooley, MA AF Zhang, Mary H. Na, Beeya Schiller, Nelson B. Whooley, Mary A. TI Resistin, exercise capacity, and inducible ischemia in patients with stable coronary heart disease: Data from the Heart and Soul study SO ATHEROSCLEROSIS LA English DT Article DE Resistin; Coronary heart disease (CHD); Ischemia; Exercise capacity; Inflammation ID C-REACTIVE PROTEIN; INSULIN-RESISTANCE; ARTERY-DISEASE; NONDIABETIC PATIENTS; METABOLIC SYNDROME; STATIN THERAPY; RENAL-DISEASE; OBESITY; HUMANS; ECHOCARDIOGRAPHY AB Objective: Resistin is an adipocytokine involved in insulin resistance, inflammation, and atherosclerosis. Its role in the development and progression of coronary heart disease (CHD) is not yet well-characterized. We performed a cross-sectional study to evaluate the association between serum resistin levels, exercise capacity, and exercise-induced cardiac ischemia among patients with stable CHD. Methods and results: We measured serum resistin concentrations and determined treadmill exercise capacity and inducible ischemia by stress echocardiography in 899 outpatients with documented CHD. Of these, 215 (24%) had poor exercise capacity (<5 metabolic equivalent tasks), and 217 (24%) had inducible ischemia. As compared with participants who had resistin levels in the lowest quartile, those with resistin levels in the highest quartile were more likely to have poor exercise capacity (33% versus 16%, odds ratio [OR] 2.68, P < 0.0001) and inducible ischemia (30% versus 17%, OR 2.08, P = 0.001). Both associations remained robust after adjusting for numerous clinical risk factors, metabolic variables, and markers of insulin resistance (poor exercise capacity adjusted OR 1.73, P = 0.04; inducible ischemia adjusted OR 1.82, P = 0.01). However, further adjustments for C-reactive protein, interleukin-6, and tumor necrosis factor-alpha eliminated the association with poor exercise capacity (adjusted OR 1.50, P = 0.14) and substantially weakened the association with inducible ischemia (adjusted OR 1.72, P = 0.03). Conclusions: Elevated serum resistin is associated with poor exercise capacity and exercise-induced cardiac ischemia in patients with stable coronary disease. Adjustment for inflammatory markers attenuated these associations, suggesting a possible role for resistin in inflammation and CHD pathophysiology. Published by Elsevier Ireland Ltd. C1 [Schiller, Nelson B.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Zhang, Mary H.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Na, Beeya; Whooley, Mary A.] Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. RP Whooley, MA (reprint author), Univ Calif San Francisco, Dept Med, 4150 Clement St 111A1, San Francisco, CA 94121 USA. EM Mary.Whooley@ucsf.edu FU American Heart Association; American Federation for Aging Research; Philanthropic Educational Organization; Department of Veterans Affairs; National Heart, Lung and Blood Institute [R01 HL079235]; Robert Wood Johnson Foundation; Ischemia Research and Education Foundation; Nancy Kirwan Heart Research Fund FX Dr. Zhang was supported by research grants from the American Heart Association (Medical Student Research Program), the American Federation for Aging Research (Program for Medical Student Training in Aging Research), and the Philanthropic Educational Organization (Scholars Program). The Heart and Soul Study was supported by grants from the Department of Veterans Affairs (Epidemiology Merit Review Program), the National Heart, Lung and Blood Institute (R01 HL079235), the Robert Wood Johnson Foundation (Generalist Physician Faculty Scholars Program), the American Federation for Aging Research (Paul Beeson Faculty Scholars in Aging Research Program), the Ischemia Research and Education Foundation, and the Nancy Kirwan Heart Research Fund. None of these funding sources had any role in the collection of data, interpretation of results, or preparation of this manuscript. NR 37 TC 10 Z9 10 U1 1 U2 7 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 DEC PY 2010 VL 213 IS 2 BP 604 EP 610 DI 10.1016/j.atherosclerosis.2010.09.015 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 688RM UT WOS:000284869700043 PM 20951381 ER PT J AU Keough, ME Riccardi, CJ Timpano, KR Mitchell, MA Schmidt, NB AF Keough, Meghan E. Riccardi, Christina J. Timpano, Kiara R. Mitchell, Melissa A. Schmidt, Norman B. TI Anxiety Symptomatology: The Association With Distress Tolerance and Anxiety Sensitivity SO BEHAVIOR THERAPY LA English DT Article ID SOCIAL-INTERACTION ANXIETY; COMORBIDITY SURVEY REPLICATION; STATE WORRY QUESTIONNAIRE; BECK DEPRESSION INVENTORY; PANIC-ATTACKS; PSYCHOMETRIC PROPERTIES; PERSONALITY-DISORDER; GENERALIZED ANXIETY; BODILY SENSATIONS; PHOBIA SCALE AB Research focused on psychological risk factors for anxiety psychopathology has led to better conceptualization of these conditions as well as pointed toward preventative interventions. Anxiety sensitivity (AS) has been well-established as an anxiety risk factor, while distress tolerance (DT) is a related construct that has received little empirical exploration within the anxiety psychopathology literature. The current investigation sought to extend the existing literature by examining both DT and the relationship between DT and AS across a number of anxiety symptom dimensions, including panic, generalized anxiety, social anxiety, and obsessive-compulsive anxiety. Participants (N=418) completed a number of measures that assessed DT, AS, anxiety symptomatology, and negative affect. Findings indicated that DT was uniquely associated with panic, obsessive compulsive, general worry, and social anxiety symptoms, but that DT and AS were not synergistically associated with each of these symptom dimensions. These findings indicate that an inability to tolerate emotional distress is associated with an increased vulnerability to experience certain anxiety symptoms. C1 [Keough, Meghan E.; Riccardi, Christina J.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Timpano, Kiara R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schmidt, NB (reprint author), Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. EM schmidt@psy.fsu.edu RI Timpano, Kiara/C-8760-2012; OI Timpano, Kiara/0000-0002-0665-8722 FU NIMH NIH HHS [F31 MH086174, 1F31 MH086174-01] NR 54 TC 64 Z9 64 U1 3 U2 16 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD DEC PY 2010 VL 41 IS 4 BP 567 EP 574 PG 8 WC Psychology, Clinical SC Psychology GA 682IC UT WOS:000284393600011 PM 21035619 ER PT J AU D'Andrea, AD AF D'Andrea, Alan D. TI Targeting DNA repair pathways in AML SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE acute myeloid leukemia; AML; DNA repair pathway; Fanconi anemia; FA; poly-ADP-ribose polymerase (PARP); inhibitors; synthetic lethality ID LEUKEMIA AB Cancer cells often have DNA repair pathway deficiencies, which render cancer more sensitive to treatment but can also cause resistance if the DNA repair pathway is restored. By using DNA repair pathway inhibitors, cancers can be resensitized to conventional therapies, such as radiation and chemotherapy. There are 6 major DNA repair pathways, and each pathway has druggable targets and biomarkers to identify pathway activity. DNA repair inhibitors, such as poly-ADP-ribose polymerase (PARP) inhibitors, may be useful in a small subset of acute myeloid leukemia (AML) patients, especially those who have complex karyotypes or those with secondary AML Biomarkers in the Fanconi anemia repair pathway may provide a predictor to identify this subset of patients who are sensitive to this new class of drugs. (C) 2010 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Fuller Amer Canc Soc, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Fuller Amer Canc Soc, 44 Binney St, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu NR 6 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2010 VL 23 IS 4 BP 469 EP 473 DI 10.1016/j.beha.2010.09.005 PG 5 WC Hematology SC Hematology GA 705QW UT WOS:000286154000004 PM 21130409 ER PT J AU Huang, XB Morse, LR Xu, Y Zahradka, J Sychrova, H Stashenko, P Fan, FY Battaglino, RA AF Huang, Xiaobin Morse, Leslie R. Xu, Yan Zahradka, Jaromir Sychrova, Hana Stashenko, Phil Fan, Feiyue Battaglino, Ricardo A. TI Mutational analysis of NHAoc/NHA2 in Saccharomyces cerevisiae SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE Osteclast; Antiporter; Bone resorption; Yeast; Salt tolerance ID NA+/H+ ANTIPORTER; EXCHANGER; YEAST; GENE; NHA-OC/NHA2; EXPRESSION; TRANSPORT; SEQUENCE; NHAA; PH AB Background: NHAoc/NHA2 is highly and selectively expressed in osteoclasts and plays a role(s) in normal osteoclast differentiation, apoptosis and bone resorptive function in vitro. Extensive mutational analysis of a bacterial homologue, NhaA, has revealed a number of amino acid residues essential for its activity. Some of these residues are evolutionarily conserved and have been shown to be essential not only for activity of NhaA in bacteria, but also of NHAoc/NHA2 in eukaryotes. Methods: The salt-sensitive Saccharomyces cerevisiae strain BW31a was used for heterologous expression of mutants of NHAoc/NHA2. Membrane expression of NHAoc/NHA2 was confirmed by confocal microscopy. Intracellular concentration of Na+ (a measure of Na+ antiporter activity) was estimated by atomic absorption spectroscopy. The growth phenotypes of cells expressing NHAoc/NHA2 mutants were studied on YNB agar supplemented with NaCl and by growth curves in YNB broth. Results: Mutations in amino acid residues V161 and F357 reduced the ability of transfected BW31a cells to remove intracellular sodium and to grow in NaCl-containing medium. Yeast expressing the double mutant F357 F437 cannot grow in 0.4 M NaCl, suggesting that these residues are also essential for antiporter activity. Conclusions: Evolutionarily conserved amino acids are required for full antiporter function. General Significance: Mutations in these amino acid residues may impact NHAoc activity and therefore osteoclast function in vitro and in vivo. (C) 2010 Elsevier B.V. All rights reserved. C1 [Morse, Leslie R.; Stashenko, Phil; Battaglino, Ricardo A.] Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. [Huang, Xiaobin; Fan, Feiyue] Tsinghua Univ, Coll Med, Chinese Acad Med Sci, Inst Radiat Med, Beijing, Peoples R China. [Morse, Leslie R.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Xu, Yan] Kunming Med Univ, Kunming, Yunnan Province, Peoples R China. [Zahradka, Jaromir; Sychrova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Membrane Transport, Vvi, CR-14220 Prague, Czech Republic. RP Battaglino, RA (reprint author), Forsyth Inst, Dept Cytokine Biol, Boston, MA USA. EM rbattaglino@forsyth.org RI Sychrova, Hana /B-1350-2012; Morse, Leslie/C-9442-2015; battaglino, ricardo/D-2892-2015 OI Morse, Leslie/0000-0002-7426-6341; FU NIH-NIAMS [R21AR057915-01A1]; GA AS CR [IAA500110801]; MSMT COST [OC10012]; [AV0Z 50110509] FX This work was supported by the following grants: NIH-NIAMS R21AR057915-01A1 (RAB), GA AS CR IAA500110801 (HS), MSMT COST OC10012 (HS), and AV0Z 50110509 (HS). NR 19 TC 5 Z9 5 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD DEC PY 2010 VL 1800 IS 12 BP 1241 EP 1247 DI 10.1016/j.bbagen.2010.08.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 682HY UT WOS:000284393200003 PM 20713131 ER PT J AU Kahle, KT Rinehart, J Lifton, RP AF Kahle, Kristopher T. Rinehart, Jesse Lifton, Richard P. TI Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Review DE WNK kinase; NKCC1; KCC2; KCC3; Na-K-2Cl cotransporter; K-Cl cotransporter; SPAK; OSR1; Cell volume regulation; GABA ID CATION-CHLORIDE COTRANSPORTERS; RICH STE20-RELATED KINASE; TEMPORAL-LOBE EPILEPSY; CELL-VOLUME; PROTEIN-KINASE; MOLECULAR PHYSIOLOGY; ERYTHROCYTE DEHYDRATION; SUPRACHIASMATIC NUCLEUS; NEURONAL COMMUNICATION; CAENORHABDITIS-ELEGANS AB Precise regulation of the intracellular concentration of chloride [Cl ]i is necessary for proper cell volume regulation, transepithelial transport, and GABA neurotransmission. The Na-K-2Cl (NKCCs) and K-Cl (KCCs) cotransporters, related SLC12A transporters mediating cellular chloride influx and efflux, respectively, are key determinants of [Cl-]i in numerous cell types, including red blood cells, epithelial cells, and neurons. A common "chloride/volume-sensitive kinase", or related system of kinases, has long been hypothesized to mediate the reciprocal but coordinated phosphoregulation of the NKCCs and the KCCs, but the identity of these kinase(s) has remained unknown. Recent evidence suggests that the WNK (with no lysine = K) serine-threonine kinases directly or indirectly via the downstream Ste20-type kinases SPAK/OSR1, are critical components of this signaling pathway. Hypertonic stress (cell shrinkage), and possibly decreased [Cl-]i, triggers the phosphorylation and activation of specific WNKs, promoting NKCC activation and KCC inhibition via net transporter phosphorylation. Silencing WNK kinase activity can promote NKCC inhibition and KCC activation via net transporter dephosphorylation, revealing a dynamic ability of the WNKs to modulate [Cl-]. This pathway is essential for the defense of cell volume during osmotic perturbation, coordination of epithelial transport, and gating of sensory information in the peripheral system. Commiserate with their importance in serving these critical roles in humans, mutations in WNKs underlie two different Mendelian diseases, pseudohypoaldosteronism type II (an inherited form of salt-sensitive hypertension), and hereditary sensory and autonomic neuropathy type 2. WNKs also regulate ion transport in lower multicellular organisms, including Caenorhabditis elegans, suggesting that their functions are evolutionarily-conserved. An increased understanding of how the WNKs regulate the Na-K-2Cl and K-Cl cotransporters may provide novel opportunities for the selective modulation of these transporters, with ramifications for common human diseases like hypertension, sickle cell disease, neuropathic pain, and epilepsy. (c) 2010 Elsevier B.V. All rights reserved. C1 [Kahle, Kristopher T.] Harvard Univ, Sch Med, Dept Neurosurg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rinehart, Jesse; Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, Howard Hughes Med Inst, New Haven, CT 06510 USA. RP Kahle, KT (reprint author), Harvard Univ, Sch Med, Dept Neurosurg, Massachusetts Gen Hosp, 55 Fruit St,Grey Bigelow Bldg Room 502, Boston, MA 02114 USA. EM kkahle@genetics.med.harvard.edu FU Howard Hughes Medical Institute NR 89 TC 81 Z9 88 U1 0 U2 14 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 DEC PY 2010 VL 1802 IS 12 SI SI BP 1150 EP 1158 DI 10.1016/j.bbadis.2010.07.009 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 682HW UT WOS:000284393000004 PM 20637866 ER PT J AU Brohawn, KH Offringa, R Pfaff, DL Hughes, KC Shin, LM AF Brohawn, Kathryn Handwerger Offringa, Reid Pfaff, Danielle L. Hughes, Katherine C. Shin, Lisa M. TI The Neural Correlates of Emotional Memory in Posttraumatic Stress Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Amygdala; emotion; hippocampus; magnetic resonance imaging; memory; neuroimaging; posttraumatic; stress disorders ID MEDIAL PREFRONTAL CORTEX; CEREBRAL-BLOOD-FLOW; CHILDHOOD SEXUAL-ABUSE; BRAIN ACTIVITY; TEMPORAL-LOBE; HIPPOCAMPAL FUNCTION; SYMPTOM PROVOCATION; AMYGDALA RESPONSE; IMPLICIT MEMORY; PTSD AB Background: Posttraumatic stress disorder (PTSD) is marked by intrusive, chronic, and distressing memories of highly emotional events. Previous research has highlighted the role of the amygdala and its interactions with the hippocampus in mediating the effect of enhanced memory for emotional information in healthy individuals. As the functional integrity of these regions may be compromised in PTSD, the current study examined the neural correlates of emotional memory in PTSD. Methods: We used functional magnetic resonance imaging and an event-related subsequent memory recognition paradigm to study amygdala and hippocampus activation in 18 individuals with PTSD and 18 trauma-exposed non-PTSD control participants. Results: Memory enhancement for negative, relative to neutral, pictures was found across all subjects, without significant differences between groups. Relative to the trauma-exposed non-PTSD group, the PTSD group showed exaggerated amygdala activation during the encoding of negative versus neutral pictures. This effect was even more pronounced when the analysis included data from only pictures that were subsequently remembered 1 week later. In the PTSD group, degree of amygdala activation during the encoding of negative versus neutral pictures was positively correlated with hippocampal activation and current PTSD symptom severity. The PTSD group also showed exaggerated hippocampal activation in response to negative pictures that were remembered versus forgotten. Finally, hippocampal activation associated with the successful encoding of negative relative to neutral pictures was significantly greater in the PTSD group. Conclusions: Exaggerated amygdala activation during the encoding of emotionally negative stimuli in PTSD is related to symptom severity and to hippocampal activation. C1 [Brohawn, Kathryn Handwerger; Pfaff, Danielle L.; Hughes, Katherine C.; Shin, Lisa M.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Brohawn, Kathryn Handwerger; Hughes, Katherine C.; Shin, Lisa M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Pfaff, Danielle L.] McLean Hosp, Schizophrenia & Bipolar Disorders Program, Belmont, MA 02178 USA. RP Brohawn, KH (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM katiebrohawn@gmail.com FU National Science Foundation; Tufts University; National Alliance for Research on Schizophrenia and Depression Young Investigator Award FX KHB was supported by a National Science Foundation graduate student fellowship. LMS received support from Tufts University and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award. NR 58 TC 38 Z9 40 U1 2 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2010 VL 68 IS 11 BP 1023 EP 1030 DI 10.1016/j.biopsych.2010.07.018 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 688FG UT WOS:000284834600010 PM 20855060 ER PT J AU Storch, EA Murphy, TK Goodman, WK Geffken, GR Lewin, AB Henin, A Micco, JA Sprich, S Wilhelm, S Bengtson, M Geller, DA AF Storch, Eric A. Murphy, Tanya K. Goodman, Wayne K. Geffken, Gary R. Lewin, Adam B. Henin, Aude Micco, Jamie A. Sprich, Susan Wilhelm, Sabine Bengtson, Michael Geller, Daniel A. TI A Preliminary Study of D-Cycloserine Augmentation of Cognitive-Behavioral Therapy in Pediatric Obsessive-Compulsive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Children; cognitive-behavioral therapy; D-cycloserine; obsessive-compulsive disorder; outcome; treatment ID RANDOMIZED CONTROLLED-TRIAL; SOCIAL ANXIETY DISORDER; EXPOSURE THERAPY; CHILDREN; ADOLESCENTS; EXTINCTION; RELIABILITY; VALIDITY; SCALE; FEAR AB Background: Research on the neural circuitry underlying fear extinction has led to the examination of D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate receptor in the amygdala, as a method to enhance exposure therapy outcome. Preliminary results have supported the use of DCS to augment exposure therapy in adult anxiety disorders; however, no data have been reported in any childhood anxiety disorder. Thus, we sought to preliminarily examine whether weight-adjusted DCS doses (25 or 50 mg) enhanced the overall efficacy of cognitive-behavioral therapy (CBT) for pediatric obsessive-compulsive disorder (OCD). Method: Participants were 30 youth (aged 8-17) with a primary diagnosis of OCD. The study design was a randomized, double-blinded, placebo-controlled augmentation trial examining CBT + DCS versus CBT + Placebo (15 youth per group). All patients received seven exposure and response prevention sessions paired with DCS or placebo taken 1 hour before sessions. Results: Although not significantly different, compared with the CBT + Placebo group, youth in the CBT + DCS arm showed small-tomoderate treatment effects (d = .31-.47 on primary outcomes). No adverse events were recorded. Conclusions: These results complement findings in adult OCD and non-OCD anxiety disorders and provide initial support for a more extensive study of DCS augmentation of CBT among youth with OCD. C1 [Storch, Eric A.; Murphy, Tanya K.; Lewin, Adam B.; Bengtson, Michael] Univ S Florida, Dept Pediat & Psychiat, St Petersburg, FL 33701 USA. [Goodman, Wayne K.] Mt Sinai Hosp, Dept Psychiat, New York, NY 10029 USA. [Geffken, Gary R.] Univ Florida, Dept Psychiat, Gainesville, FL 32611 USA. [Geller, Daniel A.] Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. [Henin, Aude; Micco, Jamie A.; Sprich, Susan; Wilhelm, Sabine] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Storch, EA (reprint author), Univ S Florida, Dept Pediat, Rothman Ctr Neuropsychiat, Box 7523,800 6th St S, St Petersburg, FL 33701 USA. EM estorch@health.usf.edu RI Storch, Eric/I-4935-2012; Lewin, Adam/A-9832-2013 FU National Institutes of Health [MH076775, L40 MH081950-02]; National Alliance for Research on Schizophrenia and Affective Disorders; National Institute of Mental Health (NIMH); National Institute of Child Health and Human Development; All Children's Hospital Research Foundation; Centers for Disease Control; Obsessive-Compulsive Foundation; Tourette Syndrome Association; Janssen Pharmaceuticals; Foundation for Research on Prader-Willi Syndrome; Forest Laboratories; Endo; International OCD Foundation; Joseph Drown Foundation; Friends of the Semel Institute; Oxford University Press; AstraZeneca; Lilly; McNeil Pediatrics; Shire; Forest Laboratories, Inc.; Sanofi Aventis; Janssen; Pfizer; Bristol-Myers Squibb; Michael A. Jenike Endowed Fund; Food and Drug Administration; Elsevier Publications; Guilford Publications; New Harbinger Publications; Boehringer Ingelheim; National Institute of Neurological Disorders and Stroke; Eli Lilly and Co.; GlaxoSmithKline; Otsuka; Wallace Foundation; Pediatric Obsessive Compulsive and Related Disorders; McIngvale Family Foundation FX This work was supported by grants to the first author from the National Institutes of Health (Grant Nos. MH076775 and L40 MH081950-02) and National Alliance for Research on Schizophrenia and Affective Disorders (Robidoux Foundation Young Investigator Award). We acknowledge the contributions of Alex De Nadai; Alyssa Faro; Marni Jacob; Mark Lewis, Ph.D.; Elizabeth Mancuso; Jessica Morgan; Emily Ricketts; and Mark Yang, Ph.D.; Dr. Storch receives grant funding from the National Institute of Mental Health (NIMH), National Institute of Child Health and Human Development, All Children's Hospital Research Foundation, Centers for Disease Control, National Alliance for Research on Schizophrenia and Affective Disorders, Obsessive-Compulsive Foundation, Tourette Syndrome Association, Janssen Pharmaceuticals, and Foundation for Research on Prader-Willi Syndrome. He receives textbook honoraria from Springer Publishers and Lawrence Erlbaum. Dr. Storch has been an educational consultant for Rogers Memorial Hospital. Dr. Murphy has received research support from NIMH, Forest Laboratories, Janssen Pharmaceuticals, Endo, Obsessive-Compulsive Foundation, Tourette Syndrome Association, All Children's Hospital Research Foundation, Centers for Disease Control, and National Alliance for Research on Schizophrenia and Affective Disorders. Dr. Murphy is on the Medical Advisory Board for the Tourette Syndrome Association. She receives textbook honorarium from Lawrence Erlbaum. Dr. Lewin reports research support funding from the National Alliance for Research on Schizophrenia and Affective Disorders, the International OCD Foundation, the Joseph Drown Foundation, and the Friends of the Semel Institute. Dr. Geffken receives grant funding from the NIMH. Dr. Henin has received honoraria from Shire, Abbott Laboratories, and American Academy of Child and Adolescent Psychiatry. She receives royalties from Oxford University Press. She has also received honoraria from Reed Medical Education (a company working as a logistics collaborator for the Massachusetts General Hospital [MGH] Psychiatry Academy). The education programs conducted by the MGH Psychiatry Academy were supported in part though Independent Medical Education grants from pharmaceutical companies, including AstraZeneca, Lilly, McNeil Pediatrics, Shire, Forest Laboratories, Inc., Sanofi Aventis, Janssen, Bristol-Myers Squibb, and Pfizer. Dr. Micco receives grant funding from the NIMH. Dr. Sprich receives grant funding from the NIMH and receives funding from the Michael A. Jenike Endowed Fund and royalties from Oxford University Press. Dr. Wilhelm has received research support from NIMH, the Food and Drug Administration, the Obsessive-Compulsive Foundation, and the Tourette Syndrome Association. Forest Laboratories provided her with medication for an NIMH funded study. Dr. Wilhelm is a presenter for the MGH Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies; she has received royalties from Elsevier Publications, Guilford Publications, New Harbinger Publications, and Oxford University Press. Dr. Wilhelm has also received speaking honoraria from various academic institutions. Dr. Bengtson has received research support from Boehringer Ingelheim. Dr. Geller has received research support from the National Institute of Neurological Disorders and Stroke, NIMH, Eli Lilly and Co., Forest Laboratories, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Otsuka, Obsessive-Compulsive Foundation, Tourette Syndrome Association, Wallace Foundation, Pediatric Obsessive Compulsive and Related Disorders fund (philanthropic), and McIngvale Family Foundation (philanthropic). He has received speaker honoraria from Alza, Bristol-Myers-Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Novartis, Pfizer, Shire, and Wyeth. Dr. Geller is on the medical advisory board or consults for the following companies: Eli Lilly, Solvay, Lundbeck, and GlaxoSmithKline.; He has been an educatioal consultant for Rogers Memorial Hospital and received honorarium from American Psychiatric Publishing. Dr. Goodman reports no biomedical financial interests or potential conflicts of interest. NR 20 TC 84 Z9 86 U1 7 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2010 VL 68 IS 11 BP 1073 EP 1076 DI 10.1016/j.biopsych.2010.07.015 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 688FG UT WOS:000284834600017 PM 20817153 ER PT J AU Levine, JE Logan, B Wu, JA Alousi, AM Ho, V Bolanos-Meade, J Weisdorf, D AF Levine, John E. Logan, Brent Wu, Juan Alousi, Amin M. Ho, Vincent Bolanos-Meade, Javier Weisdorf, Daniel CA Blood Marrow Transplant Clinical TI Graft-versus-Host Disease Treatment: Predictors of Survival SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE GVHD; BMT; Allogeneic; Prognosis; Survival; Response ID CELL TRANSPLANTATION; GRADING SYSTEMS; PROPHYLAXIS; REGIMENS; THERAPY AB Acute graft versus-host disease (aGVHD) following allogeneic hematopoietic cell transplant (HCT) is the major reason for nonrelapse mortality (NRM) and thus is a major determinant of long-term survival Clinical trials of new aGVHD treatments are needed to identify approaches that will ultimately improve upon HCT survival At present it is not clear how quickly response to GVHD treatment needs to be established to reliably categorize patients at high risk for death or to promptly identify those who might benefit from alternate treatment Therefore we analyzed time to response from onset of aGVHD treatment in 180 patients who were enrolled on a national randomized phase 11 aGVHD treatment clinical trial whose initial treatment of GVHD consisted of high dose steroids plus a second immunosuppressive agent The aim of this analysis was to determine whether time to aGVHD treatment response predicts patient outcomes especially survival We used response at 14 28 and 56 days from initiation of aGVHD treatment to categorize patients for NRM and survival Multivariate analyses and specificity/sensitivity analyses identified that day 28 response (complete or partial response) best categorized patients by NRM and survival at 9 months from start of aGVHD treatment If verified as a reliable predictor of late outcomes following other aGVHD treatment approaches day 28 response should serve as a standard early endpoint for future trials of aGVHD therapy Biol Blood Marrow Transplant 16 1693-1699 (2010) (C) 2010 American Society for Blood and Marrow Transplantation C1 [Levine, John E.