FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Beirne, OR Busaidy, KF Eisig, SB Larsen, PE White, RP Dodson, TB Rafetto, LK AF Beirne, O. Ross Busaidy, Kamal F. Eisig, Sidney B. Larsen, Peter E. White, Raymond P., Jr. Dodson, Thomas B. Rafetto, Louis K. TI Summary of the Third Molar Clinical Trials: Report of the AAOMS Task Force for Third Molar Summary SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID QUALITY-OF-LIFE; PERIODONTAL INFLAMMATORY DISEASE; CORONARY-HEART-DISEASE; YOUNG-ADULTS; 3RD-MOLAR SURGERY; CARIES EXPERIENCE; ASYMPTOMATIC 3RD-MOLARS; ATHEROSCLEROSIS RISK; TOPICAL MINOCYCLINE; OLDER AMERICANS C1 [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren Bldg,Suite 1201, Boston, MA 02114 USA. EM tbdodson@partners.org FU American Association of Oral and Maxillofacial Surgeons; Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital FX This report was funded in part by the American Association of Oral and Maxillofacial Surgeons and the Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital. NR 50 TC 0 Z9 0 U1 1 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD SEP PY 2012 VL 70 IS 9 BP 2238 EP 2248 DI 10.1016/j.joms.2012.06.180 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 999NG UT WOS:000308319900039 ER PT J AU Gros, DF Price, M Gros, KS Paul, LA McCauley, JL Ruggiero, KJ AF Gros, Daniel F. Price, Matthew Gros, Kirstin Stauffacher Paul, Lisa A. McCauley, Jenna L. Ruggiero, Kenneth J. TI Relations between Loss of Services and Psychiatric Symptoms in Urban and Non-Urban Settings following a Natural Disaster SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE PTSD; Depression; Worry; Preparedness; Disaster; Urban; Non-urban ID MENTAL-HEALTH PROBLEMS; PSYCHOMETRIC PROPERTIES; PTSD CHECKLIST; VICTIMS SPEAK; PREPAREDNESS; CONTEXT; IMPACT; MODEL AB Disasters have been associated with both acute and prolonged distress and significant post-disaster psychiatric symptoms. These outcomes may be further complicated by extended periods without vital services and supplies, such as electricity and drinking water. The present study investigated the relations between post-disaster loss of services and psychiatric symptoms in urban/non-urban disaster victims. Random-digit-dial methodology was used to interview 1,249 victims of Hurricane Ike, a strong storm that hit Galveston, TX in 2008. Findings demonstrated significant relations between loss of services and post-disaster symptoms of posttraumatic stress disorder (PTSD), depression, and worry. These relations varied by urban/non-urban settings; there were significant positive relations between loss of services and symptoms of depression in non-urban settings, but not in urban settings. Similarly, a stronger relation between loss of services and symptoms of PTSD also was demonstrated in non-urban compared to urban settings. Findings highlight the potential importance of pre-disaster preparation, post-disaster restoration of services, and post-disaster community support in post-disaster psychiatric outcomes, with a particular emphasis in non-urban settings. C1 [Gros, Daniel F.] Ralph H Johnson VAMC, Mental Hlth Serv 116, Charleston, SC 29401 USA. [Gros, Daniel F.; Price, Matthew; Gros, Kirstin Stauffacher; Paul, Lisa A.; McCauley, Jenna L.; Ruggiero, Kenneth J.] Med Univ S Carolina, Charleston, SC 29425 USA. RP Gros, DF (reprint author), Ralph H Johnson VAMC, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu FU NIMH NIH HHS [R01 MH081056, T32 MH018869, R34 MH077149] NR 29 TC 2 Z9 2 U1 3 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2012 VL 34 IS 3 BP 343 EP 350 DI 10.1007/s10862-012-9290-9 PG 8 WC Psychology, Clinical SC Psychology GA 995GW UT WOS:000307997200005 PM 23105170 ER PT J AU Sinclair, SJ Bello, I Nyer, M Slavin-Mulford, J Stein, MB Renna, M Antonius, D Blais, MA AF Sinclair, Samuel Justin Bello, Iruma Nyer, Maren Slavin-Mulford, Jenelle Stein, Michelle B. Renna, Megan Antonius, Daniel Blais, Mark A. TI The Suicide (SPI) and Violence Potential Indices (VPI) from the Personality Assessment Inventory: A Preliminary Exploration of Validity in an Outpatient Psychiatric Sample SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Personality assessment inventory; Risk assessment; Suicide potential; Violence potential ID NATIONAL INTELLIGENCE; FORENSIC EVALUATION; PCL-R; ATTEMPTERS; PAI; IDEATION; SCALES; OFFENDERS; VETERANS; DISORDER AB Assessing risk of harm to self and others is an important component of psychological assessment, although methods for risk assessment vary considerably. The Personality Assessment Inventory (PAI) is frequently administered to evaluate general psychological functioning, as well as to provide information about suicide and violence risk. The purpose of this study was to evaluate the construct validity of the PAI Suicide (SPI) and Violence Potential (VPI) indices in a sample of 158 psychiatric outpatients referred for psychological and neuropsychological assessment within a large northeastern academic medical center between 2007 and 2011. Results generally supported the convergent and divergent validity of both SPI and VPI when evaluating groups with and without a history of suicide and violence risk, and effect sizes were moderate to large even after controlling for other covariates. SPI and VPI scores were also found to vary significantly across different psychiatric groups in ways that would be expected. Finally, we explored the relationship between SPI and VPI, and executive functioning impairment-a neuropsychological variable found to be associated with impulsive self and other-harming behaviors. Consistent with prior research, SPI and VPI were found to be significantly elevated in groups demonstrating executive dysfunction. The implications of these findings and specifically the utility of using SPI and VPI in the assessment of risk are discussed. C1 [Sinclair, Samuel Justin; Bello, Iruma; Nyer, Maren; Slavin-Mulford, Jenelle; Stein, Michelle B.; Renna, Megan; Blais, Mark A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sinclair, Samuel Justin; Bello, Iruma; Nyer, Maren; Slavin-Mulford, Jenelle; Stein, Michelle B.; Renna, Megan; Blais, Mark A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Antonius, Daniel] SUNY Buffalo, Buffalo, NY 14260 USA. [Antonius, Daniel] NYU, Sch Med, New York, NY USA. RP Sinclair, SJ (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM SJSinclair@Partners.org NR 47 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2012 VL 34 IS 3 BP 423 EP 431 DI 10.1007/s10862-012-9277-6 PG 9 WC Psychology, Clinical SC Psychology GA 995GW UT WOS:000307997200013 ER PT J AU Gutierrez, OM Katz, R Peralta, CA de Boer, IH Siscovick, D Wolf, M Roux, AD Kestenbaum, B Nettleton, JA Ix, JH AF Gutierrez, Orlando M. Katz, Ronit Peralta, Carmen A. de Boer, Ian H. Siscovick, David Wolf, Myles Roux, Ana Diez Kestenbaum, Bryan Nettleton, Jennifer A. Ix, Joachim H. TI Associations of Socioeconomic Status and Processed Food Intake With Serum Phosphorus Concentration in Community-Living Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) SO JOURNAL OF RENAL NUTRITION LA English DT Article ID NUTRITION EXAMINATION SURVEY; CHRONIC KIDNEY-DISEASE; 3RD NATIONAL-HEALTH; GROWTH-FACTOR 23; DIETARY PHOSPHATE; MORTALITY; MEN; HEMODIALYSIS; CALCIUM; QUESTIONNAIRE AB Objective: Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus concentration, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus concentration. Design: Cross-sectional analysis. Setting and Participants: We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States. Predictor Variables: Socioeconomic status, the intake of foods commonly enriched with phosphorus-based food additives (processed meats, sodas), and frequency of fast-food consumption. Outcomes: Fasting morning serum phosphorus concentrations. C1 [Gutierrez, Orlando M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Gutierrez, Orlando M.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Peralta, Carmen A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Peralta, Carmen A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [de Boer, Ian H.; Siscovick, David; Kestenbaum, Bryan] Univ Washington, Dept Med, Seattle, WA USA. [de Boer, Ian H.; Siscovick, David; Kestenbaum, Bryan] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Wolf, Myles] Univ Miami, Dept Med, Miami, FL USA. [Roux, Ana Diez] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Ix, Joachim H.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. RP Gutierrez, OM (reprint author), Univ Alabama Birmingham, Dept Med, ZRB 614,1530 3rd Ave S, Birmingham, AL 35294 USA. EM ogutierr@uab.edu FU associated ARRA supplement [R21HL091217-01A2S1]; National Institutes of Health [N01-HC-95169]; [K23DK081673]; [R21HL091217]; [N01-HC95159]; [N01-HC95160]; [N01-HC95161]; [N01-HC95162]; [N01-HC95163]; [N01-HC95164]; [N01-HC-95165] FX This study was supported by grants K23DK081673 (O.M.G.), R21HL091217 and an associated ARRA supplement R21HL091217-01A2S1 (JHI), and contracts N01-HC95159 through N01-HC-95165 and N01-HC-95169 from the National Institutes of Health. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 43 TC 9 Z9 9 U1 0 U2 30 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD SEP PY 2012 VL 22 IS 5 BP 480 EP 489 DI 10.1053/j.jrn.2011.08.008 PG 10 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 997YB UT WOS:000308202800006 PM 22217539 ER PT J AU McCoy, AB Wright, A Laxmisan, A Ottosen, MJ McCoy, JA Butten, D Sittig, DF AF McCoy, Allison B. Wright, Adam Laxmisan, Archana Ottosen, Madelene J. McCoy, Jacob A. Butten, David Sittig, Dean F. TI Development and evaluation of a crowdsourcing methodology for knowledge base construction: identifying relationships between clinical problems and medications SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ELECTRONIC HEALTH RECORDS; PROVIDER ORDER ENTRY; UNINTENDED CONSEQUENCES; DRUG KNOWLEDGE; SYSTEM; INFORMATION; INTERNET; QUALITY; ERRORS AB Objective We describe a novel, crowdsourcing method for generating a knowledge base of problem-medication pairs that takes advantage of manually asserted links between medications and problems. Methods Through iterative review, we developed metrics to estimate the appropriateness of manually entered problem-medication links for inclusion in a knowledge base that can be used to infer previously unasserted links between problems and medications. Results Clinicians manually linked 231 223 medications (55.30% of prescribed medications) to problems within the electronic health record, generating 41 203 distinct problem-medication pairs, although not all were accurate. We developed methods to evaluate the accuracy of the pairs, and after limiting the pairs to those meeting an estimated 95% appropriateness threshold, 11 166 pairs remained. The pairs in the knowledge base accounted for 183 127 total links asserted (76.47% of all links). Retrospective application of the knowledge base linked 68 316 medications not previously linked by a clinician to an indicated problem (36.53% of unlinked medications). Expert review of the combined knowledge base, including inferred and manually linked problem-medication pairs, found a sensitivity of 65.8% and a specificity of 97.9%. Conclusion Crowdsourcing is an effective, inexpensive method for generating a knowledge base of problememedication pairs that is automatically mapped to local terminologies, up-to-date, and reflective of local prescribing practices and trends. C1 [McCoy, Allison B.; Sittig, Dean F.] Univ Texas Hlth Sci Ctr Houston UTHealth, Sch Biomed Informat, Houston, TX 77030 USA. [McCoy, Allison B.; Ottosen, Madelene J.; Sittig, Dean F.] Univ Texas Houston, Mem Hermann Ctr Healthcare Qual & Safety, Houston, TX USA. [Wright, Adam] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Laxmisan, Archana; Butten, David] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. [Laxmisan, Archana; Butten, David] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [McCoy, Jacob A.] Univ Texas Med Sch Houston, Houston, TX USA. RP McCoy, AB (reprint author), Univ Texas Hlth Sci Ctr Houston UTHealth, Sch Biomed Informat, 6410 Fannin St,UTPB 1100, Houston, TX 77030 USA. EM allison.b.mccoy@uth.tmc.edu RI McCoy, Allison/I-1951-2013 OI McCoy, Allison/0000-0003-2292-9147 FU Office of the National Coordinator for Health Information Technology [10510592]; NCRR [3UL1RR024148] FX This project was supported in part by Grant No. 10510592 for Patient-Centered Cognitive Support under the Strategic Health IT Advanced Research Projects Program (SHARP) from the Office of the National Coordinator for Health Information Technology. The UTHealth Clinical Data Warehouse is supported by NCRR Grant 3UL1RR024148. NR 32 TC 18 Z9 18 U1 2 U2 30 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2012 VL 19 IS 5 BP 713 EP 718 DI 10.1136/amiajnl-2012-000852 PG 6 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 994MJ UT WOS:000307934600005 PM 22582202 ER PT J AU Schnipper, JL Gandhi, TK Wald, JS Grant, RW Poon, EG Volk, LA Businger, A Williams, DH Siteman, E Buckel, L Middleton, B AF Schnipper, Jeffrey L. Gandhi, Tejal K. Wald, Jonathan S. Grant, Richard W. Poon, Eric G. Volk, Lynn A. Businger, Alexandra Williams, Deborah H. Siteman, Elizabeth Buckel, Lauren Middleton, Blackford TI Effects of an online personal health record on medication accuracy and safety: a cluster-randomized trial SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ADVERSE DRUG EVENTS; PATIENT; IMPACT; CARE AB Objective To determine the effects of a personal health record (PHR)-linked medications module on medication accuracy and safety. Design From September 2005 to March 2007, we conducted an on-treatment sub-study within a cluster-randomized trial involving 11 primary care practices that used the same PHR. Intervention practices received access to a medications module prompting patients to review their documented medications and identify discrepancies, generating 'eJournals' that enabled rapid updating of medication lists during subsequent clinical visits. Measurements A sample of 267 patients who submitted medications eJournals was contacted by phone 3 weeks after an eligible visit and compared with a matched sample of 274 patients in control practices that received a different PHR-linked intervention. Two blinded physician adjudicators determined unexplained discrepancies between documented and patient-reported medication regimens. The primary outcome was proportion of medications per patient with unexplained discrepancies. Results Among 121 046 patients in eligible practices, 3979 participated in the main trial and 541 participated in the sub-study. The proportion of medications per patient with unexplained discrepancies was 42% in the intervention arm and 51% in the control arm (adjusted OR 0.71, 95% CI 0.54 to 0.94, p = 0.01). The number of unexplained discrepancies per patient with potential for severe harm was 0.03 in the intervention arm and 0.08 in the control arm (adjusted RR 0.31, 95% CI 0.10 to 0.92, p = 0.04). Conclusions When used, concordance between documented and patient-reported medication regimens and reduction in potentially harmful medication discrepancies can be improved with a PHR medication review tool linked to the provider's medical record. Trial registration number This study was registered at ClinicalTrials.gov (NCT00251875). C1 [Schnipper, Jeffrey L.; Gandhi, Tejal K.; Wald, Jonathan S.; Poon, Eric G.; Businger, Alexandra; Middleton, Blackford] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02120 USA. [Schnipper, Jeffrey L.; Gandhi, Tejal K.; Wald, Jonathan S.; Grant, Richard W.; Poon, Eric G.; Middleton, Blackford] Harvard Univ, Sch Med, Boston, MA USA. [Gandhi, Tejal K.] Partners HealthCare Syst, Patient Safety, Boston, MA USA. [Wald, Jonathan S.] RTI Int, Waltham, MA USA. [Grant, Richard W.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Grant, Richard W.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Volk, Lynn A.; Williams, Deborah H.; Siteman, Elizabeth; Buckel, Lauren] Partners HealthCare Syst, Clin & Qual Anal, Boston, MA USA. [Middleton, Blackford] Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. RP Schnipper, JL (reprint author), Brigham & Womens Hosp, Div Gen Med, 1620 Tremont St, Boston, MA 02120 USA. EM jschnipper@partners.org OI Middleton, Blackford/0000-0002-1819-1234; Grant, Richard/0000-0002-6164-8025 FU AHRQ [R01-HS013660-02]; National Heart, Lung, and Blood Institute [1 K08 HL072806-01]; Sanofi Aventis FX This work was supported by AHRQ Grant R01-HS013660-02: Shared Online Health Records for Patient Safety and Quality. Dr Schnipper was also supported by a mentored career development award from the National Heart, Lung, and Blood Institute (1 K08 HL072806-01). AHRQ and NHLBI were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.; Drs Schnipper, Gandhi, and Poon are consultants to QuantiaMD, for whom they have created on-line educational materials for both providers and patients regarding patient safety, including medication safety. The findings of this study are not a part of those materials and the work with QuantiaMD in no way influenced the content of this manuscript. Dr Schnipper has received grant funding from Sanofi Aventis for an investigator-initiated study to design and evaluate an intensive discharge and follow-up intervention in patients with diabetes. The funder has no role in the design of the study, and the content is not relevant to the current manuscript. Dr Poon is a consultant to Becton, Dickinson, and Company, for whom he has presented at an internal educational forum. The findings of this study are not a part of those materials and the work with Becton, Dickinson, and Company in no way influenced the content of this manuscript. No other authors have any financial interests in the subject matter or materials discussed in the manuscript. NR 22 TC 29 Z9 29 U1 3 U2 12 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2012 VL 19 IS 5 BP 728 EP 734 DI 10.1136/amiajnl-2011-000723 PG 7 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 994MJ UT WOS:000307934600007 PM 22556186 ER PT J AU Akins, CW AF Akins, Cary W. TI An issue of accountability SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Cardiac Surg, Boston, MA 02114 USA. RP Akins, CW (reprint author), Massachusetts Gen Hosp, Dept Cardiac Surg, White 503-55 Fruit St, Boston, MA 02114 USA. EM cakins@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP 530 EP 531 DI 10.1016/j.jtcvs.2012.05.052 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200031 PM 22704286 ER PT J AU Agnihotri, A AF Agnihotri, Arvind TI 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: Executive summary SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Agnihotri, Arvind] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Agnihotri, Arvind] Harvard Univ, Sch Med, Boston, MA USA. RP Agnihotri, A (reprint author), Massachusetts Gen Hosp, Dept Surg, COX 642,55 Fruit St, Boston, MA 02114 USA. EM aagnihotri@partners.org NR 0 TC 7 Z9 8 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP 534 EP 537 DI 10.1016/j.jtcvs.2012.07.021 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200033 PM 22898502 ER PT J AU Heon, S Johnson, BE AF Heon, Stephanie Johnson, Bruce E. TI Adjuvant chemotherapy for surgically resected non-small cell lung cancer SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch ID SYNCHRONOUS BRAIN METASTASES; VINORELBINE PLUS CISPLATIN; POOLED ANALYSIS; TRIAL; METAANALYSIS AB Despite surgical resection, patients with early-stage (I to IIIA) non-small cell lung cancer (NSCLC) are at considerable risk of recurrence and death from their lung cancer. In recent years, multiple, large, randomized trials assessing the efficacy of adjuvant chemotherapy for resected NSCLC have been reported. Three of 6 trials with 300 or more patients with early-stage NSCLC have demonstrated that adjuvant cisplatin-based chemotherapy can significantly improve 5-year survival in carefully selected patients with resected NSCLC. These benefits have been confirmed in a meta-analysis of modern cisplatin-based adjuvant trials. The most consistent benefit has been reported in patients with resected stage II and IIIA NSCLC. The benefit of adjuvant chemotherapy in patients with resected stage IB NSCLC is less concrete. Herein, we review the results of the major adjuvant chemotherapy trials and their implications for the treatment of patients with completely resected NSCLC. A future challenge will be to identify the subsets of patients who will derive the greatest benefit from adjuvant chemotherapy. Current trials are also under-way to define the role of novel targeted therapies, such as inhibitors of the epidermal growth factor receptor and monoclonal antibodies, in adjuvant treatment strategies. (J Thorac Cardiovasc Surg 2012; 144:S39-42) C1 [Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, 450 Brookline Ave,Dana Bldg 1234, Boston, MA 02215 USA. EM bejohnson@partners.org NR 19 TC 16 Z9 16 U1 0 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S39 EP S42 DI 10.1016/j.jtcvs.2012.03.039 PG 4 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200019 PM 22502967 ER PT J AU Lagisetty, KH Gangadharan, SP AF Lagisetty, Kiran H. Gangadharan, Sidhu P. TI Tracheobronchoplasty for the treatment of tracheobronchomalacia SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch ID AIRWAY STABILIZATION; COLLAPSE C1 [Lagisetty, Kiran H.; Gangadharan, Sidhu P.