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Levine, John E.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Logan, Brent] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Wu, Juan] EMMES Corp, Rockville, MD USA. [Alousi, Amin M.] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. [Ho, Vincent] Dana Farber Canc Inst, Dept Med Oncol Hematol Malignancies, Boston, MA 02115 USA. [Bolanos-Meade, Javier] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. RP Levine, JE (reprint author), Univ Michigan, Dept Pediat, 5303 Canc Ctr,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. OI Levine, John/0000-0002-9133-0800 FU National Heart, Lung, and Blood Institute; National Cancer Institute FX Financial disclosure This work was supported in part by the National Heart, Lung, and Blood Institute and the National Cancer Institute The author, gratefully acknowledge the participating centers and coinvestigators for the BMT CTN 0302 study MD Anderson Cancer Research Center (Amin M Alousi, MD), Johns Hopkins University (Javier Bolanos-Meade, MD, and Georgia Vogelsang, MD), University of Minnesota (Daniel Weisdorf, MD), Dana Farber Brigham Women's Partners (Vincent Ho, MD, Robert Soiffer, MD, and Joseph Antin, MD), University of Michigan (John Levine, MD, MS, and James L Ferrara, MD), Oregon Health Sciences University (Eneid Nemecek, MD), University of Florida College of Medicine (John Wingard, MD), University of Pennsylvania Hospital Center (Steven Goldstein, MD, and Edward Stadtmauer, MD), University of Nebraska Medical Center (Marcel Devetten, MD), Washington University of St Louis (John DiPersio, MD, and Peter Westervelt, MD), Stanford Hospital and Clinics (Laura Johnston, MD), University of California at San Diego (Edward Ball, MD), Duke University Medical Center (Nelson Chao, MD, and Joanne Kurtzberg, MD), University Hospitals of Cleveland (CWRU) (Hillard Lazarus, MD), Memorial Sloan-Kettering Cancer Center (Nancy Kernan, MD, and Miguel-Angel Perales, MD), Texas Transplant Institute (Carlos Bachier, MD, Michael Grimley, MD, and Paul Shaughnessy, MD), City of Hope National Medical Center (Pablo Parker, MD), Fred Hutchinson Cancer Research Center (Richard Nash, MD), and Hackensack University Medical Center (Joel Brochstein, MD) NR 18 TC 33 Z9 33 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2010 VL 16 IS 12 BP 1693 EP 1699 DI 10.1016/j.bbmt.2010.05.019 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 684RL UT WOS:000284566900008 PM 20541024 ER PT J AU Xu, GG Vogel, KS McMahan, CA Herbert, DC Walter, CA AF Xu, Guogang Vogel, Kristine S. McMahan, C. Alex Herbert, Damon C. Walter, Christi A. TI BAX and Tumor Suppressor TRP53 Are Important in Regulating Mutagenesis in Spermatogenic Cells in Mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE apoptosis; gamete biology; ionizing radiation; mutant frequency; spermatogenesis ID BASE EXCISION-REPAIR; DNA-POLYMERASE-BETA; MALE GERM-CELLS; BCL-2 PROTEIN FAMILY; OLD MICE; MITOCHONDRIAL-MEMBRANE; INTERCELLULAR BRIDGES; P53-RELATED PROTEIN; IONIZING-RADIATION; HETEROZYGOUS MICE AB During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage apoptosis was markedly decreased in Bax-null mice and was accompanied by a significantly increased spontaneous mutant frequency in seminiferous tubule cells compared to that of wild-type mice. Apoptosis profiles in the seminiferous tubules for Trp53-null were similar to control mice. Spontaneous mutant frequencies in pachytene spermatocytes and in round spermatids from Trp53-null mice were not significantly different from those of wild-type mice. However, epididymal spermatozoa from Trp53-mill mice displayed a greater spontaneous mutant frequency compared to that from wild-type mice. A greater proportion of spontaneous transversions and a greater proportion of insertions/deletions 15 days after ionizing radiation were observed in Trp53-null mice compared to wildtype mice. Base excision repair activity in mixed germ cell nuclear extracts prepared from Trp53-null mice was significantly lower than that for wild-type controls. These data indicate that BAX-mediated apoptosis plays a significant role in regulating spontaneous mutagenesis in seminiferous tubule cells obtained from neonatal mice, whereas tumor suppressor TRP53 plays a significant role in regulating spontaneous mutagenesis between postmeiotic round spermatid and epididymal spermatozoon stages of spermiogenesis. C1 [Xu, Guogang; Vogel, Kristine S.; Herbert, Damon C.; Walter, Christi A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [McMahan, C. Alex] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Walter, Christi A.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Walter, Christi A.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Walter, CA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. EM walter@uthscsa.edu FU National Institute on Aging of the National Institutes of Health (NIH) [AG21163] FX Supported by grant AG21163 from the National Institute on Aging of the National Institutes of Health (NIH). The contents are solely the responsibility of the authors and do not necessarily reflect the view of the NIH or the Veteran's Health Care System. NR 74 TC 15 Z9 15 U1 0 U2 2 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 DEC PY 2010 VL 83 IS 6 BP 979 EP 987 DI 10.1095/biolreprod.110.085415 PG 9 WC Reproductive Biology SC Reproductive Biology GA 686YH UT WOS:000284737600013 PM 20739667 ER PT J AU Mei, Y Hollister-Lock, J Bogatyrev, SR Cho, SW Weir, GC Langer, R Anderson, DG AF Mei, Ying Hollister-Lock, Jennifer Bogatyrev, Said R. Cho, Seung-Woo Weir, Gordon C. Langer, Robert Anderson, Daniel G. TI A high throughput micro-array system of polymer surfaces for the manipulation of primary pancreatic islet cells SO BIOMATERIALS LA English DT Article DE Pancreatic islet cells; Cell type specific adhesion; Polymer array; High throughput screening ID HUMAN-PLASMA FIBRONECTIN; EMBRYONIC STEM-CELLS; RAT BETA-CELLS; INTEGRIN BINDING; ADHESION; BIOMATERIALS; MATRIX; IDENTIFICATION; SECRETION; SCIENCE AB We developed a high throughput micro-arrayed polymer system for the study of polymer surfaces for islet cell culture. A micro-arrayed library with 496 different polymers was synthesized and used to examine attachment and insulin expression of islet cells. While most polymers were not supportive, several related polymers were identified as suitable ("hit's"). The "hit" arrays composed of "hit" polymers with 36 replicates were fabricated to confirm their capacities to support the attachment of islet cells, and these capacities were further validated in large surfaces. Notably, the attachment of islet cells on these synthetic polymeric films has been found to be as supportive as 804G supernatant coated tissue culture polystyrene dishes, one of the most extensively used substrates for the islet cell attachment. Interestingly, the polymeric surfaces optimal for a different cell type, hES derived cells, were distinct, highlighting the utility of these approaches for identifying cell type specific surfaces. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Mei, Ying; Bogatyrev, Said R.; Langer, Robert; Anderson, Daniel G.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Hollister-Lock, Jennifer; Weir, Gordon C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transportat & Cell Biol, Boston, MA 02215 USA. [Cho, Seung-Woo] Yonsei Univ, Dept Biotechnol, Seoul 120749, South Korea. [Langer, Robert; Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA. [Langer, Robert; Anderson, Daniel G.] MIT, Harvard MIT Div Hlth Sci Technol, Cambridge, MA 02142 USA. RP Anderson, DG (reprint author), MIT, Dept Chem Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM dgander@mit.edu FU NIH [R01 (DE016516-03)]; Juvenile Diabetes Research Foundation FX We gratefully acknowledge Ed Luther for the help with the laser scanning cytometry. Funding was kindly provided by NIH grant R01 (DE016516-03) and juvenile Diabetes Research Foundation. NR 25 TC 13 Z9 13 U1 0 U2 18 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 DEC PY 2010 VL 31 IS 34 BP 8989 EP 8995 DI 10.1016/j.biomaterials.2010.08.029 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 675GJ UT WOS:000283814600019 PM 20828808 ER PT J AU Cao, L Arany, PR Kim, J Rivera-Feliciano, J Wang, YS He, ZH Rask-Madsen, C King, GL Mooney, DJ AF Cao, Lan Arany, Praveen R. Kim, Jaeyun Rivera-Feliciano, Jose Wang, Yuan-Shuo He, Zhiheng Rask-Madsen, Christian King, George L. Mooney, David J. TI Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice SO BIOMATERIALS LA English DT Article DE VEGF; Angiogenesis; Notch Signaling; Diabetes; Ischemia; Alginate ID PROGENITOR-CELL DYSFUNCTION; GROWTH-FACTOR EXPRESSION; INHIBITS TUMOR-GROWTH; ENDOTHELIAL-CELLS; VASCULAR DEVELOPMENT; VEGF RESPONSIVENESS; INSULIN-RESISTANCE; ANGIOGENESIS; MELLITUS; MYOCARDIUM AB Diabetes can diminish the responsiveness to angiogenic factors (e.g., VEGF) important for wound healing and the treatment of ischemic diseases, and this study investigated the hypothesis that this effect can be reversed by altering Notch signaling. Aortic endothelial cells (ECs) isolated from diabetic mice demonstrated reduced sprouting capability in vitro, but adding a Notch inhibitor (DAPT) led to cell-density and VEGF-dose dependent enhancement of proliferation, migration and sprouting, in both 2-D and 3-D cultures, as compared to VEGF alone. The in vivo effects of VEGF and DAPT were tested in the ischemic hind limbs of diabetic mice. Combining VEGF and DAFT delivery resulted in increased blood vessel density (similar to 150%) and improved tissue perfusion (similar to 160%), as compared to VEGF alone. To examine if DAFT would interfere with vessel maturation, DAPT was also delivered with a combination of VEGF and platelet derived growth factor (PDGF). DAPT and PDGF did not interfere with the effects of the other, and highly functional and mature networks of vessels could be formed with appropriate delivery. In summary, modulating Notch signaling enhances neovascularization and perfusion recovery in diabetic mice suffering from ischemia, suggesting this approach could have utility for human diabetics. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Cao, Lan; Arany, Praveen R.; Kim, Jaeyun; Rivera-Feliciano, Jose; Wang, Yuan-Shuo; Mooney, David J.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Cao, Lan; Kim, Jaeyun; Mooney, David J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Arany, Praveen R.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Arany, Praveen R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [He, Zhiheng; Rask-Madsen, Christian; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA. RP Mooney, DJ (reprint author), Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. EM mooneyd@seas.harvard.edu OI Kim, Jaeyun/0000-0002-4687-6732 FU NIH [RO1 HL069957]; Juvenile Diabetes Research Foundation [1-2008-330]; Harvard Presidential Fellowship; National Eye Institute (NEI) [R01 EY016150-04, K08 EY018677] FX The authors acknowledge the financial support from the NIH (RO1 HL069957), and the Biological Resources Branch of the National Cancer Institute for providing VEGF for our studies. Profs. Yihai Cao (Karolinska Institute), Michal Neeman (Weizmann Institute), and Jean-Sebastien Silvestre (INSERM) are acknowledged for their helpful advice. Dmitry Shvartsman is acknowledged for helpful comments. LC is a recipient of the Juvenile Diabetes Research Foundation International Postdoctoral Fellowship. PRA is a recipient of a Harvard Presidential Fellowship. GLK was supported by grant number 1-2008-330 from the Juvenile Diabetes Research Foundation and grant R01 EY016150-04 from the National Eye Institute (NEI). CRM was supported by grant K08 EY018677 from the NEI. NR 48 TC 14 Z9 17 U1 1 U2 12 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 DEC PY 2010 VL 31 IS 34 BP 9048 EP 9056 DI 10.1016/j.biomaterials.2010.08.002 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 675GJ UT WOS:000283814600026 PM 20800279 ER PT J AU Liu, DP Zhou, XH AF Liu, Danping Zhou, Xiao-Hua TI A Model for Adjusting for Nonignorable Verification Bias in Estimation of the ROC Curve and Its Area with Likelihood-Based Approach SO BIOMETRICS LA English DT Article DE Alzheimer's disease; Nonignorable missing data; ROC curve; Verification bias ID OPERATING CHARACTERISTIC CURVE; MULTIVARIATE INCOMPLETE DATA; PATTERN-MIXTURE MODELS; DIAGNOSTIC-TESTS; ALZHEIMERS-DISEASE AB P>In estimation of the ROC curve, when the true disease status is subject to nonignorable missingness, the observed likelihood involves the missing mechanism given by a selection model. In this article, we proposed a likelihood-based approach to estimate the ROC curve and the area under the ROC curve when the verification bias is nonignorable. We specified a parametric disease model in order to make the nonignorable selection model identifiable. With the estimated verification and disease probabilities, we constructed four types of empirical estimates of the ROC curve and its area based on imputation and reweighting methods. In practice, a reasonably large sample size is required to estimate the nonignorable selection model in our settings. Simulation studies showed that all four estimators of ROC area performed well, and imputation estimators were generally more efficient than the other estimators proposed. We applied the proposed method to a data set from research in Alzheimer's disease. C1 [Liu, Danping; Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, NW HSR&D Ctr Excellence, Seattle, WA 98108 USA. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM dpliu@u.washington.edu; azhou@u.washington.edu RI Liu, Danping/D-2544-2013 FU NIH/NIA [U01AG016976]; National Science Foundation of China [NSFC30728019] FX The authors want to thank Dr Thomas Koepsell and Dr Walter Kukull for the helpful discussions and their insightful comments. The work was supported in part by NIH/NIA grant U01AG016976 and National Science Foundation of China grant NSFC30728019. This article does not necessarily represent the findings and conclusions of VA HSR&D. NR 18 TC 7 Z9 7 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2010 VL 66 IS 4 BP 1119 EP 1128 DI 10.1111/j.1541-0420.2010.01397.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 693DN UT WOS:000285204900013 PM 20222937 ER PT J AU Kojic, N Huang, A Chung, E Ivanovic, M Filipovic, N Kojic, M Tschumperlin, DJ AF Kojic, Nikola Huang, Austin Chung, Euiheon Ivanovic, Milos Filipovic, Nenad Kojic, Milos Tschumperlin, Daniel J. TI A 3-D Model of Ligand Transport in a Deforming Extracellular Space SO BIOPHYSICAL JOURNAL LA English DT Article ID EPITHELIAL-CELLS; MECHANOTRANSDUCTION; DIFFERENTIATION AB Cells communicate through shed or secreted ligands that traffic through the interstitium Force induced changes in interstitial geometry can initiate mechanotransduction responses through changes in local ligand concentrations To gain insight into the temporal and spatial evolution of such mechanotransduction responses we developed a 3 D computational model that couples geometric changes observed in the lateral intercellular space (LIS) of mechanically loaded airway epithelial cells to the diffusion convection equations that govern ligand transport By solving the 3 D fluid field under changing boundary geometries and then coupling the fluid velocities to the ligand transport equations we calculated the temporal changes in the 3 D ligand concentration field Our results illustrate the steady state heterogeneities in ligand distribution that arise from local variations in interstitial geometry and demonstrate that highly localized changes in ligand concentration can be induced by mechanical loading depending on both local deformations and ligand convection effects The occurrence of inhomogeneities at steady state and in response to mechanical loading suggest that local variations in ligand concentration may have important effects on cell to cell variations in basal signaling state and localized mechanotransduction responses C1 [Kojic, Milos; Tschumperlin, Daniel J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ivanovic, Milos; Filipovic, Nenad] Univ Kragujevac, Kragujevac, Serbia. [Chung, Euiheon] Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab, Boston, MA 02114 USA. [Kojic, Nikola; Huang, Austin] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Tschumperlin, DJ (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. FU National Institutes of Health [RO1 HL88028, HL082856] FX This work was supported by National Institutes of Health grants RO1 HL88028 and HL082856 NR 25 TC 8 Z9 8 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD DEC 1 PY 2010 VL 99 IS 11 BP 3517 EP 3525 DI 10.1016/j.bpj.2010.09.044 PG 9 WC Biophysics SC Biophysics GA 690UL UT WOS:000285033800003 PM 21112275 ER PT J AU Orman, MA Arai, K Yarmush, ML Androulakis, IP Berthiaume, F Ierapetritou, MG AF Orman, Mehmet A. Arai, Kosuke Yarmush, Martin L. Androulakis, Ioannis P. Berthiaume, Francois Ierapetritou, Marianthi G. TI Metabolic Flux Determination in Perfused Livers by Mass Balance Analysis: Effect of Fasting SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE perfused rat livers; flux variability approach; monte carlo sampling; SVD analysis ID SINGULAR-VALUE DECOMPOSITION; RED-BLOOD-CELL; HYPERMETABOLIC LIVERS; CULTURED-HEPATOCYTES; GLUCOSE-METABOLISM; FAILURE MODEL; BURN INJURY; RAT; NETWORK; MATRICES AB Isolated perfuscd livers from fasted rats have been extensively studied to understand the underlying mechanisms of injury induced acute and chronic changes in liver metabolism In this study we investigated the impact of fasting on perfused liver metabolism The methodology we used combines a flux variability approach, sampling analysis and singular value decomposition (SVD) to analyze the data wing the same metabolic reaction network for both fed and fasted livers Considering both experimental observations and mathematical analysis, the results show that 2411 fasting results in a limited glucose production from glycogen and up-regulation of gluconeogenic pathway Glutamate metabolism and fatty acid oxidation are also slightly up regulated whereas aspartate metabolism is down-regulated after fasting Moreover, SVD analysis elucidates that glycogen breakdown mainly affects the pentose phosphate path way in fasted state whereas co-occurrence pattern associated with glycogen breakdown and glycolysis observed in flux samples of fed state is dominant In conclusion, this analysis provides a detailed description of the metabolic changes in two different states, considering the entire steady state flux space and dominant flux patterns that capture the system variations within the flux space Biotechnol Bioeng 2010,107 825-835 (C) 2010 Wiley Periodicals Inc C1 [Arai, Kosuke; Yarmush, Martin L.; Berthiaume, Francois] Harvard Univ, Shriners Hosp Children, Ctr Engn Med, Massachusetts Gen Hosp,Surg Serv,Med Sch, Boston, MA 02163 USA. [Orman, Mehmet A.; Androulakis, Ioannis P.; Ierapetritou, Marianthi G.] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ 08854 USA. [Yarmush, Martin L.; Androulakis, Ioannis P.; Berthiaume, Francois] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Berthiaume, F (reprint author), Harvard Univ, Shriners Hosp Children, Ctr Engn Med, Massachusetts Gen Hosp,Surg Serv,Med Sch, Boston, MA 02163 USA. FU USEPA [832721 010]; NIH [GM082974 GM58125] FX Contract grant sponsor USEPA; Contract grant number 832721 010; Contract grant sponsor NIH; Contract grant number GM082974 GM58125 NR 29 TC 9 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD DEC 1 PY 2010 VL 107 IS 5 BP 825 EP 835 DI 10.1002/bit.22878 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 677EV UT WOS:000283972800008 PM 20661905 ER PT J AU D'Amico, AV Chen, MH Sun, L Lee, WR Mouraviev, V Robertson, CN Walther, PJ Polascik, TJ Albala, DM Moul, JW AF D'Amico, Anthony V. Chen, Ming-Hui Sun, Leon Lee, W. Robert Mouraviev, Vladimir Robertson, Cary N. Walther, Philip J. Polascik, Thomas J. Albala, David M. Moul, Judd W. TI Adjuvant versus salvage radiation therapy for prostate cancer and the risk of death SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; radical prostatectomy; radiation therapy; mortality ID RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; RADIOTHERAPY; MORTALITY; TRIAL; PSA AB OBJECTIVE To investigate whether salvage radiation therapy (RT) for prostate-specific antigen (PSA) failure can provide the same result as adjuvant RT, which decreases the risk of all-cause mortality (ACM) for men with positive margins (R1), or extra-capsular or seminal vesicle extension (pT3). METHODS We studied 1638 men at Duke University who underwent radical prostatectomy for unfavourable-risk prostate cancer and whose postoperative PSA was undetectable. Cox regression was used to evaluate whether salvage vs adjuvant RT in men with a rapid (< 10 months) or slow (>= 10 months) PSA doubling time (DT) was associated with the risk of ACM, adjusting for adverse features (pT3, R1, Gleason score 8-10), age, preoperative PSA level, comorbidity and hormonal therapy use. RESULTS Despite fewer men with two or more adverse features (61 vs 82%; P = 0.016), salvage for a rapid PSA DT vs adjuvant RT increased the risk of ACM [adjusted hazard ratio (AHR) = 3.42; 95% confidence interval (CI) = 1.27-9.20; P = 0.015]. There was no difference (AHR = 1.39; 95% CI = 0.50-3.90; P = 0.53) in the risk of ACM among men who received salvage for a slow PSA DT or adjuvant RT. Nearly all (90%) men with a slow PSA DT had Gleason score < 7 and the majority (59%) had at most pT3 or R1 disease. CONCLUSION Radiation therapy after PSA failure as compared with adjuvant RT was not associated with an increased risk of ACM in men with Gleason score < 7 and pT3R0 or pT2R1 disease. C1 [D'Amico, Anthony V.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Sun, Leon; Mouraviev, Vladimir; Robertson, Cary N.; Walther, Philip J.; Polascik, Thomas J.; Albala, David M.; Moul, Judd W.] Duke Univ, Div Urol Surg, Durham, NC USA. [Sun, Leon; Mouraviev, Vladimir; Robertson, Cary N.; Walther, Philip J.; Polascik, Thomas J.; Albala, David M.; Moul, Judd W.] Duke Univ, Dept Surg, Duke Prostate Ctr, Durham, NC USA. [Lee, W. Robert] Duke Univ, Dept Radiat Oncol, Durham, NC USA. RP D'Amico, AV (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. EM adamico@partners.org NR 16 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2010 VL 106 IS 11 BP 1618 EP 1622 DI 10.1111/j.1464-410X.2010.09447.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 680ZE UT WOS:000284275200014 PM 20553253 ER PT J AU Land, WH Margolis, D Gottlieb, R Krupinski, EA Yang, JY AF Land, Walker H. Margolis, Dan Gottlieb, Ronald Krupinski, Elizabeth A. Yang, Jack Y. TI Improving CT prediction of treatment response in patients with metastatic colorectal carcinoma using statistical learning theory SO BMC GENOMICS LA English DT Article ID ONCOLOGIC DRUG DEVELOPMENT; SOLID TUMORS; LUNG-CANCER; END-POINTS; VOLUMETRIC MEASUREMENTS; PULMONARY NODULES; ODDS RATIO; RECIST; BIOMARKERS; CRITERIA AB Background: Significant interest exists in establishing radiologic imaging as a valid biomarker for assessing the response of cancer to a variety of treatments. To address this problem, we have chosen to study patients with metastatic colorectal carcinoma to learn whether statistical learning theory can improve the performance of radiologists using CT in predicting patient treatment response to therapy compared with the more traditional RECIST (Response Evaluation Criteria in Solid Tumors) standard. Results: Predictions of survival after 8 months in 38 patients with metastatic colorectal carcinoma using the Support Vector Machine (SVM) technique improved 30% when using additional information compared to WHO (World Health Organization) or RECIST measurements alone. With both Logistic Regression (LR) and SVM, there was no significant difference in performance between WHO and RECIST. The SVM and LR techniques also demonstrated that one radiologist consistently outperformed another. Conclusions: This preliminary research study has demonstrated that SLT algorithms, properly used in a clinical setting, have the potential to address questions and criticisms associated with both RECIST and WHO scoring methods. We also propose that tumor heterogeneity, shape, etc. obtained from CT and/or MRI scans be added to the SLT feature vector for processing. C1 [Land, Walker H.; Margolis, Dan] SUNY Binghamton, Dept Bioengn, Binghamton, NY 13903 USA. [Gottlieb, Ronald; Krupinski, Elizabeth A.] Univ Arizona, Dept Radiol, Tucson, AZ 85724 USA. [Yang, Jack Y.] Univ Calif San Diego, Ctr Res Biol Syst, La Jolla, CA 92093 USA. [Yang, Jack Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Ctr Canc, Boston, MA 02114 USA. [Yang, Jack Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Land, WH (reprint author), SUNY Binghamton, Dept Bioengn, Binghamton, NY 13903 USA. EM wland@binghamton.edu FU International Society of Intelligent Biological Medicine (ISIBM) FX Publication of this supplement was made possible with support from the International Society of Intelligent Biological Medicine (ISIBM). NR 42 TC 0 Z9 0 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 1 PY 2010 VL 11 SU 3 AR S15 DI 10.1186/1471-2164-11-S3-S15 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 745WC UT WOS:000289200400016 PM 21143782 ER PT J AU Yang, JY Niemierko, A Bajcsy, R Xu, D Athey, BD Zhang, AD Ersoy, OK Li, GZ Borodovsky, M Zhang, JC Arabnia, HR Deng, YP Dunker, AK Liu, YL Ghafoor, A AF Yang, Jack Y. Niemierko, Andrzej Bajcsy, Ruzena Xu, Dong Athey, Brian D. Zhang, Aidong Ersoy, Okan K. Li, Guo-zheng Borodovsky, Mark Zhang, Joe C. Arabnia, Hamid R. Deng, Youping Dunker, A. Keith Liu, Yunlong Ghafoor, Arif TI 2K09 and thereafter: the coming era of integrative bioinformatics, systems biology and intelligent computing for functional genomics and personalized medicine research SO BMC GENOMICS LA English DT Article ID GENE; PREDICTION; EXPRESSION; ALGORITHM; NETWORK AB Significant interest exists in establishing synergistic research in bioinformatics, systems biology and intelligent computing. Supported by the United States National Science Foundation (NSF), International Society of Intelligent Biological Medicine (http://www.ISIBM.org), International Journal of Computational Biology and Drug Design (IJCBDD) and International Journal of Functional Informatics and Personalized Medicine, the ISIBM International Joint Conferences on Bioinformatics, Systems Biology and Intelligent Computing (ISIBM IJCBS 2009) attracted more than 300 papers and 400 researchers and medical doctors world-wide. It was the only inter/multidisciplinary conference aimed to promote synergistic research and education in bioinformatics, systems biology and intelligent computing. The conference committee was very grateful for the valuable advice and suggestions from honorary chairs, steering committee members and scientific leaders including Dr. Michael S. Waterman (USC, Member of United States National Academy of Sciences), Dr. Chih-Ming Ho (UCLA, Member of United States National Academy of Engineering and Academician of Academia Sinica), Dr. Wing H. Wong (Stanford, Member of United States National Academy of Sciences), Dr. Ruzena Bajcsy (UC Berkeley, Member of United States National Academy of Engineering and Member of United States Institute of Medicine of the National Academies), Dr. Mary Qu Yang (United States National Institutes of Health and Oak Ridge, DOE), Dr. Andrzej Niemierko (Harvard), Dr. A. Keith Dunker (Indiana), Dr. Brian D. Athey (Michigan), Dr. Weida Tong (FDA, United States Department of Health and Human Services), Dr. Cathy H. Wu (Georgetown), Dr. Dong Xu (Missouri), Drs. Arif Ghafoor and Okan K Ersoy (Purdue), Dr. Mark Borodovsky (Georgia Tech, President of ISIBM), Dr. Hamid R. Arabnia (UGA, Vice-President of ISIBM), and other scientific leaders. The committee presented the 2009 ISIBM Outstanding Achievement Awards to Dr. Joydeep Ghosh (UT Austin), Dr. Aidong Zhang (Buffalo) and Dr. Zhi-Hua Zhou (Nanjing) for their significant contributions to the field of intelligent biological medicine. C1 [Yang, Jack Y.; Niemierko, Andrzej] Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Boston, MA 02114 USA. [Yang, Jack Y.; Niemierko, Andrzej] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yang, Jack Y.; Ersoy, Okan K.; Ghafoor, Arif] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. [Yang, Jack Y.; Dunker, A. Keith; Liu, Yunlong] Indiana Univ Purdue Univ, Ctr Computat Biol & Bioinformat, Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Bajcsy, Ruzena] Univ Calif Berkeley, Ctr Informat Technol Res Interest Soc, Berkeley, CA 94720 USA. [Xu, Dong] Univ Missouri, Dept Comp Sci, Columbia, MO 65211 USA. [Athey, Brian D.] Univ Michigan, NCIBI, Ann Arbor, MI 48109 USA. [Athey, Brian D.] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. [Zhang, Aidong] SUNY Buffalo, Dept Comp Sci, Buffalo, NY 14260 USA. [Li, Guo-zheng] Tongji Univ, Dept Control Sci & Engn, Shanghai 201804, Peoples R China. [Borodovsky, Mark] Georgia Inst Technol, Ctr Bioinformat & Computat Genom, Atlanta, GA 30332 USA. [Arabnia, Hamid R.] Univ Georgia, Dept Comp Sci, Athens, GA 30602 USA. [Zhang, Joe C.; Deng, Youping] Univ So Mississippi, Hattisburg, MS 39402 USA. [Zhang, Joe C.; Deng, Youping] Int Soc Intelligent Biol Med, Vicksburg, MS 39180 USA. [Zhang, Joe C.; Deng, Youping] SpecPro Inc, Vicksburg, MS 39180 USA. RP Yang, JY (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Radiat Oncol, Boston, MA 02114 USA. EM dr.yang@jhu.edu; aniemierko@partners.org; xudong@missouri.edu; chaoyang.zhang@usm.edu; ghafoor@ecn.purdue.edu OI Li, Guo-Zheng /0000-0001-5568-0347; Athey, Brian/0000-0002-9793-535X NR 24 TC 0 Z9 0 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 1 PY 2010 VL 11 SU 3 AR I1 DI 10.1186/1471-2164-11-S3-I1 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 745WC UT WOS:000289200400001 PM 21143775 ER PT J AU Lopez-Larson, M Breeze, JL Kennedy, DN Hodge, SM Tang, LN Moore, C Giuliano, AJ Makris, N Caviness, VS Frazier, JA AF Lopez-Larson, Melissa Breeze, Janis L. Kennedy, David N. Hodge, Steven M. Tang, Lena Moore, Constance Giuliano, Anthony J. Makris, Nikos Caviness, Verne S. Frazier, Jean A. TI Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Bipolar disorder; Corpus callosum; Neuroimaging; Youths; MRI ID WHITE-MATTER ABNORMALITIES; MAGNETIC-RESONANCE; TOPOGRAPHIC PARCELLATION; HUMAN BRAIN; MRI; CHILDREN; SCHIZOPHRENIA; ADOLESCENTS; ACTIVATION; CHILDHOOD AB Corpus callosum (CC) area abnormalities have been reported in magnetic resonance imaging (MRI) studies of adults and youths with bipolar disorder (BPD), suggesting interhemispheric communication may be abnormal in BPD and may be present early in the course of illness and affect normal neuromaturation of this structure throughout the lifecycle. Neuroimaging scans from 44 youths with DSM-IV BPD and 22 healthy controls (HC) were analyzed using cross-sectional area measurements and a novel method of volumetric parcellation. Univariate analyses of variance were conducted on CC subregions using both volume and traditional area measurements. Youths with BPD had smaller middle and posterior callosal regions, and reduced typical age-related increases in CC size. The cross-sectional area and novel volumetric methodologies resulted in similar findings. Future longitudinal assessments of CC development would track the evolution of callosal abnormalities in youths with BPD and allow exploration of the functional significance of these findings. C1 [Lopez-Larson, Melissa] Univ Utah, Inst Brain, Salt Lake City, UT 84108 USA. [Lopez-Larson, Melissa] Univ Utah, Sch Med, Salt Lake City, UT 84108 USA. [Breeze, Janis L.; Kennedy, David N.; Moore, Constance; Giuliano, Anthony J.; Makris, Nikos; Caviness, Verne S.] Harvard Univ, Sch Med, Boston, MA USA. [Breeze, Janis L.] Cambridge Hlth Alliance, Child & Adolescent Neuropsychiat Res Program, Cambridge, MA USA. [Kennedy, David N.; Makris, Nikos; Caviness, Verne S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kennedy, David N.; Hodge, Steven M.; Tang, Lena; Makris, Nikos; Caviness, Verne S.] MGH, Ctr Morphometr Anal, Charlestown, MA USA. [Moore, Constance] McLean Hosp, Brain Imaging Ctr, Belmont, MA 02178 USA. [Kennedy, David N.; Hodge, Steven M.; Frazier, Jean A.] Univ Massachusetts, Sch Med, Child & Adolescent Neurodev Initiat, Worcester, MA USA. [Kennedy, David N.; Hodge, Steven M.; Frazier, Jean A.] UMASS Mem Med Ctr, Dept Psychiat, Worcester, MA USA. RP Lopez-Larson, M (reprint author), Univ Utah, Inst Brain, 383 Colorow Dr, Salt Lake City, UT 84108 USA. EM Melissa.Lopez-Larson@hsc.utah.edu RI Kennedy, David/H-3627-2012 FU NIH [K08 MH01573, U24 RR021382, K01 MH01798] FX This work was supported by several research grants from NIH: K08 MH01573 to JAF, U24 RR021382 to DNK, and K01 MH01798 to CM NR 58 TC 17 Z9 19 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2010 VL 4 IS 3-4 BP 220 EP 231 DI 10.1007/s11682-010-9101-4 PG 12 WC Neuroimaging SC Neurosciences & Neurology GA 658SB UT WOS:000282508600003 PM 20686873 ER PT J AU Dylewski, ML Prelack, K Weber, JM Keaney, T Ryan, CM Sheridan, RL Fagan, SP AF Dylewski, Maggie L. Prelack, Kathy Weber, Joan M. Keaney, Timothy Ryan, Colleen M. Sheridan, Robert L. Fagan, Shawn P. TI Malnutrition among pediatric burn patients: A consequence of delayed admissions SO BURNS LA English DT Article DE Malnutrition; Burns; Pediatric ID CATABOLISM; INFECTION AB Early definitive burn treatment is assumed to improve prognosis in part because open wounds rapidly stimulate muscle catabolism and systemic inflammation This study describes the incidence and management of injury associated malnutrition among pediatric burn patients transferred for definitive care 21-166 days following burn injury Medical records of patients admitted to our hospital between January 2003 and January 2009 at least 3 weeks after burn injury were retrospectively reviewed Only children with an initial total body surface area (TBSA) burn of >= 20% were included in this study (n = 36) Patients were classified as acutely well nourished or malnourished by the medical team All patients were admitted with chronic open wounds (31 +/- 16% TBSA) Sixty one percent (n = 22) of patients were diagnosed with malnutrition These patients had a significantly longer delay to transfer (26-166 days) than well nourished patients who transferred at 21-138 days (p < 0 05) Average protein (2 8 +/- 0 18 g/kg) and kilocalorie (1 6 +/- 0 1% basal metabolic rate) provision did not differ between groups Incidence of infection was not different between well nourished and malnourished patients Malnutrition occurs frequently among pediatric burn patients with delayed admissions Adequate surgical care infection control and nutrition are required for wound healing (C) 2010 Elsevier Ltd and ISBI All rights reserved C1 [Dylewski, Maggie L.; Prelack, Kathy; Weber, Joan M.; Keaney, Timothy; Ryan, Colleen M.; Sheridan, Robert L.; Fagan, Shawn P.] Shriners Hosp Children, Boston, MA 02114 USA. [Ryan, Colleen M.; Sheridan, Robert L.; Fagan, Shawn P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dylewski, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. NR 12 TC 4 Z9 5 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-4179 J9 BURNS JI Burns PD DEC PY 2010 VL 36 IS 8 BP 1185 EP 1189 DI 10.1016/j.burns.2010.04.009 PG 5 WC Critical Care Medicine; Dermatology; Surgery SC General & Internal Medicine; Dermatology; Surgery GA 684TA UT WOS:000284571000005 PM 20547002 ER PT J AU Mandal, CC Drissi, H Choudhury, GG Ghosh-Choudhury, N AF Mandal, Chandi Charan Drissi, Hicham Choudhury, Goutam Ghosh Ghosh-Choudhury, Nandini TI Integration of Phosphatidylinositol 3-Kinase, Akt Kinase, and Smad Signaling Pathway in BMP-2-Induced Osterix Expression SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Bone morphogenetic protein; Osterix; PI 3-kinase; Smad; Gene transcription regulation; Osteoblast ID MESENCHYMAL STEM-CELLS; OSTEOBLAST DIFFERENTIATION; BONE-FORMATION; BMP-2 GENE; CROSS-TALK; TRANSCRIPTION; WNT; HEDGEHOG; TARGETS; RUNX2 AB Osterix (Osx), a BMP-2-regulated transcription factor, controls expression of genes essential for osteoblast differentiation. Using progressive deletion of the Osx promoter, we characterized a Smad binding element (SBE) between -552 and -839 bp from its transcription start site. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed binding and in vivo recruitment of Smads 1 and 5 to the Osx SBE. Inactivation of PI 3-kinase by the pharmacologic inhibitor Ly294002 or by dominant negative (DN) enzyme significantly blocked BMP-2-induced Osx protein and mRNA expression and Osx transcription. Finally, both DN PI 3-kinase and DN Akt significantly attenuated Smad 5-dependent transcription of Osx, demonstrating the first evidence for a concerted action of PI 3-kinase/Akt signaling with BMP-specific Smads for expression of Osx. C1 [Mandal, Chandi Charan; Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Drissi, Hicham] Univ Connecticut, Ctr Hlth, Dept Orthoped Surg, New England Musculoskeletal Inst, Farmington, CT USA. [Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Choudhury, Goutam Ghosh; Ghosh-Choudhury, Nandini] S Texas Vet Hlth Care Syst, VA Res, San Antonio, TX USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. EM choudhury@uthscsa.edu FU NIH [RO1 AR52425, RO1 DK50190]; VA Medical Research Service Merit Review; VA Merit Review; Juvenile Diabetes Research Foundation; Department of Veterans Affairs FX This work was supported by grants from the NIH (RO1 AR52425) and VA Medical Research Service Merit Review (to N. G.-C.) and grants from the NIH (RO1 DK50190), VA Merit Review, and Juvenile Diabetes Research Foundation (to G. G. C.). G. G. C. is a recipient of the Research Career Scientist Award from the Department of Veterans Affairs. NR 34 TC 15 Z9 16 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD DEC PY 2010 VL 87 IS 6 BP 533 EP 540 DI 10.1007/s00223-010-9419-3 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 679JT UT WOS:000284158400007 PM 20872216 ER PT J AU Abdelmalak, B Abdelmalak, JB Knittel, J Christiansen, E Mascha, E Zimmerman, R Argalious, M Foss, J AF Abdelmalak, Basem Abdelmalak, Joseph B. Knittel, Justin Christiansen, Eric Mascha, Edward Zimmerman, Robert Argalious, Maged Foss, Joseph TI The prevalence of undiagnosed diabetes in non-cardiac surgery patients, an observational study SO CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE LA English DT Article ID MYOCARDIAL-INFARCTION; GLUCOSE; RESUSCITATION; HYPERGLYCEMIA; MORTALITY; MELLITUS; RISK; CARE AB Given that preoperative hyperglycemia is associated with poor outcomes and many non-diabetic patients have high plasma glucose (PG) levels, the purpose of our study was to estimate the prevalence of undiagnosed diabetes among non-cardiac surgery patients and to identify predictors of hyperglycemia in non-diabetics. We included all non-cardiac surgery patients with complete records in the Clinical Database of the Anesthesiology Institute at the Cleveland Clinic during January 2007 to April 2009, and we estimated the prevalence of undiagnosed diabetes and impaired fasting glucose (IFG) among the non-diabetic patients. The mean glucose levels for known diabetics and undiagnosed diabetics were compared using two-tailed Student's t tests, and we assessed the association between PG levels and demographic variables within the non-diabetics. Of the 39,434 patients analyzed, 5,511 (14%) were known diabetics. Of the 33,923 known non-diabetics, 3,426 (10 %) were undiagnosed diabetics and another 3,549 (11%) had IFG. Thus, 6,975 patients (21%) of the non-diabetic patients presented with abnormally high glucose. Previously undiagnosed diabetics had higher preoperative glucose levels compared with known diabetics, with a mean +/- standard deviation (SD) of 161 +/- 48 vs 146 +/- 67 mg center dot dL(-1) (8.9 +/- 2.7 vs 8.1 +/- 3.7 mmoL center dot L(-1)), respectively. The difference remained highly significant after adjusting for body mass index, age, sex, and American Society of Anesthesiologists (ASA) physical status (P < 0.001). Among non-diabetics, older age, obesity, male sex, and a higher ASA physical status were collectively significant predictors of hyperglycemia, with a c-statistic (95% confidence interval) of 0.67 (0.66-0.68). A significant proportion of non-cardiac surgery patients have previously undiagnosed diabetes and pre-diabetes. Previously undiagnosed patients have higher fasting glucose levels compared with diabetic patients. Further studies should be conducted to identify the implications of these findings on patient outcomes. C1 [Abdelmalak, Basem; Argalious, Maged; Foss, Joseph] Cleveland Clin, Inst Anesthesiol, Dept Gen Anesthesiol, Cleveland, OH 44195 USA. [Abdelmalak, Basem; Mascha, Edward] Cleveland Clin, Inst Anesthesiol, Dept Outcomes Res, Cleveland, OH 44195 USA. [Knittel, Justin] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Mascha, Edward] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Zimmerman, Robert] Cleveland Clin, Inst Med, Dept Endocrinol, Cleveland, OH 44195 USA. RP Abdelmalak, B (reprint author), Cleveland Clin, Inst Anesthesiol, Dept Gen Anesthesiol, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM abdelmb@ccf.org RI Foss, Joseph/B-8342-2008 OI Foss, Joseph/0000-0002-4050-7151 NR 19 TC 15 Z9 15 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0832-610X J9 CAN J ANESTH JI Can. J. Anesth. PD DEC PY 2010 VL 57 IS 12 BP 1058 EP 1064 DI 10.1007/s12630-010-9391-4 PG 7 WC Anesthesiology SC Anesthesiology GA 682SZ UT WOS:000284424600002 PM 20922587 ER PT J AU Murphy, JM Gilman, SE Lesage, A Horton, NJ Rasic, D Trinh, NH Alamiri, B Sobol, AM Fava, M Smoller, JW AF Murphy, Jane M. Gilman, Stephen E. Lesage, Alain Horton, Nicholas J. Rasic, Daniel Trinh, Nhi-Ha Alamiri, Bibi Sobol, Arthur M. Fava, Maurizio Smoller, Jordan W. TI Time Trends in Mortality Associated With Depression: Findings From the Stirling County Study SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Article DE mortality risks; depression; alcoholism; smoking; sex differences; epidemiology; time trends; proportional hazards models ID FOLLOW-UP; GENERAL-POPULATION; PSYCHIATRIC-DISORDERS; 40-YEAR PERSPECTIVE; MAJOR DEPRESSION; EXCESS MORTALITY; MENTAL-DISORDERS; COMMUNITY; SMOKING; DEATH AB Objective: To address the question of whether a mortality risk associated with depression in a 1952 representative sample of Stirling County adults changed in a new sample in 1970, and whether there was a change in associations with cigarette smoking and alcoholism. Method: Sample members were interviewed about depression and cigarette smoking. General physicians were interviewed by psychiatrists regarding alcoholism. Information about death as of December 31, 1992, was provided by Statistics Canada. Proportional hazards models were fitted in the 2 samples to assess the mortality risks associated with depression among men and women during 20 years of follow-up, and additionally among men with heavy smoking and alcoholism. Specific causes of death were investigated. Results: Hazard ratios representing the association between depression and premature death among men were 2.6 (95% CI 1.4 to 4.9) and 2.8 (95% CI 1.5 to 5.1), respectively, in the 1952 and 1970 samples for the first 10 years of follow-up. Hazard ratios for women were 1.4 (95% CI 0.6 to 3.2) and 1.2 (95% CI 0.5 to 2.9). The risk associated with depression among men was independent of alcoholism and heavy smoking. Depression and alcoholism were significantly associated with death by external causes and circulatory disease; heavy smoking was significantly associated with malignant neoplasms. Conclusion: The mortality associated with depression did not change during the period from 1952 to 1970. Depressed men experienced a significant mortality risk that was not matched among depressed women and also was not due to alcoholism and heavy smoking. C1 [Murphy, Jane M.; Trinh, Nhi-Ha; Alamiri, Bibi; Sobol, Arthur M.; Fava, Maurizio; Smoller, Jordan W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Murphy, Jane M.; Fava, Maurizio] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, Jane M.; Gilman, Stephen E.; Smoller, Jordan W.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Lesage, Alain] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Lesage, Alain] Hop Louis H Lafontaine, Ctr Rech Fernand Seguin, Montreal, PQ, Canada. [Horton, Nicholas J.] Smith Coll, Dept Math & Stat, Northampton, MA 01063 USA. [Rasic, Daniel] Dalhousie Univ, Fac Med, Dept Psychiat, Halifax, NS, Canada. RP Murphy, JM (reprint author), Room 215,5 Longfellow Pl, Boston, MA 02114 USA. EM murphy.jane@mgh.harvard.edu RI Gilman, Stephen/E-7632-2010; OI Gilman, Stephen/0000-0002-8331-6419; Horton, Nicholas/0000-0003-3332-4311 FU US National Institute of Mental Health of the National Institutes of Health [R01-MH39576-25] FX This research was supported by grant R01-MH39576-25 from the US National Institute of Mental Health of the National Institutes of Health awarded to Dr Murphy. Grateful appreciation is expressed to Martha Fair, Maureen Carpenter, and Pierre Lalonde of the Occupational and Environmental Health Research Section of Statistics Canada, without whose help this study would not have been possible. The assistance of the vital statistics registrars in the provinces and territories of Canada is also acknowledged with gratitude. Special thanks go to Professor Richard Monson and Professor Nan Laird who gave careful guidance during the early phase of preparing this report and to Julie Barbara Burns, Patricia Merritt, and Ellen Krystofik for field management, data entry, and manuscript preparation. To the late Professor Alexander Leighton, who started the Stirling County Study, we give most appreciative acknowledgement. NR 56 TC 8 Z9 8 U1 2 U2 3 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD DEC PY 2010 VL 55 IS 12 BP 776 EP 783 PG 8 WC Psychiatry SC Psychiatry GA 694YI UT WOS:000285337400005 PM 21172098 ER PT J AU Snyder, CF Frick, KD Blackford, AL Herbert, RJ Neville, BA Carducci, MA Earle, CC AF Snyder, Claire F. Frick, Kevin D. Blackford, Amanda L. Herbert, Robert J. Neville, Bridget A. Carducci, Michael A. Earle, Craig C. TI How Does Initial Treatment Choice Affect Short-Term and Long-Term Costs for Clinically Localized Prostate Cancer? SO CANCER LA English DT Article DE prostate cancer; treatment; costs; patterns of care; health services ID SEER-MEDICARE DATA; COMORBIDITY INDEX; PROPENSITY SCORE; DOSE-RESPONSE; CARE; THERAPY; TRENDS; STAGE AB BACKGROUND. Data regarding costs of prostate cancer treatment are scarce. This study investigates how initial treatment choice affects short-term and long-term costs. METHODS. This retrospective, longitudinal cohort study followed prostate-cancer cases diagnosed in 2000 for 5 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Men age >= 66 years, in Medicare fee for service, diagnosed with clinically localized prostate cancer in 2000 while residing in a SEER region, were matched to noncancer controls using age, sex, race, region, comorbidity, and survival. On the basis of treatment received during the first 9 months postdiagnosis, patients were assigned to watchful waiting, radiation, hormonal therapy, hormonal + radiation, and surgery (may have received other treatments). Incremental costs for prostate cancer were the difference in costs for prostate cancer cases versus matched controls. Costs were divided into initial treatment (months -1 to 12), long-term (each 12 months thereafter), and total (months -1 to 60). Sensitivity analyses excluded the last 12 months of life. RESULTS. A total of 13,769 prostate-cancer cases were matched to 13,769 noncancer controls. Watchful waiting had the lowest initial treatment ($4270) and 5-year total costs ($9130). Initial treatment costs were highest for hormonal + radiation ($17,474) and surgery ($15,197). At $26,896, 5-year total costs were highest for hormonal therapy only followed by hormonal + radiation ($25,097) and surgery ($19,214). After excluding the last 12 months of life, total costs were highest for hormonal + radiation ($23,488) and hormonal therapy ($23,199). CONCLUSIONS. Patterns of costs vary widely based on initial treatment. These data can inform patients and clinicians considering treatment options and policy makers interested in patterns of costs. Cancer 2010;116:5391-9. (C) 2010 American Cancer Society C1 [Snyder, Claire F.] Johns Hopkins Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Snyder, Claire F.; Blackford, Amanda L.; Carducci, Michael A.] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Snyder, Claire F.; Frick, Kevin D.; Herbert, Robert J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. [Earle, Craig C.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Neville, Bridget A.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. RP Snyder, CF (reprint author), Johns Hopkins Sch Med, Dept Med, Div Gen Internal Med, 624 N Broadway,Room 657, Baltimore, MD 21205 USA. EM csnyder@jhsph.edu FU Johns Hopkins Bloomberg School of Public Health; American Cancer Society [MRSG-08-011-01-CPPB] FX Supported by the Ho Ching Yang Memorial Faculty Fellowship Award from the Johns Hopkins Bloomberg School of Public Health. Drs. Snyder and Carducci are also supported by a Mentored Research Scholar Grant from the American Cancer Society (MRSG-08-011-01-CPPB). NR 24 TC 32 Z9 32 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2010 VL 116 IS 23 BP 5391 EP 5399 DI 10.1002/cncr.25517 PG 9 WC Oncology SC Oncology GA 685ZB UT WOS:000284665500011 PM 20734396 ER PT J AU Zama, IN Hutson, TE Elson, P Cleary, JM Choueiri, TK Heng, DYC Ramaiya, N Michaelson, MD Garcia, JA Knox, JJ Escudier, B Rini, BI AF Zama, Ivan N. Hutson, Thomas E. Elson, Paul Cleary, James M. Choueiri, Toni K. Heng, Daniel Y. C. Ramaiya, Nikhil Michaelson, M. Dror Garcia, Jorge A. Knox, Jennifer J. Escudier, Bernard Rini, Brian I. TI Sunitinib Rechallenge in Metastatic Renal Cell Carcinoma Patients SO CANCER LA English DT Article DE renal cell carcinoma; sunitinib; rechallenge; VEGF ID ENDOTHELIAL GROWTH-FACTOR; KINASE DOMAIN MUTATIONS; PHASE-III TRIAL; INTERFERON-ALPHA; INTRATUMORAL HETEROGENEITY; ANTITUMOR-ACTIVITY; TARGETED THERAPY; OVARIAN-CANCER; DOUBLE-BLIND; LUNG-CANCER AB BACKGROUND: Sunitinib was a standard initial therapy in metastatic renal cell carcinoma (mRCC). Given the fact that many patients progressed through many available therapies and antitumor activity had been demonstrated with sequential vascular endothelial growth factor-targeting approaches, a retrospective review was performed of the experience of rechallenge with sunitinib in sunitinib-refractory mRCC. METHODS: mRCC patients who received sunitinib therapy after disease progression on prior sunitinib and other therapy were retrospectively identified. Patient characteristics, toxicity, clinical outcome, Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate, and progression-free survival (PFS) were recorded. RESULTS: Twenty-three mRCC patients who were rechallenged with sunitinib were identified. Upon rechallenge, 5 patients (22%) achieved an objective partial response. The median PFS with initial treatment was 13.7 months and 7.2 months with rechallenge. Patients with >6-month interval between sunitinib treatments had a longer PFS with rechallenge than patients who started the rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P = .03). There was no significant difference in outcome to sunitinib rechallenge based on number or mechanism of intervening treatments. Substantial new toxicity or significantly increased severity of prior toxicity was not seen during rechallenge in this cohort. CONCLUSIONS: Sunitinib rechallenge had potential benefits and was tolerated in select metastatic RCC patients. Additional prospective investigation was warranted. Cancer 2010;116:5400-6. (C) 2010 American Cancer Society. C1 [Zama, Ivan N.; Elson, Paul; Garcia, Jorge A.; Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44195 USA. [Hutson, Thomas E.] Texas Oncol PA, Baylor Sammons Canc Ctr, GU Oncol Program, Dallas, TX USA. [Cleary, James M.; Choueiri, Toni K.; Ramaiya, Nikhil] Harvard Univ, Brigham & Womens Hosp, Lank Ctr Genitourinary Oncol, Sch Med,Dana Farber Canc Inst, Boston, MA 02115 USA. [Heng, Daniel Y. C.] Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. [Michaelson, M. Dror] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Knox, Jennifer J.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [Escudier, Bernard] Inst Gustave Roussy, Villejuif, France. RP Rini, BI (reprint author), Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, 9500 Euclid Ave,Desk R35, Cleveland, OH 44195 USA. EM rinib2@ccf.org OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer; Glaxo Smith Kline; Genentech; Aveo; Novartis FX Brian Rini is a consultant to and on the advisory board of Pfizer. Toni K. Choueiri is a consultant to and on the advisory boards of Pfizer, Novartis, Genentech, Glaxo Smith Kline, Abbot, Bayer/Onyx, and Ei Lilly. Thomas Hutson is a consultant to, on the advisory boards of, a speaker for, and receives research funds from Pfizer, Glaxo Smith Kline, Genentech, Aveo, and Novartis. Bernard Escudier has received honoraria from Bayer, Pfizer, Novartis, and Roche. NR 34 TC 72 Z9 73 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2010 VL 116 IS 23 BP 5400 EP 5406 DI 10.1002/cncr.25583 PG 7 WC Oncology SC Oncology GA 685ZB UT WOS:000284665500012 PM 21105118 ER PT J AU Furman, RR Martin, P Ruan, J Cheung, YKK Vose, JM LaCasce, AS Elstrom, R Coleman, M Leonard, JP AF Furman, Richard R. Martin, Peter Ruan, Jia Cheung, Ying-Kuen K. Vose, Julie M. LaCasce, Ann S. Elstrom, Rebecca Coleman, Morton Leonard, John P. TI Phase 1 Trial of Bortezomib Plus R-CHOP in Previously Untreated Patients With Aggressive Non-Hodgkin Lymphoma SO CANCER LA English DT Article DE bortezomib; cyclophosphamide; doxorubicin; vincristine; and prednisone (CHOP); rituximab; diffuse large B-cell lymphoma; mantle cell lymphoma; non-Hodgkin lymphoma; maximum tolerated dose; toxicity ID B-CELL LYMPHOMA; PROTEASOME INHIBITOR BORTEZOMIB; CONTINUAL REASSESSMENT METHOD; I CLINICAL-TRIALS; NF-KAPPA-B; RITUXIMAB; CHEMOTHERAPY; EFFICACY; SURVIVAL; INDOLENT AB BACKGROUND: Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). METHODS: Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m(2) [n = 4 patients], 1.0 mg/m(2) [n = 9 patients], or 1.3 mg/m(2) [n = 7 patients]) administered on Days 1 and 4 of each cycle. RESULTS: The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m(2) dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m(2) of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%. CONCLUSIONS: Bortezomib at a dose of 1.3 mg/m(2) twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing. Cancer 2010;116:5432-9. (C) 2010 American Cancer Society. C1 [Leonard, John P.] Cornell Univ, Weill Cornell Med Coll, Ctr Lymphoma & Myeloma, New York, NY 10021 USA. [Furman, Richard R.; Martin, Peter; Ruan, Jia; Elstrom, Rebecca; Coleman, Morton; Leonard, John P.] New York Presbyterian Hosp, New York, NY USA. [Cheung, Ying-Kuen K.] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA. [Vose, Julie M.] Univ Nebraska Med Ctr, Div Hematol Oncol, Omaha, NE USA. [LaCasce, Ann S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Leonard, JP (reprint author), Cornell Univ, Weill Cornell Med Coll, Ctr Lymphoma & Myeloma, 520 E 70th St,Starr 340, New York, NY 10021 USA. EM jpleonar@med.cornell.edu FU Millennium Pharmaceuticals, Inc; Lymphoma Research Foundation; Lymphoma Foundation FX Supported in part by Millennium Pharmaceuticals, Inc, and grants from the Lymphoma Research Foundation (to J.P.L.) and the Lymphoma Foundation (to J.P.L.) NR 41 TC 28 Z9 28 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2010 VL 116 IS 23 BP 5432 EP 5439 DI 10.1002/cncr.25509 PG 8 WC Oncology SC Oncology GA 685ZB UT WOS:000284665500016 PM 20665890 ER PT J AU Lobb, R Ayanian, JZ Allen, JD Emmons, KM AF Lobb, Rebecca Ayanian, John Z. Allen, Jennifer D. Emmons, Karen M. TI Stage of Breast Cancer at Diagnosis Among Low-Income Women With Access to Mammography SO CANCER LA English DT Article DE healthcare disparities; socioeconomic factors; health policy; early detection of cancer; breast cancer ID EARLY-DETECTION PROGRAM; SOCIOECONOMIC-STATUS; UNITED-STATES; SCREENING MAMMOGRAPHY; CERVICAL-CANCER; DISPARITIES; CARE; INSURANCE; RACE; ASSOCIATION AB BACKGROUND: This study assessed the relationship between area-level poverty and stage of breast cancer at diagnosis among low-income women when screening mammography was available at no cost. METHODS: The authors identified women diagnosed with breast cancer from 1999 to 2005 through the Massachusetts Cancer Registry, and compared the odds of advanced stage disease for women with low incomes (n = 546) for whom screening mammography and diagnostic services were available at no cost through the Massachusetts Breast and Cervical Cancer Early Detection Program, relative to a nonparticipating comparison group (n = 1287) residing in the same neighborhoods with similar distribution of age, race, and ethnicity as Massachusetts Breast and Cervical Cancer Early Detection Program participants. Among Massachusetts Breast and Cervical Cancer Early Detection Program participants, the odds of advanced stage disease were estimated by mammography use. RESULTS: Although screening mammography was available at no cost, only 36% of program participants diagnosed with breast cancer used screening mammography. Stage of breast cancer at diagnosis was not associated with area-level poverty among Massachusetts Breast and Cervical Cancer Early Detection Program participants. For the comparison group, advanced stage disease was more likely for residents in high-poverty areas, relative to low-poverty areas (49% vs 37%, P < .01). The adjusted odds of advanced stage disease at diagnosis was greater for women aged 41 to 49 years, compared with those aged 50 to 64 years (P = .01). CONCLUSIONS: Programs that ensure breast cancer screening and diagnostic services are available at no cost to low-income women can mitigate the adverse effect of area-level poverty on stage of breast cancer. However, such programs require effective strategies to encourage use of screening mammography to promote diagnosis at an earlier stage. Cancer 2010;116:5487-96. (C) 2010 American Cancer Society. C1 [Lobb, Rebecca] St Michaels Hosp, Ctr Res Inner City Hlth, Toronto, ON M5B 1W8, Canada. [Lobb, Rebecca; Ayanian, John Z.; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Ayanian, John Z.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Ayanian, John Z.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Allen, Jennifer D.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Allen, Jennifer D.; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Lobb, R (reprint author), St Michaels Hosp, Ctr Res Inner City Hlth, 30 Bond St, Toronto, ON M5B 1W8, Canada. EM lobbr@smh.toronto.on.ca RI Allen, Jennifer/M-2113-2015; OI Lobb, Rebecca/0000-0003-3503-0675 FU National Cancer Institute Cancer Prevention and Control Fellowship [5 R25 CA057711-15]; National Institutes of Health, Harvard Catalyst/Harvard Clinical and Translational Science Center [1 UL1 RR 025758-01]; National Cancer Institute, MassCONECT [5 U01 CA114644, K05CA124415] FX This work was supported by the National Cancer Institute Cancer Prevention and Control Fellowship (5 R25 CA057711-15 to R.L.); the National Institutes of Health, Health Disparities Research Program of the Harvard Catalyst/Harvard Clinical and Translational Science Center (1 UL1 RR 025758-01 and financial contributions from participating institutions to J.Z.A); and the National Cancer Institute, MassCONECT (5 U01 CA114644 and K05CA124415 to K.M.E). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute's Center to Reduce Cancer Health Disparities. NR 47 TC 6 Z9 6 U1 1 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 1 PY 2010 VL 116 IS 23 BP 5487 EP 5496 DI 10.1002/cncr.25331 PG 10 WC Oncology SC Oncology GA 685ZB UT WOS:000284665500022 PM 21171232 ER PT J AU Panigrahy, D Kaipainen, A Greene, ER Huang, S AF Panigrahy, Dipak Kaipainen, Arja Greene, Emily R. Huang, Sui TI Cytochrome P450-derived eicosanoids: the neglected pathway in cancer SO CANCER AND METASTASIS REVIEWS LA English DT Review DE Cytochrome P450; Arachidonic acid; HETEs; EETs; Cancer; Metastasis ID SOLUBLE EPOXIDE HYDROLASE; ARACHIDONIC-ACID EPOXYGENASE; ACTIVATED-RECEPTOR-ALPHA; ENDOTHELIAL-CELL PROLIFERATION; ASTROCYTIC EPOXYEICOSATRIENOIC ACID; NF-KAPPA-B; 20-HYDROXYEICOSATETRAENOIC ACID; TUMOR-GROWTH; IN-VIVO; HYDROXYEICOSATETRAENOIC ACIDS AB Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: omega-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed. C1 [Panigrahy, Dipak; Greene, Emily R.] Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Panigrahy, Dipak; Greene, Emily R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Kaipainen, Arja] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Huang, Sui] Univ Calgary, Inst Biocomplex & Informat, Calgary, AB, Canada. RP Panigrahy, D (reprint author), Childrens Hosp, Vasc Biol Program, 300 Longwood Ave, Boston, MA 02115 USA. EM dipak.panigrahy@childrens.harvard.edu; ahkaipai@ucalgary.ca; emily.greene@childrens.harvard.edu; sui.huang@ucalgary.ca FU National Cancer Institute [RO1CA148633-O1A1] FX We thank Catherine Butterfield for suggestions in preparing the manuscript; Kristin Johnson preparation of the figures and cover; and Tadanori Mammoto for confocal imaging in the cover. This work was supported by National Cancer Institute grant RO1CA148633-O1A1 (DP). NR 134 TC 66 Z9 68 U1 1 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD DEC PY 2010 VL 29 IS 4 BP 723 EP 735 DI 10.1007/s10555-010-9264-x PG 13 WC Oncology SC Oncology GA 669OX UT WOS:000283361200012 PM 20941528 ER PT J AU Wang, XD AF Wang, Xiaodong TI Identify cancer stem cells in gallbladder carcinoma A platform for novel therapeutic targets SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE gallbladder carcinoma; cancer stem cell; CD44; CD133; signaling pathway; hedgehog-Gli; ABCG2; therapeutic target ID BREAST-CANCER; MYELOID-LEUKEMIA; NOTCH; HEDGEHOG; ABCG2; PATHWAY; GLIOBLASTOMA; RENEWAL; GROWTH; TUMORS C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Wang, XD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM xiaodong_wang@dfci.harvard.edu NR 32 TC 1 Z9 1 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD DEC 1 PY 2010 VL 10 IS 11 BP 1192 EP 1194 DI 10.4161/cbt.10.11.13944 PG 3 WC Oncology SC Oncology GA 688UI UT WOS:000284879000018 PM 21099373 ER PT J AU Sorensen, G Stoddard, A Quintiliani, L Ebbeling, C Nagler, E Yang, M Pereira, L Wallace, L AF Sorensen, Glorian Stoddard, Anne Quintiliani, Lisa Ebbeling, Cara Nagler, Eve Yang, May Pereira, Lesley Wallace, Lorraine TI Tobacco use cessation and weight management among motor freight workers: results of the gear up for health study SO CANCER CAUSES & CONTROL LA English DT Article DE Cancer prevention; Tobacco use cessation; Weight maintenance; Worksite health promotion ID SMOKING-CESSATION; RANDOMIZED-TRIAL; WORKING-CLASS; VEGETABLE CONSUMPTION; CANCER PREVENTION; TREND STATEMENT; SOCIAL-CONTEXT; UNITED-STATES; INTERVENTION; DIRECTIONS AB Objectives To present the results of a study of a worksite-based intervention to promote tobacco use cessation and improve weight management among motor freight workers. Methods This study used a pre-test/post-test, non-randomized design to assess the effectiveness of a four-month intervention that addressed the social context of the work setting. We evaluated 7-day tobacco quit prevalence among baseline tobacco users, and successful weight management, defined as no weight gain in workers with BMI <25 at baseline and any weight loss among overweight and obese workers. Results At baseline, 40% were current tobacco users, and 88% had a BMI of 25 or greater. Of 542 workers invited to participate, 227 agreed to participate and received at least the first telephone call (42%). Ten-month post-baseline, baseline tobacco users who participated in the intervention were more likely to have quit using tobacco than non-participants: 23.8% vs. 9.1% (p = 0.02). There was no significant improvement in weight management. Conclusions Incorporating work experiences and job conditions into messages of health behavior change resulted in significant tobacco use cessation among participating motor freight workers. C1 [Sorensen, Glorian; Quintiliani, Lisa; Nagler, Eve; Pereira, Lesley; Wallace, Lorraine] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Sorensen, Glorian; Quintiliani, Lisa; Nagler, Eve] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Stoddard, Anne; Yang, May] New England Res Inst, Watertown, MA 02172 USA. [Quintiliani, Lisa] Boston Univ, Boston Med Ctr, Boston, MA 02215 USA. [Ebbeling, Cara] Childrens Hosp, Boston, MA 02115 USA. RP Sorensen, G (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM glorian_sorensen@dfci.harvard.edu; Astoddard@neriscience.com; Lisa.Quintiliani@bmc.org; Cara.Ebbeling@childrens.harvard.edu; Eve_Nagler@dfci.harvard.edu; myang@neriscience.com; bennettlesley@yahoo.com; Lorraine_Wallace@dfci.harvard.edu OI Quintiliani, Lisa/0000-0002-3328-6768 FU Centers for Disease Control and Prevention [5 R01 DP000099-03]; National Institutes of Health [5 K05 CA108663, 2 R25 CA057713] FX This work was conducted with the support of a grant from the Centers for Disease Control and Prevention (grant number 5 R01 DP000099-03 to G. S.) and grants from the National Institutes of Health (grant numbers 5 K05 CA108663 and 2 R25 CA057713 to G. S.). NR 57 TC 14 Z9 14 U1 2 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2010 VL 21 IS 12 SI SI BP 2113 EP 2122 DI 10.1007/s10552-010-9630-6 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 737ZR UT WOS:000288609600018 PM 20725775 ER PT J AU Bao, Y Nimptsch, K Meyerhardt, JA Chan, AT Ng, K Michaud, DS Brand-Miller, JC Willett, WC Giovannucci, E Fuchs, CS AF Bao, Ying Nimptsch, Katharina Meyerhardt, Jeffrey A. Chan, Andrew T. Ng, Kimmie Michaud, Dominique S. Brand-Miller, Jennie C. Willett, Walter C. Giovannucci, Edward Fuchs, Charles S. TI Dietary Insulin Load, Dietary Insulin Index, and Colorectal Cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PLASMA C-PEPTIDE; GROWTH-FACTOR-I; COLON-CANCER; DIABETES-MELLITUS; PHYSICAL-ACTIVITY; BINDING-PROTEINS; GLYCEMIC LOAD; BODY-SIZE; RISK; WOMEN AB Background: Circulating insulin levels have been positively associated with risk of colorectal cancer; however, it remains unclear whether a diet inducing an elevated insulin response influences colorectal cancer risk. On the basis of a novel insulin index for individual foods, we estimated insulin demand for overall diets and assessed its association with colorectal cancer in the Nurses' Health Study and Health Professionals Follow-up Study. Methods: We followed 86,740 women and 46,146 men who were free of cancer and diabetes at baseline and identified a total of 2,481 colorectal cancer cases during up to 26 years of follow-up. Dietary insulin load was calculated as a function of food insulin index and the energy content of individual foods was reported on food frequency questionnaires. Average dietary insulin index was calculated by dividing the dietary insulin load by the total energy intake. Results: Dietary insulin load and dietary insulin index were not associated with risk of colorectal cancer. Comparing the highest with the lowest quintiles, the pooled multivariate relative risks of colorectal cancer were 0.91 (95% CI - 0.79-1.05) for dietary insulin load and 0.93 (95% CI - 0.81-1.08) for dietary insulin index. Body mass index and physical activity did not modify the association of dietary insulin load or index with colorectal cancer. Conclusion: A diet high in foods that increase postprandial insulin levels did not increase the risk of colorectal cancer in this large prospective study. Impact: This study is the first to investigate insulin index and load in relation to colorectal cancer. Cancer Epidemiol Biomarkers Prev; 19(12); 3020-6. (C) 2010 AACR. C1 [Bao, Ying; Giovannucci, Edward; Fuchs, Charles S.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Bao, Ying; Chan, Andrew T.; Giovannucci, Edward; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nimptsch, Katharina; Willett, Walter C.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Meyerhardt, Jeffrey A.; Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Michaud, Dominique S.; Willett, Walter C.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Michaud, Dominique S.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London SW7 2AZ, England. [Brand-Miller, Jennie C.] Univ Sydney, Inst Obes Nutr & Exercise, Sydney, NSW 2006, Australia. RP Bao, Y (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM ying.bao@channing.harvard.edu RI Michaud, Dominique/I-5231-2014; Brand-Miller, Jennie/A-6835-2013 OI Nimptsch, Katharina/0000-0001-7877-205X; Brand-Miller, Jennie/0000-0002-6797-8754 FU National Cancer Institute, National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003] FX This study was supported by grants from the National Cancer Institute, National Institutes of Health (P01 CA87969, P01 CA55075, and P50 CA127003). NR 26 TC 8 Z9 8 U1 0 U2 3 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 DEC PY 2010 VL 19 IS 12 BP 3020 EP 3026 DI 10.1158/1055-9965.EPI-10-0833 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 694HP UT WOS:000285285900005 PM 20924099 ER PT J AU Wolpin, BM Kraft, P Xu, MS Steplowski, E Olsson, ML Arslan, AA Bueno-De-Mesquita, HB Gross, M Helzlsouer, K Jacobs, EJ LaCroix, A Petersen, G Stolzenberg-Solomon, RZ Zheng, W Albanes, D Allen, NE Amundadottir, L Austin, MA Boutron-Ruault, MC Buring, JE Canzian, F Chanock, SJ Gaziano, JM Giovannucci, EL Hallmans, G Hankinson, SE Hoover, RN Hunter, DJ Hutchinson, A Jacobs, KB Kooperberg, C Mendelsohn, JB Michaud, DS Overvad, K Patel, AV Sanchez, MJ Sansbury, L Shu, XO Slimani, N Tobias, GS Trichopoulos, D Vineis, P Visvanathan, K Virtamo, J Wactawski-Wende, J Watters, J Yu, K Zeleniuch-Jacquotte, A Hartge, P Fuchs, CS AF Wolpin, Brian M. Kraft, Peter Xu, Mousheng Steplowski, Emily Olsson, Martin L. Arslan, Alan A. Bueno-de-Mesquita, H. Bas Gross, Myron Helzlsouer, Kathy Jacobs, Eric J. LaCroix, Andrea Petersen, Gloria Stolzenberg-Solomon, Rachael Z. Zheng, Wei Albanes, Demetrius Allen, Naomi E. Amundadottir, Laufey Austin, Melissa A. Boutron-Ruault, Marie-Christine Buring, Julie E. Canzian, Federico Chanock, Stephen J. Gaziano, J. Michael Giovannucci, Edward L. Hallmans, Goeran Hankinson, Susan E. Hoover, Robert N. Hunter, David J. Hutchinson, Amy Jacobs, Kevin B. Kooperberg, Charles Mendelsohn, Julie B. Michaud, Dominique S. Overvad, Kim Patel, Alpa V. Sanchez, Maria-Jose Sansbury, Leah Shu, Xiao-Ou Slimani, Nadia Tobias, Geoffrey S. Trichopoulos, Dimitrios Vineis, Paolo Visvanathan, Kala Virtamo, Jarmo Wactawski-Wende, Jean Watters, Joanne Yu, Kai Zeleniuch-Jacquotte, Anne Hartge, Patricia Fuchs, Charles S. TI Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID VON-WILLEBRAND-FACTOR; GENOME-WIDE ASSOCIATION; GENETIC-VARIANTS; GROUP ANTIGENS; A-TRANSFERASE; LOCUS; DISEASE; SUSCEPTIBILITY; MUTATIONS; SEQUENCE AB Background: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. Methods: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. Results: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P-value, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). Conclusions: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. Impact: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34. Cancer Epidemiol Biomarkers Prev; 19(12); 3140-9. (C) 2010 AACR. C1 [Wolpin, Brian M.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wolpin, Brian M.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Canzian, Federico] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Kraft, Peter; Xu, Mousheng; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Michaud, Dominique S.; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Steplowski, Emily] Informat Management Serv Inc, Silver Spring, MD USA. [Olsson, Martin L.] Lund Univ, Div Hematol & Transfus Med, Dept Lab Med, Lund, Sweden. [Arslan, Alan A.] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Dept Environm Med, Sch Med, New York, NY 10016 USA. [Bueno-de-Mesquita, H. Bas; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY 10016 USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Gross, Myron] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Helzlsouer, Kathy] Univ Minnesota, Sch Med, Dept Lab Med Pathol, Minneapolis, MN 55455 USA. [Helzlsouer, Kathy] St Johns Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Jacobs, Eric J.; Visvanathan, Kala] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Jacobs, Eric J.; Visvanathan, Kala] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [LaCroix, Andrea; Patel, Alpa V.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Petersen, Gloria; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Stolzenberg-Solomon, Rachael Z.