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Thorac Surg & Intervent Pulmonol, Sch Med, Boston, MA 02215 USA. RP Gangadharan, SP (reprint author), Thorac Surg Beth Israel Deaconess Med Ctr, Chest Dis Ctr, 185 Pilgrim Rd W,DC 201, Boston, MA 02215 USA. EM sgangadh@bidmc.harvard.edu NR 7 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S58 EP S59 DI 10.1016/j.jtcvs.2012.05.025 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200023 PM 22676978 ER PT J AU Wee, JO Morse, CR AF Wee, Jon O. Morse, Christopher R. TI Minimally invasive Ivor Lewis esophagectomy SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article; Proceedings Paper CT 3rd International Biennial Minimally Invasive Thoracic Surgery Summit CY OCT 07-08, 2011 CL Harvard Med Sch, Boston, MA HO Harvard Med Sch C1 [Wee, Jon O.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Morse, Christopher R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wee, JO (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jwee@partners.org NR 9 TC 6 Z9 6 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2012 VL 144 IS 3 BP S60 EP S62 DI 10.1016/j.jtcvs.2011.12.051 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 996DL UT WOS:000308064200024 PM 22305551 ER PT J AU Gorrostieta, C Ombao, H Prado, R Patel, S Eskandar, E AF Gorrostieta, Cristina Ombao, Hernando Prado, Raquel Patel, Shaun Eskandar, Emad TI Exploring dependence between brain signals in a monkey during learning SO JOURNAL OF TIME SERIES ANALYSIS LA English DT Article DE Bivariate time series; cross-coherence; dual frequency coherence; coherence between amplitudes; Fourier transform; harmonizable processes; lagged coherence; Loeve spectrum; spectral analysis ID FUNCTIONAL CONNECTIVITY; OSCILLATIONS; COHERENCE AB Our goal is to investigate dependence between brain wave oscillations in the nucleus accumbens (NAc) and the hippocampus (Hc) regions of a macaque monkey during a learning association task. The classical approach to studying dependence in the spectral domain is via cross-coherence. It is computed for each frequency (or band) and identifies the frequency bands that drive the linear association between the components in a multi-variate time series. However, cross-coherence may not fully capture the complex dependence structure in brain signals such as local field potentials. In this article, we develop new tools for discovering associations between the theta (48 Hz) and gamma (3250 Hz) activities at both contemporaneous blocks and lagged time blocks. We propose a class of piecewise harmonizable processes under which we give a precise definition of these dependence measures and develop simple estimators in the case where the time-series data are recorded over several replicated trials. Our analysis clearly demonstrates strong dependence between the theta and gamma oscillations in the NAc and the Hc regions of a macaque monkey during learning. Moreover, we determined the lagged dependence that differentiate the correct responses (i.e., the monkey was able to identify the correct association) from the incorrect responses. C1 [Ombao, Hernando] Univ Calif Irvine, Dept Stat, Donald Bren Sch Informat & Comp Sci, Irvine, CA 92697 USA. [Gorrostieta, Cristina; Ombao, Hernando] Brown Univ, Providence, RI 02912 USA. [Prado, Raquel] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Patel, Shaun; Eskandar, Emad] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ombao, H (reprint author), Univ Calif Irvine, Dept Stat, Donald Bren Sch Informat & Comp Sci, Bren Hall 2019, Irvine, CA 92697 USA. EM hombao@uci.edu FU CONACyT Mexico; NSF DMS; NSF SSE; Conte Center FX This research was supported in part by CONACyT Mexico (Gorrostieta), NSF DMS (Ombao), NSF SSE (Ombao and Prado) and the Conte Center Grant (Eskandar and Ombao). NR 17 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0143-9782 J9 J TIME SER ANAL JI J. Time Ser. Anal. PD SEP PY 2012 VL 33 IS 5 SI SI BP 771 EP 778 DI 10.1111/j.1467-9892.2011.00767.x PG 8 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 996KB UT WOS:000308083800007 ER PT J AU Abularrage, CJ Patel, VI Conrad, MF Schneider, EB Cambria, RP Kwolek, CJ AF Abularrage, Christopher J. Patel, Virendra I. Conrad, Mark F. Schneider, Eric B. Cambria, Richard P. Kwolek, Christopher J. TI Improved results using Onyx glue for the treatment of persistent type 2 endoleak after endovascular aneurysm repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Eastern-Vascular-Society CY SEP 22-24, 2011 CL Washington, DC SP Eastern Vasc Soc ID ABDOMINAL AORTIC-ANEURYSM; II ENDOLEAKS; RANDOMIZED-TRIAL; COST-EFFECTIVENESS; OUTCOMES; EMBOLIZATION; EVAR AB Objective: Persistent type 2 (PT2) endoleaks (present >= 6 months) after endovascular aneurysm repair are associated with adverse outcomes, and selective secondary intervention is indicated in those patients with an expanding aneurysm sac. This study evaluated the outcomes of secondary intervention for PT2. Methods: From 1999 to 2007, 136 patients who underwent endovascular aneurysm repair developed PT2 and comprised the study cohort. Primary end points included PT2 resolution (secondary interventional success) and survival, and were evaluated using multiple logistic regression and Kaplan-Meier analyses, respectively. Results: Fifty-one patients underwent a total of 68 secondary interventions for PT2 with expanding aneurysm sacs with a median postsecondary interventional follow-up of 13.7 months. Secondary interventions included 20 inferior mesenteric artery coil embolizations, 17 Onyx glue embolizations, 11 aneurysm sac coil embolizations, 10 non-Onyx glue embolizations, 7 lumbar artery coil embolizations, 2 open lumbar ligations, and 1 graft explant. The overall secondary interventional success rate was 43% (29 of 68). Onyx glue embolization was associated with a greater success rate when used as the initial secondary intervention (odds ratio, 59.61; 95% confidence interval, 4.78-742.73; P < .001). There was no difference in success between the different techniques when multiple secondary interventions were required. Five-year survival was 72% +/- 0.08% and was unrelated to any of the secondary interventional techniques. Conclusions: Secondary intervention for PT2 is associated with success in less than half of all cases. Onyx glue embolization was associated with greater long-term success when used as the initial secondary intervention. (J Vasc Surg 2012;56:630-6.) C1 [Abularrage, Christopher J.; Patel, Virendra I.; Conrad, Mark F.; Cambria, Richard P.; Kwolek, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Abularrage, Christopher J.] Johns Hopkins Univ Hosp, Div Vasc Surg & Endovasc Therapy, Baltimore, MD 21287 USA. [Schneider, Eric B.] Johns Hopkins Univ Hosp, Ctr Surg Trials & Outcomes Res, Baltimore, MD 21287 USA. RP Kwolek, CJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Vasc & Endovasc Surg, WAC440,15 Parkman St, Boston, MA 02114 USA. EM ckwolek@partners.org NR 24 TC 31 Z9 31 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2012 VL 56 IS 3 BP 630 EP 636 DI 10.1016/j.jvs.2012.02.038 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 996KM UT WOS:000308085500007 PM 22572009 ER PT J AU Jones, DW Stone, DH Conrad, MF Baribeau, YR Westbrook, BM Likosky, DS Cronenwett, JL Goodney, PP AF Jones, Douglas W. Stone, David H. Conrad, Mark F. Baribeau, Yvon R. Westbrook, Benjamin M. Likosky, Donald S. Cronenwett, Jack L. Goodney, Philip P. TI Regional use of combined carotid endarterectomy/coronary artery bypass graft and the effect of patient risk SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID NORTHERN NEW-ENGLAND; HOSPITAL VOLUME; CORONARY-BYPASS; STATEWIDE ANALYSIS; OUTCOMES; SURGERY; REVASCULARIZATION; DISEASE; STROKE; ASSOCIATION AB Introduction: Although carotid artery stenosis and coronary artery disease often coexist, many debate which patients are best served by combined concurrent revascularization (carotid endarterectomy [CEA]/coronary artery bypass graft [CABG]). We studied the use of CEA/CABG in New England and compared indications and outcomes, including stratification by risk, symptoms, and performing center. Methods: Using data from the Vascular Study Group of New England from 2003 to 2009, we studied all patients who underwent combined CEA/CABG across six centers in New England. Our main outcome measure was in-hospital stroke or death. We compared outcomes between all patients undergoing combined CEA/CABG to a baseline CEA risk group comprised of patients undergoing isolated CEA at non-CEA/CABG centers. Further, we compared in-hospital stroke and death rates between high and low neurologic risk patients, defining high neurologic risk patients as those who had at least one of the following clinical or anatomic features: (1) symptomatic carotid disease, (2) bilateral carotid stenosis >70%, (3) ipsilateral stenosis >70% and contralateral occlusion, or (4) ipsilateral or bilateral occlusion. Results: Overall, compared to patients undergoing isolated CEA at non-CEA/CABG centers (n = 1563), patients undergoing CEA/CABG (n = 109) were more likely to have diabetes (44% vs 29%; P = .001), creatinine >1.8 mg/dL (11% vs 5%; P = .007), and congestive heart failure (23% vs 10%; P < .001). Patients undergoing CEA/CABG were also more likely to take preoperative beta-blockers (94% vs 75%; P < .001) and less likely to take preoperative clopidogrel (7% vs 25%; P < .001). Patients undergoing CEA/CABG had higher rates of contralateral carotid occlusion (13% vs 5%; P = .001) and were more likely to undergo an urgent/emergent procedure (30% vs 15%; P < .001). The risk of complications was higher in CEA/CABG compared to isolated CEA, including increased risk of stroke (5.5% vs 1.2%; P < . 001), death (5.5% vs 0.3%; P < . 001), and return to the operating room for any reason (7.6% vs 1.2%; P < . 001). Of 109 patients undergoing CEA/CABG, 61 (56%) were low neurologic risk and 48 (44%) were high neurologic risk but showed no demonstrable difference in stroke (4.9% vs 6.3%; P = .76), death, (4.9 vs 6.3%; P = .76), or return to the operating room (10.2% vs 4.3%; P = .25). Conclusions: Although practice patterns in the use of CEA/CABG vary across our region, the risk of complications with CEA/CABG remains significantly higher than in isolated CEA. Future work to improve patient selection in CEA/CABG is needed to improve perioperative results with combined coronary and carotid revascularization. (J Vasc Surg 2012;56:668-76.) C1 [Jones, Douglas W.] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Surg, New York, NY USA. [Stone, David H.; Cronenwett, Jack L.; Goodney, Philip P.] Dartmouth Hitchcock Med Ctr, Dept Vasc Surg, Lebanon, NH 03766 USA. [Conrad, Mark F.] Massachusetts Gen Hosp, Dept Vasc Surg, Boston, MA 02114 USA. [Baribeau, Yvon R.; Westbrook, Benjamin M.] Cathol Med Ctr, Dept Cardiothorac Surg, Manchester, Lancs, England. [Likosky, Donald S.] Dartmouth Med Sch, Dartmouth Inst Hlth Policy & Clin Practice, Hannover, Germany. [Goodney, Philip P.] VA Med Ctr, White River Junct Outcomes Grp, White River Jct, VT USA. RP Jones, DW (reprint author), Weill Cornell Med Ctr, Dept Surg, 525 E 68th St, New York, NY 10065 USA. EM doj9016@gmail.com FU NHLBI NIH HHS [1K08HL05676-01, K08 HL105676]; NIMHD NIH HHS [L32 MD006323] NR 31 TC 2 Z9 2 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2012 VL 56 IS 3 BP 668 EP 676 DI 10.1016/j.jvs.2012.02.028 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 996KM UT WOS:000308085500013 PM 22560308 ER PT J AU Finzi, A Pacheco, B Xiang, SH Pancera, M Herschhorn, A Wang, LP Zeng, X Desormeaux, A Kwong, PD Sodroski, J AF Finzi, Andres Pacheco, Beatriz Xiang, Shi-Hua Pancera, Marie Herschhorn, Alon Wang, Liping Zeng, Xing Desormeaux, Anik Kwong, Peter D. Sodroski, Joseph TI Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding SO JOURNAL OF VIROLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN TRIMERS; INFECTIOUS MOLECULAR CLONES; T-LYMPHOTROPIC RETROVIRUS; HIV-1 GP120; AIDS PATIENTS; INNER DOMAIN; HTLV-III; TRANSMEMBRANE GLYCOPROTEIN; CD4-BOUND CONFORMATION; MACROPHAGE TROPISM AB Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SW) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain beta-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding. C1 [Finzi, Andres; Pacheco, Beatriz; Xiang, Shi-Hua; Herschhorn, Alon; Wang, Liping; Zeng, Xing; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Med, Div Aids, Dept Microbiol & Immunobiol, Boston, MA USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Pancera, Marie; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sodroski, Joseph] MIT & Harvard, Massachusetts Gen Hosp, Ragon Inst, Charlestown, MA USA. [Desormeaux, Anik] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu FU VRC; NIAID; National Institutes of Health [AI24755, GM56550, AI67854]; International AIDS Vaccine Initiative; William F. McCarty-Cooper; amfAR Mathilde Krim Fellowship in Basic Biomedical Research [107963-49-RKVA, 108092-50-RKVA]; Canada Foundation for Innovation Program [29866]; CIHR [257792] FX This work was supported by intramural funding by the VRC, NIAID, and by grants from the National Institutes of Health (AI24755, GM56550, and AI67854), by the International AIDS Vaccine Initiative, by the late William F. McCarty-Cooper (to J.S.), and by an amfAR Mathilde Krim Fellowship in Basic Biomedical Research (phase I, 107963-49-RKVA; phase II, 108092-50-RKVA), by a Canada Foundation for Innovation Program Leader grant (no. 29866), and by a CIHR operating grant, 257792, to A.F. NR 80 TC 15 Z9 15 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2012 VL 86 IS 17 BP 8974 EP 8986 DI 10.1128/JVI.01076-12 PG 13 WC Virology SC Virology GA 990JW UT WOS:000307627800005 PM 22696649 ER PT J AU Finer, G Schnaper, HW Kanwar, YS Liang, XY Lin, HY Hayashida, T AF Finer, Gal Schnaper, H. William Kanwar, Yashpal S. Liang, Xiaoyan Lin, Herbert Y. Hayashida, Tomoko TI Divergent roles of Smad3 and PI3-kinase in murine adriamycin nephropathy indicate distinct mechanisms of proteinuria and fibrogenesis SO KIDNEY INTERNATIONAL LA English DT Article DE cell signaling; fibrosis; glomerulosclerosis; podocyte; TGF-beta ID COLLAGEN-I EXPRESSION; HUMAN MESANGIAL CELLS; KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; SIGNAL-TRANSDUCTION; BETA; KINASE; MICE; PI3K-GAMMA; PODOCYTES AB Multiple transforming growth factor (TGF)-beta-induced fibrogenic signals have been described in vitro. To evaluate mechanisms in vivo, we used an adriamycin nephropathy model in 129x1/Svj mice that display massive proteinuria by days 5 to 7 and pathological findings similar to human focal segmental glomerulosclerosis by day 14. TGF-beta mRNA expression increased after day 7 along with nuclear translocation of the TGF-beta receptor-specific transcription factor Smad3. Inhibiting TGF-beta prevented both pathological changes and type-I collagen and fibronectin mRNA expression, but proteinuria persisted. Renal Akt was phosphorylated in adriamycin-treated mice, suggesting PI3-kinase activation. Expression of mRNA for the p110 gamma isozyme of PI3-kinase was specifically increased and p110 gamma colocalized with nephrin by immunohistochemistry early in disease. Nephrin levels subsequently decreased. Inhibition of p110 gamma by AS605240 preserved nephrin expression and prevented proteinuria. In cultured podocytes, adriannycin stimulated p110 gamma expression. AS605240, but not a TGF-beta receptor kinase inhibitor, prevented adriamycin-induced cytoskeletal disorganization and apoptosis, supporting a role for p110 gamma in podocyte injury. AS605240, at a dose that decreased proteinuria, prevented renal collagen mRNA expression in vivo but did not affect TGF-beta-stimulated collagen induction in vitro. Thus, PI3-kinase p110 gamma mediates initial podocyte injury and proteinuria, both of which precede TGF-beta-mediated glomerular scarring. C1 [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Childrens Mem Hosp, Div Kidney Dis, Chicago, IL 60614 USA. [Finer, Gal; Schnaper, H. William; Liang, Xiaoyan; Hayashida, Tomoko] Childrens Mem Hosp, Childrens Mem Res Ctr, Chicago, IL 60614 USA. [Kanwar, Yashpal S.] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Lin, Herbert Y.] Massachusetts Gen Hosp, Program Membrane Biol, Ctr Syst Biol, Div Nephrol,Dept Med, Boston, MA 02114 USA. [Lin, Herbert Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Hayashida, T (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Pediat, 310 Super St,Morton 4-685, Chicago, IL 60611 USA. EM hayashida@northwestern.edu RI Finer, Gal/C-7858-2015; OI Hayashida, Tomoko/0000-0002-4160-7859 FU Amgen Fellowship; NCI [CCSG P30 CA060553]; [R01-DK049362]; [R01-DK075663]; [R01-DK060635]; [R01-DK069533]; [R01-DK071837] FX This study was supported in part by grants R01-DK049362, R01-DK075663 (HWS), R01-DK060635 (YSK), and R01-DK069533 and R01-DK071837 (HYL). GF was the recipient of an Amgen Fellowship. The Cell Imaging Facility and Mouse Histology and Phenotyping Laboratory of the Northwestern University are supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. We thank members of the Schnaper lab for helpful discussions. NR 40 TC 14 Z9 14 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2012 VL 82 IS 5 BP 525 EP 536 DI 10.1038/ki.2012.139 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 992TS UT WOS:000307803200006 PM 22534961 ER PT J AU Skupien, J Warram, JH Smiles, AM Niewczas, MA Gohda, T Pezzolesi, MG Cantarovich, D Stanton, R Krolewski, AS AF Skupien, Jan Warram, James H. Smiles, Adam M. Niewczas, Monika A. Gohda, Tomohito Pezzolesi, Marcus G. Cantarovich, Diego Stanton, Robert Krolewski, Andrzej S. TI The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease SO KIDNEY INTERNATIONAL LA English DT Article DE creatinine; diabetes mellitus ID GLOMERULAR-FILTRATION-RATE; KIDNEY-FUNCTION DECLINE; OLDER-ADULTS; SERUM CREATININE; NEPHROPATHY; PROGRESSION; AGE; FAILURE; DYSFUNCTION; ERRORS AB The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min per 1.73 m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5 ml/min per 1.73m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD. C1 [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Stanton, Robert; Krolewski, Andrzej S.