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Zheng, Wei; Albanes, Demetrius; Amundadottir, Laufey; Chanock, Stephen J.; Hoover, Robert N.; Hutchinson, Amy; Jacobs, Kevin B.; Mendelsohn, Julie B.; Tobias, Geoffrey S.; Yu, Kai; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Allen, Naomi E.; Shu, Xiao-Ou] Vanderbilt Univ, Div Epidemiol, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Allen, Naomi E.; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Amundadottir, Laufey] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Austin, Melissa A.; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Boutron-Ruault, Marie-Christine] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Boutron-Ruault, Marie-Christine] Univ Washington, Inst Publ Hlth Genet, Sch Publ Hlth, Seattle, WA 98195 USA. [Buring, Julie E.] INSERM, Villejuif, France. [Buring, Julie E.] Inst Gustave Roussy, Villejuif, France. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Phys Hlth Study, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Div Aging, Phys Hlth Study, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Phys Hlth Study, Boston, MA 02115 USA. [Gaziano, J. Michael] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Giovannucci, Edward L.] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hallmans, Goeran] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hutchinson, Amy] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Jacobs, Kevin B.; Michaud, Dominique S.] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Overvad, Kim] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Sanchez, Maria-Jose] Aarhus Univ, Dept Epidemiol, Sch Publ Hlth, Aalborg, Denmark. [Slimani, Nadia; Watters, Joanne] NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Trichopoulos, Dimitrios] Int Agcy Res Canc, F-69372 Lyon, France. [Vineis, Paolo] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Virtamo, Jarmo] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, Sch Publ Hlth, London, England. [Wactawski-Wende, Jean] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM bwolpin@partners.org RI Boutron Ruault, Marie-Christine/G-3705-2013; Boutron, Marie-Christine/K-8168-2013; Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016 OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253 FU NCI [R01CA034588, R01CA098661, CA105069, CA73790, P30CA016087, K07 CA140790, R01 CA82729, R01 CA70867]; National Institute of Environmental Health Sciences [ES000260]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; National Institutes of Health [CA 97193, CA 34944, CA 40360, HL 26490, HL 34595]; National Cancer Institute, National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908]; Howard Hughes Medical Institute; Intramural Research Program of National Cancer Institute (Division of Cancer Epidemiology and Genetics); Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004, HHSN261201000006C]; European Commission (DG-SANCO); International Agency for Research on Cancer (Denmark); Danish Cancer Society (Denmark); Ligue contre le Cancer (France); Societe 3M (France); Mutuelle Generale de l'Education Nationale (France); Institut National de la Sante et de la Recherche Medicale (France); Deutsche Krebshilfe (Germany); Deutsches Krebsforschungszentrum (Germany); Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity (Greece); Stavros Niarchos Foundation (Greece); Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) (Italy); National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds (Zorg Onderzoek Nederland); Dutch Prevention Funds (Zorg Onderzoek Nederland); Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF) (The Netherlands); Statistics Netherlands (The Netherlands); Health Research Fund (FIS) (Spain); Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (Spain) [RD06/0020]; Swedish Cancer Society (Sweden); Swedish Scientific Council (Sweden); Regional Government of Skane and Vasterbotten (Sweden); Cancer Research UK (United Kingdom); Medical Research Council (United Kingdom); Stroke Association (United Kingdom); British Heart Foundation (United Kingdom); Department of Health, Food Standards Agency (United Kingdom); Wellcome Trust (United Kingdom); National Institute of Aging [5U01AG018033]; American Cancer Society FX The NYU Women's Health Study is supported by research grants R01CA034588, R01CA098661, center grant P30CA016087 from the NCI, and the center grant ES000260 from the National Institute of Environmental Health Sciences.; The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators is available. (54).; P.H.S. was supported by grants CA 97193, CA 34944, CA 40360, HL 26490, and HL 34595 from the National Institutes of Health.; The NHS, HPFS, and WHS at Harvard were supported by the National Cancer Institute, National Institutes of Health (Grants No. P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908). Brian Wolpin, MD, MPH, was supported by NCI K07 CA140790, an American Society of Clinical Oncology Career Development Award, and a Howard Hughes Medical Institute Early Career Physician-Scientist Award.; The Shanghai Men's Health Study was supported by the National Cancer Institute extramural research grant [R01 CA82729]. The Shanghai Women's Health Study was supported by the National Cancer Institute extramural research grant [R01 CA70867] and, partially for biological sample collection, by the Intramural Research Program of National Cancer Institute (Division of Cancer Epidemiology and Genetics).; PLCO 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.; The ATBC Study was supported by U.S. Public Health Service contractsN01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services, and by funding from the Intramural Research Program of the National Cancer Institute.; For the EPIC cohorts, all coauthors coordinated the initial recruitment and management of the studies. All authors contributed to the final paper. The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue contre le Cancer, Societe 3M, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (United Kingdom).; CLUE II was supported by National Institute of Aging grant (5U01AG018033) and National Cancer Institute grants (CA105069, CA73790). The authors express their appreciation to the participants of the CLUE II cohort and thank the staff at the George W. Comstock Center for Public Health Research and Prevention for their dedication and contributions to the study: Judy Hoffman-Bolton, Clara Krumpe, Kitty Spoonire, and Betty Miner.; The Cancer Prevention Study II Nutrition Cohort is supported by the American Cancer Society. The authors thank all of the men and women in the Cancer Prevention Study II Nutrition Cohort for their many years of dedicated participation in the study.; This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 53 TC 39 Z9 41 U1 0 U2 9 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 DEC PY 2010 VL 19 IS 12 BP 3140 EP 3149 DI 10.1158/1055-9965.EPI-10-0751 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 694HP UT WOS:000285285900015 PM 20971884 ER PT J AU Heerema, NA Byrd, JC Dal Cin, PS Aquila, MLD Koduru, PRK Aviram, A Smoley, SA Rassenti, LZ Greaves, AW Brown, JR Rai, KR Kipps, TJ Kay, NE Van Dyke, DL AF Heerema, Nyla A. Byrd, John C. Dal Cin, Paola S. Aquila, Marie L. Dell' Koduru, Prasad R. K. Aviram, Ayala Smoley, Stephanie A. Rassenti, Laura Z. Greaves, Andrew W. Brown, Jennifer R. Rai, Kanti R. Kipps, Thomas J. Kay, Neil E. Van Dyke, Daniel L. CA Chronic Lymphocytic Leukemia Res C TI Stimulation of chronic lymphocytic leukemia cells with CpG oligodeoxynucleotide gives consistent karyotypic results among laboratories: a CLL Research Consortium (CRC) Study SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID IN-SITU HYBRIDIZATION; CHROMOSOMAL-ABNORMALITIES; METAPHASE CYTOGENETICS; IMMUNOGENIC PHENOTYPE; B-CELLS; OLIGONUCLEOTIDE; ABERRATIONS; PROGNOSIS; FLUDARABINE; RITUXIMAB AB Cytogenetic abnormalities are important prognostic indicators in CLL. Historically, only interphase cytogenetics was clinically useful in CLL, because traditional mitogens are not effective mitotic stimulants. Recently, CpG-oligodeoxynucleotide (ODN) stimulation has shown effectiveness in CLL cells. The CLL Research Consortium tested the effectiveness and reproducibility of CpG-ODN stimulation for detecting chromosomally abnormal clones by five laboratories. More clonal abnormalities were observed after culture of CLL cells with CpG-ODN than with the traditional pokeweed mitogen plus 12-O-tetradecanoylphorbol-13-acetate (PWM+TPA). All clonal abnormalities in PWM+TPA cultures were observed in CpG-ODN cultures, whereas CpG-ODN identified some clones not found by PWM+TPA. CpG-ODN stimulation of one normal control sample and 12 CLL samples showed that, excepting clones of del(13q) in low frequencies and one translocation, results in all five laboratories were consistent, and all abnormalities were concordant with FISH. Abnormal clones in CLL were more readily detected with CpG-ODN stimulation than with traditional B-cell mitogens. With CpG-ODN stimulation, abnormalities were reproducible among cytogenetic laboratories. CpG-ODN did not appear to induce aberrations in cell culture, but did enhance detection of abnormalities and complexity in CLL. Because karyotypic complexity is prognostic and is not detectable by standard FISH analyses, stimulation with CpG-ODN is useful for identifying this additional prognostic factor in CLL. (C) 2010 Elsevier Inc. All rights reserved. C1 [Heerema, Nyla A.; Byrd, John C.] Ohio State Univ, Columbus, OH 43210 USA. [Dal Cin, Paola S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Aquila, Marie L. Dell'; Rassenti, Laura Z.; Greaves, Andrew W.; Kipps, Thomas J.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Koduru, Prasad R. K.; Aviram, Ayala] N Shore Hosp, Manhasset, NY 11030 USA. [Smoley, Stephanie A.; Kay, Neil E.; Van Dyke, Daniel L.] Mayo Clin, Rochester, MN 55905 USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rai, Kanti R.] N Shore Long Isl Jewish Med Ctr, New Hyde Pk, NY 11040 USA. [Chronic Lymphocytic Leukemia Res C] Univ Calif San Diego, CLL Res Consortium, La Jolla, CA 92093 USA. RP Heerema, NA (reprint author), Ohio State Univ, 1645 Neil Ave,129 Hamilton Hall, Columbus, OH 43210 USA. EM nyla.heerema@osumc.edu FU CLL Research Consortium [P01 CA081534-07A1] FX This study was funded by CLL Research Consortium award P01 CA081534-07A1. NR 30 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD DEC PY 2010 VL 203 IS 2 BP 134 EP 140 DI 10.1016/j.cancergencyto.2010.07.128 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 702AK UT WOS:000285866100004 PM 21156225 ER PT J AU Smoley, SA Van Dyke, DL Kay, NE Heerema, NA Aquila, MLD Dal Cin, P Koduru, P Aviram, A Rassenti, L Byrd, JC Rai, KR Brown, JR Greaves, AW Eckel-Passow, J Neuberg, D Kipps, TJ Dewald, GW AF Smoley, Stephanie A. Van Dyke, Daniel L. Kay, Neil E. Heerema, Nyla A. Aquila, Marie L. Dell' Dal Cin, Paola Koduru, Prasad Aviram, Ayala Rassenti, Laura Byrd, John C. Rai, Kanti R. Brown, Jennifer R. Greaves, Andrew W. Eckel-Passow, Jeanette Neuberg, Donna Kipps, Thomas J. Dewald, Gordon W. TI Standardization of fluorescence in situ hybridization studies on chronic lymphocytic leukemia (CLL) blood and marrow cells by the CLL Research Consortium SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID PROBES; EXPERIENCE; DIAGNOSIS; SURVIVAL; FISH AB Five laboratories in the Chronic Lymphocytic Leukemia (CLL) Research Consortium (CRC) investigated standardizing and pooling of fluorescence in situ hybridization (FISH) results as a collaborative research project. This investigation used fixed bone marrow and blood cells available from previous conventional cytogenetic or FISH studies in two pilot studies, a one-day workshop, and proficiency test. Multiple FISH probe strategies were used to detect 6q-, 11q-, +12, 13q-, 17p-, and IGH rearrangements. Ten specimens were studied by participants who used their own probes (pilot study 1). Of 312 FISH interpretations, 224 (72%) were true-negative, 74 (24%) true-positive, 6 (2%) false-negative, and 8 (3%) false-positive. In pilot study no. 2, each participant studied two specimens using identical FISH probe sets to control for variation due to probe sets and probe strategies. Of 80 FISH interpretations, no false interpretations were identified. At a subsequent workshop, discussions produced agreement on scoring criteria. The proficiency test that followed produced no false-negative results and 4% (3/68) false-positive interpretations. Interpretation disagreements among laboratories were primarily attributable to inadequate normal cutoffs, inconsistent scoring criteria, and the use of different FISH probe strategies. Collaborative organizations that use pooled FISH results may wish to impose more conservative empiric normal cutoff values or use an equivocal range between the normal cutoff and the abnormal reference range to eliminate false-positive interpretations. False-negative results will still occur, and would be expected in low-percentage positive cases; these would likely have less clinical significance than false positive results. Individual laboratories can help by closely following rigorous quality assurance guidelines to ensure accurate and consistent FISH studies in their clinical practice and research. (C) 2010 Elsevier Inc. All rights reserved. C1 [Smoley, Stephanie A.; Van Dyke, Daniel L.; Eckel-Passow, Jeanette; Dewald, Gordon W.] Mayo Clin & Mayo Fdn, Dept Lab Med, Div Lab Genet, Rochester, MN 55905 USA. [Kay, Neil E.] Mayo Clin, Div Hematol Oncol, Rochester, MN 55905 USA. [Heerema, Nyla A.] Ohio State Univ, Columbus, OH 43210 USA. [Aquila, Marie L. Dell'; Greaves, Andrew W.; Kipps, Thomas J.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Dal Cin, Paola] Brigham & Womens Hosp, Ctr Adv Mol Diagnost, Boston, MA 02115 USA. [Koduru, Prasad; Aviram, Ayala; Neuberg, Donna] N Shore Hosp, Div Cytogenet & Mol Pathol, Manhasset, NY 11030 USA. [Rassenti, Laura] Moores UCSD Canc Ctr, Dept Med, La Jolla, CA 92093 USA. [Byrd, John C.] Ohio State Univ, Dept Clin Pathol, Columbus, OH 43210 USA. [Rai, Kanti R.] Long Isl Jewish Med Ctr, Div Hematol & Oncol, New Hyde Pk, NY 11040 USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Van Dyke, DL (reprint author), Mayo Clin & Mayo Fdn, Dept Lab Med, Div Lab Genet, 200 1st St SW, Rochester, MN 55905 USA. EM VanDyke.Daniel@mayo.edu FU CRC [PO1-CA81534]; NIH [CA95241] FX This work was partially supported National Insitutes of Health (NIH) grant PO1-CA81534 of the CRC and NIH grant CA95241 of PI Neil Kay. We acknowledge the CRC members and thank the staff of the CRC Cytogenetics Laboratories for their expert technical support. NR 18 TC 7 Z9 7 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD DEC PY 2010 VL 203 IS 2 BP 141 EP 148 DI 10.1016/j.cancergencyto.2010.08.009 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 702AK UT WOS:000285866100005 PM 21156226 ER PT J AU Song, XF Tian, ZW Wang, SX Peng, ZH Feng, J AF Song, Xiangfeng Tian, Zhongwei Wang, Shuxing Peng, Zhenhui Feng, Jie TI Restoration of Fragile Histidine Triad (FHIT) Expression Inhibits Cell Growth and Induces Apoptosis in Cutaneous T-cell Lymphoma Cell Line SO CANCER INVESTIGATION LA English DT Article DE Human cutaneous T-cell lymphoma; Tumor suppressor gene; Gene therapy; Apoptosis ID PROTEIN EXPRESSION; GASTRIC-CANCER; BREAST-CANCER; GENE; CARCINOMA; THERAPY AB To investigate the effects of fragile histidine triad (FHIT) restoration on cell proliferation and apoptosis in human cutaneous T-cell lymphoma cell line, Hut-78, in vitro and in nude mouse. Wild-type FHIT gene was transfected by liposome into the Hut-78 cells. The alteration of cell growth curve and soft agar colony formation was studied in vitro and in nude mice. The FHIT gene was stably expressed in Hut-78 cells after the transfection. Compared with the controls, restoration of FHIT expression inhibited cell growth and induced apoptosis. Tumor formation in vivo was strongly suppressed by FHIT gene restoration. Our data demonstrate restoration of FHIT gene expression inhibit the tumor cell growth and provide an option for the treatment. C1 [Tian, Zhongwei] Xinxiang Med Univ, Teaching Hosp 1, Dept Dermatol, Xinxiang City 453003, Henan Province, Peoples R China. [Song, Xiangfeng] Xinxiang Med Univ, Dept Immunol, Xingxiang, Peoples R China. [Wang, Shuxing] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Anesthesia & Crit Care, Pain Res Grp,Massachusetts Gen Hosp Pain Ctr, Boston, MA USA. [Peng, Zhenhui; Feng, Jie] Xi An Jiao Tong Univ, Hosp 2, Dept Dermatol, Xian 710049, Peoples R China. RP Tian, ZW (reprint author), Xinxiang Med Univ, Teaching Hosp 1, Dept Dermatol, Xinxiang City 453003, Henan Province, Peoples R China. EM zhonwt@xxmu.edu.cn FU Xinxiang Medical University FX This work was supported by a Research Contract from Xinxiang Medical University. The authors acknowledge Prof. Cao Yunxin for help with FACS analyses. NR 20 TC 3 Z9 3 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0735-7907 J9 CANCER INVEST JI Cancer Invest. PD DEC PY 2010 VL 28 IS 10 BP 1019 EP 1023 DI 10.3109/07357900902849608 PG 5 WC Oncology SC Oncology GA 680GH UT WOS:000284219900006 PM 20690795 ER PT J AU Vaid, M Sharma, SD Katiyar, SK AF Vaid, Mudit Sharma, Som D. Katiyar, Santosh K. TI Proanthocyanidins Inhibit Photocarcinogenesis through Enhancement of DNA Repair and Xeroderma Pigmentosum Group A-Dependent Mechanism SO CANCER PREVENTION RESEARCH LA English DT Article ID INDUCED OXIDATIVE STRESS; GREEN TEA POLYPHENOLS; SKH-1 HAIRLESS MICE; NF-KAPPA-B; GRAPE SEEDS; EXCISION-REPAIR; SKIN-CANCER; INDUCED IMMUNOSUPPRESSION; PYRIMIDINE DIMERS; TUMOR-REGRESSION AB Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD(+) cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD(+) cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB-induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD(+) cells in xeroderma pigmentosum complementation group A (XPA)proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms. Cancer Prev Res; 3(12); 1621-9. (C) 2010 AACR. C1 [Vaid, Mudit; Sharma, Som D.; Katiyar, Santosh K.] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Katiyar, SK (reprint author), Univ Alabama, Dept Dermatol, 1670 Univ Blvd,Volker Hall 557, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration FX This work was financially supported by the Veterans Administration Merit Review Award (S. K. K.). NR 37 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 DEC PY 2010 VL 3 IS 12 BP 1621 EP 1629 DI 10.1158/1940-6207.CAPR-10-0137 PG 9 WC Oncology SC Oncology GA 692XO UT WOS:000285189400015 PM 20947490 ER PT J AU Bourgier, C Pichenot, C Verstraet, R Heymann, S Biron, B Balleyguier, C Delaloge, S Mathieu, MC Uzan, C Garbay, JR Bourhis, J Taghian, A Marsiglia, H AF Bourgier, C. Pichenot, C. Verstraet, R. Heymann, S. Biron, B. Balleyguier, C. Delaloge, S. Mathieu, M. -C. Uzan, C. Garbay, J. -R. Bourhis, J. Taghian, A. Marsiglia, H. TI Accelerated partial breast irradiation: Bifractionated 40 Gy in one week. A French pilot phase II study SO CANCER RADIOTHERAPIE LA French DT Article DE Accelerated partial breast irradiation; 3D conformal; Hypofractionation ID CONFORMAL EXTERNAL-BEAM; INTRAOPERATIVE RADIATION-THERAPY; INTENSITY-MODULATED RADIOTHERAPY; BRACHYTHERAPY REGISTRY TRIAL; INITIAL CLINICAL-EXPERIENCE; DOSE-RATE BRACHYTHERAPY; 20-YEAR FOLLOW-UP; RANDOMIZED-TRIAL; QUALITY-ASSURANCE; AMERICAN SOCIETY AB Purpose. - Since 2009, accelerated partial breast irradiation (APBI) in North America has been allowed to be used for selected group of patients outside a clinical trial according to the ASTRO consensus statement. In France, accelerated partial breast irradiation is still considered investigational, several clinical trials have been conducted using either intraoperative (Montpellier) or Mammosite (R) (Lille) or brachytherapy modality (PAC GERICO/FNCLCC). Here, we report the original dosimetric results of this technique. Patients and methods. - Since October 2007, Institut Gustave-Roussy has initiated a phase II trial using 3D-conformal accelerated partial breast irradiation (40 Gy in 10 fractions BID in 1 week). Twenty-five patients with pT1N0 breast cancer were enrolled and were treated by two minitangent photons beams (6 MV) and an "en face" electron beam (6-22 MeV). Results. - The mean clinical target volume and planning target volume were respectively 15.1 cm(3) (range: 5.2-28.7 cm(3)) and 117 cm(3) (range: 52-185 cm(3)). The planning target volume coverage was adequate with at least a mean of 99% of the volume encompassed by the isodose 40 Gy. The mean dose to the planning target volume was 41.8 Gy (range: 41-42.4 Gy). Dose inhomogeneity did not exceed 5%. Mean doses to the ipsilateral lung and heart were 1.6 Gy (range: 1.0-2.3 Gy) and 1.2 Gy (range: 1.0-1.6 Gy), respectively. Conclusion. - The 3D conformal accelerated partial breast irradiation using two minitangent and "en face" electron beams using a total dose of 40 Gy in 10 fractions BID over 5 days achieves appropriate planning target volume coverage and offers significant normal-tissue sparing (heart, lung). Longer follow-up is needed to evaluate the tissue tolerance to this radiation dose. (C) 2010 Societe francaise de radiotherapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved. C1 [Bourgier, C.; Heymann, S.; Bourhis, J.; Marsiglia, H.] Inst Gustave Roussy, Dept Oncol Radiotherapie, F-94800 Villejuif, France. [Pichenot, C.; Verstraet, R.; Biron, B.] Inst Gustave Roussy, Dept Phys, F-94800 Villejuif, France. [Balleyguier, C.] Inst Gustave Roussy, Dept Radiol, F-94800 Villejuif, France. [Delaloge, S.] Inst Gustave Roussy, Dept Med Oncol, F-94800 Villejuif, France. [Mathieu, M. -C.] Inst Gustave Roussy, Dept Anat Pathol, F-94800 Villejuif, France. [Uzan, C.; Garbay, J. -R.; Marsiglia, H.] Inst Gustave Roussy, Dept Chirurg Senol, F-94800 Villejuif, France. [Taghian, A.] Harvard Univ, Dept Oncol Radiotherapie, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Bourgier, C.; Pichenot, C.; Verstraet, R.; Heymann, S.; Biron, B.; Balleyguier, C.; Delaloge, S.; Mathieu, M. -C.; Uzan, C.; Garbay, J. -R.; Bourhis, J.; Taghian, A.; Marsiglia, H.] Univ Florence, I-50121 Florence, Italy. RP Bourgier, C (reprint author), Inst Gustave Roussy, Dept Oncol Radiotherapie, 39 Rue Camille Desmoulins, F-94800 Villejuif, France. EM bourgier@igr.fr NR 74 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 1278-3218 J9 CANCER RADIOTHER JI Cancer Radiother. PD DEC PY 2010 VL 14 IS 8 BP 718 EP 726 DI 10.1016/j.canrad.2010.05.006 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 696HF UT WOS:000285431800006 PM 20674444 ER PT J AU Delgado, DC Hank, JA Kolesar, J Lorentzen, D Gan, J Seo, S Kim, K Shusterman, S Gillies, SD Reisfeld, RA Yang, R Gadbaw, B DeSantes, KB London, WB Seeger, RC Maris, JM Sondel, PM AF Delgado, David C. Hank, Jacquelyn A. Kolesar, Jill Lorentzen, David Gan, Jacek Seo, Songwon Kim, KyungMann Shusterman, Suzanne Gillies, Stephen D. Reisfeld, Ralph A. Yang, Richard Gadbaw, Brian DeSantes, Kenneth B. London, Wendy B. Seeger, Robert C. Maris, John M. Sondel, Paul M. TI Genotypes of NK Cell KIR Receptors, Their Ligands, and Fc gamma Receptors in the Response of Neuroblastoma Patients to Hu14.18-IL2 Immunotherapy SO CANCER RESEARCH LA English DT Article ID TARGETED INTERLEUKIN-2 THERAPY; ANTI-GD2 ANTIBODY; HLA GENOTYPES; BONE-MARROW; TRANSPLANTATION; POLYMORPHISMS; LYMPHOMA; CANCER; METASTASES; RITUXIMAB AB Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-Fc gamma R alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific Fc gamma R alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the Fc gamma R2A 131-H/H genotype showing a higher response rate than other Fc gamma R2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response. Cancer Res; 70(23); 9554-61. (C) 2010 AACR. C1 [Delgado, David C.; DeSantes, Kenneth B.; Sondel, Paul M.] Univ Wisconsin, Dept Pediat, Madison, WI 53705 USA. [Hank, Jacquelyn A.; Gan, Jacek; Yang, Richard; Gadbaw, Brian; Sondel, Paul M.] Univ Wisconsin, Dept Human Oncol, Madison, WI 53705 USA. [Lorentzen, David] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Seo, Songwon; Kim, KyungMann] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53705 USA. [Kolesar, Jill] Univ Wisconsin, Sch Pharm, Carbone Canc Ctr, Madison, WI 53705 USA. [Shusterman, Suzanne; London, Wendy B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Shusterman, Suzanne; London, Wendy B.] Childrens Hosp, Boston, MA 02115 USA. [Gillies, Stephen D.] Provenance Biopharmaceut Corp, Waltham, MA USA. [Reisfeld, Ralph A.] Scripps Res Inst, La Jolla, CA 92037 USA. [London, Wendy B.] Childrens Oncol Grp COG Stat, Gainesville, FL USA. [London, Wendy B.] Ctr Data, Gainesville, FL USA. [Seeger, Robert C.] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Maris, John M.] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. [Maris, John M.] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA. [Maris, John M.] Univ Penn, Philadelphia, PA 19104 USA. RP Sondel, PM (reprint author), Univ Wisconsin, Dept Pediat, 1159 WIMR,1111 Highland Ave, Madison, WI 53705 USA. EM pmsondel@humonc.wisc.edu FU U10 CA98413; COG Statistics and Data Center [R01-CA-32685-25, P30-CA14520, CA87025, CA81403, RR03186, K12 CA087718]; Midwest Athletes for Childhood Cancer Fund; Crawdaddy Foundation; St. Baldrick's Foundation; Evan Dunbar Foundation; Abbie's Fund; [U10CA98543] FX This work was supported by U10CA98543 COG Group Chair Grant, U10 CA98413 COG Statistics and Data Center, R01-CA-32685-25, P30-CA14520, CA87025, CA81403, RR03186, K12 CA087718, and grants from the Midwest Athletes for Childhood Cancer Fund, The Crawdaddy Foundation, The St. Baldrick's Foundation, The Evan Dunbar Foundation, and Abbie's Fund. NR 23 TC 73 Z9 74 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2010 VL 70 IS 23 BP 9554 EP 9561 DI 10.1158/0008-5472.CAN-10-2211 PG 8 WC Oncology SC Oncology GA 690YJ UT WOS:000285045900005 PM 20935224 ER PT J AU Antoniou, AC Beesley, J McGuffog, L Sinilnikova, OM Healey, S Neuhausen, SL Ding, YC Rebbeck, TR Weitzel, JN Lynch, HT Isaacs, C Ganz, PA Tomlinson, G Olopade, OI Couch, FJ Wang, XS Lindor, NM Pankratz, VS Radice, P Manoukian, S Peissel, B Zaffaroni, D Barile, M Viel, A Allavena, A Dall'Olio, V Peterlongo, P Szabo, CI Zikan, M Claes, K Poppe, B Foretova, L Mai, PL Greene, MH Rennert, G Lejbkowicz, F Glendon, G Ozcelik, H Andrulis, IL Thomassen, M Gerdes, AM Sunde, L Cruger, D Jensen, UB Caligo, M Friedman, E Kaufman, B Laitman, Y Milgrom, R Dubrovsky, M Cohen, S Borg, A Jernstrom, H Lindblom, A Rantala, J Stenmark-Askmalm, M Melin, B Nathanson, K Domchek, S Jakubowska, A Lubinski, J Huzarski, T Osorio, A Lasa, A Duran, M Tejada, MI Godino, J Benitez, J Hamann, U Kriege, M Hoogerbrugge, N van der Luijt, RB van Asperen, CJ Devilee, P Meijers-Heijboer, EJ Blok, MJ Aalfs, CM Hogervorst, F Rookus, M Cook, M Oliver, C Frost, D Conroy, D Evans, DG Lalloo, F Pichert, G Davidson, R Cole, T Cook, J Paterson, J Hodgson, S Morrison, PJ Porteous, ME Walker, L Kennedy, MJ Dorkins, H Peock, S Godwin, AK Stoppa-Lyonnet, D de Pauw, A Mazoyer, S Bonadona, V Lasset, C Dreyfus, H Leroux, D Hardouin, A Berthet, P Faivre, L Loustalot, C Noguchi, T Sobol, H Rouleau, E Nogues, C Frenay, M Venat-Bouvet, L Hopper, JL Daly, MB Terry, MB John, EM Buys, SS Yassin, Y Miron, A Goldgar, D Singer, CF Dressler, AC Gschwantler-Kaulich, D Pfeiler, G Hansen, TVO Jnson, L Agnarsson, BA Kirchhoff, T Offit, K Devlin, V Dutra-Clarke, A Piedmonte, M Rodriguez, GC Wakeley, K Boggess, JF Basil, J Schwartz, PE Blank, SV Toland, AE Montagna, M Casella, C Imyanitov, E Tihomirova, L Blanco, I Lazaro, C Ramus, SJ Sucheston, L Karlan, BY Gross, J Schmutzler, R Wappenschmidt, B Engel, C Meindl, A Lochmann, M Arnold, N Heidemann, S Varon-Mateeva, R Niederacher, D Sutter, C Deissler, H Gadzicki, D Preisler-Adams, S Kast, K Schonbuchner, I Caldes, T de la Hoya, M Aittomaki, K Nevanlinna, H Simard, J Spurdle, AB Holland, H Chen, XQ Platte, R Chenevix-Trench, G Easton, DF AF Antoniou, Antonis C. Beesley, Jonathan McGuffog, Lesley Sinilnikova, Olga M. Healey, Sue Neuhausen, Susan L. Ding, Yuan Chun Rebbeck, Timothy R. Weitzel, Jeffrey N. Lynch, Henry T. Isaacs, Claudine Ganz, Patricia A. Tomlinson, Gail Olopade, Olufunmilayo I. Couch, Fergus J. Wang, Xianshu Lindor, Noralane M. Pankratz, Vernon S. Radice, Paolo Manoukian, Siranoush Peissel, Bernard Zaffaroni, Daniela Barile, Monica Viel, Alessandra Allavena, Anna Dall'Olio, Valentina Peterlongo, Paolo Szabo, Csilla I. Zikan, Michal Claes, Kathleen Poppe, Bruce Foretova, Lenka Mai, Phuong L. Greene, Mark H. Rennert, Gad Lejbkowicz, Flavio Glendon, Gord Ozcelik, Hilmi Andrulis, Irene L. Thomassen, Mads Gerdes, Anne-Marie Sunde, Lone Cruger, Dorthe Jensen, Uffe Birk Caligo, Maria Friedman, Eitan Kaufman, Bella Laitman, Yael Milgrom, Roni Dubrovsky, Maya Cohen, Shimrit Borg, Ake Jernstroem, Helena Lindblom, Annika Rantala, Johanna Stenmark-Askmalm, Marie Melin, Beatrice Nathanson, Kate Domchek, Susan Jakubowska, Ania Lubinski, Jan Huzarski, Tomasz Osorio, Ana Lasa, Adriana Duran, Mercedes Tejada, Maria-Isabel Godino, Javier Benitez, Javier Hamann, Ute Kriege, Mieke Hoogerbrugge, Nicoline van der Luijt, Rob B. van Asperen, Christi J. Devilee, Peter Meijers-Heijboer, E. J. Blok, Marinus J. Aalfs, Cora M. Hogervorst, Frans Rookus, Matti Cook, Margaret Oliver, Clare Frost, Debra Conroy, Don Evans, D. Gareth Lalloo, Fiona Pichert, Gabriella Davidson, Rosemarie Cole, Trevor Cook, Jackie Paterson, Joan Hodgson, Shirley Morrison, Patrick J. Porteous, Mary E. Walker, Lisa Kennedy, M. John Dorkins, Huw Peock, Susan Godwin, Andrew K. Stoppa-Lyonnet, Dominique de Pauw, Antoine Mazoyer, Sylvie Bonadona, Valerie Lasset, Christine Dreyfus, Helene Leroux, Dominique Hardouin, Agnes Berthet, Pascaline Faivre, Laurence Loustalot, Catherine Noguchi, Tetsuro Sobol, Hagay Rouleau, Etienne Nogues, Catherine Frenay, Marc Venat-Bouvet, Laurence Hopper, John L. Daly, Mary B. Terry, Mary B. John, Esther M. Buys, Saundra S. Yassin, Yosuf Miron, Alexander Goldgar, David Singer, Christian F. Dressler, Anne Catharina Gschwantler-Kaulich, Daphne Pfeiler, Georg Hansen, Thomas V. O. Jnson, Lars Agnarsson, Bjarni A. Kirchhoff, Tomas Offit, Kenneth Devlin, Vincent Dutra-Clarke, Ana Piedmonte, Marion Rodriguez, Gustavo C. Wakeley, Katie Boggess, John F. Basil, Jack Schwartz, Peter E. Blank, Stephanie V. Toland, Amanda Ewart Montagna, Marco Casella, Cinzia Imyanitov, Evgeny Tihomirova, Laima Blanco, Ignacio Lazaro, Conxi Ramus, Susan J. Sucheston, Lara Karlan, Beth Y. Gross, Jenny Schmutzler, Rita Wappenschmidt, Barbara Engel, Christoph Meindl, Alfons Lochmann, Magdalena Arnold, Norbert Heidemann, Simone Varon-Mateeva, Raymonda Niederacher, Dieter Sutter, Christian Deissler, Helmut Gadzicki, Dorothea Preisler-Adams, Sabine Kast, Karin Schoenbuchner, Ines Caldes, Trinidad de la Hoya, Miguel Aittomaeki, Kristiina Nevanlinna, Heli Simard, Jacques Spurdle, Amanda B. Holland, Helene Chen, Xiaoqing Platte, Radka Chenevix-Trench, Georgia Easton, Douglas F. CA Ontario Canc Genetics Network SWE-BRCA HEBON EMBRACE GEMO Breast Canc Family Registry kConFab CIMBA TI Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; ESTROGEN-RECEPTOR; LOCI; VARIANTS AB The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% C1 [Antoniou, Antonis C.; McGuffog, Lesley; Cook, Margaret; Oliver, Clare; Frost, Debra; Peock, Susan] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. [Beesley, Jonathan; Healey, Sue; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing] Queensland Inst Med Res, Brisbane, Qld, Australia. [Sinilnikova, Olga M.] Univ Lyon 1, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Ctr Hosp, F-69365 Lyon, France. [Neuhausen, Susan L.; Ding, Yuan Chun] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Rebbeck, Timothy R.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Weitzel, Jeffrey N.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Lynch, Henry T.] Creighton Univ, Omaha, NE 68178 USA. [Weitzel, Jeffrey N.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Tomlinson, Gail] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Olopade, Olufunmilayo I.; Easton, Douglas F.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [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. [Pankratz, Vernon S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Radice, Paolo; Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Dept Expt Oncol & Mol Med, Milan, Italy. [Radice, Paolo; Peterlongo, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela] Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy. [Barile, Monica] IEO, Div Canc Prevent & Genet, Milan, Italy. [Viel, Alessandra] IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy. [Allavena, Anna] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Dall'Olio, Valentina] Cogentech, Consortium Genom Technol, Milan, Italy. [Szabo, Csilla I.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Zikan, Michal] Charles Univ Prague, Fac Med 1, Dept Biochem & Expt Oncol, Prague, Czech Republic. [Claes, Kathleen; Poppe, Bruce] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Mai, Phuong L.; Greene, Mark H.] US Natl Canc Inst, Clin Genet Branch, Rockville, MD USA. [Rennert, Gad; Lejbkowicz, Flavio] Technion Israel Inst Technol, Carmel Med Ctr, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. [Glendon, Gord; Andrulis, Irene L.] OCGN, Toronto, ON, Canada. [Ozcelik, Hilmi; Andrulis, Irene L.] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Samuel Lunenfeld Res Inst, New York, NY 10029 USA. [Ozcelik, Hilmi; Andrulis, Irene L.] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Thomassen, Mads] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark. [Gerdes, Anne-Marie] Rigshosp, Dept Clin Genet, Odense, Denmark. [Sunde, Lone] Aalborg Hosp, Dept Clin Genet, Aalborg, Denmark. [Cruger, Dorthe] Vejle Hosp, Dept Clin Genet, Velje, Denmark. [Jensen, Uffe Birk] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Caligo, Maria] Univ Pisa, Div Surg Mol & Ultrastruct Pathol, Dept Oncol, Pisa, Italy. [Caligo, Maria] Pisa Univ Hosp, Pisa, Italy. [Friedman, Eitan; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit] Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Kaufman, Bella] Sheba Med Ctr, Inst Oncol, Tel Hashomer, Israel. [Borg, Ake; Jernstroem, Helena] Lund Univ, Dept Oncol, Lund, Sweden. [Lindblom, Annika; Rantala, Johanna] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Stenmark-Askmalm, Marie] Linkoping Univ, Dept Oncol, Linkoping, Sweden. [Melin, Beatrice] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Nathanson, Kate; Domchek, Susan] Univ Penn, Philadelphia, PA 19104 USA. [Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland. [Osorio, Ana] Spanish Natl Canc Res Ctr, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain. [Lasa, Adriana] Hosp Santa Creu & Sant Pau, Genet Serv, Barcelona, Spain. [Duran, Mercedes] Univ Valladolid, Inst Biol & Mol Genet, IBGM UVA, Valladolid, Spain. [Tejada, Maria-Isabel] Cruces Hosp Barakaldo, Mol Genet Lab, Dept Biochem, Bizkaia, Spain. [Godino, Javier] Univ Lozano Blesa, Hosp Clin, Oncol Serv, Zaragoza, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain. [Hamann, Ute] Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany. [Kriege, Mieke] Daniel Denhoed Canc Ctr, Erasmus MC, Dept Med Oncol, Family Canc Clin, Rotterdam, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Nijmegen Med Ctr, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands. [van der Luijt, Rob B.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [van Asperen, Christi J.] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, Dept Pathol, NL-2300 RA Leiden, Netherlands. [Meijers-Heijboer, E. J.] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Blok, Marinus J.] Univ Med Ctr, Dept Genet & Cell Biol, Maastricht, Netherlands. [Aalfs, Cora M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Hogervorst, Frans] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Conroy, Don] 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. [Pichert, Gabriella] Guys & St Thomas NHS Fdn Trust, London, England. [Davidson, Rosemarie] Ferguson Smith Ctr Clin Genet, Glasgow, Lanark, Scotland. [Cole, Trevor] Birmingham Womens Hosp Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Cook, Jackie] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Paterson, Joan] Addenbrookes Hosp, Dept Clin Genet, E Anglian Reg Genet Serv, Cambridge, England. [Hodgson, Shirley] Univ London, Dept Clin Genet, St Georges Hosp, London, England. [Morrison, Patrick J.] Belfast City Hosp, Northern Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Porteous, Mary E.] Western Gen Hosp, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Kennedy, M. John] St James Hosp, Canc Genet Program, Hope Directorate, Dublin, Ireland. [Dorkins, Huw] Kennedy Galton Ctr, NW Thames Reg Genet Serv, Harrow, Middx, England. [Godwin, Andrew K.; Daly, Mary B.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Stoppa-Lyonnet, Dominique; de Pauw, Antoine] Univ Paris 05, INSERM, U509, Serv Genet Oncol,Inst Curie, Paris, France. [Mazoyer, Sylvie] Univ Lyon 1, CNRS, Ctr Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France. [Bonadona, Valerie; Lasset, Christine] Univ Lyon 1, CNRS, UMR5558, F-69365 Lyon, France. [Bonadona, Valerie; Lasset, Christine] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, F-69373 Lyon, France. [Dreyfus, Helene; Leroux, Dominique] CHU Grenoble, Dept Genet, F-38043 Grenoble, France. [Dreyfus, Helene; Leroux, Dominique] Univ Grenoble, Inst Albert Bonniot, Grenoble, France. [Hardouin, Agnes; Berthet, Pascaline] Ctr Francois Baclesse, F-14021 Caen, France. [Faivre, Laurence] Ctr Hosp Univ Dijon, Ctr Genet, Dijon, France. [Faivre, Laurence; Loustalot, Catherine] Ctr Lutte Canc Georges Francois Leclerc, Dijon, France. [Noguchi, Tetsuro; Sobol, Hagay] INSERM, Inst Paoli Calmettes, UMR599, Dept Oncol Genet, F-13258 Marseille, France. [Rouleau, Etienne] Ctr Rene Huguenin, INSERM, U735, St Cloud, France. [Frenay, Marc] Ctr Antoine Lacassagne, F-06054 Nice, France. [Venat-Bouvet, Laurence] Ctr Hosp Univ Limoges, Dept Oncol, Limoges, France. [Terry, Mary B.] Columbia Univ, New York, NY USA. [Hopper, John L.] Univ Melbourne, Melbourne, Vic, Australia. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT USA. [Yassin, Yosuf; Miron, Alexander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldgar, David] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg] Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. [Hansen, Thomas V. O.; Jnson, Lars] Univ Copenhagen, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark. [Agnarsson, Bjarni A.] Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Agnarsson, Bjarni A.] Univ Iceland, Sch Med, Reykjavik, Iceland. [Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rodriguez, Gustavo C.] NorthShore Univ Hlth Syst, Evanston NW Healthcare, Evanston, IL USA. [Wakeley, Katie] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. [Boggess, John F.] Univ N Carolina, Chapel Hill, NC USA. [Schwartz, Peter E.] Yale Univ, Sch Med, New Haven, CT USA. [Basil, Jack] St Elizabeth Hosp, Edgewood, KY USA. [Blank, Stephanie V.] NYU, Sch Med, New York, NY USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med & Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA. [Toland, Amanda Ewart] Ohio State Univ, Ctr Comprehens Canc, Dept Immunol & Med Genet, Div Human Canc Genet, Columbus, OH 43210 USA. [Montagna, Marco; Casella, Cinzia] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [Tihomirova, Laima] Latvian Biomed Res & Study Ctr, Riga, Latvia. [Imyanitov, Evgeny] NN Petrov Inst Oncol, St Petersburg, Russia. [Blanco, Ignacio; Lazaro, Conxi] Catalan Inst Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain. [Ramus, Susan J.] Univ London Imperial Coll Sci Technol & Med, Gynaecol Oncol Unit, UCL EGA Inst Womens Hlth, London, England. [Sucheston, Lara] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Karlan, Beth Y.; Gross, Jenny] Cedars Sinai Med Ctr, Womens Canc Res Inst, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Schmutzler, Rita; Wappenschmidt, Barbara] Univ Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita; Wappenschmidt, Barbara] Univ Cologne, CIO, Cologne, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, Alfons; Lochmann, Magdalena] Tech Univ Munich, Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-8000 Munich, Germany. [Arnold, Norbert] Univ Kiel, Dept Obstet & Gynaecol, Univ Hosp Schleswig Holstein, Kiel, Germany. [Heidemann, Simone] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein, Kiel, Germany. [Varon-Mateeva, Raymonda] Campus Virchow Klinikum, Charite Berlin, Inst Human Genet, Berlin, Germany. [Niederacher, Dieter] Univ Dusseldorf, Dept Obstet & Gynaecol, Div Mol Genet, Univ Hosp Dusseldorf, Dusseldorf, Germany. [Sutter, Christian] Univ Heidelberg, Inst Human Genet, Div Mol Diagnost, Heidelberg, Germany. [Deissler, Helmut] Univ Hosp Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany. [Preisler-Adams, Sabine] Univ Hosp Muenster, Inst Human Genet, Munster, Germany. [Kast, Karin] Tech Univ Dresden, Dept Obstet & Gynaecol, Univ Hosp Carl Gustav Carus, Dresden, Germany. [Schoenbuchner, Ines] Univ Wurzburg, Inst Human Genet, Div Med Genet, Wurzburg, Germany. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaeki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Simard, Jacques] Ctr Hosp Univ Quebec, Canada Res Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada. [Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing] Familial Breast Canc Peter MacCallum Canc Ctr, Kathleen Cuningham Consortium Res, Melbourne, Vic, Australia. RP Antoniou, AC (reprint author), Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM antonis@srl.cam.ac.uk RI Osorio, Ana/I-4324-2014; Ehrencrona, Hans/M-5619-2014; Jakubowska, Anna/O-8050-2014; GLADIEFF, Laurence/O-5129-2014; Ligtenberg, Marjolijn/N-9666-2013; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Oosterwijk, Jan C./G-5770-2011; Arnold, Norbert/E-3012-2010; Lester, Jenny/B-5933-2012; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Leroux, Dominique/G-7309-2014; Hereditario, Cancer/E-3311-2012; M Isabel, Tejada/E-2394-2012; Andrulis, Irene/E-7267-2013; Sunde, Lone/H-7402-2013; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Blanco, Ignacio/D-2565-2013; Spurdle, Amanda/A-4978-2011; OI Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Nordling, Margareta/0000-0002-4047-4994; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; TEJADA, Maria-Isabel/0000-0002-7334-1864; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Blanco, Ignacio/0000-0002-7414-7481; VENAT-BOUVET, Laurence/0000-0002-0716-2550; Evans, Gareth/0000-0002-8482-5784; Ramus, Susan/0000-0003-0005-7798; Spurdle, Amanda/0000-0003-1337-7897; Sunde, Lone/0000-0002-8479-165X; Kleibl, Zdenek/0000-0003-2050-9667; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364 FU Cancer Research UK; Associazione Italiana per la Ricerca sul Cancro FX The Consortium of Investigators of Modifiers of BRCA1/2 is supported by grants from Cancer Research UK. All study-specific grants are listed in the acknowledgments section. NR 26 TC 94 Z9 95 U1 4 U2 21 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2010 VL 70 IS 23 BP 9742 EP 9754 DI 10.1158/0008-5472.CAN-10-1907 PG 13 WC Oncology SC Oncology GA 690YJ UT WOS:000285045900024 PM 21118973 ER PT J AU Chen, Z Sasaki, T Tan, XH Carretero, J Shimamura, T Li, DN Xu, CX Wang, YC Adelmant, GO Capelletti, M Lee, HJ Rodig, SJ Borgman, C Park, SI Kim, HR Padera, R Marto, JA Gray, NS Kung, AL Shapiro, GI Janne, PA Wong, KK AF Chen, Zhao Sasaki, Takaaki Tan, Xiaohong Carretero, Julian Shimamura, Takeshi Li, Danan Xu, Chunxiao Wang, Yuchuan Adelmant, Guillaume O. Capelletti, Marzia Lee, Hyun Joo Rodig, Scott J. Borgman, Christa Park, Seung-il Kim, Hyeong Ryul Padera, Robert Marto, Jarrod A. Gray, Nathanael S. Kung, Andrew L. Shapiro, Geoffrey I. Jaenne, Pasi A. Wong, Kwok-Kin TI Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene SO CANCER RESEARCH LA English DT Article ID SMALL-CELL-LUNG; KINASE DOMAIN MUTATIONS; ANAPLASTIC LYMPHOMA; NPM-ALK; THERAPEUTIC-TARGET; SIGNALING PATHWAY; TYROSINE KINASE; GENE; CANCER; EGFR AB Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRAS or EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement. Cancer Res; 70(23); 9827-36. (C)2010 AACR. C1 [Chen, Zhao; Sasaki, Takaaki; Xu, Chunxiao; Capelletti, Marzia; Kung, Andrew L.; Shapiro, Geoffrey I.; Jaenne, Pasi A.; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chen, Zhao; Tan, Xiaohong; Carretero, Julian; Shimamura, Takeshi; Li, Danan; Borgman, Christa; Shapiro, Geoffrey I.; Jaenne, Pasi A.; Wong, Kwok-Kin] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wang, Yuchuan] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Adelmant, Guillaume O.; Marto, Jarrod A.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wang, Yuchuan] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Adelmant, Guillaume O.; Marto, Jarrod A.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Sasaki, Takaaki; Capelletti, Marzia; Shapiro, Geoffrey I.; Jaenne, Pasi A.; Wong, Kwok-Kin] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Adelmant, Guillaume O.; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Chen, Zhao; Tan, Xiaohong; Li, Danan; Xu, Chunxiao; Wong, Kwok-Kin] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. [Rodig, Scott J.; Padera, Robert] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lee, Hyun Joo; Park, Seung-il; Kim, Hyeong Ryul] Univ Ulsan, Dept Thorac Surg, Asan Med Ctr, Coll Med, Seoul, South Korea. RP Janne, PA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dana Bldg 822B, Boston, MA 02115 USA. EM pjanne@partners.org; Kwong1@partners.org RI Carretero, Julian/N-5214-2014; OI Carretero, Julian/0000-0001-7269-8506; Wang, Yuchuan/0000-0001-5111-6562; Sasaki, Takaaki/0000-0002-6505-8786; Kung, Andrew/0000-0002-9091-488X; wong, kwok kin/0000-0001-6323-235X FU National Institutes of Health [Dana-Farber/Harvard Cancer Center] [R01 CA136851, R01 CA090687, R01 AG2400401, R01 CA122794, P50 CA090578]; Kahn Family Charitable Foundation; Hazel and Samuel Bellin research fund FX This study is supported by grants from the National Institutes of HealthR01 CA136851 (P.A. Janne and N.S. Gray), R01 CA090687 (G.I. Shapiro), R01 AG2400401 (K-K. Wong), R01 CA122794 (K-K. Wong), P50 CA090578 [Dana-Farber/Harvard Cancer Center (DF/HCC) Specialized Program of Research Excellence (SPORE) in Lung Cancer (G.I. Shapiro, P.A. Janne, and K-K. Wong)], the Kahn Family Charitable Foundation Fund for Lung Cancer Research (K-K. Wong and P.A. Janne), and the Hazel and Samuel Bellin research fund (P.A. Janne). NR 50 TC 113 Z9 120 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 2010 VL 70 IS 23 BP 9827 EP 9836 DI 10.1158/0008-5472.CAN-10-1671 PG 10 WC Oncology SC Oncology GA 690YJ UT WOS:000285045900032 PM 20952506 ER PT J AU Coleman, RE Lipton, A Roodman, GD Guise, TA Boyce, BF Brufsky, AM Clezardin, P Croucher, PI Gralow, JR Hadji, P Holen, I Mundy, GR Smith, MR Suva, LJ AF Coleman, Robert E. Lipton, Allan Roodman, G. David Guise, Theresa A. Boyce, Brendon F. Brufsky, Adam M. Clezardin, Philippe Croucher, Peter I. Gralow, Julie R. Hadji, Peyman Holen, Ingunn Mundy, Gregory R. Smith, Matthew R. Suva, Larry J. TI Metastasis and bone loss: Advancing treatment and prevention SO CANCER TREATMENT REVIEWS LA English DT Review DE Metastasis; Bisphosphonate; RANK; Bone targeted; PTHrP; Bone loss; Denosumab; Zoledronic acid ID ANDROGEN-DEPRIVATION THERAPY; ADJUVANT CLODRONATE TREATMENT; BREAST-CANCER PATIENTS; INFLAMMATORY PROTEIN 1-ALPHA; RANDOMIZED CONTROLLED-TRIAL; HORMONE-RELATED PROTEIN; MULTIPLE-MYELOMA; AROMATASE INHIBITOR; PROSTATE-CANCER; ZOLEDRONIC ACID AB Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors. Research on the bone microenvironment and its role in metastasis suggests a complex role in tumor growth. Parallel preclinical and clinical investigations into the role of adjuvant bone-targeted agents in preventing metastasis and avoiding cancer therapy-induced bone loss have recently reported exciting and intriguing results. A multidisciplinary consensus conference convened to review recent progress in basic and clinical research, assess gaps in current knowledge and prioritize recommendations to advance research over the next 5 years. The program addressed three topics: advancing understanding of metastasis prevention in the context of bone pathophysiology; developing therapeutic approaches to prevent metastasis and defining strategies to prevent cancer therapy-induced bone loss. Several priorities were identified: (1) further investigate the effects of bone-targeted therapies on tumor and immune cell interactions within the bone microenvironment; (2) utilize and further develop preclinical models to study combination therapies; (3) conduct clinical studies of bone-targeted therapies with radiation and chemotherapy across a range of solid tumors; (4) develop biomarkers to identify patients most likely to benefit from bone-targeted therapies; (5) educate physicians on bone loss and fracture risk; (6) define optimal endpoints and new measures of efficacy for future clinical trials; and (7) define the optimum type, dose and schedule of adjuvant bone-targeted therapy. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Coleman, Robert E.] Weston Pk Hosp, Acad Unit Clin Oncol, Sheffield S10 2SJ, S Yorkshire, England. [Lipton, Allan] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Med & Oncol, Hershey, PA 17033 USA. [Roodman, G. David] VA Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15240 USA. [Guise, Theresa A.] Indiana Univ, Div Endocrinol, Dept Internal Med, Indianapolis, IN 46202 USA. [Boyce, Brendon F.] Univ Rochester, Med Ctr, Dept Pathol & Lab Med, Rochester, NY 14642 USA. [Brufsky, Adam M.] UPMC, Magee Womens Hosp, Ctr Canc, Dept Med, Pittsburgh, PA 15123 USA. [Clezardin, Philippe] INSERM, U664, Res Unit, Fac Med Laennec, F-69372 Lyon 08, France. [Croucher, Peter I.] Univ Sheffield, Sch Med, Dept Human Metab, Sheffield S10 2RX, S Yorkshire, England. [Gralow, Julie R.] Univ Washington, Seattle Canc Care Alliance, Dept Med Oncol, Seattle, WA 98109 USA. [Hadji, Peyman] Univ Hosp Giessen, Dept Endocrinol Reprod Med & Osteoporosis, Marburg, Germany. [Hadji, Peyman] Marburg GmbH, Marburg, Germany. [Hadji, Peyman] Dept Gynecol, D-35033 Marburg, Germany. [Holen, Ingunn] Univ Sheffield, Sch Med, Acad Unit Clin Oncol, Acad Unit Oncol, Sheffield S10 2RX, S Yorkshire, England. [Mundy, Gregory R.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Dept Genitourinary Med Oncol, Boston, MA 02114 USA. [Suva, Larry J.] Univ Arkansas Med Sci, Ctr Orthopaed Res, Dept Orthopaed Surg, Little Rock, AR 72205 USA. RP Coleman, RE (reprint author), Weston Pk Hosp, Acad Unit Clin Oncol, Whitham Rd, Sheffield S10 2SJ, S Yorkshire, England. EM r.e.colemar@sheffield.ac.uk; alipton@psu.edu; roodmangd@upmc.edu; tguise@iupui.edu; brendan_boyce@urmc.rochester.edu; brufskyam@upmc.edu; philippe.clezardin@inserm.fr; p.croucher@sheffield.ac.uk; pink@u.washington.edu; hadji@med.uni-marburg.de; i.holen@sheffield.ac.uk; gregory.r.mundy@vanderbilt.edu; smith.matthew@mgh.harvard.edu; suvalarryj@uams.edu RI Clezardin, Philippe/M-8071-2014; OI Holen, Ingunn/0000-0002-8759-6913 FU Amgen Inc.; Novartis Pharmaceuticals; Novartis; Acceleron Pharma; Abraxane; Amgen; Bristol-Myers Squibb; Genentech; Eli Lilly; Hoffmann-La Roche; Scios; Galapagos; Monogram Biosciences; Oncogene Sciences FX The consensus conference was supported by educational grants provided by Amgen Inc. and Novartis Pharmaceuticals. Editorial assistance was provided by Melinda Lindquist of InforMEDical Communications, Inc., Carlisle, MA.; Brendan F. Boyce: Nothing to disclose.; Adam M. Brufsky: Consultant: Novartis; Honoraria: Novartis; Research Funding: Novartis; Royalties: Novartis.; Philippe Clezardin: Honoraria: Novartis; Research Funding: Novartis.; Robert E. ColemanConsultant: Novartis, Amgen; Research Funding: Novartis; Speakers' Bureau: Novartis, Amgen; Expert Testimony: Novartis.; Peter I. Croucher: Research Funding: Acceleron Pharma; Speakers' Bureau: Amgen.; Julie R. Gralow: Research Funding: Abraxane, Amgen, Bristol-Myers Squibb, Genentech, Eli Lilly, Hoffmann-La Roche, Novartis.; Theresa A. Guise: Consultant: Amgen; Research Funding: Scios; Speakers' Bureau: Amgen, Merck, Novartis.; Peyman Hadji: Consultant: Amgen, AstraZeneca, Hoffmann-La Roche, Novartis, Pfizer; Honoraria: Amgen, AstraZeneca, Hoffmann-La Roche, Novartis, Pfizer.; Ingunn Holen: Research Funding: Novartis, Galapagos; Speakers' Bureau: Novartis.; Allan Lipton: Expert Testimony: Novartis; Research Funding: Novartis, Monogram Biosciences, Oncogene Sciences; Speakers' Bureau: Amgen, Novartis, Genentech, GlaxoSmithKline.; Gregory R. Mundy: Nothing to disclose.; G. David Roodman: Consultant: Acceleron, Amgen, Celgene, Novartis; Research Funding: Novartis; Speaker's Bureau: Novartis.; Matthew R. Smith: Consultant: Amgen, GTX, Novartis.; Larry J. Suva: Nothing to disclose. NR 61 TC 51 Z9 54 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD DEC PY 2010 VL 36 IS 8 BP 615 EP 620 DI 10.1016/j.ctrv.2010.04.003 PG 6 WC Oncology SC Oncology GA 701NS UT WOS:000285825300005 PM 20478658 ER PT J AU Lee, MS Su, L Mark, EJ Wain, JC Christiani, DC AF Lee, Mi-Sun Su, Li Mark, Eugene J. Wain, John C. Christiani, David C. TI Genetic modifiers of carcinogen DNA adducts in target lung and peripheral blood mononuclear cells SO CARCINOGENESIS LA English DT Article ID METHYLENE-TETRAHYDROFOLATE REDUCTASE; CUMULATIVE CIGARETTE-SMOKING; MICROSOMAL EPOXIDE HYDROLASE; CANCER-RISK; PHYSICIANS HEALTH; POLYMORPHISMS; DAMAGE; SUSCEPTIBILITY; ASSOCIATION; REPAIR AB Measurement of carcinogen DNA adducts in blood has been used as a surrogate for the target lung tissue. We aimed to examine whether genetic polymorphisms in several metabolic pathway genes modify the relation between DNA adducts in target lung and blood. One hundred and thirty-five early-stage lung cancer patients from the Massachusetts General Hospital were studied. DNA adducts were measured by the (32)P-postlabeling assay in lung and blood mononuclear cells (MNCs) in a subset of 53 who had paired blood samples. Single-nucleotide polymorphisms (SNPs) were assessed in genes involved in phase II (GSTs, NAT2, EPHX and NQO1), DNA repair (ERCC1, ERCC2 and XRCC1) and DNA methylation (MTHFR C677T and A1298C) pathways. There was a significant correlation between DNA adduct levels in lung and blood within the different genotypes, with one exception. Significant modifications in adducts were found by variants in genes for phase II metabolism [NAT2 (1.51 for rapid versus 0.76 for slow, P = 0.022)], DNA repair [ERCC1 C118T (P = 0.014), ERCC2 (P = 0.003) and XRCC1 (P = 0.025)] and MTHFR [C677T (P = 0.005) and A1298C (P = 0.005)]. The relation between DNA adducts in blood MNCs and target lung tissue was significantly modified by the single-nucleotide polymorphisms in the three main pathways. Despite the relatively small sample size, our results suggest that genetic factors may need to be considered when assessing the association of DNA adducts using surrogate tissue in studies of lung cancer. Further studies are needed to better understand their role and the mechanisms. C1 [Lee, Mi-Sun; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Mark, Eugene J.; Wain, John C.; Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mark, Eugene J.; Wain, John C.; Christiani, David C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg 1,Room 1401, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU National Institutes of Health [CA074386, CA092824, CA090578] FX National Institutes of Health (CA074386, CA092824, CA090578). NR 30 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 2010 VL 31 IS 12 BP 2091 EP 2096 DI 10.1093/carcin/bgq208 PG 6 WC Oncology SC Oncology GA 689TZ UT WOS:000284953900008 PM 20935060 ER PT J AU Suzuki, R Lee, K Jing, EX Biddinger, SB McDonald, JG Montine, TJ Craft, S Kahn, CR AF Suzuki, Ryo Lee, Kevin Jing, Enxuan Biddinger, Sudha B. McDonald, Jeffrey G. Montine, Thomas J. Craft, Suzanne Kahn, C. Ronald TI Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism SO CELL METABOLISM LA English DT Article ID ALZHEIMERS-DISEASE; LIPID RAFTS; SIGNALING PATHWAY; COGNITIVE DECLINE; RECEPTOR; MICE; EXPRESSION; NEURONS; HYPERINSULINEMIA; HYPERGLYCEMIA AB The brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states. C1 [Suzuki, Ryo; Lee, Kevin; Jing, Enxuan; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Biddinger, Sudha B.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [McDonald, Jeffrey G.] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98108 USA. [Craft, Suzanne] Univ Washington, Ctr Geriatr Res Educ & Clin, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Craft, Suzanne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU LIPID MAPS [GM069338]; NIH [GM069338, DK31036, 33210, 60937, ADRC AG05136, P30 DK036836]; Manpei Suzuki Diabetes Foundation of Tokyo, Japan; Uehara Memorial Foundation, Japan FX We thank David Russell (University of Texas Southwestern Medical School) for helpful discussion and the LIPID MAPS Large Scale Collaborative Grant (GM069338) for assay of brain sterols. We also thank Jay Horton and Guosheng Liang for providing SREBP-1 and SREBP-2 antibodies; and Wenyu Jiang and Diane Mathis for providing NOD diabetic mice. We are grateful to M. Rourk and G. Smyth for animal care; C. Cahill (Joslin DERC Advanced Microscopy Core); and A. Clermont, M. Poillucci (DERC Physiology Core), H. Li (DERC Specialized Assay Core), and J. Schroeder (DERC Genomics Core) for technical assistance. This work was supported by NIH grants DK31036, 33210, and 60937 (to C. R. K.), ADRC AG05136 (to S. C.), GM069338 (to J. G. M), and P30 DK036836 (Joslin DERC Core Facilities). R.S. is a recipient of research fellowships from the Manpei Suzuki Diabetes Foundation of Tokyo, Japan, and the Uehara Memorial Foundation, Japan. NR 58 TC 52 Z9 54 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 1 PY 2010 VL 12 IS 6 BP 567 EP 579 DI 10.1016/j.cmet.2010.11.006 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 698CM UT WOS:000285569100006 PM 21109190 ER PT J AU Kaneko, K Ueki, K Takahashi, N Hashimoto, S Okamoto, M Awazawa, M Okazaki, Y Ohsugi, M Inabe, K Umehara, T Yoshida, M Kakei, M Kitamura, T Luo, J Kulkarni, RN Kahn, CR Kasai, H Cantley, LC Kadowaki, T AF Kaneko, Kazuma Ueki, Kohjiro Takahashi, Noriko Hashimoto, Shinji Okamoto, Masayuki Awazawa, Motoharu Okazaki, Yukiko Ohsugi, Mitsuru Inabe, Kazunori Umehara, Toshihiro Yoshida, Masashi Kakei, Masafumi Kitamura, Tadahiro Luo, Ji Kulkarni, Rohit N. Kahn, C. Ronald Kasai, Haruo Cantley, Lewis C. Kadowaki, Takashi TI Class IA Phosphatidylinositol 3-Kinase in Pancreatic beta Cells Controls Insulin Secretion by Multiple Mechanisms SO CELL METABOLISM LA English DT Article ID RECEPTOR SUBSTRATE 2; PHOSPHOINOSITIDE 3-KINASE; MICE LACKING; REGULATORY SUBUNIT; SIGNALING PATHWAYS; GLUCOSE; RESISTANCE; EXPRESSION; P85-ALPHA; EXOCYTOSIS AB Type 2 diabetes is characterized by insulin resistance and pancreatic beta cell dysfunction, the latter possibly caused by a defect in insulin signaling in beta cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in beta cells and the pik3r2 gene systemically (beta DKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. beta cells of beta DKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of beta DKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in beta cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes. C1 [Kaneko, Kazuma; Ueki, Kohjiro; Hashimoto, Shinji; Okamoto, Masayuki; Awazawa, Motoharu; Okazaki, Yukiko; Ohsugi, Mitsuru; Inabe, Kazunori; Umehara, Toshihiro; Kadowaki, Takashi] Univ Tokyo, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo 1138655, Japan. [Ueki, Kohjiro] Univ Tokyo, Translat Syst Biol & Med Initiat, Tokyo 1138655, Japan. [Takahashi, Noriko; Kasai, Haruo] Univ Tokyo, Div Biophys, Ctr Dis Biol & Integrat Med, Fac Med, Tokyo 1138655, Japan. [Yoshida, Masashi; Kakei, Masafumi] Jichi Med Univ, Dept Comprehens Med 1, Saitama Med Ctr, Sch Med, Saitama 3308503, Japan. [Kitamura, Tadahiro] Gunma Univ, Metab Signal Res Ctr, Lab Metab Signal, Inst Mol & Cellular Regulat, Gunma 3718512, Japan. [Luo, Ji; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02215 USA. [Kulkarni, Rohit N.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Kadowaki, Takashi] Natl Inst Hlth & Nutr, Div Appl Nutr, Tokyo 1628636, Japan. RP Ueki, K (reprint author), Univ Tokyo, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo 1138655, Japan. EM ueki-tky@umin.ac.jp RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health and Welfare FX We thank J. Nakae for providing the FoxO1-3A and FoxO1-ADA adenoviruses and F. Takahashi, R. Hoshino, Y. Kanto, E. Hirata, and H. Chiyonobu for their excellent technical assistance. This work was supported by a grant-in-aid for Scientific Research in Priority Areas (B) (to K.U.) and a grant-in-aid for Scientific Research in Priority Areas (S) (to T. Kadowaki) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. It was also supported by a grant for TSBMI from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. Kadowaki) and Health Science Research grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare (to T. Kadowaki). K.K. is a Research Fellow of Japan Society for the Promotion of Science. NR 51 TC 46 Z9 49 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 1 PY 2010 VL 12 IS 6 BP 619 EP 632 DI 10.1016/j.cmet.2010.11.005 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 698CM UT WOS:000285569100010 PM 21109194 ER PT J AU Shimazu, T Hirschey, MD Hua, L Dittenhafer-Reed, KE Schwer, B Lombard, DB Li, Y Bunkenborg, J Alt, FW Denu, JM Jacobson, MP Verdin, E AF Shimazu, Tadahiro Hirschey, Matthew D. Hua, Lan Dittenhafer-Reed, Kristin E. Schwer, Bjoern Lombard, David B. Li, Yu Bunkenborg, Jakob Alt, Frederick W. Denu, John M. Jacobson, Matthew P. Verdin, Eric TI SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production SO CELL METABOLISM LA English DT Article ID FATTY-ACID OXIDATION; LYSINE ACETYLATION; FORCE-FIELD; MOLECULAR-DYNAMICS; ENZYME; PROTEINS; PHOSPHORYLATION; IDENTIFICATION; SIMULATIONS; PEPTIDE AB The mitochondrial sirtuin SIRT3 regulates metabolic homeostasis during fasting and calorie restriction. We identified mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) as an acetylated protein and a possible target of SIRT3 in a proteomics survey in hepatic mitochondria from Sirt3(-/-) (SIRT3KO) mice. HMGCS2 is the rate-limiting step in beta-hydroxybutyrate synthesis and is hyperacetylated at lysines 310, 447, and 473 in the absence of SIRT3. HMGCS2 is deacetylated by SIRT3 in response to fasting in wild-type mice, but not in SIRT3KO mice. HMGCS2 is deacetylated in vitro when incubated with SIRT3 and in vivo by overexpression of SIRT3. Deacetylation of HMGCS2 lysines 310, 447, and 473 by incubation with wild-type SIRT3 or by mutation to arginine enhances its enzymatic activity. Molecular dynamics simulations show that in silico deacetylation of these three lysines causes conformational changes of HMGCS2 near the active site. Mice lacking SIRT3 show decreased beta-hydroxybutyrate levels during fasting. Our findings show SIRT3 regulates ketone body production during fasting and provide molecular insight into how protein acetylation can regulate enzymatic activity. C1 [Shimazu, Tadahiro; Hirschey, Matthew D.; Schwer, Bjoern; Verdin, Eric] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Shimazu, Tadahiro; Hirschey, Matthew D.; Schwer, Bjoern; Verdin, Eric] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Hua, Lan; Jacobson, Matthew P.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Dittenhafer-Reed, Kristin E.; Denu, John M.] Univ Wisconsin, Dept Biomol Chem, Madison, WI 53706 USA. [Lombard, David B.; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst,Dept Genet, Program Cellular & Mol Med,Childrens Hosp,Immune, Boston, MA 02115 USA. [Li, Yu] Cell Signaling Technol, Danvers, MA 01923 USA. [Bunkenborg, Jakob] Univ So Denmark, Ctr Expt Bioinformat, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark. RP Verdin, E (reprint author), Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. EM everdin@gladstone.ucsf.edu OI Jacobson, Matthew/0000-0001-6262-655X; Verdin, Eric/0000-0003-3703-3183; Hirschey, Matthew/0000-0003-4541-5376 FU National Science Foundation (NSF); National Institute on Aging/National Institutes of Health (NIA/NIH) [AG022325]; Ellison Medical Foundation/AFAR; NIH [GM-081710, GM-065386]; Ellison Medical Foundation; J. David Gladstone Institutes; National Center for Research Resources [RR18928-01] FX Special thanks to A. Wilson and J. Carroll for figure preparation and to G. Howard and S. Ordway for editorial review. This work was supported in part by a National Science Foundation (NSF) predoctoral fellowship (K.E.D.-R.), a K08 award (AG022325) from the National Institute on Aging/National Institutes of Health (NIA/NIH) (D.B.L.), an Ellison Medical Foundation/AFAR Senior Postdoctoral Research Grant (B.S.), NIH grant GM-081710 (M.P.J.), NIH grant GM-065386 (J.M.D.), a Senior Scholarship in Aging from the Ellison Medical Foundation (F.W.A. and E.V.), and by institutional support from the J. David Gladstone Institutes. F.W.A. is an Investigator of the Howard Hughes Medical Institute. The J. David Gladstone Institutes received support from a National Center for Research Resources Grant RR18928-01. E.V. and F.W.A. are members of the scientific advisory board for Sirtris, a GSK company. M.P.J. is a member of the scientific advisory board for Schrodinger LLC. NR 38 TC 178 Z9 188 U1 4 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 1 PY 2010 VL 12 IS 6 BP 654 EP 661 DI 10.1016/j.cmet.2010.11.003 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 698CM UT WOS:000285569100013 PM 21109197 ER PT J AU Day, RT Cavaglieri, RD Tabatabaimir, H Mantravadi, V Lee, MJ Barnes, JL Kasinath, BS Feliers, D AF Day, Robert T. Cavaglieri, Rita de Cassia Tabatabaimir, Hooman Mantravadi, Vasudha Lee, Myung-Ja Barnes, Jeffrey L. Kasinath, Balakuntalam S. Feliers, Denis TI Acute hyperglycemia rapidly stimulates VEGF mRNA translation in the kidney. Role of angiotensin type 2 receptor (AT2) SO CELLULAR SIGNALLING LA English DT Article DE Kidney; Angiotensin; AT2 receptor; Vascular endothelial growth factor; Hyperglycemia; mRNA translation ID ENDOTHELIAL GROWTH-FACTOR; RENAL EPITHELIAL-CELLS; AT(2) RECEPTORS; PROTEIN-SYNTHESIS; II STIMULATION; HIGH GLUCOSE; S6 KINASE; EXPRESSION; MICE; RAT AB Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. Acute hyperglycemia increased synthesis of intrarenal Ang I and Ang II and resulted in activation of both Ang II receptors, AT1 and AT2, in the kidney. Losartan (specific AT1 antagonist) or PD123319 (specific AT2 antagonist) did not affect hyperglycemia but prevented activation of renal AT1 and AT2, respectively. In murine renal cortex, acute hyperglycemia increased VEGF protein but not mRNA content after 24 h, which suggested translational regulation. Blockade of AT2, but not AT1, prevented increase in VEGF synthesis by inhibiting translation of VEGF mRNA in renal cortex. Acute hyperglycemia increased VEGF expression in wild type but not in AT2 knockout mice. Binding of heterogeneous nuclear ribonucleoprotein K to VEGF mRNA, which stimulates its translation, was prevented by blockade of AT2, but not AT1. The Akt-mTOR-p70(S6K) signaling pathway, involved in the activation of mRNA translation, was activated in hyperglycemic kidneys and was blocked by the AT2 antagonist. Elongation phase is an important step of mRNA translation that is controlled by elongation factor 1A (eEF1A) and 2 (eEF2). Expression of eEF1A and activity of eEF2 was higher in kidney cortex from hyperglycemic mice and only the AT2 antagonist prevented these changes. To assess selectivity of translational control of VEGF expression, we measured expression of fibronectin (FN) and laminin beta 1 (lam beta 1): acute hyperglycemia increased FN expression at both protein and mRNA levels, indicating transcriptional control, and did not affect the expression of lam beta 1. To confirm results obtained with PD123319, we induced hyperglycemia in AT2 knockout mice and found that in the absence of AT2, translational control of VEGF expression by hyperglycemia was abolished. Our data show that acute hyperglycemia stimulates Ang II synthesis in murine kidney cortex, this leads to AT2 activation and stimulation of VEGF mRNA translation, via the Akt-mTOR-p70(S6K) signaling pathway. Our data show that exclusive translational control of protein expression in the kidney by acute hyperglycemia is not a general phenomenon, but do not prove that it is restricted to VEGF. (C) 2010 Elsevier Inc. All rights reserved. C1 [Day, Robert T.; Tabatabaimir, Hooman; Mantravadi, Vasudha; Lee, Myung-Ja; Barnes, Jeffrey L.; Kasinath, Balakuntalam S.; Feliers, Denis] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, OBrien Kidney Res Ctr, San Antonio, TX 78229 USA. [Cavaglieri, Rita de Cassia] Univ Sao Paulo, Med Sch Hosp, Sao Paulo, Brazil. [Barnes, Jeffrey L.; Kasinath, Balakuntalam S.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Feliers, D (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med Nephrol, OBrien Kidney Res Ctr, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM feliers@uthscsa.edu RI Cavaglieri, Claudia/C-4291-2012 OI Cavaglieri, Claudia/0000-0002-7795-6575 FU American Heart Association [SDG 0630283N]; National Institute of Health [DK061597, DK077295, RC2AGO36613]; American Diabetes Association [7-05-RA-60]; Veterans Administration Research Service FX This work has been supported by the American Heart Association (grant SDG 0630283N to DF), the National Institute of Health (grants DK061597 to BSK and JLB, DK077295 and RC2AGO36613 to BSK), the American Diabetes Association (grant 7-05-RA-60 to BSK), and the Veterans Administration Research Service (to BSK and JLB). We would like to express our gratitude to Dr Victor Dzau (Duke University) for the generous gift of the AT2KO mice. NR 45 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD DEC PY 2010 VL 22 IS 12 BP 1849 EP 1857 DI 10.1016/j.cellsig.2010.07.012 PG 9 WC Cell Biology SC Cell Biology GA 663BE UT WOS:000282857200007 PM 20667471 ER PT J AU Hess, DR Tokarczyk, A Malley, MO Gavaghan, S Sullivan, J Schmidt, U AF Hess, Dean R. Tokarczyk, Arthur Malley, Mary O. Gavaghan, Susan Sullivan, Judith Schmidt, Ulrich TI The Value of Adding a Verbal Report to Written Handoffs on Early Readmission Following Prolonged Respiratory Failure SO CHEST LA English DT Article ID MECHANICAL VENTILATION; HOSPITAL DISCHARGE; CARE-UNIT; PROGRAM; TRIAL AB Patients who survive the acute phase of respiratory failure often are transferred to units with specialized expertise These patients have a high risk of being readmitted to the acute care hospital We conducted this study to determine whether supplementing a written report with a verbal telephone report reduces readmission rates within the first 72 h after discharge and decreases hospital costs The study design was observational with a historical control group that included patients admitted to our respiratory acute care unit between November 2003 and October 2005 In November 2005, we implemented a strategy in which a written report at discharge was supplemented with a telephone report by the physician or nurse practitioner, nurse, and respiratory therapist The intervention group began in November 2005 and continued through October 2007 The primary end point was readmission to Massachusetts General Hospital within 72 h of discharge We also determined the cost related to readmission The study included 362 patients The OR for readmission if the handoff included a verbal report was 0 42 (95% CI, 0 17-1 04) The total hospital cost was significantly lower in the group where verbal report was used ($111,723 vs $148,574, P = 002) Supplementing a written report with a verbal telephone report was associated with a significant reduction in cost and an average savings of similar to$184,000 for every 100 patients discharged, representing added value in delivered care CHEST 2010, 138(6) 1475-1479 C1 [Hess, Dean R.] Massachusetts Gen Hosp, Resp Care Serv, Dept Resp Care, Boston, MA 02114 USA. [Malley, Mary O.] Massachusetts Gen Hosp, Clin Case Management Unit, Boston, MA 02114 USA. [Gavaghan, Susan; Sullivan, Judith] Massachusetts Gen Hosp, Dept Nursing, Case Management Dept, Boston, MA 02114 USA. [Schmidt, Ulrich] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Hess, Dean R.; Schmidt, Ulrich] Harvard Univ, Sch Med, Boston, MA USA. [Tokarczyk, Arthur] NorthShore Univ Hlth Syst, Dept Anesthesiol, Evanston, IL USA. [Tokarczyk, Arthur] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. RP Hess, DR (reprint author), Massachusetts Gen Hosp, Resp Care Serv, Dept Resp Care, 55 Fruit St,Ellison 401, Boston, MA 02114 USA. FU Massachusetts General Hospital FX The study was conducted at Massachusetts General Hospital using departmental funding NR 16 TC 16 Z9 16 U1 2 U2 6 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2010 VL 138 IS 6 BP 1475 EP 1479 DI 10.1378/chest.09-2140 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 697DY UT WOS:000285494000028 PM 21138883 ER PT J AU Merchant, FM Dec, GW Singh, JP AF Merchant, Faisal M. Dec, G. William Singh, Jagmeet P. TI Implantable Sensors for Heart Failure SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE heart failure, congestive; treatment, pacemaker; diagnostic testing, other; contractile function ID CARDIAC RESYNCHRONIZATION THERAPY; RATE-VARIABILITY; INTRATHORACIC IMPEDANCE; HEMODYNAMIC MONITOR; NATRIURETIC PEPTIDE; PROGNOSTIC VALUE; PRECEDING HOSPITALIZATION; DILATED CARDIOMYOPATHY; DEVICE DIAGNOSTICS; PHYSICAL-ACTIVITY C1 [Singh, Jagmeet P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Heart,Cardiol Div,Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Singh, JP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Heart,Cardiol Div,Cardiac Arrhythmia Serv, GRB 109,55 Fruit St, Boston, MA 02114 USA. EM jsingh@partners.org RI Library, Woodruff Health/A-6096-2012 FU St Jude Medical; Medtronic Inc; Boston Scientific Corp; Biotronik; Guidant Corp; Sorin Group FX Dr Singh received research grants from St Jude Medical, Medtronic Inc, Boston Scientific Corp, and Biotronik, served on advisory boards or as a consultant for Boston Scientific Corp, St Jude Medical, and Medtronic, and received honoraria or speaker fees from Medtronic Inc, Biotronik, Guidant Corp, St Jude Medical, and Sorin Group. NR 60 TC 19 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD DEC PY 2010 VL 3 IS 6 BP 657 EP 667 DI 10.1161/CIRCEP.110.959502 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 694KF UT WOS:000285295500016 PM 21156777 ER PT J AU van Loon, JE Leebeek, FWG Deckers, JW Dippel, DWJ Poldermans, D Strachan, DP Tang, WH O'Donnell, CJ Smith, NL de Maat, MPM AF van Loon, Janine E. Leebeek, Frank W. G. Deckers, Jaap W. Dippel, Diederik W. J. Poldermans, Don Strachan, David P. Tang, Weihong O'Donnell, Christopher J. Smith, Nicholas L. de Maat, Moniek P. M. TI Effect of Genetic Variations in Syntaxin-Binding Protein-5 and Syntaxin-2 on von Willebrand Factor Concentration and Cardiovascular Risk SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE von Willebrand factor; genetics; STX2; STXBP5; cardiovascular diseases ID VONWILLEBRAND-FACTOR; FACTOR-VIII; THROMBOSIS; EXOCYTOSIS; SECRETION; ARTERIAL; TWIN; AGE AB Background-Elevated von Willebrand factor (VWF) plasma levels are associated with an increased risk of cardiovascular disease. A meta-analysis of genomewide association studies on VWF identified novel candidate genes, that is, syntaxin-binding protein 5 (STXBP5) and syntaxin 2 (STX2), which are possibly involved in the secretion of VWF. We investigated whether VWF antigen levels (VWF:Ag), VWF collagen-binding activity (VWF:CB) and the risk of arterial thrombosis are affected by common genetic variations in these genes. Methods and Results-In 463 young white subjects (men <= 45 years of age and women <= 55 years of age), who were included 1 to 3 months after a first event of arterial thrombosis, and 406 control subjects, we measured VWF:Ag and VWF:CB. Nine haplotype tagging single-nucleotide polymorphisms of STXBP5 and STX2 were selected and subsequently analyzed using linear regression with additive genetic models adjusted for age, sex, and ABO blood group. The minor alleles of rs9399599 and rs1039084 in STXBP5 were associated with lower VWF plasma levels and activity, whereas the minor allele of rs7978987 in STX2 was associated with higher VWF plasma levels and activity. The minor alleles of the single-nucleotide polymorphisms in STX2 were associated with a reduced risk of arterial thrombosis (rs1236: odds ratio, 0.73 [95% confidence interval, 0.59, 0.89]; rs7978987: odds ratio, 0.81 [95% confidence interval, 0.65, 1.00]; rs11061158:odds ratio, 0.69 [95% confidence interval, 0.55, 0.88]). Conclusions-Genetic variability in STXBP5 and STX2 affects both VWF concentration and activity in young individuals with premature arterial thrombosis. Furthermore, in our study, genetic variability in STX2 is associated with the risk of arterial thrombosis. However, at this point, the underlying mechanism remains unclear. (Circ Cardiovasc Genet. 