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Skupien, Jan; Warram, James H.; Smiles, Adam M.; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Stanton, Robert; Krolewski, Andrzej S.] Joslin Diabet Ctr, Clin Div, Boston, MA 02215 USA. [Skupien, Jan; Niewczas, Monika A.; Gohda, Tomohito; Pezzolesi, Marcus G.; Krolewski, Andrzej S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. [Cantarovich, Diego] Nantes Univ Hosp, Inst Transplantat Urol & Nephrol, Nantes, France. [Stanton, Robert] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA USA. RP Krolewski, AS (reprint author), Brigham & Womens Hosp, Joslin Diabet Ctr, Dept Med, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU JDRF research grant [1-2008-1018]; NIH grant [DK41526]; JDRF fellowship grant [3-2009-397] FX This project was supported through JDRF research grant 1-2008-1018 (ASK), NIH grant DK41526 (ASK), and a JDRF fellowship grant 3-2009-397 (JS). We thank TH Hostetter and WE Mitch for their valuable comments. NR 31 TC 38 Z9 39 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2012 VL 82 IS 5 BP 589 EP 597 DI 10.1038/ki.2012.189 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 992TS UT WOS:000307803200012 PM 22622493 ER PT J AU Ponikau, JU Hamilos, DL Barreto, A Cecil, J Jones, SW Manthei, SE Collins, J AF Ponikau, Jens U. Hamilos, Daniel L. Barreto, Angelique Cecil, John Jones, Stephen W. Manthei, Scott E. Collins, Jason TI An exploratory trial of Cyclamen europaeum extract for acute rhinosinusitis SO LARYNGOSCOPE LA English DT Article DE Cyclamen europaeum; acute rhinosinusitis; sinus opacification; computed tomography scans; total symptom scores; Level of Evidence: 1b ID ACUTE SINUSITIS; ACUTE BRONCHITIS; DOUBLE-BLIND; MANAGEMENT; SINUFORTE; GUIDELINES; EFFICACY; CHILDREN; ADULTS AB Objectives/Hypothesis: An exploratory US trial in patients with acute rhinosinusitis was conducted to evaluate the efficacy and safety of Cyclamen europeaum extract, a product marketed in Europe that causes reflex nasal discharge and subsequent decongestion. Study Design: Prospective, randomized, placebo-controlled, double-blind, and parallel group. Methods: Outpatients (n = 29) with cardinal symptoms of acute rhinosinusitis and both endoscopic and radiographic (computed tomography [CT] scan) evidence at 25 US centers were randomized to receive intranasal, lyophilized, reconstituted Cyclamen europeaum extract (Cyclamen) or placebo spray for 7 days. Primary outcomes were reduction in percent sinus opacification on CT scans and reduction in PM predose instantaneous total symptom scores measured on a six-point scale. Secondary outcomes included other measures of symptom score change and endoscopic signs of mucopurulence and inflammation. Results: Cyclamen treatment significantly reduced sinus opacification compared with placebo treatment (P < .045). Although Cyclamen treatment reduced total symptom scores from baseline more than placebo treatment (-2.4 vs. -1.4), there were no significant treatment group differences (P = .312). Cyclamen treatment was well tolerated. Conclusions: Cyclamen treatment significantly reduced sinus opacification in patients with acute rhinosinusitis. Further exploration of Cyclamen treatment in larger patient populations is warranted. C1 [Ponikau, Jens U.] SUNY Buffalo, Dept Otolaryngol, Buffalo, NY 14260 USA. [Hamilos, Daniel L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barreto, Angelique] Mem Clin Res, Oklahoma City, OK USA. [Cecil, John] Four Rivers Clin Res, Paducah, KY USA. [Jones, Stephen W.] Carolina Res Ctr Inc, Shelby, NC USA. [Manthei, Scott E.] Nevada Eye & Ear, Henderson, NV USA. [Collins, Jason] Dey Pharma LP, Napa, CA USA. RP Ponikau, JU (reprint author), SUNY Buffalo, Dept Clin Otorhinolaryngol, Buffalo, NY 14260 USA. EM jponikau@buffalo.edu FU Dey Pharma, LP; Napa, California; Hartington Pharmaceutical, Barcelona, Spain FX The study sponsors were Dey Pharma, LP, Napa, California, and Hartington Pharmaceutical, Barcelona, Spain. Employees of Dey were involved in the study design and in the collection and analysis of data. Jens U. Ponikau, MD, is a consultant for Dey Pharma and Hartington Pharmaceutical. Angelique Barreto, MD, John Cecil, MD, Stephen W. Jones, MD, and Scott E. Manthei, DO, were clinical trial investigators for the clinical trial described in this article. Dr. Collins was an employee of Dey Pharma at the time of the trial. Authors were assisted by a professional medical writer, Elizabeth Field, PhD, of Field Advantage Medical Communication, LLC, in the preparation of the manuscript, funded by Hartington Pharmaceutical. NR 30 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2012 VL 122 IS 9 BP 1887 EP 1892 DI 10.1002/lary.23366 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 994VT UT WOS:000307962900002 PM 22674586 ER PT J AU Heaton, JT Kobler, JB Ottensmeyer, MP Lopez-Guerra, G Karajanagi, SS Burns, JA Zeitels, SM AF Heaton, James T. Kobler, James B. Ottensmeyer, Mark P. Lopez-Guerra, Gerardo Karajanagi, Sandeep S. Burns, James A. Zeitels, Steven M. TI Modification and testing of a pneumatic dispensing device for controlled delivery of injectable materials SO LARYNGOSCOPE LA English DT Article DE Dysphonia; larynx; phonosurgery; vocal fold injection ID VOCAL FOLD; AUTOGENOUS FAT; INJECTION AB Objectives/Hypothesis: Vocal fold (VF) injections of viscous materials are typically performed using hand-operated syringes or injection guns; however, these methods can be imprecise due to accumulation of pressure, effort-related tremor, and poor feedback regarding injection volume and rate. Study Design: Apparatus development with laboratory bench-top and animal model testing. Methods: A foot pedal-triggered device for dispensing viscous materials was modified by adding a linear transducer and display for monitoring dispensed volume. In bench tests, bovine VFs were injected with fluids/materials of different viscosities (saline, glycerol, hydrogel, and liposuctioned fat) through narrow-bore needles using a range of driving pressures and air pulse durations. The device was further evaluated in >50 in vivo VF injection experiments. Results: Device function was repeatable, with high correlations (typically R2 > 0.98) between the readout and direct measures of volume, even for small volumes (<5 mu L/pulse). Foot pedal control enabled surgeons to make steady, accurate injections into ferret and dog VFs during phonosurgery, and, because the dispenser released all driving pressure between pulses, there were no instances of clog-related overinjection when the obstruction cleared. Conclusions: This VF injection system shows promise for development to enhance human phonosurgery by increasing injection control and precision. Laryngoscope, 2012 C1 [Heaton, James T.; Kobler, James B.; Lopez-Guerra, Gerardo; Karajanagi, Sandeep S.; Burns, James A.; Zeitels, Steven M.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Heaton, James T.; Kobler, James B.; Lopez-Guerra, Gerardo; Karajanagi, Sandeep S.; Burns, James A.; Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Ottensmeyer, Mark P.] Massachusetts Gen Hosp, Dept Imaging, Simulat Grp, Cambridge, MA USA. [Karajanagi, Sandeep S.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Heaton, JT (reprint author), Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM james.heaton@mgh.harvard.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680 FU Eugene B. Casey Foundation; Voice Health Institute FX This work was supported by the Eugene B. Casey Foundation and Voice Health Institute. NR 17 TC 2 Z9 2 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X EI 1531-4995 J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2012 VL 122 IS 9 BP 2023 EP 2028 DI 10.1002/lary.23468 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 994VT UT WOS:000307962900022 PM 22865123 ER PT J AU Stone, RM Fischer, T Paquette, R Schiller, G Schiffer, CA Ehninger, G Cortes, J Kantarjian, HM DeAngelo, DJ Huntsman-Labed, A Dutreix, C del Corral, A Giles, F AF Stone, R. M. Fischer, T. Paquette, R. Schiller, G. Schiffer, C. A. Ehninger, G. Cortes, J. Kantarjian, H. M. DeAngelo, D. J. Huntsman-Labed, A. Dutreix, C. del Corral, A. Giles, F. TI Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia SO LEUKEMIA LA English DT Article DE FMS-like tyrosine kinase 3 receptor; acute myeloid leukemia; midostaurin; PKC412; newly diagnosed ID ACUTE MYELOGENOUS LEUKEMIA; RISK MYELODYSPLASTIC SYNDROME; INTERNAL TANDEM DUPLICATIONS; POOR-PROGNOSIS; MUTANT FLT3; WILD-TYPE; GROUP-B; MUTATIONS; PKC412; CYTOGENETICS AB This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261). C1 [Stone, R. M.; DeAngelo, D. J.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Fischer, T.] Otto von Guericke Univ, Med Ctr, Dept Hematol Oncol, Magdeburg, Germany. [Paquette, R.; Schiller, G.] UCLA Med Ctr, Los Angeles, CA USA. [Schiffer, C. A.] Karmanos Canc Inst, Detroit, MI USA. [Ehninger, G.] Tech Univ Dresden, D-01062 Dresden, Germany. [Cortes, J.; Kantarjian, H. M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Huntsman-Labed, A.; Dutreix, C.] Novartis Pharma AG, Basel, Switzerland. [del Corral, A.] Novartis Oncol, E Hanover, NJ USA. [Giles, F.] Natl Univ Ireland, HRB Clin Res Facil, Galway, Ireland. [Giles, F.] Trinity Coll Dublin, Dublin, Ireland. RP Stone, RM (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM rstone@partners.org FU Novartis Pharmaceuticals Corporation FX The authors acknowledge the study coordinators, nurses and physicians who contributed to this study and the patients and their families for their participation. Susie Crowley provided secretarial assistance. Sandra Harris and Erinn Goldman of Articulate Science, LLC, provided medical writing assistance. This study was sponsored by Novartis Pharmaceuticals Corporation. NR 21 TC 85 Z9 92 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2012 VL 26 IS 9 BP 2061 EP 2068 DI 10.1038/leu.2012.115 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 999VK UT WOS:000308342900011 PM 22627678 ER PT J AU Blackburn, JS Liu, S Raiser, DM Martinez, SA Feng, H Meeker, ND Gentry, J Neuberg, D Look, AT Ramaswamy, S Bernards, A Trede, NS Langenau, DM AF Blackburn, J. S. Liu, S. Raiser, D. M. Martinez, S. A. Feng, H. Meeker, N. D. Gentry, J. Neuberg, D. Look, A. T. Ramaswamy, S. Bernards, A. Trede, N. S. Langenau, D. M. TI Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency SO LEUKEMIA LA English DT Article DE thymocyte; relapse; Myc; zebrafish; self-renewal ID TRANSGENIC ZEBRAFISH; INITIATING CELLS; C-MYC; PATHWAY SIGNATURES; STEM-CELL; GENE; TRANSFORMATION; EXPRESSION; MUTATIONS; ONCOGENE AB NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs. C1 [Blackburn, J. S.; Liu, S.; Martinez, S. A.; Langenau, D. M.] Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Unit, Boston, MA 02114 USA. [Blackburn, J. S.; Liu, S.; Martinez, S. A.; Gentry, J.; Ramaswamy, S.; Bernards, A.; Langenau, D. M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Blackburn, J. S.; Liu, S.; Raiser, D. M.; Martinez, S. A.; Ramaswamy, S.; Langenau, D. M.] Harvard Stem Cell Inst, Boston, MA USA. [Neuberg, D.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Meeker, N. D.; Trede, N. S.] Univ Utah, Dept Pediat, Huntsman Canc Inst, Salt Lake City, UT USA. RP Langenau, DM (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Dept Pathol, 149 13th St,6102, Charlestown, MA 02129 USA. EM dlangenau@partners.org OI Feng, Hui/0000-0003-1318-821X FU NIH [5T32CA09126-26, K01AR05562190]; American Cancer Society Research Scholar Grant; Leukemia Research Foundation; Alex Lemonade Stand Foundation; Harvard Stem Cell Institute FX We thank Dr Ravi Mylvaganam for expert advice and assistance with cell sorting, Eric Stone and Marcellino Pena for excellent animal husbandry, and Dr Finola Moore and Tommy Jones help with data interpretation and critical review of the manuscript. JSB is supported by NIH 5T32CA09126-26. DML is supported by an American Cancer Society Research Scholar Grant, the Leukemia Research Foundation, the Alex Lemonade Stand Foundation, the Harvard Stem Cell Institute, and NIH K01AR05562190. NR 48 TC 23 Z9 25 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD SEP PY 2012 VL 26 IS 9 BP 2069 EP 2078 DI 10.1038/leu.2012.116 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 999VK UT WOS:000308342900012 PM 22538478 ER PT J AU Wolf, JL Siegel, D Goldschmidt, H Hazell, K Bourquelot, PM Bengoudifa, BR Matous, J Vij, R de Magalhaes-Silverman, M Abonour, R Anderson, KC Lonial, S AF Wolf, Jeffrey L. Siegel, David Goldschmidt, Hartmut Hazell, Katharine Bourquelot, Priscille M. Bengoudifa, Bourras R. Matous, Jeffrey Vij, Ravi de Magalhaes-Silverman, Margarida Abonour, Rafat Anderson, Kenneth C. Lonial, Sagar TI Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma SO LEUKEMIA & LYMPHOMA LA English DT Letter ID WORKING GROUP; BORTEZOMIB; LBH589; LENALIDOMIDE; PROTEASOME; SURVIVAL; CRITERIA C1 [Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Wolf, Jeffrey L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Siegel, David] Hackensack Univ, Med Ctr, Hackensack, NJ USA. [Goldschmidt, Hartmut] Heidelberg Univ, Heidelberg, Germany. [Hazell, Katharine; Bourquelot, Priscille M.; Bengoudifa, Bourras R.] Novartis Pharma AG, Basel, Switzerland. [Matous, Jeffrey] Colorado Blood Canc Inst, Denver, CO USA. [Vij, Ravi] Washington Univ, St Louis, MO USA. [de Magalhaes-Silverman, Margarida] Univ Iowa, Iowa City, IA USA. [Abonour, Rafat] Indiana Univ, Ctr Canc, Indianapolis, IN 46204 USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lonial, S (reprint author), Emory Univ, Winship Canc Inst, 1365 Clifton Rd,Bldg C,Room 4004, Atlanta, GA 30322 USA. EM sloni01@emory.edu NR 15 TC 55 Z9 55 U1 2 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD SEP PY 2012 VL 53 IS 9 BP 1820 EP 1823 DI 10.3109/10428194.2012.661175 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 985WP UT WOS:000307301500032 PM 22288662 ER PT J AU Stone, M AF Stone, Martha TI Ballerina: Sex, Scandal, and Suffering Behind the Symbol of Perfection SO LIBRARY JOURNAL LA English DT Book Review C1 [Stone, Martha] Massachusetts Gen Hosp Lib, Boston, MA USA. RP Stone, M (reprint author), Massachusetts Gen Hosp Lib, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU REED BUSINESS INFORMATION PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD SEP 1 PY 2012 VL 137 IS 14 BP 102 EP 102 PG 1 WC Information Science & Library Science SC Information Science & Library Science GA 001IY UT WOS:000308455300103 ER PT J AU Emile, JF Brahimi, S Coindre, JM Bringuier, PP Monges, G Samb, P Doucet, L Hostein, I Landi, B Buisine, MP Neuville, A Bouche, O Cervera, P Pretet, JL Tisserand, J Gauthier, A Le Cesne, A Sabourin, JC Scoazec, JY Bonvalot, S Corless, CL Heinrich, MC Blay, JY Aegerter, P AF Emile, J. F. Brahimi, S. Coindre, J. M. Bringuier, P. P. Monges, G. Samb, P. Doucet, L. Hostein, I. Landi, B. Buisine, M. P. Neuville, A. Bouche, O. Cervera, P. Pretet, J. L. Tisserand, J. Gauthier, A. Le Cesne, A. Sabourin, J. C. Scoazec, J. Y. Bonvalot, S. Corless, C. L. Heinrich, M. C. Blay, J. Y. Aegerter, P. TI Frequencies of KIT and PDGFRA mutations in the MolecGIST prospective population-based study differ from those of advanced GISTs SO MEDICAL ONCOLOGY LA English DT Article DE Epidemiology; Sarcoma; Gastrointestinal tumor; Tyrosine kinase receptor ID GASTROINTESTINAL STROMAL TUMORS; C-KIT; PROGNOSIS; IMATINIB; SURVIVAL; TRIAL AB Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma. Most of the data available on GISTs derive from retrospective studies of patients referred to oncology centers. The MolecGIST study sought to determine and correlate clinicopathological and molecular characteristics of GISTs. Tumor samples and clinical records were prospectively obtained and reviewed for patients diagnosed in France during a 24-month period. Five hundred and ninety-six patients were included, of whom 10% had synchronous metastases. GISTs originated from the stomach, small bowel or other site in 56.4, 30.2 and 13.4% of cases, respectively. The main prognostic markers, tumor localization, size and mitotic index were not independent variables (P<0.0001). Mutational status was determined in 492 (83%) patients, and 138 different mutations were identified. KIT and PDGFRA mutations were detected in 348 (71%) and 74 (15%) patients, respectively, contrasting with 82.8 and 2.1% in patients with advanced GIST (MetaGIST) (P<0.0001). Further comparison of localized GISTs in the MolecGIST cohort with advanced GISTs from previous clinical trials showed that the mutations of PDGFRA exon18 (D842V and others) as well as KIT exon11 substitutions (W557R and V559D) were more likely to be seen in patients with localized GISTs (odds ratio 7.9, 3.1, 2.7 and 2.5, respectively), while KIT exon 9 502_503dup and KIT exon 11 557_559del were more frequent in metastatic GISTs (odds ratio of 0.3 and 0.5, respectively). These data suggest that KIT and PDGFRA mutations and standardized mitotic count deserve to be investigated to evaluate the relapse risk of GISTs. C1 [Emile, J. F.] Ambroise Pare Hosp, APHP, Dept Pathol, Boulogne, France. [Emile, J. F.; Brahimi, S.; Tisserand, J.; Gauthier, A.] Versailles SQY Univ, Hop Ambroise Pare, Serv Pathol, EA4340, F-92104 Boulogne, France. [Coindre, J. M.; Hostein, I.] Bergonie Inst, Dept Pathol, Bordeaux, France. [Bringuier, P. P.; Scoazec, J. Y.] E Herriot Hosp, HCL, Lyon, France. [Monges, G.] Inst J Paoli I Calmettes, Dept Pathol, F-13009 Marseille, France. [Samb, P.; Aegerter, P.] Versailles SQY Univ, Ambroise Pare Hosp, APHP, EA2506,Publ Hlth Dept, Boulogne, France. [Doucet, L.] CHU Brest, Dept Pathol, F-29285 Brest, France. [Landi, B.] Gorges Pompidou European Hosp, APHP, Paris, France. [Buisine, M. P.] CHU Lille, Biochem & Mol Biol Dept, F-59037 Lille, France. [Neuville, A.] CHU Strasbourg, Dept Pathol, F-67000 Strasbourg, France. [Bouche, O.] CHU Reims, Reims, France. [Cervera, P.] St Antoine Hosp, APHP, Dept Pathol, Paris, France. [Pretet, J. L.] Univ Franche Comte, CHU Besancon, F-25030 Besancon, France. [Le Cesne, A.; Bonvalot, S.] Inst Gustave Roussy, Villejuif, France. [Sabourin, J. C.] CHU Rouen, Dept Pathol, Rouen, France. [Corless, C. L.; Heinrich, M. C.] Portland VA Med Ctr, OHSU Knight Canc Inst, Portland, OR USA. [Blay, J. Y.] Ctr Leon Berard, F-69373 Lyon, France. RP Emile, JF (reprint author), Ambroise Pare Hosp, APHP, Dept Pathol, Boulogne, France. EM Jean-francois.emile@apr.aphp.fr RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X FU Ligue contre le Cancer, Institut National du Cancer (INCa); Novartis Pharma FX MolecGIST study was supported by grants from Ligue contre le Cancer, Institut National du Cancer (INCa) and unrestricted grants from Novartis Pharma. The authors would like to thank patients who participated to MolecGIST study and their families, as well as all the pathologists, oncologists, surgeons, gastroenterologists, physicians and clinical research assistants who participated to the collection of the data. The list is available on http://www.gist-france.org/remerciements.html. NR 30 TC 32 Z9 33 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD SEP PY 2012 VL 29 IS 3 BP 1765 EP 1772 DI 10.1007/s12032-011-0074-y PG 8 WC Oncology SC Oncology GA 994WE UT WOS:000307964100053 PM 21953054 ER PT J AU Wiernik, PH Sun, ZX Gundacker, H Dewald, G Slovak, ML Paietta, E Kim, HT Appelbaum, FR Cassileth, PA Tallman, MS AF Wiernik, Peter H. Sun, Zhuoxin Gundacker, Holly Dewald, Gordon Slovak, Marilyn L. Paietta, Elisabeth Kim, Haesook T. Appelbaum, Frederick R. Cassileth, Peter A. Tallman, Martin S. TI Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukemia with t(15;17) SO MEDICAL ONCOLOGY LA English DT Article DE Acute promyelocytic leukemia; Karyotype; All-trans retinoic acid; t(15;17) ID ACUTE MYELOID-LEUKEMIA; TRANS-RETINOIC ACID; SECONDARY CYTOGENETIC CHANGES; IMATINIB MESYLATE; POOR-PROGNOSIS; ABERRATIONS; IMPACT; CHEMOTHERAPY; WORKSHOP; PROTOCOL AB This retrospective study performed by the Eastern Cooperative Oncology Group and the Southwest Oncology Group enrolled 140 acute promyelocytic leukemia (APL) patients with t(15;17) to determine the influence of additional karyotypic abnormalities on treatment outcome. Karyotypes were centrally reviewed by both study groups. The complete response rate after induction for patients with t(15;17) treated with chemotherapy, or all-trans retinoic acid (ATRA) as induction therapy was not affected by additional cytogenetic aberrations. Disease-free (DFS) and overall survival (OS) were unaffected by additional cytogenetic abnormalities if treatment was chemotherapy without ATRA. Patients with t(15; 17) only, treated with ATRA with or without chemotherapy, had an improved DFS (P = 0.06) and a better OS (P = 0.01) compared with ATRA-treated patients with additional cytogenetic abnormalities. Patients with APL and t(15;17) alone are significantly more sensitive to treatment with ATRA than are patients with t(15;17) and additional cytogenetic abnormalities. C1 [Wiernik, Peter H.] Roosevelt Hosp Ctr, Roosevelt Ctr, Continuum Canc Ctr New York St Lukes, New York, NY 10019 USA. [Wiernik, Peter H.; Sun, Zhuoxin; Dewald, Gordon; Paietta, Elisabeth; Kim, Haesook T.; Cassileth, Peter A.; Tallman, Martin S.] Eastern Cooperat Oncol Grp, Brookline, MA USA. [Sun, Zhuoxin; Kim, Haesook T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gundacker, Holly; Slovak, Marilyn L.; Appelbaum, Frederick R.] SW Oncol Grp, San Antonio, TX USA. [Gundacker, Holly; Appelbaum, Frederick R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Dewald, Gordon] Mayo Clin, Rochester, MN USA. [Slovak, Marilyn L.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Cassileth, Peter A.] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Wiernik, PH (reprint author), Roosevelt Hosp Ctr, Roosevelt Ctr, Continuum Canc Ctr New York St Lukes, Ste 11C-02,1000 10th Ave, New York, NY 10019 USA. EM pwiernik@chpnet.org FU National Cancer Institute, National Institutes of Health [CA21115, ECOG, CA91151, CA32102]; SWOG Leukemia; Cytogenetics Program FX Supported in part by DHHS grants from the National Cancer Institute, National Institutes of Health grants CA21115, ECOG; CA91151 (PHW), and CA32102, SWOG Leukemia, and Cytogenetics Program. Presented in part at the national meeting of the American Society of Hematology, 2001. NR 26 TC 9 Z9 9 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1357-0560 J9 MED ONCOL JI Med. Oncol. PD SEP PY 2012 VL 29 IS 3 BP 2095 EP 2101 DI 10.1007/s12032-012-0251-7 PG 7 WC Oncology SC Oncology GA 994WE UT WOS:000307964100102 PM 22729365 ER PT J AU Lipinski, B Pretorius, E Oberholzer, HM Van der Spuy, WJ AF Lipinski, Boguslaw Pretorius, Etheresia Oberholzer, Hester Magdalena Van der Spuy, Wendy Jeanette TI Iron enhances generation of fibrin fibers in human blood: Implications for pathogenesis of stroke SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE iron; fibrin fibers; plasma; stroke; hydroxyl radicals ID OXIDATIVE STRESS; ARTERIAL THROMBOSIS; INTRAVASCULAR HEMOLYSIS; HYDROXYL RADICALS; ISCHEMIC-STROKE; HEMOGLOBIN; DISEASES; OXYGEN; ATHEROSCLEROSIS; THROMBOLYSIS AB Stroke is associated with the intracerebral formation of fibrin clots which may lead to irreversible brain damage. Thrombolytic therapies employ a variety of natural and/or recombinant plasminogen activators to initiate fibrinolytic degradation of cerebral thrombi. However, such therapies when installed beyond 4- to 6-h window, may fail to achieve the expected outcome. This is due to the hydroxyl radical-induced modification of fibrin(ogen) molecules rendering them refractory to fibrinolytic degradation, but no cause of the increased free radical generation in stroke was offered. Here, we show by means of electron microscopy that iron ions added to human blood dramatically enhances fibrin fibers formation with thrombin, and significantly delays fibrinolysis during spontaneous clotting of native blood. Iron ions caused the appearance dense matted fibrin deposits, similar, if not identical, to those observed in plasma of patients with stroke. These results may explain a known relationship between thrombotic diseases and the increased body concentrations of free iron and/or hemoglobin derivatives. We conclude that any action resulting in the inhibition of hemostatic abnormalities, as well as in the reduction of body free iron and scavenging of hydroxyl radicals (e.g., by polyphenols) can potentially prevent pathological reactions associated with consequences of stroke. Microsc. Res. Tech. 75:11851190, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Pretorius, Etheresia] Univ Pretoria, Dept Physiol, Fac Hlth Sci, ZA-0007 Arcadia, South Africa. [Lipinski, Boguslaw] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Oberholzer, Hester Magdalena; Van der Spuy, Wendy Jeanette] Univ Pretoria, Dept Anat, Fac Hlth Sci, ZA-0007 Arcadia, South Africa. RP Pretorius, E (reprint author), Univ Pretoria, Dept Physiol, Fac Hlth Sci, Private Bag X323, ZA-0007 Arcadia, South Africa. EM resia.pretorius@up.ac.za RI van der Spuy, Wendy/M-7480-2013; OI van der Spuy, Wendy/0000-0003-1892-073X; Pretorius, Etheresia/0000-0002-9108-2384 NR 51 TC 21 Z9 21 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-910X J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD SEP PY 2012 VL 75 IS 9 BP 1185 EP 1190 DI 10.1002/jemt.22047 PG 6 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 994VL UT WOS:000307961900006 PM 22488824 ER PT J AU Nelson, P Lucisano, MP Da Silva, RAB Da Silva, RS Serra, MC Gerlach, RF Neto, FCR Carneiro, ZA Zamarioli, A Morse, L Battaglino, R AF Nelson-Filho, Paulo Lucisano, Marilia Pacifico Bezerra Da Silva, Raquel Assed Da Silva, Roberto Santana Serra, Monica Campos Gerlach, Raquel Fernanda Rehder Neto, Francisco Carlos Carneiro, Zumira Aparecida Zamarioli, Ariane Morse, Leslie Battaglino, Ricardo TI Systemically alendronate was incorporated into dental tissues but did not cause morphological or mechanical changes in rats teeth SO MICROSCOPY RESEARCH AND TECHNIQUE LA English DT Article DE sodium alendronate; bone mineral density; mineralized dental tissues ID 1-HYDROXYETHYLIDENE-1,1-BISPHOSPHONATE HEBP; 1-BISPHOSPHONATE HEBP; ENAMEL FORMATION; SECRETORY AMELOBLASTS; SUCCESSIVE INJECTIONS; CLINICAL-EFFICACY; INCISORS; BISPHOSPHONATES; OSTEOPOROSIS; CHILDHOOD AB This study evaluated the effect of the systemic use of sodium alendronate in rats in vivo. Forty-five Wistar rats aged 36 to 42 days and weighing 200 to 230 g were randomly assigned to a control group (n = 20), which received distilled water, and an experimental group (n = 25), which received 2 weekly doses of 1 mg/kg of chemically pure sodium alendronate. The animals were killed after 60 days of treatment. The tibias were removed for analysis of bone mineral density by dual-energy X-ray absorptiometry (DXA). Then, the maxillary incisors were extracted for analysis of the mineralized dental tissues using fluorescence spectroscopy (FS), scanning electron microscopy (SEM), bright field microscopy (BFM), and cross-sectional microhardness (CSMH) testing. DXA and CSMH data were subjected to statistical analysis by Kruskal-Wallis test (5% significance level). The experimental group presented higher bone mineral density than the control group by DXA. FS analysis revealed presence of alendronate in the mineralized dental tissues of the specimens of the experimental group. Significant morphological differences were not found by SEM and BFM. Enamel and dentin (100 and 300 mu m from the dentinoenamel junction) CSMH data did not show significant difference between the control and experimental groups. Based on the obtained results, we conclude that while alendronate increased the bone mineral density and was incorporated into the mineralized dental tissues it did not cause significant alterations in the morphology and microhardness of rat incisor enamel and dentin. Microsc. Res. Tech. 75:12651271, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Nelson-Filho, Paulo; Lucisano, Marilia Pacifico; Bezerra Da Silva, Raquel Assed; Rehder Neto, Francisco Carlos] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Pediat Clin Prevent & Community Dent, BR-14040904 Ribeirao Preto, SP, Brazil. [Da Silva, Roberto Santana; Carneiro, Zumira Aparecida] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Chem & Phys, BR-14040904 Ribeirao Preto, SP, Brazil. [Serra, Monica Campos] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Restorat Dent, BR-14040904 Ribeirao Preto, SP, Brazil. [Gerlach, Raquel Fernanda] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Morphol Stomatol & Physiol, BR-14040904 Ribeirao Preto, SP, Brazil. [Zamarioli, Ariane] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biomech Med & Rehabil Locomotor Syst, BR-14040904 Ribeirao Preto, SP, Brazil. [Morse, Leslie] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Battaglino, Ricardo] Forsyth Inst, Dept Skeletal Biol, Cambridge, MA USA. RP Nelson, P (reprint author), Univ Sao Paulo, Fac Odontol Ribeirao Preto, Dept Clin Infantil Odontol Prevent & Social, Ave Cafe S-N, BR-14040904 Ribeirao Preto, SP, Brazil. EM nelson@forp.usp.br RI Zamarioli, Ariane/K-7001-2012; Serra, Monica/E-5549-2014; battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015; Bezerra da Silva, Raquel /M-8655-2016; Nelson-Filho, Paulo/L-1272-2016 OI Zamarioli, Ariane/0000-0002-7939-0528; Morse, Leslie/0000-0002-7426-6341; Bezerra da Silva, Raquel /0000-0002-0230-1347; Nelson-Filho, Paulo/0000-0001-8802-6480 FU Brazilian Ministry of Health's Federal Agency for Support and Evaluation of Graduate Education (CAPES) FX Contract grant sponsor: Brazilian Ministry of Health's Federal Agency for Support and Evaluation of Graduate Education (CAPES) NR 43 TC 4 Z9 4 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-910X EI 1097-0029 J9 MICROSC RES TECHNIQ JI Microsc. Res. Tech. PD SEP PY 2012 VL 75 IS 9 BP 1265 EP 1271 DI 10.1002/jemt.22059 PG 7 WC Anatomy & Morphology; Biology; Microscopy SC Anatomy & Morphology; Life Sciences & Biomedicine - Other Topics; Microscopy GA 994VL UT WOS:000307961900017 PM 22508272 ER PT J AU Bergen, SE O'Dushlaine, CT Ripke, S Lee, PH Ruderfer, DM Akterin, S Moran, JL Chambert, KD Handsaker, RE Backlund, L Osby, U McCarroll, S Landen, M Scolnick, EM Magnusson, PKE Lichtenstein, P Hultman, CM Purcell, SM Sklar, P Sullivan, PF AF Bergen, S. E. O'Dushlaine, C. T. Ripke, S. Lee, P. H. Ruderfer, D. M. Akterin, S. Moran, J. L. Chambert, K. D. Handsaker, R. E. Backlund, L. Osby, U. McCarroll, S. Landen, M. Scolnick, E. M. Magnusson, P. K. E. Lichtenstein, P. Hultman, C. M. Purcell, S. M. Sklar, P. Sullivan, P. F. TI Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE schizophrenia; bipolar disorder; genetic; genome-wide association; major histocompatibility complex; copy number variation ID COMMON VARIANTS; COPY NUMBER; CONFERRING RISK; INCREASE RISK; 16P11.2; DELETIONS; AUTISM; GENES; REARRANGEMENTS; MICRODELETION AB Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P = 4.54 x 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P = 0.003, BD: P = 0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P = 0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P = 0.0035) and 22q11 deletions (P = 0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD. C1 [Bergen, S. E.; O'Dushlaine, C. T.; Lee, P. H.; Ruderfer, D. M.; Purcell, S. M.; Sklar, P.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Bergen, S. E.; O'Dushlaine, C. T.; Ripke, S.; Lee, P. H.; Ruderfer, D. M.; Moran, J. L.; Chambert, K. D.; Handsaker, R. E.; McCarroll, S.; Scolnick, E. M.; Purcell, S. M.; Sklar, P.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [O'Dushlaine, C. T.; Ripke, S.; Lee, P. H.; Ruderfer, D. M.; Purcell, S. M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Akterin, S.; Landen, M.; Magnusson, P. K. E.; Lichtenstein, P.; Hultman, C. M.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Handsaker, R. E.; McCarroll, S.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Backlund, L.; Osby, U.] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Landen, M.] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden. [Purcell, S. M.; Sklar, P.] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Sullivan, P. F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, P. F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Bergen, SE (reprint author), Broad Inst, 7 Cambridge Ctr,6055H, Cambridge, MA 02142 USA. EM sbergen@gmail.com RI Bergen, Sarah/I-8313-2012; Ruderfer, Douglas/M-5795-2016; Magnusson, Patrik/C-4458-2017; OI Ruderfer, Douglas/0000-0002-2365-386X; Bergen, Sarah/0000-0002-5888-0034; Backlund, Lena/0000-0001-9399-5024; lichtenstein, paul/0000-0003-3037-5287; Moran, Jennifer/0000-0002-5664-4716 FU Stanley Center for Psychiatric Research; Stanley Medical Research Institute; NIMH [MH077139]; Karolinska Institutet, Karolinska University Hospital; Swedish Research Council; Swedish County Council; Soderstrom Konigska Foundation FX We are deeply grateful for the participation of all subjects contributing to this research, and to the collection team that worked to recruit them: Emma Flordal-Thelander, Ann-Britt Holmgren, Marie Hallin, Marie Lundin, Ann-Kristin Sundberg, Christina Pettersson, Radja Satgunanthan-Dawoud, Sonja Hassellund, Malin Radstrom, Birgitta Ohlander, Leila Nyren, Isabelle Kizling, Louise Frisen, Inger Rohmer, Catharina Lavebratt, Malin Karn, Martina Wennberg and Agneta Carsward-Kjellin. We would also like to thank Professor Martin Schalling for facilitating collection of many subjects with BD. Funding support was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute, NIMH MH077139 (PFS), the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, ALF grant from Swedish County Council and Soderstrom Konigska Foundation. NR 52 TC 93 Z9 93 U1 2 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2012 VL 17 IS 9 BP 880 EP 886 DI 10.1038/mp.2012.73 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 996DI UT WOS:000308063900005 PM 22688191 ER PT J AU Klawiter, EC Xu, JQ Naismith, RT Benzinger, TLS Shimony, JS Lancia, S Snyder, AZ Trinkaus, K Song, SK Cross, AH AF Klawiter, Eric C. Xu, Junqian Naismith, Robert T. Benzinger, Tammie L. S. Shimony, Joshua S. Lancia, Samantha Snyder, Abraham Z. Trinkaus, Kathryn Song, Sheng-Kwei Cross, Anne H. TI Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI ID APPEARING WHITE-MATTER; TENSOR MRI; DIAGNOSTIC-CRITERIA; PRIMATE BRAIN; DAMAGE; MOUSE; DEMYELINATION; PATHOGENESIS; ANISOTROPY; PATHOLOGY AB Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared with controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and fractional anisotropy within white matter regions upstream and downstream of T2 lesions were different from controls in each disease. Conclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration. C1 [Klawiter, Eric C.; Xu, Junqian; Naismith, Robert T.; Lancia, Samantha; Snyder, Abraham Z.; Cross, Anne H.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Klawiter, Eric C.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Benzinger, Tammie L. S.; Shimony, Joshua S.; Snyder, Abraham Z.; Song, Sheng-Kwei] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Trinkaus, Kathryn] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. RP Klawiter, EC (reprint author), 15 Parkman St,WACC 835, Boston, MA 02114 USA. EM eklawiter@partners.org RI Xu, Junqian/D-2247-2009; Benzinger, Tammie/L-6104-2013 OI Xu, Junqian/0000-0001-8438-2066; FU National Institutes of Health [P01 NS059560, R01 NS047592, UL1RR024992, K23NS052430-01A1, CO6 RR020092, RR024992]; National Multiple Sclerosis Society [RG 4009]; American Academy of Neurology Foundation; National MS Society [FG 1782]; Bracco/American Roentgen Ray Society; Manny and Rosalyn Rosenthal-Dr John L Trotter Chair in Neuroimmunology of Barnes-Jewish Hospital Foundation; National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1RR024992]; NIH Roadmap for Medical Research NIH; Bayer Healthcare; Teva Neuroscience; Acorda Therapeutics; Biogen-Idec; EMD Serono; Genzyme Corp; Renovo; Avid; Biomedical Systems; ICON Medical Imaging; Hoffman-La Roche; Coronado Biosciences; Sanofi-Aventis FX This work was supported by the National Institutes of Health (P01 NS059560 to AHC, R01 NS047592 to S-KS) and the National Multiple Sclerosis Society (RG 4009 to AHC). ECK was supported by an American Academy of Neurology Foundation Clinical Research Training Fellowship and the National Institutes of Health (UL1RR024992). JX was supported by a National MS Society Postdoctoral Fellowship (FG 1782). RTN was supported by the National Institutes of Health (K23NS052430-01A1). TB was supported by a Bracco/American Roentgen Ray Society Scholar Award. AHC was supported in part by the Manny and Rosalyn Rosenthal-Dr John L Trotter Chair in Neuroimmunology of Barnes-Jewish Hospital Foundation. An institutional Clinical and Translational Science Award (UL1RR024992) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research NIH, provided funding for the Neuroclinical Research Unit where research subjects were examined. This research was also supported in part by NIH grants CO6 RR020092 and RR024992 (Washington University Institute of Clinical and Translational Sciences - Brain, Behavioral and Performance Unit).; ECK has received consulting fees and/or speaking honoraria from Bayer Healthcare and Teva Neuroscience. RTN has received consulting fees and/or speaking honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen-Idec, EMD Serono, Genzyme Corp and Teva Neuroscience. TLSB has received research grants or consulting fees from Renovo, Avid, Biomedical Systems and ICON Medical Imaging. JSS, JX, SL, AZS, KT and S-KS have nothing to disclose. AHC has received consulting fees from Teva Neuroscience, Biogen-Idec, Bayer Healthcare, Hoffman-La Roche, Coronado Biosciences and Sanofi-Aventis. NR 38 TC 19 Z9 20 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2012 VL 18 IS 9 BP 1259 EP 1268 DI 10.1177/1352458512436593 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 997BD UT WOS:000308138200050 PM 22354742 ER PT J AU Miller, JC Brown, BD Shay, T Gautier, EL Jojic, V Cohain, A Pandey, G Leboeuf, M Elpek, KG Helft, J Hashimoto, D Chow, A Price, J Greter, M Bogunovic, M Bellemare-Pelletier, A Frenette, PS Randolph, GJ Turley, SJ Merad, M AF Miller, Jennifer C. Brown, Brian D. Shay, Tal Gautier, Emmanuel L. Jojic, Vladimir Cohain, Ariella Pandey, Gaurav Leboeuf, Marylene Elpek, Kutlu G. Helft, Julie Hashimoto, Daigo Chow, Andrew Price, Jeremy Greter, Melanie Bogunovic, Milena Bellemare-Pelletier, Angelique Frenette, Paul S. Randolph, Gwendalyn J. Turley, Shannon J. Merad, Miriam CA Immunological Genome Consortium TI Deciphering the transcriptional network of the dendritic cell lineage SO NATURE IMMUNOLOGY LA English DT Article ID IN-VIVO; LYMPH-NODES; IMMUNE REGULATION; BONE-MARROW; FLT3 LIGAND; RECEPTOR; EXPRESSION; MICE; HETEROGENEITY; HEMATOPOIESIS AB Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens. C1 [Miller, Jennifer C.; Brown, Brian D.; Gautier, Emmanuel L.; Leboeuf, Marylene; Helft, Julie; Hashimoto, Daigo; Chow, Andrew; Price, Jeremy; Greter, Melanie; Bogunovic, Milena; Randolph, Gwendalyn J.; Merad, Miriam] Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. [Miller, Jennifer C.; Leboeuf, Marylene; Helft, Julie; Hashimoto, Daigo; Chow, Andrew; Price, Jeremy; Greter, Melanie; Bogunovic, Milena; Merad, Miriam] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Brown, Brian D.; Cohain, Ariella; Pandey, Gaurav] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY USA. [Shay, Tal] Broad Inst, Cambridge, MA USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Mt Sinai Sch Med, Dept Regenerat Biol, New York, NY USA. [Gautier, Emmanuel L.; Randolph, Gwendalyn J.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Jojic, Vladimir; Greter, Melanie] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA. [Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Turley, Shannon J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chow, Andrew; Frenette, Paul S.] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Merad, M (reprint author), Mt Sinai Sch Med, Inst Immunol, New York, NY 10029 USA. EM miriam.merad@mssm.edu RI Frenette, Paul/J-8272-2012; Price, Jeremy /G-1612-2013; Hashimoto, Daigo/O-1013-2013; Shay, Tal/J-4028-2016; Gautier, Emmanuel L./E-2259-2017; OI Price, Jeremy /0000-0003-0491-3176; Hashimoto, Daigo/0000-0001-9489-9704; Shay, Tal/0000-0003-0755-1350; Gautier, Emmanuel L./0000-0003-2976-7566; Malhotra, Deepali/0000-0002-8215-7639; Gazit, Roi/0000-0002-0548-2147; Kim, Charles/0000-0001-6474-8227 FU National Institute of Allergy and Infectious Diseases of the US National Institutes of Health [R24 AI072073, AI080884, HL086899, JDRF172010770, DP2DK083052-01, DK074500, AI045757, HL69438, DK056638, HL097819, HL097700, U54CA149145] FX We thank colleagues of the ImmGen Project, especially the technical team, including M. Painter, J. Ericson and S. Davis, for contributions; C. Benoist for contributions to the design and writing of the manuscript; and eBioscience and Affymetrix for support of the ImmGen Project. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to the ImmGen Project (led by C. Benoist); AI080884 and HL086899 to M.M.; JDRF172010770 and DP2DK083052-01 to B.D.B.; DK074500 and AI045757 to S.J.T.; HL69438, DK056638, HL097819 and HL097700 to P.S.F.; and U54CA149145 to V.J.). NR 58 TC 288 Z9 290 U1 5 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2012 VL 13 IS 9 BP 888 EP 899 DI 10.1038/ni.2370 PG 12 WC Immunology SC Immunology GA 993MK UT WOS:000307863600018 PM 22797772 ER PT J AU Haining, WN AF Haining, W. Nicholas TI Thinking inside the box: how T cell inhibitory receptors signal SO NATURE MEDICINE LA English DT Editorial Material ID TIM-3; PD-1; INFECTION; AUTOIMMUNE; ACTIVATION; EXHAUSTION; EXPRESSION; TOLERANCE; REGULATOR; RESPONSES C1 [Haining, W. Nicholas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Haining, W. Nicholas] Broad Inst Harvard & MIT, Boston, MA USA. RP Haining, WN (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM nicholas_haining@dfci.harvard.edu FU NIAID NIH HHS [R01 AI091493] NR 16 TC 3 Z9 4 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2012 VL 18 IS 9 BP 1338 EP 1339 DI 10.1038/nm.2921 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 001PJ UT WOS:000308472300024 PM 22961161 ER PT J AU Rangachari, M Zhu, C Sakuishi, K Xiao, S Karman, J Chen, A Angin, M Wakeham, A Greenfield, EA Sobel, RA Okada, H McKinnon, PJ Mak, TW Addo, MM Anderson, AC Kuchroo, VK AF Rangachari, Manu Zhu, Chen Sakuishi, Kaori Xiao, Sheng Karman, Jozsef Chen, Andrew Angin, Mathieu Wakeham, Andrew Greenfield, Edward A. Sobel, Raymond A. Okada, Hitoshi McKinnon, Peter J. Mak, Tak W. Addo, Marylyn M. Anderson, Ana C. Kuchroo, Vijay K. TI Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion SO NATURE MEDICINE LA English DT Article ID CHRONIC VIRAL-INFECTION; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MULTIPLE INHIBITORY RECEPTORS; TH1/TH2 CELLS; UP-REGULATION; TIM-3; ACTIVATION; EXPRESSION; PROTEIN; VIRUS AB T cell immunoglobulin and mucin domain-containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (T(H)1) cells from galectin-9-mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen-specific CD4(+) T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3(hi), interferon-gamma (IFN-gamma)(lo)CD4(+) cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3(+) T cells from mouse tumors and HIV-1-infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3-dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers. C1 [Rangachari, Manu; Zhu, Chen; Sakuishi, Kaori; Xiao, Sheng; Karman, Jozsef; Chen, Andrew; Anderson, Ana C.; Kuchroo, Vijay K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Angin, Mathieu; Addo, Marylyn M.] Ragon Inst MGH MIT & Harvard, Charlestown, MA USA. [Wakeham, Andrew; Okada, Hitoshi; Mak, Tak W.] Princess Margaret Hosp, Campbell Family Breast Canc Res Inst, Toronto, ON M4X 1K9, Canada. [Greenfield, Edward A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sobel, Raymond A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Okada, Hitoshi] Ontario Canc Inst, Div Signaling Biol, Toronto, ON M4X 1K9, Canada. [Okada, Hitoshi] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [McKinnon, Peter J.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Kuchroo, VK (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. EM vkuchroo@rics.bwh.harvard.edu OI Angin, Mathieu/0000-0002-6867-4680 FU Multiple Sclerosis Society of Canada (MSSOC); Canadian Institutes of Health Research (CIHR); EMD Serono, Canada; Multiple Sclerosis Scientific Research Foundation; Sankyo Foundation of Life Science; US National Institutes of Health [NS045937, AI073748, NS038037, K01DK090105]; Ragon Institute of MGH; MIT; Harvard; American Cancer Society; Harvard University Center for AIDS Research [P30 AI060354]; MSSOC FX We thank D. Kozoriz, D. Lee, J. Sullivan and M. King for technical assistance; J. Zhang (Brigham and Women's Hospital, Boston) for reagents; B.H. Waksman for valuable guidance and discussion; and B. Walker for critical reading of the manuscript. M. R. was previously supported by Fellowships from the Multiple Sclerosis Society of Canada (MSSOC) and the Canadian Institutes of Health Research (CIHR) and is currently supported by the EMD Serono, Canada and an MS Research and Training Network Transitional Career Development Award from the MSSOC and the Multiple Sclerosis Scientific Research Foundation. K.S. holds a Fellowship from the Sankyo Foundation of Life Science. These studies were funded by grants from the US National Institutes of Health to V.K.K. (NS045937, AI073748 and NS038037) and S.X. (K01DK090105), the Ragon Institute of MGH, MIT and Harvard (V.K.K., C.Z. and M.M.A.), the American Cancer Society (A.C.A.) and the Harvard University Center for AIDS Research (M.M.A.; P30 AI060354). NR 46 TC 61 Z9 65 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2012 VL 18 IS 9 BP 1394 EP + DI 10.1038/nm.2871 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 001PJ UT WOS:000308472300035 PM 22863785 ER PT J AU Bergwitz, C AF Bergwitz, Clemens TI Dietary phosphate modifies lifespan in Drosophila SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE CKD; drosophila; hyperphosphatemia; lifespan; phosphate metabolism ID CHRONIC KIDNEY-DISEASE; SACCHAROMYCES-CEREVISIAE; INORGANIC POLYPHOSPHATE; VASCULAR CALCIFICATION; HYPERTROPHIC CHONDROCYTES; ARTERY CALCIFICATION; PARATHYROID-HORMONE; MINERAL METABOLISM; INDUCED APOPTOSIS; PTH SECRETION AB Phosphate is required for many important cellular processes and having too little phosphate (hypophosphatemia) or too much (hyperphosphatemia) can cause disease and reduce lifespan in humans. Drosophila melanogaster has been a powerful tool to discover evolutionarily well-conserved nutrient-sensing pathways that are important for the lifespan extension. We have established Drosophila as a model system for studying the effects of dietary phosphate during development and adult life. When absorption of phosphate is blocked by sevelamer or cellular uptake is inhibited by phosphonoformic acid (PFA), larval development is delayed in a phosphate-dependent fashion. Conversely, restriction of phosphate absorption with sevelamer or reduced cellular uptake after treatment with PFA is able to extend the adult lifespan of otherwise normal flies. Gaining an understanding of the specific pathways and mediators that regulate cellular and organismic phosphate levels might ultimately lead to the development of improved dietary and therapeutic approaches to the treatment of human disorders of hypo- and hyperphosphatemia. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM cbergwitz@partners.org FU NIH [K08 DK08361] FX Funding was provided by NIH K08 DK08361. This work would not have been possible without the contributions of Mark Wee, Charles DeRobertis, Sumi Sinha, Joanne Huang, Helen H. Chen and Lawrence B. Mensah. NR 67 TC 5 Z9 5 U1 0 U2 32 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD SEP PY 2012 VL 27 IS 9 BP 3399 EP 3406 DI 10.1093/ndt/gfs362 PG 8 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 998MS UT WOS:000308244400008 PM 22942172 ER PT J AU Weaver, KJ Neal, D Hoh, DJ Mocco, J Barker, FG Hoh, BL AF Weaver, Kristin J. Neal, Dan Hoh, Daniel J. Mocco, J. Barker, Fred G., II Hoh, Brian L. TI The "July Phenomenon" for Neurosurgical Mortality and Complications in Teaching Hospitals: An Analysis of More Than 850 000 Neurosurgical Patients in the Nationwide Inpatient Sample Database, 1998 to 2008 SO NEUROSURGERY LA English DT Article DE Hemorrhage; Hydrocephalus; Retrospective; Trauma; Tumor ID LENGTH-OF-STAY; ACADEMIC YEAR; WORK HOURS; CARE; INTERNS; QUALITY; FICTION; FACT AB BACKGROUND: The evidence of or against the presence of a "July phenomenon" in resident teaching hospitals has been inconsistent. Moreover, there are limited data on the "July phenomenon" in the field of neurosurgery. OBJECTIVE: To determine whether a "July phenomenon" exists for neurosurgical mortality or complications. METHODS: A search of the National Inpatient Sample database from 1998 to 2008 was performed for all admissions for International Classification of Diseases, 9th Revision codes corresponding to nontraumatic hemorrhage, central nervous system (CNS) trauma, CNS tumor, and hydrocephalus. Generalized linear mixed-model analysis was performed, adjusted for patient demographics and hospital characteristics, for the outcomes of mortality and complications for the month of July compared with all other months in teaching hospitals. RESULTS: Generalized linear mixed-model analysis demonstrated that the risk of dying in the month of July vs any other month in a teaching hospital was not statistically different for any of the 4 diagnoses: nontraumatic hemorrhage (P=.071), CNS trauma category (P=.485), CNS tumor category (P=.578), hydrocephalus category (P=.1505). Moreover, the risk of any complication in the month of July vs any other month in a teaching hospital was not statistically different for any of the 4 diagnoses: nontraumatic hemorrhage (P=.529), CNS trauma category (P=.378), CNS tumor category (P=.461), and hydrocephalus category (P=.441). The same findings were true in an analysis of nonteaching hospitals performed as a control. CONCLUSION: No "July phenomenon" was found for neurosurgical mortality or complications in patients with nontraumatic hemorrhage, CNS trauma, CNS tumor, or hydrocephalus. C1 [Weaver, Kristin J.; Neal, Dan; Hoh, Daniel J.; Mocco, J.; Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL 32610 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Hoh, BL (reprint author), Univ Florida, Dept Neurosurg, POB 100265, Gainesville, FL 32610 USA. EM brian.hoh@neurosurgery.ufl.edu NR 22 TC 11 Z9 11 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2012 VL 71 IS 3 BP 562 EP 571 DI 10.1227/NEU.0b013e31825ea51b PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 996HB UT WOS:000308074400010 PM 22592329 ER PT J AU Barnard, Z Wakimoto, H Zaupa, C Patel, AP Klehm, J Martuza, RL Rabkin, SD Curry, WT AF Barnard, Zachary Wakimoto, Hiroaki Zaupa, Cecile Patel, Anoop P. Klehm, Jacquelyn Martuza, Robert L. Rabkin, Samuel D. Curry, William T., Jr. TI Expression of FMS-like Tyrosine Kinase 3 Ligand by Oncolytic Herpes Simplex Virus Type I Prolongs Survival in Mice Bearing Established Syngeneic Intracranial Malignant Glioma SO NEUROSURGERY LA English DT Article DE Brain tumor; Flt3-ligand; Glioma; Herpes; Immunotherapy; Oncolytic virus; Vaccine ID SYSTEMIC ANTITUMOR IMMUNITY; CELL-MEDIATED-IMMUNITY; DENDRITIC CELLS; FLT3 LIGAND; TUMOR-REGRESSION; BRAIN-TUMORS; PHASE-I; CANCER; THERAPY; G207 AB BACKGROUND: Glioblastoma is a fatal brain tumor in needing urgent effective therapy. Treatments with both oncolytic viruses and immunotherapy have shown preclinical efficacy and clinical promise. We sought to exploit possible synergies between oncolytic herpes simplex virus type 1 (oHSV-1) infection of intracranial gliomas and delivery of immune-stimulating fms-like tyrosine kinase 3 ligand (Flt3L) by engineering a herpes vector to express the cytokine. OBJECTIVE: To construct an oHSV-1 vector that expresses high levels of Flt3L and examine its antiglioma efficacy in an immunocompetent murine model. METHODS: G47 Delta and a bacterial artificial chromosome system were used to generate a novel oHSV-1, termed G47 Delta-Flt3L, expressing Flt3L. Cytokine expression was confirmed, and G47 Delta-Flt3L was injected intratumorally into established intracranial CT-2A gliomas in syngeneic C57/Bl6 mice. Animals were followed for survival and assessed by the Kaplan-Meier method. RESULTS: G47 Delta-Flt3L expressed high levels of Flt3L in culture. Expression of Flt3L affected neither viral replication nor had a cytotoxic effect on CT2A glioma cells. Direct inoculation into intracerebral CT2A glioma cells resulted in high levels of detectable Flt3L in mouse blood and was superior to parental G47 Delta in prolonging survival in glioma-bearing animals. CONCLUSION: Treatment with G47 Delta-Flt3L improves survival of glioma-bearing mice. C1 [Curry, William T., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Pappas Ctr Neurooncol, Simches Brain Tumor Res Labs,Dept Neurosurg, Boston, MA 02114 USA. RP Curry, WT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Pappas Ctr Neurooncol, Simches Brain Tumor Res Labs,Dept Neurosurg, 55 Fruit St,Y9E, Boston, MA 02114 USA. EM wcurry@partners.org OI rabkin, samuel/0000-0003-2344-2795 FU Amos Medical Faculty Development Plan of the Robert Wood Johnson Foundation; Mass General Hospital Physician Scientist Development Award; NIH [NS-032677] FX Funding provided by the Amos Medical Faculty Development Plan of the Robert Wood Johnson Foundation and Mass General Hospital Physician Scientist Development Award. This work was supported in part by NIH grant NS-032677. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 46 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2012 VL 71 IS 3 BP 741 EP 748 DI 10.1227/NEU.0b013e318260fd73 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 996HB UT WOS:000308074400049 PM 22653387 ER PT J AU Simonen, M Dali-Youcef, N Kaminska, D Venesmaa, S Kakela, P Paakkonen, M Hallikainen, M Kolehmainen, M Uusitupa, M Moilanen, L Laakso, M Gylling, H Patti, ME Auwerx, J Pihlajamaki, J AF Simonen, M. Dali-Youcef, N. Kaminska, D. Venesmaa, S. Kakela, P. Paakkonen, M. Hallikainen, M. Kolehmainen, M. Uusitupa, M. Moilanen, L. Laakso, M. Gylling, H. Patti, M. E. Auwerx, J. Pihlajamaki, Jussi TI Conjugated Bile Acids Associate with Altered Rates of Glucose and Lipid Oxidation after Roux-en-Y Gastric Bypass SO OBESITY SURGERY LA English DT Article DE Obesity surgery; Bile acids; Glucose and lipid oxidation; DIO2; CYP27A1 ID FARNESOID-X-RECEPTOR; GLUCAGON-LIKE PEPTIDE-1; BARIATRIC SURGERY; WEIGHT-LOSS; INDIRECT CALORIMETRY; ENERGY-EXPENDITURE; MORBID-OBESITY; HOMEOSTASIS; METABOLISM; ACTIVATION AB Laparoscopic Roux-en-Y gastric bypass (RYGB) induces a more favorable metabolic profile than expected by weight loss alone. In this study, we investigated the effect of RYGB on serum bile acid levels and their relation to clinical outcomes. We included 30 obese patients who underwent RYGB (BMI = 46.1 +/- 5.9 kg/m(2)). Clinical measurements and laboratory determinations were performed before surgery and 1 year after surgery. Fasting serum bile acids were measured by an enzymatic method and individual bile acids were quantified by HLPC-tandem mass spectrometry. Indirect calorimetry was performed to measure the rates of energy expenditure and substrate oxidation. Fasting total serum bile acid levels increased twofold after RYGB (pre, 3.68 +/- 2.03 vs. post, 7.06 +/- 9.65 mu mol/l, +92 %, p = 0.002). This increase in total bile acids was accompanied by a decrease in conjugated bile acids, which correlated with decreased glucose oxidation (r = 0.571, p = 0.002) and with increased lipid oxidation (r = -0.626, p = 0.0004). The change in taurine-conjugated bile acids correlated with altered DIO2 mRNA expression in adipose tissue (r = -0.498, p = 0.013) potentially linking bile acid conjugation to substrate oxidation through DIO2. Fasting serum bile acid levels increase after RYGB. More specifically, changes in bile acid conjugation after RYGB associate with altered energy metabolism. C1 [Kaminska, D.; Hallikainen, M.; Kolehmainen, M.; Uusitupa, M.; Gylling, H.; Pihlajamaki, Jussi] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Pihlajamaki, Jussi] Kuopio Univ Hosp, Dept Clin Nutr, SF-70210 Kuopio, Finland. [Simonen, M.; Moilanen, L.; Laakso, M.] Univ Eastern Finland, Dept Med, Kuopio, Finland. [Dali-Youcef, N.] Univ Strasbourg, Hop Univ Strasbourg, Strasbourg, France. [Dali-Youcef, N.] Univ Strasbourg, Inst Genet Biol Mol & Cellulaire, Strasbourg, France. [Venesmaa, S.; Kakela, P.; Paakkonen, M.] Univ Eastern Finland, Dept Surg, Kuopio, Finland. [Patti, M. E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Auwerx, J.] Ecole Polytech Fed Lausanne, Lab Integrat Syst Physiol, Lausanne, Switzerland. [Pihlajamaki, Jussi] Kuopio Univ Hosp, Obes Ctr, SF-70210 Kuopio, Finland. RP Pihlajamaki, J (reprint author), Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. EM jussi.pihlajamaki@uef.fi RI DALI-YOUCEF, Nassim/O-2549-2016; OI DALI-YOUCEF, Nassim/0000-0001-6958-1331; Kaminska, Dorota/0000-0003-1829-576X FU Finnish Diabetes Research Foundation; Academy of Finland [120979, 138006]; EU Ideas program [ERC-2008-AdG-23118]; Swiss National Science Foundation (FNS); Ecole Polytechnique Federale de Lausanne FX This study was supported by the Finnish Diabetes Research Foundation (to JPI). JPI has an Academy of Finland Clinical Researcher fellowship (grant 120979 2008-2010 and 138006 2011-2013). JA acknowledges grant support of the EU Ideas program (ERC-2008-AdG-23118), the Swiss National Science Foundation (FNS), and the Ecole Polytechnique Federale de Lausanne. NR 33 TC 51 Z9 52 U1 1 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0960-8923 J9 OBES SURG JI Obes. Surg. PD SEP PY 2012 VL 22 IS 9 BP 1473 EP 1480 DI 10.1007/s11695-012-0673-5 PG 8 WC Surgery SC Surgery GA 996ER UT WOS:000308067800460 PM 22638681 ER PT J AU Scholl, J Durfee, SM Russell, MA Heard, AJ Iyer, C Alammari, R Coletta, J Craigo, SD Fuchs, KM D'Alton, M House, M Jennings, RW Ecker, J Panda, B Tanner, C Wolfberg, A Benson, CB AF Scholl, Jessica Durfee, Sara M. Russell, Michelle A. Heard, Asha J. Iyer, Chitra Alammari, Roa Coletta, Jaclyn Craigo, Sabrina D. Fuchs, Karin M. D'Alton, Mary House, Michael Jennings, Russell W. Ecker, Jeffrey Panda, Britta Tanner, Cassandre Wolfberg, Adam Benson, Carol B. TI First-Trimester Cystic Hygroma: Relationship of Nuchal Translucency Thickness and Outcomes SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID 1ST TRIMESTER; FETUSES; DIAGNOSIS; ANOMALIES; DEFECTS; EDEMA AB OBJECTIVE: To estimate the relationship between nuchal translucency thickness and abnormal karyotype, major congenital anomaly, perinatal loss, and composite abnormal outcome in fetuses with first-trimester nuchal cystic hygroma. METHODS: We performed a retrospective cohort study of first-trimester fetuses with ultrasound-diagnosed nuchal cystic hygroma collected over a 10-year period. RESULTS: There were 944 first-trimester fetuses with nuchal cystic hygroma. A karyotype abnormality occurred in 54.9% (400 of 729) of fetuses. A major congenital anomaly occurred in 28.8% (61 of 212) of fetuses with a normal karyotype. Perinatal loss occurred in 39% (115 of 295) of fetuses not electively terminated. Overall, an abnormal outcome occurred in 86.6% (543 of 627) of fetuses. After adjusting for potential confounders, every 1-mm increase in nuchal translucency thickness increased the odds of an abnormal karyotype by 44% (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.29 -1.60, P<.001), the odds of major congenital anomaly by 26% (adjusted OR 1.26, 95% CI, 1.08 -1.47, P=.003), the odds of perinatal loss by 47% (adjusted OR 1.47, 95% CI 1.07-2.02, P=.019), and the odds of a composite abnormal outcome by 77% (adjusted OR 1.77, 95% CI 1.15-2.74, P=.01). CONCLUSION: First-trimester nuchal cystic hygroma is associated with high rates of karyotype abnormality, major congenital anomaly, perinatal loss, and abnormal outcome. As the thickness of the nuchal translucency increases, the odds of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome increase. (Obstet Gynecol 2012; 120: 551-9) DOI: http://10.1097/AOG.0b013e318264f829 LEVEL OF EVIDENCE: II C1 [Scholl, Jessica] Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, Lebanon, NH 03756 USA. Childrens Hosp, Brigham & Womens Hosp, Tufts Med Ctr, Boston, MA 02115 USA. Columbia Univ, Med Ctr, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Scholl, J (reprint author), Dartmouth Hitchcock Med Ctr, Dept Obstet & Gynecol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM Jessica.E.Scholl@Hitchcock.org NR 19 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 551 EP 559 DI 10.1097/AOG.0b013e318264f829 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300009 PM 22872145 ER PT J AU Tracy, EE Haas, S Lauria, MR AF Tracy, Erin E. Haas, Susan Lauria, Michele R. TI Newborn Care and Safety The Black Box of Obstetric Practices and Residency Training SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INFANT SLEEPING ENVIRONMENT; DEATHS EXPANSION; SIDS; RECOMMENDATIONS AB Certain causes of newborn mortality such as sudden unexpected infant death, which includes sleep-related infant death and sudden unexplained infant death syndrome, are potentially preventable. Obstetricians are uniquely positioned to counsel new parents about safe practices regarding newborn sleep, feeding, and transportation. Patients often do not develop a relationship with their pediatricians until the neonate has been discharged, and the newborn period is a time of particular vulnerability. Newborn safety should be routinely taught in obstetric curricula, and the American College/Congress of Obstetricians and Gynecologists and the American Academy of Pediatrics (AAP) should partner to disseminate updated literature and guidelines to health care providers regarding newborn safety. Current guidelines from the Academy of Pediatrics Task Force on Sudden Infant Syndrome are summarized in this article. (Obstet Gynecol 2012; 120: 643-6) DOI: http://10.1097/AOG.0b013e318265af0a C1 [Tracy, Erin E.] Massachusetts Gen Hosp, Harvard Vanguard Med Associates Atrius Hlth, Vincent Obstet & Gynecol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. RP Tracy, EE (reprint author), Massachusetts Gen Hosp, Harvard Vanguard Med Associates Atrius Hlth, Vincent Obstet & Gynecol, 55 Fruit St,406 Founders House, Boston, MA 02114 USA. EM EETracy@partners.org NR 24 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 643 EP 646 DI 10.1097/AOG.0b013e318265af0a PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300021 PM 22914475 ER PT J AU Minkoff, H Ecker, J AF Minkoff, Howard Ecker, Jeffrey TI When Legislators Play Doctor The Ethics of Mandatory Preabortion Ultrasound Examinations SO OBSTETRICS AND GYNECOLOGY LA English DT Article AB Many states have proposed or enacted laws that mandate that women undergo ultrasonography before electing pregnancy termination. In some cases, the legislation prescribes the form of ultrasound examination, requires that a woman review the images produced, or both. Although ultrasonography may be a part of good and standard care before many abortion procedures, we argue that legislating imaging procedures inappropriately limits women's autonomy and undermines the physician-patient relationship as well as the physician's professional obligations to the patient. The timing, context, and way in which ultrasonography, or any medical test, is used and viewed should be decisions made between patient and provider, not decisions scripted by law. (Obstet Gynecol 2012; 120: 647-9) DOI: http://10.1097/AOG.0b013e318265e101 C1 [Minkoff, Howard] SUNY Downstate, Maimonides Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. Harvard Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Minkoff, H (reprint author), SUNY Downstate, Maimonides Med Ctr, Dept Obstet & Gynecol, 967 48th St, Brooklyn, NY 11219 USA. EM hminkoff@maimonidesmed.org NR 5 TC 1 Z9 1 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2012 VL 120 IS 3 BP 647 EP 649 DI 10.1097/AOG.0b013e318265e101 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 999EX UT WOS:000308293300022 PM 22914476 ER PT J AU Schiotz, M Frolich, A Krasnik, A Taylor, W Hsu, J AF Schiotz, Michaela Frolich, Anne Krasnik, Allan Taylor, Warren Hsu, John TI Social organization of self-management support of persons with diabetes: A health systems comparison SO SCANDINAVIAN JOURNAL OF PRIMARY HEALTH CARE LA English DT Article DE Denmark; diabetes mellitus; general practice; health system; international comparison; patient education; self-management support ID KAISER-PERMANENTE; GENERAL-PRACTICE; CARE; DENMARK; PROGRAM; NHS AB Objective. Identify important organizational elements for providing self-management support (SMS). Design. Semi-structured qualitative interviews conducted in two healthcare systems. Setting. Kaiser Permanente Northern California and the Danish Health Care System. Subjects. 