2010; 3:507-512.) C1 [van Loon, Janine E.; Leebeek, Frank W. G.; de Maat, Moniek P. M.] Erasmus Univ, Med Ctr, Dept Hematol, NL-3000 CA Rotterdam, Netherlands. [Deckers, Jaap W.] Erasmus Univ, Med Ctr, Dept Cardiol, NL-3000 CA Rotterdam, Netherlands. [Dippel, Diederik W. J.] Erasmus Univ, Med Ctr, Dept Neurol, NL-3000 CA Rotterdam, Netherlands. Erasmus Univ, Med Ctr, Dept Vasc Surg, NL-3000 CA Rotterdam, Netherlands. [Poldermans, Don] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London, England. [Tang, Weihong] Univ Minnesota, Div Biostat Epidemiol & Community Hlth, Minneapolis, MN USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP de Maat, MPM (reprint author), Erasmus Univ, Med Ctr, Dept Hematol, Room L-431,POB 2040, NL-3000 CA Rotterdam, Netherlands. EM m.demaat@erasmusmc.nl FU Netherlands Heart Foundation [2007B159]; Thrombosis Foundation Holland [2010-3] FX This work was supported by a grant of the Netherlands Heart Foundation (2007B159) and the Thrombosis Foundation Holland (2010-3). NR 18 TC 22 Z9 22 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2010 VL 3 IS 6 BP 507 EP 512 DI 10.1161/CIRCGENETICS.110.957407 PG 6 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 694KG UT WOS:000285295600005 PM 21156930 ER PT J AU Yang, QO Kottgen, A Dehghan, A Smith, AV Glazer, NL Chen, MH Chasman, DI Aspelund, T Eiriksdottir, G Harris, TB Launer, L Nalls, M Hernandez, D Arking, DE Boerwinkle, E Grove, ML Li, M Kao, WHL Chonchol, M Haritunians, T Li, G Lumley, T Psaty, BM Shlipak, M Hwang, SJ Larson, MG O'Donnell, CJ Upadhyay, A van Duijn, CM Hofman, A Rivadeneira, F Stricker, B Uitterlinden, AG Pare, G Parker, AN Ridker, PM Siscovick, DS Gudnason, V Witteman, JC Fox, CS Coresh, J AF Yang, Qiong Koettgen, Anna Dehghan, Abbas Smith, Albert V. Glazer, Nicole L. Chen, Ming-Huei Chasman, Daniel I. Aspelund, Thor Eiriksdottir, Gudny Harris, Tamara B. Launer, Lenore Nalls, Michael Hernandez, Dena Arking, Dan E. Boerwinkle, Eric Grove, Megan L. Li, Man Kao, W. H. Linda Chonchol, Michel Haritunians, Talin Li, Guo Lumley, Thomas Psaty, Bruce M. Shlipak, Michael Hwang, Shih-Jen Larson, Martin G. O'Donnell, Christopher J. Upadhyay, Ashish van Duijn, Cornelia M. Hofman, Albert Rivadeneira, Fernando Stricker, Bruno Uitterlinden, Andre G. Pare, Guillaume Parker, Alex N. Ridker, Paul M. Siscovick, David S. Gudnason, Vilmundur Witteman, Jacqueline C. Fox, Caroline S. Coresh, Josef TI Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE uric acid; gout; cardiovascular diseases; risk factors; genome-wide association study; Mendelian randomization analysis ID GENOME-WIDE ASSOCIATION; BLOOD-PRESSURE; URIC-ACID; TRANSPORTER; EPIDEMIOLOGY; PROTEIN; VARIANT; ABCG2 AB Background-Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). Methods and Results-Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4x10(-8) to 2x10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 mu mol/L; P=3x10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. Conclusions-The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD. (Circ Cardiovasc Genet. 2010;3:523-530.) C1 [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Yang, Qiong; Chen, Ming-Huei; Hwang, Shih-Jen; Larson, Martin G.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Koettgen, Anna; Li, Man; Kao, W. H. Linda; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21287 USA. [Dehghan, Abbas; van Duijn, Cornelia M.; Hofman, Albert; Stricker, Bruno; Witteman, Jacqueline C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Glazer, Nicole L.; Li, Guo] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Glazer, Nicole L.; Li, Guo; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Harris, Tamara B.; Launer, Lenore] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Boerwinkle, Eric; Grove, Megan L.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol, Houston, TX USA. [Arking, Dan E.] Johns Hopkins Med Inst, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. [Kao, W. H. Linda; Coresh, Josef] Johns Hopkins Univ, Dept Med, Baltimore, MD 21287 USA. [Chonchol, Michel] Univ Colorado Denver & Hlth Sci Ctr, Div Renal Dis & Hypertens, Aurora, CO USA. [Haritunians, Talin] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Grp Hlth, Ctr Hlth Studies, Seattle, WA USA. [Shlipak, Michael] Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Chen, Ming-Huei] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Upadhyay, Ashish] Boston Med Ctr, Renal Sect, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Siscovick, David S.] Univ Washington, Dept Med & Epidemiol, Seattle, WA 98195 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Metab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Coresh, Josef] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Chasman, Daniel I.; Pare, Guillaume; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Nalls, Michael; Hernandez, Dena] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Parker, Alex N.] Amgen Inc, Cambridge, MA USA. RP Coresh, J (reprint author), Johns Hopkins Univ, Dept Epidemiol, 2024 E Monument,Ste 2-630, Baltimore, MD 21287 USA. EM coresh@jhu.edu RI Kottgen, Anna/D-2920-2012; Li, Guo/E-5613-2012; Yang, Qiong/G-5438-2014; Gudnason, Vilmundur/K-6885-2015; Rivadeneira, Fernando/O-5385-2015; Smith, Albert/K-5150-2015; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008 OI Gudnason, Vilmundur/0000-0001-5696-0084; Rivadeneira, Fernando/0000-0001-9435-9441; Smith, Albert/0000-0003-1942-5845; Dehghan, Abbas/0000-0001-6403-016X; Aspelund, Thor/0000-0002-7998-5433 FU National Institutes of Health, NIA; NIH [N01-AG-12100, HHSN268200625226C]; NIA; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NHLBI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, U01 HL080295, R01 HL087652, R01 AG027002, HL 043851]; National Human Genome Research Institute (NHGRI) [U01HG004402]; NIH Roadmap for Medical Research; Donald W. Reynolds Clinical Cardiovascular Research Center; National Center for Research Resources (NCRR) [UL1 RR 025005, M01RR00069]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NHLBI's FHS [N01-HC-25195]; Erasmus Medical Center; Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NOW); The Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; NWO [175.010.2005.011, 911.03.012, 918-76-619]; The Netherlands Genomics Initiative/NWO; National Cancer Institute [CA 047988]; Amgen, Inc.; [UL1RR025005]; [R01DK076770]; [K01DK067207]; [N01-HC-85079]; [N01-HC-85086]; [N01-HC-35129]; [N01-HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133]; [N02-HL-6-4278] FX We acknowledge the essential role of the CHARGE consortium in development and support of this manuscript. CHARGE members include The Netherland's RS), the National Heart, Lung, and Blood Institute's (NHLBI's) FHS, the CHS, the NHLBI's ARIC, and the Icelandic Heart Association's and National Institute on Aging's (NIA's) Iceland AGES Reykjavik Study. This research was supported in part by the Intramural Research Program of the National Institutes of Health, NIA.; The AGES study has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The ARIC study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute (NHGRI) contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Drs Coresh, Kottgen, and Man Li are supported by R01DK076770 and Dr Arking by a Donald W. Reynolds Clinical Cardiovascular Research Center grant. Dr Kao was supported by K01DK067207 and Dr Coresh by R01DK076770. The project described was supported by grant number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the NIH and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at www.ncrr.nih.gov. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp. The CHS 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 and grant numbers U01 HL080295, R01 HL087652, and R01 AG027002 from NHLBI. Genotyping was supported, in part, by NCRR grant M01RR00069 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491. The FHS was supported by the NHLBI's FHS (N01-HC-25195), and Affymetrix genotyping was supported by contract N02-HL-6-4278. The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NOW); The Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the NWO (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly. This study was further supported by The Netherlands Genomics Initiative/NWO project number 050-060-810. Dr Dehghan is supported by a grant from NWO (vici, 918-76-619). The WGHS was supported by the NHLBI (HL 043851) and the National Cancer Institute (CA 047988). Collaborative scientific and genotyping support was provided by Amgen, Inc.; Dr Yang has received research grant support from the NHLBI for the FHS. Dr Kottgen has ownership interest in a pending patent for ABCG2 urate transport used in the treatment of gout. Dr Smith has received research grant support for genetics of diabetes and thermophidic bacteria from the Iceland Research Council. Dr Chasman has received research grant support from NIH for the Women's Health Study (R01 HL080467, Buring PI); PARC (U01 HL069757, Krauss PI); PRE-DETERMINE (R01 HL091069, Albert PI); Genetics of AMD (R01 EY017362, Schaumberg PI); Genetics of Migraine (R01 NS061836, Kurth PI); and Gene Networks GWAS (R01 submitted, Chasman PI). Dr Boerwinkle has received grant support from NIH/NHLBI, NIH/NHGRI, and NIH/National Institute of General Medical Sciences. Dr Chonchol has received NIH research grant support from R01, "Vitamin D and Dialysis"; R01, "Adiporectin and Dialysis"; and U01, "BP and CKD." Dr Ridker has received research grant support from NHLBI; Amgen, Inc; and Celera and other research support from Amgen, Inc. Dr Coresh has received research grant support from NIH for the ARIC cohort and ARIC kidney disease and related conditions including genetics studies and has ownership interest in a pending patent on using ABCG2 to treat hyperuricemia. Dr Parker is an employee of Amgen, Inc. Drs Dehghan, Glazer, Chen, Aspelund, Harris, Launer, Nalls, Arking, Kao, Haritunians, Lumley, Psaty, Shlipak, Hwang, Larson, O'Donnell, Upadhyay, van Dujin, Hofman, Rivadeneira, Stricker, Uitterlinden, Pare, Siscovick, Gudnason, Witteman, and Fox and Mss Eiriksdottir, Hernandez, Grove, M. Li, and G. Li have no conflicts to disclose. NR 25 TC 134 Z9 150 U1 5 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1942-325X EI 1942-3268 J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2010 VL 3 IS 6 BP 523 EP 530 DI 10.1161/CIRCGENETICS.110.934455 PG 8 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 694KG UT WOS:000285295600007 PM 20884846 ER PT J AU Baccarelli, A Rienstra, M Benjamin, EJ AF Baccarelli, Andrea Rienstra, Michiel Benjamin, Emelia J. TI Cardiovascular Epigenetics Basic Concepts and Results From Animal and Human Studies SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE DNA methylation; histones; risk factors; cardiovascular diseases ID DNA METHYLATION; GENE PROMOTER; DISEASE; BLOOD; HYPERHOMOCYSTEINEMIA; ATHEROSCLEROSIS; HYPERTENSION; HOMOCYSTEINE; EXPOSURE C1 [Baccarelli, Andrea] Harvard Univ, Sch Publ Hlth, Lab Environm Epigenet, Exposure Epidemiol & Risk Program,Landmark Ctr, Boston, MA 02115 USA. [Rienstra, Michiel] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Rienstra, Michiel; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Rienstra, Michiel; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Rienstra, Michiel] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Prevent Med Sect, Boston, MA 02118 USA. RP Baccarelli, A (reprint author), Harvard Univ, Sch Publ Hlth, Lab Environm Epigenet, Exposure Epidemiol & Risk Program,Landmark Ctr, Room 415E W,POB 15677,401 Pk Dr, Boston, MA 02115 USA. EM abaccare@hsph.harvard.edu OI Baccarelli, Andrea/0000-0002-3436-0640; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU The Netherlands Organization for Scientific Research [825.09.020]; National Institutes of Health [1R01HL092577, 1RC1HL101056, 1R01HL102214, R01AG028321]; Baccarelli [ES000002, 1R21ES019773] FX Dr Rienstra is supported by a grant from The Netherlands Organization for Scientific Research (Rubicon grant 825.09.020). This work was supported by grants from the National Institutes of Health to Drs Benjamin (1R01HL092577, 1RC1HL101056, 1R01HL102214, R01AG028321) and Baccarelli (ES000002, 1R21ES019773). NR 23 TC 73 Z9 78 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2010 VL 3 IS 6 BP 567 EP 573 DI 10.1161/CIRCGENETICS.110.958744 PG 7 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 694KG UT WOS:000285295600012 PM 21156932 ER PT J AU Ebersole, JL Steffen, MJ Holt, SC Kesavalu, L Chu, L Cappelli, D AF Ebersole, J. L. Steffen, M. J. Holt, S. C. Kesavalu, L. Chu, L. Cappelli, D. TI Systemic inflammatory responses in progressing periodontitis during pregnancy in a baboon model SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE antibody; baboons; inflammation; periodontitis; pregnancy ID LIGATURE-INDUCED PERIODONTITIS; NONHUMAN-PRIMATES; EXPERIMENTAL GINGIVITIS; BACTERIAL VAGINOSIS; CYNOMOLGUS MONKEY; IMMUNE PARAMETERS; INNATE IMMUNITY; INDUCED DISEASE; PRETERM LABOR; INFECTIONS AB P>This study tested the hypothesis that pregnant female baboons exhibit increased levels of various inflammatory mediators in serum resulting from ligature-induced periodontitis, and that these profiles would relate to periodontal disease severity/extent in the animals. The animals were sampled at baseline (B), mid-pregnancy (MP; two quadrants ligated) and at delivery (D; four quadrants ligated). All baboons developed increased plaque, gingival inflammation and bleeding, pocket depths and attachment loss following placement of the ligatures. By MP, both prostaglandin E(2) (PGE(2)) and bactericidal permeability inducing factor (BPI) were greater than baseline, while increased levels of interleukin (IL)-6 occurred in the experimental animals by the time of delivery. IL-8, MCP-1 and LBP all decreased from baseline through the ligation phase of the study. Stratification of the animals by baseline clinical presentation demonstrated that PGE(2), LBP, IL-8 and MCP-1 levels were altered throughout the ligation interval, irrespective of baseline clinical values. IL-6, IL-8 and LBP were significantly lower in the subset of animals that demonstrated the least clinical response to ligation, indicative of progressing periodontal disease. PGE(2), macrophage chemotactic protein (MCP)-1, regulated upon activation, normal T cell expressed and secreted (RANTES) and LBP were decreased in the most diseased subset of animals at delivery. Systemic antibody responses to Fusobacterium nucleatum, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Campylobacter rectus were associated most frequently with variations in inflammatory mediator levels. These results provide a profile of systemic inflammatory mediators during ligature-induced periodontitis in pregnant baboons. The relationship of the oral clinical parameters to systemic inflammatory responses is consistent with a contribution to adverse pregnancy outcomes in a subset of the animals. C1 [Ebersole, J. L.] Univ Kentucky, Albert B Chandler Med Ctr, Coll Dent, Ctr Oral Hlth Res, Lexington, KY 40536 USA. [Holt, S. C.] Forsyth Inst, Boston, MA USA. [Kesavalu, L.] Univ Florida, Sch Dent, Dept Periodont, Gainesville, FL USA. [Chu, L.; Cappelli, D.] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent Med, San Antonio, TX 78229 USA. RP Ebersole, JL (reprint author), Univ Kentucky, Albert B Chandler Med Ctr, Coll Dent, Ctr Oral Hlth Res, HSRB422, Lexington, KY 40536 USA. EM jleber2@uky.edu FU National Institute of Dental and Craniofacial Research [DE13958] FX This work was supported by USPHS grant DE13958 from the National Institute of Dental and Craniofacial Research. We would like to thank Scott Eddy, Robert Ayala and Malini Bharadwaj for technical support in developing and managing these data. We acknowledge the crucial contribution of Drs Kathleen Brasky, Karen Rice and the scientific and technical staff at the Southwest Foundation for Biomedical Research and contribution from USPHS grant 13986 in support of the Southwest National Primate Research Center at the Foundation. NR 59 TC 13 Z9 14 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD DEC PY 2010 VL 162 IS 3 BP 550 EP 559 DI 10.1111/j.1365-2249.2010.04202.x PG 10 WC Immunology SC Immunology GA 678IX UT WOS:000284068400018 PM 21070210 ER PT J AU Guo, YQ Nemeth, J O'Brien, C Susa, M Liu, XZ Zhang, Z Choy, E Mankin, H Hornicek, F Duan, ZF AF Guo, Yuqi Nemeth, Jeffrey O'Brien, Colin Susa, Michiro Liu, Xianzhe Zhang, Zhan Choy, Edwin Mankin, Henry Hornicek, Francis Duan, Zhenfeng TI Effects of Siltuximab on the IL-6-Induced Signaling Pathway in Ovarian Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; MULTIPLE-MYELOMA; PACLITAXEL RESISTANCE; DRUG-RESISTANCE; PROSTATE-CANCER; CARCINOMA-CELLS; PRECLINICAL MODELS; SERUM-LEVELS; IN-VITRO; INTERLEUKIN-6 AB Purpose: To explore potential therapeutic strategies for interrupting the interleukin-6 (IL-6) signaling pathway, we measured IL-6 expression in ovarian cancer tissues, and evaluated the effects of a monoclonal anti-IL-6 antibody; siltuximab (CNTO 328), on levels of IL-6-induced Stat3 phosphorylation, Stat3 nuclear translocation, and Stat3 downstream antiapoptotic genes. We then looked for enhancing paclitaxel sensitivity in multidrug-resistant ovarian cancer cell lines. Experimental Design: Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. Effects of siltuximab on IL-6-induced activation of Stat3 in an ovarian cancer cell line were determined by Western blot and real-time analysis of Stat3 nucleocytoplasmic translocation. Influence of combination of siltuximab and paclitaxel on tumor growth was evaluated in a xenograft mouse mode in vivo. Results: Metastatic and drug-resistant recurrent tumors have significantly higher IL-6 expression when compared with the matched primary tumors. Siltuximab specifically suppressed IL-6-induced Stat3 phosphorylation and Stat3 nuclear translocation. Treatment with siltuximab significantly decreased the levels of Stat3 downstream proteins such as MCL-1, Bcl-X(L), and survivin. Treatment with siltuximab reduced expression of multiple IL-6-induced genes in these cell lines. Furthermore, siltuximab increased the cytotoxic effects of paclitaxel in a paclitaxel resistant ovarian cancer cell line in vitro, but combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth in vivo. Conclusions: These results show that siltuximab effectively block the IL-6 signaling pathways and IL-6-induced gene expression. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer. Clin Cancer Res; 16(23); 5759-69. (C)2010 AACR. C1 [Guo, Yuqi; O'Brien, Colin; Susa, Michiro; Liu, Xianzhe; Choy, Edwin; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Guo, Yuqi; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Zhengzhou, Peoples R China. [Nemeth, Jeffrey] Ortho Biotech Oncol Res & Dev, Div Centocor, Horsham, PA USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, 100 Blossom St,Jackson 1115, Boston, MA 02114 USA. EM zduan@partners.org RI Susa, Michiro/L-2291-2013; OI Choy, Edwin/0000-0001-9896-8084 FU Ortho Biotech Oncology Research & Development, Division of Centocor; National Cancer Institute, NIH; Ovarian Cancer Research Foundation (OCRF) FX This project was supported by a grant from Ortho Biotech Oncology Research & Development, Division of Centocor. Dr. Duan is supported, in part, through a grant from the National Cancer Institute, NIH (Nanotechnology Platform.) and a grant from the Ovarian Cancer Research Foundation (OCRF). NR 47 TC 45 Z9 47 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2010 VL 16 IS 23 BP 5759 EP 5769 DI 10.1158/1078-0432.CCR-10-1095 PG 11 WC Oncology SC Oncology GA 690XU UT WOS:000285044200016 PM 20699329 ER PT J AU Alexander, BM Sprott, K Farrow, DA Wang, X D'Andrea, AD Schnitt, SJ Collins, LC Weaver, DT Garber, JE AF Alexander, Brian M. Sprott, Kam Farrow, D. Allan Wang, XiaoZhe D'Andrea, Alan D. Schnitt, Stuart J. Collins, Laura C. Weaver, David T. Garber, Judy E. TI DNA Repair Protein Biomarkers Associated with Time to Recurrence in Triple-Negative Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID INTERSTRAND CROSS-LINKS; FANCONI-ANEMIA PATHWAY; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; INCREASED SENSITIVITY; MAPKAP KINASE-2; CISPLATIN; DAMAGE; CELLS; MUTATIONS AB Purpose: To evaluate the prognostic utility of immunohistochemical assessment of key proteins in multiple DNA repair pathways in triple-negative breast cancer (TNBC; estrogen receptor negative, progesterone receptor negative, and HER2/neu negative by immunohistochemistry). Experimental Design: Archived clinically annotated tumor specimens from 112 women with TNBC were immunostained with antibodies against DNA repair proteins and scored using digital image analysis. The cohort was divided into training and test sets for development of a multiantibody model. Scores were combined with clinical data to assess association with outcome. Results: Low XPF (P = 0.005), pMK2 (P = 0.01), MLH; P = 0.002), and FANCD2 (P = 0.001) were each associated with shorter time to recurrence (TTR) in univariate analysis. A 4-antibody model could segregate high-risk and low-risk groups on the basis of TTR in both the training (relative risk [RR] = 3.52; P = 9.05E-07) and test (RR 2.67; P = 0.019) cohorts. Conclusions: DNA repair proteins may be useful as prognostic markers in TNBC. Further study in larger, uniformly treated cohorts with additional clinical parameters is warranted. Clin Cancer Res; 16(23); 5796-804. (C)2010 AACR. C1 [Alexander, Brian M.; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Alexander, Brian M.] Harvard Radiat Oncol Program, Boston, MA USA. [Sprott, Kam; Farrow, D. Allan; Wang, XiaoZhe; Weaver, David T.] On Q Ity Inc, Waltham, MA USA. [Schnitt, Stuart J.; Collins, Laura C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Garber, JE (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM judy_garber@dfci.harvard.edu FU NCI NIH HHS [P50 CA089393] NR 56 TC 22 Z9 22 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2010 VL 16 IS 23 BP 5796 EP 5804 DI 10.1158/1078-0432.CCR-10-0292 PG 9 WC Oncology SC Oncology GA 690XU UT WOS:000285044200019 PM 21138871 ER PT J AU Heon, S Yeap, BY Britt, GJ Costa, DB Rabin, MS Jackman, DM Johnson, BE AF Heon, Stephanie Yeap, Beow Y. Britt, Gregory J. Costa, Daniel B. Rabin, Michael S. Jackman, David M. Johnson, Bruce E. TI Development of Central Nervous System Metastases in Patients with Advanced Non-Small Cell Lung Cancer and Somatic EGFR Mutations Treated with Gefitinib or Erlotinib SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; CHEMOTHERAPY-NAIVE PATIENTS; TYROSINE KINASE INHIBITOR; BRAIN METASTASES; PHASE-I; RISK; RESISTANCE; THERAPY; ADENOCARCINOMA; CARCINOMA AB Purpose: Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non-small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases. Experimental Design: Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months. Conclusions: Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients. Clin Cancer Res; 16(23); 5873-82. (C)2010 AACR. C1 [Heon, Stephanie; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02115 USA. [Yeap, Beow Y.; Costa, Daniel B.; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Britt, Gregory J.; Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, 44 Binney St,Dana Bldg 1234C, Boston, MA 02115 USA. EM bejohnson@partners.org OI Costa, Daniel/0000-0002-0689-395X FU American Society of Clinical Oncology Cancer Foundation; NIH [5R01-CA114465]; Dana-Farber Cancer Institute FX This work was funded in part by the American Society of Clinical Oncology Cancer Foundation Translational Research Professorship (B.E.J.), NIH grant 5R01-CA114465 (B.E.J. and B.Y.Y.), and the Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at Dana-Farber Cancer Institute (D.M.J.). NR 44 TC 85 Z9 93 U1 1 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 DEC 1 PY 2010 VL 16 IS 23 BP 5873 EP 5882 DI 10.1158/1078-0432.CCR-10-1588 PG 10 WC Oncology SC Oncology GA 690XU UT WOS:000285044200027 PM 21030498 ER PT J AU Al-Turkmani, MR Law, T Narla, A Kellogg, MD AF Al-Turkmani, M. Rabie Law, Terence Narla, Anupama Kellogg, Mark D. TI Difficulty Measuring Methotrexate in a Patient with High-Dose Methotrexate-Induced Nephrotoxicity SO CLINICAL CHEMISTRY LA English DT Editorial Material ID PLASMA C1 [Al-Turkmani, M. Rabie; Law, Terence; Kellogg, Mark D.] Childrens Hosp Boston, Dept Lab Med, Boston, MA 02115 USA. [Narla, Anupama] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA 02115 USA. [Narla, Anupama] Harvard Univ, Sch Med, Boston, MA USA. RP Kellogg, MD (reprint author), Childrens Hosp Boston, Dept Lab Med, 300 Longwood Ave, Boston, MA 02115 USA. EM mark.kellogg@childrens.harvard.edu OI Kellogg, Mark/0000-0003-1868-2153 NR 9 TC 8 Z9 9 U1 1 U2 1 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 DEC PY 2010 VL 56 IS 12 BP 1792 EP 1794 DI 10.1373/clinchem.2010.144824 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 687EI UT WOS:000284759700004 PM 21119035 ER EF