36 managers and healthcare professionals in the two healthcare systems. Main outcome measures. Elements important to providing self-management support to persons with diabetes. Results. Healthcare professionals 'provision of SMS was influenced by healthcare system organization and their perceptions of SMS, the capability and responsibility of healthcare systems, and their roles in the healthcare organization. Enabling factors for providing SMS included: strong leadership; aligned incentives; use of an integrated health information technology (HIT) system; multidisciplinary healthcare provider teams; ongoing training for healthcare professionals; outreach; and quality goals. Barriers to providing SMS included lack of collaboration between providers and skeptical attitudes towards prevention and outreach. Conclusions and implications. Implementation of SMS can be improved by an understanding of the elements that enhance its provision: (1) initiatives seeking to improve collaboration and integration between providers; (2) implementation of an integrated HIT system; and (3) ongoing training of healthcare professionals. C1 [Schiotz, Michaela] Steno Diabet Ctr, Steno Hlth Promot Ctr, DK-2820 Gentofte, Denmark. [Frolich, Anne] Copenhagen Hosp Cooperat, Copenhagen, Denmark. [Krasnik, Allan] Univ Copenhagen, Fac Hlth Sci, Dept Publ Hlth, Sect Hlth Serv Res, Copenhagen, Denmark. [Taylor, Warren] Massachusetts Gen Hosp, Permanente Med Grp, Boston, MA 02114 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Schiotz, M (reprint author), Steno Diabet Ctr, Steno Hlth Promot Ctr, Niels Steensens Vej 8, DK-2820 Gentofte, Denmark. EM mlsz@steno.dk FU Rockwool Foundation FX The authors would like to thank the Rockwool Foundation who funded this study. Jennifer Green provided English text revision and correction.; We received Institutional Review Board approval to conduct the study in KP. It was not necessary to obtain ethical approval in the DHS. The study was funded by the Rockwool Foundation. WT and JH were employed by KP during the study period. AF was employed by the DHS during the study period. NR 26 TC 3 Z9 3 U1 2 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0281-3432 J9 SCAND J PRIM HEALTH JI Scand. J. Prim. Health Care PD SEP PY 2012 VL 30 IS 3 BP 189 EP 194 DI 10.3109/02813432.2012.704810 PG 6 WC Health Care Sciences & Services; Primary Health Care; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 997UV UT WOS:000308193300013 PM 22839353 ER PT J AU Kuna, ST Maislin, G Pack, FM Staley, B Hachadoorian, R Coccaro, EF Pack, AI AF Kuna, Samuel T. Maislin, Greg Pack, Frances M. Staley, Bethany Hachadoorian, Robert Coccaro, Emil F. Pack, Allan I. TI Heritability of Performance Deficit Accumulation During Acute Sleep Deprivation in Twins SO SLEEP LA English DT Article DE Sleep homeostasis; sleep deprivation; twins ID NUMBER TANDEM REPEAT; CLOCK GENE PERIOD3; HUMAN PER3 GENE; LENGTH POLYMORPHISM; DIURNAL PREFERENCE; COLLABORATIVE CROSS; CAGE QUESTIONNAIRE; VIGILANT ATTENTION; CIRCADIAN PHASE; EEG SLEEP AB Study Objectives: To determine if the large and highly reproducible interindividual differences in rates of performance deficit accumulation during sleep deprivation, as determined by the number of lapses on a sustained reaction time test, the Psychomotor Vigilance Task (PVT), arise from a heritable trait. Design: Prospective, observational cohort study. Setting: Academic medical center. Participants: There were 59 monozygotic (mean age 29.2 +/- 6.8 [SD] yr; 15 male and 44 female pairs) and 41 dizygotic (mean age 26.6 +/- 7.6 yr; 15 male and 26 female pairs) same-sex twin pairs with a normal polysomnogram. Interventions: Thirty-eight hr of monitored, continuous sleep deprivation. Measurements and Results: Patients performed the 10-min PVT every 2 hr during the sleep deprivation protocol. The primary outcome was change from baseline in square root transformed total lapses (response time >= 500 ms) per trial. Patient-specific linear rates of performance deficit accumulation were separated from circadian effects using multiple linear regression. Using the classic approach to assess heritability, the intraclass correlation coefficients for accumulating deficits resulted in a broad sense heritability (h(2)) estimate of 0.834. The mean within-pair and among-pair heritability estimates determined by analysis of variance-based methods was 0.715. When variance components of mixed-effect multilevel models were estimated by maximum likelihood estimation and used to determine the proportions of phenotypic variance explained by genetic and non-genetic factors, 51.1% (standard error = 8.4%, P < 0.0001) of twin variance was attributed to combined additive and dominance genetic effects. Conclusion: Genetic factors explain a large fraction of interindividual variance among rates of performance deficit accumulations on PVT during sleep deprivation. C1 [Kuna, Samuel T.] Philadelphia VA Med Ctr, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Maislin, Greg; Pack, Frances M.; Staley, Bethany; Hachadoorian, Robert; Pack, Allan I.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Maislin, Greg; Pack, Frances M.; Staley, Bethany; Hachadoorian, Robert; Pack, Allan I.] Univ Penn, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Coccaro, Emil F.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. RP Kuna, ST (reprint author), Philadelphia VA Med Ctr, Dept Med, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM skuna@mail.med.upenn.edu FU NIH from National Center for Research Resources [P50 HL060287, P01 HL094307, UL1RR024134]; Philips-Respironics; Philips-Respironics Foundation; Azevan Pharmaceuticals, Inc. FX This study was supported by NIH P50 HL060287, P01 HL094307 and UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The Penn Twins Cohort and the MidAtlantic Twins Registry assisted in recruitment of the twin pairs. The contributions of Melissa Fernando, Michele Pliner, Marian Whitlock, and Colleen Crowley to the study are gratefully acknowledged and to Daniel Barrett for assistance in manuscript preparation.; Dr. Kuna receives grant support from Philips-Respironics. Mr. Maislin is the owner of Biomedical Statistical Consulting Services. Dr. Coccaro is a member of the Scientific Advisory Board of Azevan Pharmaceuticals, Inc. and receives grant support from that company. Dr. Pack is The John L. Miclot Professor of Medicine at the University of Pennsylvania. Funds for this endowment were provided by the Philips-Respironics Foundation. The other authors have indicated no financial conflicts of interest. NR 64 TC 31 Z9 32 U1 0 U2 10 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD SEP 1 PY 2012 VL 35 IS 9 BP 1223 EP 1233 DI 10.5665/sleep.2074 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 000AY UT WOS:000308360100009 PM 22942500 ER PT J AU Szabo, S Tache, Y Somogyi, A AF Szabo, Sandor Tache, Yvette Somogyi, Arpad TI The legacy of Hans Selye and the origins of stress research: A retrospective 75 years after his landmark brief "Letter" to the Editor of Nature SO STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS LA English DT Article DE Anti-inflammatory drugs; corticosteroids; distress; eustress; Hans Selye; stress ID STEROIDS; SPIRONOLACTONE; CLASSIFICATION; CYSTEAMINE; HORMONES; ULCERS; MODEL; RAT AB Hans Selye's single author short letter to Nature (1936, 138(3479): 32) inspired a huge and still growing wave of medical research. His experiments with rats led to recognition of the "general adaptation syndrome", later renamed by Selye "stress response": the triad of enlarged adrenal glands, lymph node and thymic atrophy, and gastric erosions/ulcers. Because of the major role of glucocorticoids (named by Selye), he performed extensive structure-activity studies in the 1930s-1940s, resulting in the first rational classification of steroid hormones, e. g. corticoids, testoids/androgens, and folliculoids/estrogens. During those years, he recognized the respective anti-and pro-inflammatory actions of gluco- and mineralocorticoids in animal models, several years before demonstration of anti-rheumatic actions of cortisone and adrenocorticotrophic hormones in patients. Nevertheless, Selye did not receive a Nobel Prize, which was awarded in 1950 to the clinician Hench and the two chemists who isolated and synthesized some of the glucocorticoids. Nonetheless, Selye was internationally recognized as a world authority in endocrinology, steroid chemistry, experimental surgery, and pathology. He wrote over 1500 original and review articles, singly authored 32 books, and trained 40 PhD students, one of whom (Roger Guillemin) won a Nobel Prize for isolating the hypothalamic releasing factors/hormones. Here, we consider the main implications of his first article launching the biological stress concept and the key ideas and problems that occupied him. Selye considered "Stress in heath and disease is medically, sociologically, and philosophically the most meaningful subject for humanity that I can think of". C1 [Szabo, Sandor] Univ Calif Irvine, VA Med Ctr, VA Long Beach Healthcare Syst, Long Beach, CA 90822 USA. [Szabo, Sandor] Univ Calif Irvine, Dept Pathol, Long Beach, CA 90822 USA. [Szabo, Sandor] Univ Calif Irvine, Dept Pharmacol, Long Beach, CA 90822 USA. [Tache, Yvette] Univ Calif Los Angeles, Dept Med, Oppenheimer Family Ctr Ctr Neurobiol Stress, Digest Dis Div,CURE Digest Dis Res Ctr, Los Angeles, CA 90024 USA. [Tache, Yvette] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Somogyi, Arpad] EU Select Inc, Brussels, Belgium. RP Szabo, S (reprint author), Univ Calif Irvine, VA Med Ctr, VA Long Beach Healthcare Syst, 5901 E 7th St, Long Beach, CA 90822 USA. EM sandor.szabo@va.gov NR 49 TC 43 Z9 46 U1 5 U2 46 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1025-3890 J9 STRESS JI Stress PD SEP PY 2012 VL 15 IS 5 BP 472 EP 478 DI 10.3109/10253890.2012.710919 PG 7 WC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences SC Behavioral Sciences; Endocrinology & Metabolism; Neurosciences & Neurology GA 994AW UT WOS:000307904200002 PM 22845714 ER PT J AU Kopeikina, KJ Hyman, BT Spires-Jones, TL AF Kopeikina, Katherine J. Hyman, Bradley T. Spires-Jones, Tara L. TI Soluble forms of tau are toxic in Alzheimer's disease SO TRANSLATIONAL NEUROSCIENCE LA English DT Review DE Alzheimer; Tauopathy; Neurofibrillary tangle; Hyperphosphorylated tau ID TANGLE-BEARING NEURONS; INDUCIBLE MOUSE MODELS; WILD-TYPE TAU; AXONAL-TRANSPORT; TRANSGENIC MICE; AMYLOID-BETA; NEURODEGENERATIVE DISEASES; MITOCHONDRIAL DYSFUNCTION; DENDRITIC SPINES; IN-VIVO AB Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer's disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer's disease and other tauopathies. C1 [Kopeikina, Katherine J.; Hyman, Bradley T.; Spires-Jones, Tara L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Kopeikina, Katherine J.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. RP Kopeikina, KJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. EM tspires@partners.org OI Spires-Jones, Tara/0000-0003-2530-0598 FU National Institute of Health [AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134]; Alzheimer's Association Zenith Award FX This work was supported by National Institute of Health Grants AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134 and the Alzheimer's Association Zenith Award. We thank Rose Pitstick and George Carlson at the McLaughlin Research Institute for animal breeding and genotyping. NR 133 TC 43 Z9 45 U1 1 U2 24 PU VERSITA PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD SEP PY 2012 VL 3 IS 3 BP 223 EP 233 DI 10.2478/s13380-012-0032-y PG 11 WC Neurosciences SC Neurosciences & Neurology GA 996FN UT WOS:000308070300001 PM 23029602 ER PT J AU Eisner, BH AF Eisner, Brian H. TI A New Scoring System for Predicting Stone-free Rate After Retrograde Intrarenal Surgery: The "Resorlu-Unsal Stone Score" EDITORIAL COMMENT SO UROLOGY LA English DT Editorial Material ID SHOCK-WAVE LITHOTRIPSY; NOMOGRAM C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. RP Eisner, BH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA 02114 USA. NR 5 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 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 BP 517 EP 517 DI 10.1016/j.urology.2012.02.073 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 000FX UT WOS:000308373000009 PM 22840864 ER PT J AU Evans, CS Harris, NS AF Evans, C. Scott Harris, N. Stuart TI Ultrasound and Ski Resort Clinics: Mapping Out the Potential Benefits SO WILDERNESS & ENVIRONMENTAL MEDICINE LA English DT Article; Proceedings Paper CT Wilderness and Mountain Medicine Conference of the Wilderness-Medical-Society CY FEB 05-09, 2011 CL Pk City, UT SP Wilderness Med Soc DE bedside ultrasound; skier injury; snowboarder injury; prehospital ultrasound; mountainside clinic ID ACUTE MOUNTAIN-SICKNESS; ANTERIOR SHOULDER DISLOCATION; OPTIC-NERVE ULTRASONOGRAPHY; ALTITUDE PULMONARY-EDEMA; INTRACRANIAL-PRESSURE; EMERGENCY-DEPARTMENT; SNOWBOARDING INJURIES; FOCUSED ASSESSMENT; CHEST RADIOGRAPHY; NASAL FRACTURES AB Background.-Skiing and snowboarding are popular activities that involve high kinetic energies, often at altitude, and injuries are common. As a portable imaging modality, ultrasound may be a useful adjunct for mountainside clinics. This review briefly discusses skier and snowboarder injury profiles and focuses on the role of ultrasound for each injury type. Methods.-Twenty-two sources including 17 reviews and observational studies were obtained describing skier and snowboarder injuries. Forty-nine studies were identified defining ultrasound applications for these injuries, including 38 reviews and observational studies, 6 case reports or case series, 3 cross-sectional studies, and 2 randomized, blinded studies. Results.-Approximately 200 000 rider injuries are evaluated in the Unites States seasonally. Musculoskeletal injuries are the most common, and head, face, neck, and abdominal injuries are also prevalent, as are exacerbations of preexisting disease. Ultrasound has been shown to be useful and accurate for evaluating the aforementioned injury types, including joint, ligament, tendon, and fracture evaluation. Ultrasound has not been extensively studied in the prehospital setting, and only limited data address the utility of how it might influence management in a mountainside clinic setting. Conclusions.-Ultrasound has the potential to be a useful diagnostic modality in ski resort clinics. The most promising areas for future, applied studies include evaluation of musculoskeletal injuries (especially injuries to joints and tendons and ruling out fractures), assessing for elevated intracranial pressure in minor head injuries and symptoms of altitude illness, and focused assessment with sonography for trauma and extended focused assessment with sonography for trauma examinations for cases of chest and abdominal trauma of unknown significance. C1 [Evans, C. Scott] Duke Univ, Med Ctr, Div Emergency Med, Dept Surg, Durham, NC 27710 USA. [Harris, N. Stuart] Massachusetts Gen Hosp, Dept Emergency Med, Div Wilderness Med, Boston, MA 02114 USA. RP Evans, CS (reprint author), Duke Univ, Med Ctr, Div Emergency Med, Dept Surg, DUMC Box 3935,2301 Erwin Rd,Suite 2600, Durham, NC 27710 USA. EM scott.evans@duke.edu NR 71 TC 3 Z9 3 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1080-6032 J9 WILD ENVIRON MED JI Wildern. Environ. Med. PD FAL PY 2012 VL 23 IS 3 BP 239 EP 247 PG 9 WC Public, Environmental & Occupational Health; Sport Sciences SC Public, Environmental & Occupational Health; Sport Sciences GA 999BR UT WOS:000308284600009 PM 22704080 ER PT J AU Aspinall, SL Cunningham, FE Zhao, XH Boresi, JS Tonnu-Mihara, IQ Smith, KJ Stone, RA Good, CB AF Aspinall, Sherrie L. Cunningham, Francesca E. Zhao, Xinhua Boresi, Joy S. Tonnu-Mihara, Ivy Q. Smith, Kenneth J. Stone, Roslyn A. Good, Chester B. CA ESA Clinic Study Grp TI Impact of Pharmacist-Managed Erythropoiesis-Stimulating Agents Clinics for Patients With Non-Dialysis-Dependent CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; anemia; erythropoietin ID CHRONIC KIDNEY-DISEASE; IMPLEMENTED ANEMIA MANAGEMENT; STAGE RENAL-DISEASE; ECONOMIC-BENEFITS; HEMOGLOBIN LEVEL; VARIABILITY; MORTALITY; PROTOCOL; PROGRAM; TARGET AB Background: Erythropoiesis-stimulating agents (ESAs) are associated with serious adverse events, and maintaining hemoglobin levels within a narrow range can be difficult. We examined the quality of ESA prescribing and monitoring in pharmacist-managed ESA clinics versus usual care in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Study Design: Historical cohort. Setting & Participants: Outpatients receiving ESAs for NDD-CKD at 10 Veterans Affairs Medical Centers with both pharmacist-managed ESA clinics (n = 314) and physician-based care (ie, usual care; n = 91) and 6 sites with usual care only (n = 167) on January 1, 2009, were followed up for 6 months. Predictor: Type/site of care (ie, pharmacist-managed ESA clinic, usual care at ESA clinic site, usual-care site). Outcomes: Primary outcomes were proportion of hemoglobin values in the target range of 10-12 g/dL, ESA dose, and frequency of hemoglobin monitoring. Factors associated with hemoglobin values out of target range were identified using multinomial logistic regression. Results: More hemoglobin values were in the target range in pharmacist-managed ESA clinics (71.1% vs 56.9% for usual-care sites; P < 0.001). The average 30-day dose of darbepoetin was 163 mu g in pharmacist-managed ESA clinic patients versus 240 mu g in usual-care site patients and 258 mu g in usual-care patients at ESA clinic sites. For epoetin, corresponding average 30-day doses were 44,890 versus 47,141 and 57,436 IU. Veterans in pharmacist-managed ESA clinics had more hemoglobin measurements on average (5.8 vs 3.6 in usual-care sites and 3.8 in usual care at ESAclinic sites; P = 0.007). In the multinomial model, usual care was associated with hemoglobin levels out of target range, whereas heart failure and diabetes were associated with values in range. Limitations: We could not assess whether different hemoglobin targets were used by usual-care providers. Conclusions: Relative to usual care, pharmacist-managed clinics provided improved quality of ESA dosing and monitoring for patients with NDD-CKD. Am J Kidney Dis. 60(3): 371-379. 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 [Aspinall, Sherrie L.; Cunningham, Francesca E.; Good, Chester B.] Vet Affairs Ctr Medicat Safety, Hines, IL USA. [Aspinall, Sherrie L.; Zhao, Xinhua; Stone, Roslyn A.; Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Aspinall, Sherrie L.; Good, Chester B.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Good, Chester B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Stone, Roslyn A.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Smith, Kenneth J.] Univ Pittsburgh, Div Clin Modeling & Decis Sci, Pittsburgh, PA USA. [Boresi, Joy S.] St Louis Vet Affairs Med Ctr, St Louis, MO USA. [Tonnu-Mihara, Ivy Q.] Vet Affairs Long Beach Healthcare Syst, Long Beach, CA USA. RP Aspinall, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM sherrie.aspinall@va.gov OI Smith, Kenneth J/0000-0001-8088-566X FU VA Center for Medication Safety/VA Pharmacy Benefits Management Services, Hines, IL; VA Pittsburgh Healthcare System, Pittsburgh, PA; VA medical centers FX There was no specific funding support for the work. However, these findings are the result of work supported in kind by the VA Center for Medication Safety/VA Pharmacy Benefits Management Services, Hines, IL; VA Pittsburgh Healthcare System, Pittsburgh, PA; and the other VA medical centers that participated in the study. The views expressed in this report are those of the authors, and no official endorsement by the Department of Veteran Affairs or the United States Government is intended or should be inferred. NR 25 TC 8 Z9 8 U1 1 U2 6 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 SEP PY 2012 VL 60 IS 3 BP 371 EP 379 DI 10.1053/j.ajkd.2012.04.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 994OT UT WOS:000307941200011 PM 22633556 ER PT J AU Jutras-Aswad, D Widlitz, M Scimeca, MM AF Jutras-Aswad, Didier Widlitz, Michelle Scimeca, Michael M. TI Treatment of Buprenorphine Precipitated Withdrawal: A Case Report SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID METHADONE C1 [Jutras-Aswad, Didier; Widlitz, Michelle; Scimeca, Michael M.] James J Peters Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY 10468 USA. [Jutras-Aswad, Didier; Widlitz, Michelle; Scimeca, Michael M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Jutras-Aswad, Didier] Univ Montreal, Dept Psychiat, Quebec City, PQ, Canada. [Jutras-Aswad, Didier] Ctr Hosp Univ Montreal, CRCHUM, Quebec City, PQ, Canada. RP Scimeca, MM (reprint author), James J Peters Vet Affairs Med Ctr, Dept Psychiat, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM scimecas@aol.com NR 5 TC 0 Z9 0 U1 2 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP-OCT PY 2012 VL 21 IS 5 BP 492 EP 493 DI 10.1111/j.1521-0391.2012.00262.x PG 2 WC Substance Abuse SC Substance Abuse GA 986WT UT WOS:000307377400016 PM 22882402 ER PT J AU Shefner, J Cedarbaum, JM Cudkowicz, ME Maragakis, N Lee, J Jones, D Watson, ML Mahoney, K Chen, M Saikali, K Mao, J Russell, AJ Hansen, RL Malik, F Wolff, AA AF Shefner, Jeremy Cedarbaum, Jesse M. Cudkowicz, Merit E. Maragakis, Nicholas Lee, Jacqueline Jones, Drew Watson, Mary Lou Mahoney, Katy Chen, Michael Saikali, Khalil Mao, John Russell, Alan J. Hansen, Richard L. Malik, Fady Wolff, Andrew A. CA NEALS Cytokinetics Study Team TI Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Amyotrophic lateral sclerosis; clinical trials; muscle; riluzole; pharmacokinetics ID PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; PSEUDOBULBAR AFFECT; PULMONARY-FUNCTION; ALS; TRIAL AB This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted. C1 [Shefner, Jeremy] Upstate Med Univ, HSC Syracuse, Dept Neurol, Syracuse, NY 13210 USA. [Cedarbaum, Jesse M.; Lee, Jacqueline; Jones, Drew; Chen, Michael; Saikali, Khalil; Mao, John; Russell, Alan J.; Hansen, Richard L.; Malik, Fady; Wolff, Andrew A.] Cytokinet Inc, San Francisco, CA USA. [Cudkowicz, Merit E.; Mahoney, Katy] Massachusetts Gen Hosp, Neurol Clin Trial Unit, Charlestown, MA USA. [Maragakis, Nicholas] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Shefner, J (reprint author), Upstate Med Univ, HSC Syracuse, Dept Neurol, 750 E Adams St, Syracuse, NY 13210 USA. EM shefnerj@upstate.edu FU Cytokinetics, Inc. South San Francisco, CA; Teva Pharmaceuticals; Neurostem; Isis Pharmaceuticals; Cytokinetics; Glaxo SmithKline; Biogen-Idec; Knopp Pharmaceuticals; Sanofi-Aventis; NIH; ALS Association; INDS; NINDS; US Department of Defense; Cytokinetics, Inc.; UpToDate-AmyotrophicLateralSclerosis FX The authors wish to thank ACI for copyediting assistance. This study was sponsored by Cytokinetics, Inc. South San Francisco, CA.; Jeremy Shefner serves as a consultant for Cytokinetics, Glaxo-SmithKline, Trophos and Biogenidec; he receives or has received research support from Teva Pharmaceuticals, Neurostem, Isis Pharmaceuticals, Cytokinetics, Glaxo SmithKline, Biogen-Idec, Knopp Pharmaceuticals, Sanofi-Aventis, NIH and the ALS Association. He is the neuromuscular section editor for UpToDate, and receives royalties for his services.; Merit E. Cudkowicz has served as a consultant to Cytokinetics and to Trophos; she has received research support from Biogen-Idec, Cytokinetics, Trophos, INDS and the ALS Association. Nicholas Maragakis has been a scientific advisor to Q Therapeutics (2009-2011), serves as a consultant to Johnson & Johnson, Inc. and has received research support from NINDS, the US Department of Defense, and Cytokinetics, Inc. He receives royalties from UpToDate-AmyotrophicLateralSclerosis. NR 21 TC 23 Z9 23 U1 0 U2 6 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 SEP PY 2012 VL 13 IS 5 BP 430 EP 438 DI 10.3109/17482968.2012.684214 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 989UD UT WOS:000307585200004 PM 22591195 ER PT J AU Rutkove, SB Caress, JB Cartwright, MS Burns, TM Warder, J David, WS Goyal, N Maragakis, NJ Clawson, L Benatar, M Usher, S Sharma, KR Gautam, S Narayanaswami, P Raynor, EM Watson, ML Shefner, JM AF Rutkove, Seward B. Caress, James B. Cartwright, Michael S. Burns, Ted M. Warder, Judy David, William S. Goyal, Namita Maragakis, Nicholas J. Clawson, Lora Benatar, Michael Usher, Sharon Sharma, Khema R. Gautam, Shiva Narayanaswami, Pushpa Raynor, Elizabeth M. Watson, Mary Lou Shefner, Jeremy M. TI Electrical impedance myography as a biomarker to assess ALS progression SO AMYOTROPHIC LATERAL SCLEROSIS LA English DT Article DE Clinical trials; amyotrophic lateral sclerosis; electrical impedance myography ID AMYOTROPHIC-LATERAL-SCLEROSIS; CLINICAL-TRIALS; DEGENERATION; ATROPHY AB Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM's potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique's correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials. C1 [Rutkove, Seward B.; Narayanaswami, Pushpa; Raynor, Elizabeth M.] Beth Israel Deaconess Med Ctr, Div Neuromuscular Dis, Boston, MA 02215 USA. [Caress, James B.; Cartwright, Michael S.] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC USA. [Burns, Ted M.; Warder, Judy] Univ Virginia, Dept Neurol, Charlottesville, VA USA. [David, William S.; Goyal, Namita] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Maragakis, Nicholas J.; Clawson, Lora] Johns Hopkins Med Ctr, Dept Neurol, Baltimore, MD 21218 USA. [Benatar, Michael; Sharma, Khema R.] Univ Miami, Dept Neurol, Miami, FL USA. [Usher, Sharon] Univ S Florida, Tampa, FL USA. [Gautam, Shiva] Beth Israel Deaconess Med Ctr, Gen Clin Res Ctr, Boston, MA 02215 USA. [Watson, Mary Lou; Shefner, Jeremy M.] Upstate Med Ctr, Dept Neurol, Syracuse, NY USA. RP Rutkove, SB (reprint author), Beth Israel Deaconess Med Ctr, Div Neuromuscular Dis, 330 Brookline Ave,TCC-810, Boston, MA 02215 USA. EM srutkove@bidmc.harvard.edu OI Caress, James/0000-0002-5814-6083 FU ALS Association; Neuralstem, Inc.; GlaxoSmithKline, Inc.; UpToDate; NIH; NASA; Spinal Muscular Atrophy Foundation; Knopp Neurosciences Inc.; Myasthenia Gravis Foundation of America; Michael S. Ansari Gift Fund for basic science research; Sangamo BioSciences, Inc.; TEDCO-Maryland Stem Cell Research Fund; NIH/NINDS; U.S. Department of Defense; ALS Association Packard Center for ALS Research at Johns Hopkins; Neuromuscular Disease; BluePrints in Neurology; Field of Vision: A Manual and Atlas of Perimetry; CytRx Corporation; Muscular Dystrophy Association; Food and Drug Administration; Centers for Disease Control and Prevention; Woodruff Health Sciences Center (Emory University); Teva Pharmaceutical Industries Ltd.; Gilead Sciences, Inc.; GlaxoSmithKline; Trophos; BrainGate; Isis Pharmaceuticals, Inc.; Sanofi-Aventis FX This study was funded by the ALS Association. We thank Lindsay Garmirian, Connie Lin, Philip Mongiovi, Lucy Wang, Tuhin Srivastava, and Andrew Spieker for their assistance with this project.; S. B. Rutkove serves as a consultant and holds equity in Convergence Medical Devices, Inc. He has also receives consulting fees from Neuralstem, Inc., GlaxoSmithKline, Inc. and royalties from UpToDate. He also has two patent applications submitted in the field of electrical impedance. He receives grant funding from NIH, NASA, and the Spinal Muscular Atrophy Foundation. J. B. Caress receives grant funding from NIH.; M. S. Cartwright receives grant funding from NIH. T. Burns serves as Podcast Section Editor for Neurology (R); has served as a consultant for Bayhill Therapeutics; and has received research support from Knopp Neurosciences Inc. and the Myasthenia Gravis Foundation of America.; N. Maragakis serves on a scientific advisory board for Q Therapeutics, Inc.; received support from the Michael S. Ansari Gift Fund for basic science research; serves as a contributor to UpToDate; has served as a consultant for California Institute for Regenerative Medicine (CIRM); and receives/has received research support from Cytokinetics Inc., Sangamo BioSciences, Inc., TEDCO-Maryland Stem Cell Research Fund, NIH/NINDS, U.S. Department of Defense, and the ALS Association Packard Center for ALS Research at Johns Hopkins. M. Benatar has served as a consultant for Bayhill Therapeutics and Cytokinetics Inc.; receives publishing royalties for Neuromuscular Disease: Evidence and Analysis in Clinical Neurology (Humana Press, 2006), BluePrints in Neurology (Lippincott Williams & Wilkins, 2002), and Field of Vision: A Manual and Atlas of Perimetry (Humana Press, 2010); receives/has received research support from CytRx Corporation, the Muscular Dystrophy Association, the ALS Association, the Food and Drug Administration, and the Centers for Disease Control and Prevention, theWoodruff Health Sciences Center (Emory University), and the NIH; and has participated in medico-legal cases. J. M. Shefner serves on a DSMB for the NIH; serves as Neuromuscular Section Editor for and receives publishing royalties from UpToDate; has served as a consultant for Teva Pharmaceutical Industries Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Trophos, and BrainGate; and receives research support from Isis Pharmaceuticals, Inc., Neuralstem, Inc., GlaxoSmithKline, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Knopp Neurosciences Inc., Cytokinetics Inc., the NIH, and the ALS Association. NR 26 TC 42 Z9 42 U1 0 U2 6 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 SEP PY 2012 VL 13 IS 5 BP 439 EP 445 DI 10.3109/17482968.2012.688837 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 989UD UT WOS:000307585200005 PM 22670883 ER PT J AU Horibe, M Nair, BG Yurina, G Neradilek, MB Rozet, I AF Horibe, Mayumi Nair, Bala G. Yurina, Gary Neradilek, Moni B. Rozet, Irene TI A Novel Computerized Fading Memory Algorithm for Glycemic Control in Postoperative Surgical Patients SO ANESTHESIA AND ANALGESIA LA English DT Article ID CRITICALLY-ILL PATIENTS; INTENSIVE INSULIN THERAPY; GLUCOSE CONTROL; DELIVERY; VARIABILITY; MORTALITY; INFUSION; RELEASE; TRIAL AB BACKGROUND: Hyperglycemia is commonly encountered in critically ill patients and is associated with increased mortality and morbidity. To better control blood glucose levels, we previously developed a new computerized fading memory (FM) algorithm.(1) In this study we evaluated the safety and efficacy of this algorithm in surgical intensive care unit (SICU) patients and compared its performance against the existing insulin-infusion algorithm (named VA algorithm) used in our institution. METHODS: A computer program was developed to run the FM and VA algorithms. Forty eight patients, who were scheduled to have elective surgery, were randomly assigned to receive insulin infusion on the basis of either the FM or VA algorithm. On SICU admission, an insulin infusion was either continued from the operating room or initiated when the glucose level exceeded the target level of 140 mg/dL. Hourly blood glucose measurements were performed and entered into the computer program, which then prescribed the next insulin dose. The randomly assigned algorithm was applied for the first 8 hours of SICU stay, after which the VA algorithm was used. The number of episodes of hypoglycemia (glucose <60 mg/dL) and excessive hyperglycemia (>300 mg/dL) were noted. Additionally, the time required to bring the glucose level within target range (140 +/- 20 mg/dL), the number of glucose measurements within the target range, glycemic variability, and insulin usage were analyzed and compared between the 2 algorithms. RESULTS: Patient demographics and starting glucose levels were similar between the groups. With the existing VA algorithm, 1 episode of severe hypoglycemia was observed. Three patients did not reach the target range within 8 hours. With the FM algorithm no hypoglycemia occurred, and all patients achieved the target range within 8 hours. Glycemic variability measured by the SD of mean glucose levels was 28% (95% confidence interval, 14% to 39%) lower for the FM algorithm (P < 0.001). The FM algorithm used 1.1 U/h less insulin than did the VA algorithm (P = 0.043). CONCLUSION: The novel computerized FM algorithm for glycemic control, which emulates physiologic biphasic insulin secretion, managed glucose better than the existing algorithm without any episodes of hypoglycemia. The FM algorithm had less glycemic variability and used less insulin when compared to the conventional clinical algorithm. (Anesth Analg 2012;115:580-7) C1 [Horibe, Mayumi; Yurina, Gary; Rozet, Irene] VA Puget Sound Hlth Care Syst, Dept Anesthesiol, Seattle, WA 98108 USA. [Horibe, Mayumi; Nair, Bala G.; Rozet, Irene] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Neradilek, Moni B.] Mt Whisper Light Stat, Seattle, WA USA. RP Horibe, M (reprint author), VA Puget Sound Hlth Care Syst, Dept Anesthesiol, Mail Stop S-112-ANES,1660 S Columbian Way, Seattle, WA 98108 USA. EM Mayumi.Horibe@va.gov FU Anesthesiology and Pain Medicine Department of the University of Washington; Washington State Society of Anesthesiologists FX This study was funded by a new investigator seed fund provided by the Anesthesiology and Pain Medicine Department of the University of Washington as well as a Seafair Education and Research Grant by the Washington State Society of Anesthesiologists. NR 32 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2012 VL 115 IS 3 BP 580 EP 587 DI 10.1213/ANE.0b013e318259ee31 PG 8 WC Anesthesiology SC Anesthesiology GA 994PI UT WOS:000307942900015 PM 22669346 ER PT J AU Frick, CG Blobner, M Martyn, JAJ AF Frick, Christiane G. Blobner, Manfred Martyn, J. A. Jeevendra TI Animal Studies with Botulinum Toxins May Produce Misleading Results Response SO ANESTHESIA AND ANALGESIA LA English DT Letter ID MUSCULOSKELETAL-TISSUE ALLOGRAFTS; NEUROMUSCULAR BLOCKADE; DRUG-USERS; INFECTIONS C1 [Frick, Christiane G.; Blobner, Manfred] Tech Univ Munich, Klin Anaesthesiol, Munich, Germany. [Martyn, J. A. Jeevendra] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Martyn, J. A. Jeevendra] Harvard Univ, Shriners Hosp Children, Sch Med, Boston, MA USA. RP Frick, CG (reprint author), Tech Univ Munich, Klin Anaesthesiol, Munich, Germany. EM c.frick@lrz.tu-muenchen.de NR 10 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD SEP PY 2012 VL 115 IS 3 BP 736 EP 737 DI 10.1213/ANE.0b013e318263c911 PG 2 WC Anesthesiology SC Anesthesiology GA 994PI UT WOS:000307942900039 ER PT J AU Gao, S Seker, E Casali, M Wang, FJ Bale, SS Price, GM Yarmush, ML AF Gao, Shan Seker, Erkin Casali, Monica Wang, Fangjing Bale, Shyam Sundhar Price, Gavrielle M. Yarmush, Martin L. TI Ex Vivo Gene Delivery to Hepatocytes: Techniques, Challenges, and Underlying Mechanisms SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE Non-viral transfection; Lentiviruses; Primary rat hepatocytes; Huh7.5.1; Transfection efficiency; Hepatic function ID LIVING CELL ARRAY; C VIRUS-INFECTION; LENTIVIRAL VECTORS; RETROVIRAL VECTORS; STEM-CELLS; IN-VIVO; SANDWICH CONFIGURATION; ADENOASSOCIATED VIRUS; EXTRACELLULAR-MATRIX; REPORTER CELLS AB Gene delivery to primary hepatocytes is an important tool for a number of applications including the study of liver cell biology and pathology, drug screening, and gene therapy. Robust transfection of primary hepatocytes, however, is significantly more difficult to achieve than in cell lines or readily dividing primary cells. In this report, we investigated in vitro gene delivery to both primary rat hepatocytes and Huh7.5.1 cells (a hepatoma cell line) using a number of viral and non-viral methods, including Lipofectamine 2000, FuGene HD, Nucleofection, Magnetofection, and lentiviruses. Our results showed that Lipofectamine 2000 is the most efficient reagent for green fluorescent protein (GFP) gene delivery to primary rat hepatocytes (33.3 +/- A 1.8% transfection efficiency) with minimal adverse effect on several hepatic functions, such as urea and albumin secretion. The lentiviral vectors used in this study exhibited undetectable gene delivery to primary rat hepatocytes but significant delivery to Huh7.5.1 cells (> 80% transfection efficiency). In addition, we demonstrated lentiviral-based and spatially defined delivery of the GFP gene to Huh7.5.1 cells for use in biological microelectromechanical systems. C1 [Gao, Shan; Casali, Monica; Wang, Fangjing; Bale, Shyam Sundhar; Price, Gavrielle M.; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Gao, Shan; Casali, Monica; Wang, Fangjing; Bale, Shyam Sundhar; Price, Gavrielle M.; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Seker, Erkin] Univ Calif Davis, Dept Elect & Comp Engn, Davis, CA 95616 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org OI Seker, Erkin/0000-0003-2401-3562 FU NIH/NBIB [(P41) EB002503]; Shriners Hospitals for Children in Boston; Massachusetts General Hospital Fund for Medical Discovery award [217035] FX We thank Drs. Stelios Andreadis and Feng Zhang for providing us dual fluorescent lentivirses (GAS-RE), pVSV-G and p Delta vectors, respectively. Authors gratefully acknowledge support by NIH/NBIB (P41) EB002503 and Shriners Hospitals for Children in Boston. ES acknowledges support by Massachusetts General Hospital Fund for Medical Discovery award 217035. NR 43 TC 5 Z9 5 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD SEP PY 2012 VL 40 IS 9 BP 1851 EP 1861 DI 10.1007/s10439-012-0555-y PG 11 WC Engineering, Biomedical SC Engineering GA 987FB UT WOS:000307400900001 PM 22484829 ER PT J AU Skwara, AJ Karwoski, TE Czambel, RK Rubin, RT Rhodes, ME AF Skwara, Amanda J. Karwoski, Tracy E. Czambel, R. Kenneth Rubin, Robert T. Rhodes, Michael E. TI Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Environmental enrichment; HPA axis; Mecamylamine; Nicotine; Sexual diergism; Withdrawal ID CENTRAL-NERVOUS-SYSTEM; SEXUAL DIERGISM; AXIS RESPONSES; CHOLINERGIC STIMULATION; PSYCHOLOGICAL STRESS; MESOLIMBIC DOPAMINE; ADRENOCORTICAL AXIS; ABSTINENCE SYNDROME; COCAINE ADDICTION; LABORATORY RATS AB In the present study, we determined the effects of environmental enrichment (EE; Kong Toys (R) and Nestlets (R)) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women. (C) 2012 Elsevier B.V. All rights reserved. C1 [Skwara, Amanda J.; Rhodes, Michael E.] St Vincent Coll, Dept Biol, Latrobe, PA 15650 USA. [Karwoski, Tracy E.; Czambel, R. Kenneth] Allegheny Gen Hosp, Neurosci Res Ctr, Pittsburgh, PA 15212 USA. [Rubin, Robert T.] VA Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. [Rubin, Robert T.] Univ Calif Los Angeles, Dept Psychiat, Pittsburgh, PA USA. RP Rhodes, ME (reprint author), St Vincent Coll, Dept Biol, 300 Fraser Purchase Rd, Latrobe, PA 15650 USA. EM michael.rhodes@email.stvincent.edu FU Department of Health Tobacco Settlement Funds; NIH [MH28380] FX The technical assistance of Natalie E. Gentile and Julie D. Andrekanic is gratefully acknowledged. Supported by 2004 Department of Health Tobacco Settlement Funds to MER and by NIH grant MH28380 to RTR. NR 82 TC 19 Z9 19 U1 3 U2 8 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 SEP 1 PY 2012 VL 234 IS 1 BP 1 EP 10 DI 10.1016/j.bbr.2012.06.003 PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 991HV UT WOS:000307693000001 PM 22705101 ER PT J AU Dhonnchadha, BAN Lovascio, BF Shrestha, N Lin, A Leite-Morris, KA Man, HY Kaplan, GB Kantak, KM AF Dhonnchadha, B. A. Nic Lovascio, B. F. Shrestha, N. Lin, A. Leite-Morris, K. A. Man, H. Y. Kaplan, G. B. Kantak, K. M. TI Changes in expression of c-Fos protein following cocaine-cue extinction learning SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Basolateral amygdala; c-Fos protein; Cocaine; Extinction learning; GluR2 protein; Self-administration ID DRUG-SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; FEAR EXTINCTION; AMPA RECEPTORS; INDUCED REINSTATEMENT; NUCLEUS-ACCUMBENS; CONDITIONED CUES; RATS; CONSOLIDATION; INACTIVATION AB Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2 h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. (C) 2012 Elsevier B.V. All rights reserved. C1 [Dhonnchadha, B. A. Nic; Lovascio, B. F.; Shrestha, N.; Kantak, K. M.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Lin, A.; Man, H. Y.] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Leite-Morris, K. A.; Kaplan, G. B.] VA Boston Healthcare, Res & Mental Hlth Serv, Boston, MA USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Leite-Morris, K. A.; Kaplan, G. B.] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02215 USA. RP Kantak, KM (reprint author), Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. EM kkantak@bu.edu OI Leite-Morris, Kimberly/0000-0003-3407-7375 FU Boston University Center for Neuroscience; [DA024315]; [DA024315-S1] FX This study was supported by DA024315, DA024315-S1 and seed funding from the Boston University Center for Neuroscience. We thank Carolyn Kirkman, Angela J. Young and Marsha D. Guy for expert technical assistance. NR 54 TC 8 Z9 8 U1 2 U2 8 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 SEP 1 PY 2012 VL 234 IS 1 BP 100 EP 106 DI 10.1016/j.bbr.2012.06.010 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 991HV UT WOS:000307693000014 ER PT J AU Faje, AT Fazeli, PK Katzman, DK Miller, KK Breggia, A Rosen, CJ Mendes, N Klibanski, A Misra, M AF Faje, Alexander T. Fazeli, Pouneh K. Katzman, Debra K. Miller, Karen K. Breggia, Anne Rosen, Clifford J. Mendes, Nara Klibanski, Anne Misra, Madhusmita TI Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls SO BONE LA English DT Article DE Anorexia nervosa; Sclerostin; Osteoporosis ID SERUM SCLEROSTIN; POSTMENOPAUSAL WOMEN; PRIMARY HYPERPARATHYROIDISM; CIRCULATING SCLEROSTIN; PARATHYROID-HORMONE; SOST; ESTROGEN; DENSITY; OSTEOPOROSIS; METABOLISM AB Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal-weight controls) 13-18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r=0.67 and 0.53, p=0.0002 and 0.005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group. (C) 2012 Elsevier Inc. All rights reserved. C1 [Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Klibanski, Anne; Misra, Madhusmita] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Katzman, Debra K.] Hosp Sick Children, Div Adolescent Med, Toronto, ON M5G 1X8, Canada. [Breggia, Anne; Rosen, Clifford J.] Maine Med Ctr, Res Inst, Portland, ME 04074 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, 55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/E-4682-2013; Mendes Estella, Nara/A-1469-2015 FU NIH [UL1 RR025758-01, R01 DK062249] FX This study was supported by NIH grants UL1 RR025758-01 and R01 DK062249. NR 36 TC 16 Z9 16 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2012 VL 51 IS 3 BP 474 EP 479 DI 10.1016/j.bone.2012.06.006 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990FW UT WOS:000307617400020 PM 22728230 ER PT J AU Battaglino, RA Sudhakar, S Lazzari, AA Garshick, E Zafonte, R Morse, LR AF Battaglino, Ricardo A. Sudhakar, Supreetha Lazzari, Antonio A. Garshick, Eric Zafonte, Ross Morse, Leslie R. TI Circulating sclerostin is elevated in short-term and reduced in long-term SCI SO BONE LA English DT Article DE Osteoporosis; Sclerostin; Spinal cord injury; Rehabilitation medicine ID SPINAL-CORD-INJURY; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; SERUM SCLEROSTIN; OSTEOPOROSIS; CORRELATE AB Spinal cord injury (SCI) causes profound bone loss due to muscle paralysis resulting in the inability to walk. Sclerostin, a Wnt signaling pathway antagonist produced by osteocytes, is a potent inhibitor of bone formation. Short-term studies in rodent models have demonstrated increased sclerostin in response to mechanical unloading that is reversed with reloading. Although sclerostin inhibition has been proposed as a potential therapy for bone loss, it is not known if sclerostin levels vary with duration of SCI in humans. We analyzed circulating sclerostin in 155 men with varying degrees of SCI who were 1 year or more post-injury. We report that sclerostin levels are greatest in subjects with short-term SCI (<= 5 years post-injury) and decrease significantly over the first 5 years post-injury. There was no association between sclerostin and injury duration in subjects with long-term SCI (>5 years post-injury). In subjects with long-term SCI, sclerostin levels were positively associated with lower extremity bone density and bone mineral content. These data suggest that sclerostin levels are initially increased after SCI in response to mechanical unloading. This response is time-limited and as bone loss progresses, circulating sclerostin is lowest in subjects with severe osteoporosis. These findings support a dual role for sclerostin after SCI: a therapeutic target in acute SCI, and a biomarker of osteoporosis severity in chronic SCI. (C) 2012 Elsevier Inc. All rights reserved. C1 [Zafonte, Ross; Morse, Leslie R.] Harvard Univ, Sch Med, Dept PMR, Boston, MA 02114 USA. [Battaglino, Ricardo A.; Morse, Leslie R.] Forsyth Inst, Cambridge, MA USA. [Battaglino, Ricardo A.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02114 USA. [Sudhakar, Supreetha; Zafonte, Ross; Morse, Leslie R.] Spaulding Rehabil Hosp, Spaulding Harvard SCI Model Syst, Boston, MA USA. [Lazzari, Antonio A.] VA Boston Healthcare Syst, Primary Care Sect, Boston, MA USA. [Lazzari, Antonio A.] VA Boston Healthcare Syst, Rheumatol Sect, Boston, MA USA. [Lazzari, Antonio A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Garshick, Eric] VA Boston Healthcare Syst, Med Serv, Pulm & Crit Care Med Sect, Boston, MA USA. [Garshick, Eric] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02114 USA. RP Morse, LR (reprint author), Harvard Univ, Sch Med, Dept PMR, 125 Nashua St, Boston, MA 02114 USA. EM lmorse4@partners.org RI battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015 OI Morse, Leslie/0000-0002-7426-6341 FU National Institute of Child Health and Human Development [R21HD057030, R21HD057030-02S1]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-02]; Office of Research and Development, Rehabilitation Research and Development [B6618R]; Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs FX 0This study received support from: the National Institute of Child Health and Human Development [R21HD057030 and R21HD057030-02S1], the National Institute of Arthritis and Musculoskeletal and Skin Diseases [1R01AR059270-02], the Office of Research and Development, Rehabilitation Research and Development [Merit Review Grant B6618R], and the Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs. NR 18 TC 16 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD SEP PY 2012 VL 51 IS 3 BP 600 EP 605 DI 10.1016/j.bone.2012.04.019 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 990FW UT WOS:000307617400036 PM 22575440 ER PT J AU Azagury, DE Ryou, M Shaikh, SN Estepar, RS Lengyel, BI Jagadeesan, J Vosburgh, KG Thompson, CC AF Azagury, D. E. Ryou, M. Shaikh, S. N. Estepar, R. San Jose Lengyel, B. I. Jagadeesan, J. Vosburgh, K. G. Thompson, C. C. TI Real-time computed tomography-based augmented reality for natural orifice transluminal endoscopic surgery navigation SO BRITISH JOURNAL OF SURGERY LA English DT Article ID LAPAROSCOPIC PERITONEOSCOPY; TRANSGASTRIC NOTES; METASTASES; TRIAL AB Background: Natural orifice transluminal endoscopic surgery (NOTES) is technically challenging owing to endoscopic short-sighted visualization, excessive scope flexibility and lack of adequate instrumentation. Augmented reality may overcome these difficulties. This study tested whether an image registration system for NOTES procedures (IR-NOTES) can facilitate navigation. Methods: In three human cadavers 15 intra-abdominal organs were targeted endoscopically with and without IR-NOTES via both transgastric and transcolonic routes, by three endoscopists with different levels of expertise. Ease of navigation was evaluated objectively by kinematic analysis, and navigation complexity was determined by creating an organ access complexity score based on the same data. Results: Without IR-NOTES, 21 (11.7 per cent) of 180 targets were not reached (expert endoscopist 3, advanced 7, intermediate 11), compared with one (1 per cent) of 90 with IR-NOTES (intermediate endoscopist) (P = 0.002). Endoscope movements were significantly less complex in eight of the 15 listed organs when using IR-NOTES. The most complex areas to access were the pelvis and left upper quadrant, independently of the access route. The most difficult organs to access were the spleen (5 failed attempts; 3 of 7 kinematic variables significantly improved) and rectum (4 failed attempts; 5 of 7 kinematic variables significantly improved). The time needed to access the rectum through a transgastric approach was 206.3 s without and 54.9 s with IR-NOTES (P = 0.027). Conclusion: The IR-NOTES system enhanced both navigation efficacy and ease of intra-abdominal NOTES exploration for operators of all levels. The system rendered some organs accessible to non-expert operators, thereby reducing one impediment to NOTES procedures. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. C1 [Ryou, M.; Shaikh, S. N.; Thompson, C. C.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Estepar, R. San Jose; Lengyel, B. I.; Vosburgh, K. G.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Azagury, D. E.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. [Jagadeesan, J.] Massachusetts Gen Hosp, Ctr Integrat Med, Boston, MA 02114 USA. [Jagadeesan, J.] Massachusetts Gen Hosp, Innovat Technol Image Guidance Lab, Boston, MA 02114 USA. RP Thompson, CC (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St,ASB 2, Boston, MA 02115 USA. EM cthompson@hms.harvard.edu OI Azagury, Dan/0000-0002-3992-8792 FU Center for Integration of Medicine and Innovative Technology under US Army Medical Research Acquisition Activity Cooperative Agreement [W81XWH-09-2-0001]; National Heart Lung and Blood Institute [K25HL104085]; National Institutes of Health [R25 CA089017] FX The authors thank Vaibhav Patil, Inbar Spofford, Keith Obstein and Michele B. Ryan for their invaluable time and contribution throughout this project. This work was supported by the Center for Integration of Medicine and Innovative Technology under US Army Medical Research Acquisition Activity Cooperative Agreement W81XWH-09-2-0001. R.S.J.E. was supported by award no. K25HL104085 from the National Heart Lung and Blood Institute, and B.I.L. by National Institutes of Health grant R25 CA089017. The information contained herein is solely the responsibility of the authors and does not necessarily reflect the position or policy of the Government, the National Heart Lung and Blood Institute or the National Institutes of Health, and no official endorsement should be inferred. NR 19 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1323 J9 BRIT J SURG JI Br. J. Surg. PD SEP PY 2012 VL 99 IS 9 BP 1246 EP 1253 DI 10.1002/bjs.8838 PG 8 WC Surgery SC Surgery GA 982UO UT WOS:000307071100014 PM 22864885 ER PT J AU Maan, A Padmanabhan, R Shaikh, AY Mansour, M Ruskin, JN Heist, EK AF Maan, Abhishek Padmanabhan, Ram Shaikh, Amir Y. Mansour, Moussa Ruskin, Jeremy N. Heist, E. Kevin TI Newer Anticoagulants in Cardiovascular Disease A Systematic Review of the Literature SO CARDIOLOGY IN REVIEW LA English DT Review DE oral anticoagulants; vitamin K antagonist; factor Xa inhibitor; direct thrombin inhibitor ID FACTOR-XA INHIBITOR; DIRECT THROMBIN INHIBITOR; ORAL DIRECT THROMBIN; NONVALVULAR ATRIAL-FIBRILLATION; ACUTE CORONARY SYNDROME; TOTAL KNEE REPLACEMENT; TOTAL HIP-REPLACEMENT; HEALTHY MALE-SUBJECTS; RANDOMIZED CONTROLLED-TRIAL; VITAMIN-K ANTAGONISTS AB Vitamin K antagonists (VKAs) such as warfarin have traditionally been the major therapeutic option for anticoagulation in clinical practice. VKAs are effective and extensively recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease. Despite its effectiveness, warfarin is limited by factors such as a narrow therapeutic index, drug-drug interactions, food interactions, slow onset and offset of action, hemorrhage, and routine anticoagulation monitoring to maintain therapeutic international normalized ratio. During the last 2 decades, the approval of anticoagulants, such as low-molecular-weight heparins, indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, lepirudin, and desirudin), have expanded the number of available antithrombotic compounds with additional targets within the anticoagulation pathway. Although these medications offer several potential therapeutic advantages, they all require parenteral or subcutaneous administration and are substantially more expensive than VKAs. Thus, VKAs, despite several limitations, have remained the major option for most patients requiring chronic anticoagulation. These limitations have prompted interest in the development of newer oral anticoagulants. Novel anticoagulants targeting inhibition of factor Xa and thrombin (factor Ha) have now been incorporated into clinical practice based on the results of large randomized clinical trials, with the recent U.S. Food and Drug Administration approval of dabigatran for stroke prevention in atrial fibrillation and rivaroxaban for deep vein thrombosis and stroke prevention in atrial fibrillation, with multiple other agents in various stages of development for these and other indications. This review discusses the pharmacological properties, clinical results, and therapeutic applications of novel and new anticoagulants, thereby providing an outline for the future of anticoagulation in cardiovascular disease. C1 [Mansour, Moussa; Ruskin, Jeremy N.; Heist, E. Kevin] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Maan, Abhishek; Padmanabhan, Ram; Shaikh, Amir Y.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Mansour, Moussa; Ruskin, Jeremy N.; Heist, E. Kevin] Harvard Univ, Sch Med, Boston, MA USA. RP Heist, EK (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM kheist@partners.org FU Endosense; MC10; St. Jude Medical; Voyage Medical; Boston Scientific FX M.M.: Biosense-Webster (consultant), Boston Scientific (consultant), Cardiofocus (research grant), Endosense (research grant), MC10 (research grant), Medtronic (consultant), St. Jude Medical (consultant, research grant), Voyage Medical (research grant). J.N.R.: Astellas/Cardiome-Consultant (significant); Biosense Webster-Consultant (modest) and Fellowship Support (significant); Boston Scientific-Fellowship Support (significant); CardioFocus-Clinical Oversight Committee (no compensation); Cardiolnsight-Scientific Advisory Board (modest); CryoCath-Scientific Steering Committee (no compensation); Medtronic-Consultant (modest) and Fellowship Support (significant); Med-IQ-Honoraria (modest); Pfizer-Consultant and Scientific Steering Committee (modest); Portola-Consultant and equity (modest); Sanofi-Consultant (modest), St. Jude Medical -Fellowship Support (significant); Third Rock Ventures- consultant (significant). E.K.H.: (all modest in amount): Biotronik (research grant, honoraria), Boston Scientific (research grant, consultant, honoraria), Medtronic (honoraria), Sanofi (consultant), Sorin (consultant, honoraria), St. Jude Medical (research grant, consultant, honoraria). The remaining authors have not disclosed any potential conflicts of interest. NR 128 TC 14 Z9 14 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1061-5377 J9 CARDIOL REV JI Cardiol. Rev. PD SEP-OCT PY 2012 VL 20 IS 5 BP 209 EP 221 DI 10.1097/CRD.0b013e3182503e2d PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 991BV UT WOS:000307676700001 PM 22370770 ER PT J AU Zappaterra, MW Lehtinen, MK AF Zappaterra, Mauro W. Lehtinen, Maria K. TI The cerebrospinal fluid: regulator of neurogenesis, behavior, and beyond SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Cerebrospinal fluid; Choroid plexus; Neurogenesis; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; CENTRAL-NERVOUS-SYSTEM; FIBROBLAST-GROWTH-FACTOR; FOCAL CEREBRAL-ISCHEMIA; REDUCES INFARCT VOLUME; TUMOR-NECROSIS-FACTOR; HINDBRAIN CHOROID-PLEXUS; BINDING-PROTEINS IGFBPS; CORTICAL IMPACT INJURY; FACTOR-II GENE AB The cerebrospinal fluid (CSF) has attracted renewed interest as an active signaling milieu that regulates brain development, homeostasis, and disease. Advances in proteomics research have enabled an improved characterization of the CSF from development through adulthood, and key neurogenic signaling pathways that are transmitted via the CSF are now being elucidated. Due to its immediate contact with neural stem cells in the developing and adult brain, the CSF's ability to swiftly distribute signals across vast distances in the central nervous system is opening avenues to novel and exciting therapeutic approaches. In this review, we will discuss the development of the choroid plexus-CSF system, and review the current literature on how the CSF actively regulates mammalian brain development, behavior, and responses to traumatic brain injury. C1 [Lehtinen, Maria K.] Harvard Univ, Childrens Hosp Boston, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Zappaterra, Mauro W.] VA Greater Los Angeles Healthcare Syst, Dept Phys Med & Rehabil, Los Angeles, CA 90073 USA. RP Lehtinen, MK (reprint author), Harvard Univ, Childrens Hosp Boston, Dept Pathol, Sch Med, 300 Longwood Ave, Boston, MA 02115 USA. EM mauro.zappaterra@ucla.edu; maria.lehtinen@childrens.harvard.edu FU Eleanor and Miles Shore Fellowship Program for Scholars in Medicine/Children's Hospital Boston Career Development Award; NIH [R00 NS072192] FX We thank V. Ho and A. Malesz for critical reading of this manuscript. We are grateful for support from the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine/Children's Hospital Boston Career Development Award, and the NIH (Award number R00 NS072192). M.K.L. is an Alfred P. Sloan Research Fellow. NR 183 TC 44 Z9 46 U1 1 U2 15 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD SEP PY 2012 VL 69 IS 17 BP 2863 EP 2878 DI 10.1007/s00018-012-0957-x PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 988UQ UT WOS:000307516600005 PM 22415326 ER PT J AU Fatemi, SH Aldinger, KA Ashwood, P Bauman, ML Blaha, CD Blatt, GJ Chauhan, A Chauhan, V Dager, SR Dickson, PE Estes, AM Goldowitz, D Heck, DH Kemper, TL King, BH Martin, LA Millen, KJ Mittleman, G Mosconi, MW Persico, AM Sweeney, JA Webb, SJ Welsh, JP AF Fatemi, S. Hossein Aldinger, Kimberly A. Ashwood, Paul Bauman, Margaret L. Blaha, Charles D. Blatt, Gene J. Chauhan, Abha Chauhan, Ved Dager, Stephen R. Dickson, Price E. Estes, Annette M. Goldowitz, Dan Heck, Detlef H. Kemper, Thomas L. King, Bryan H. Martin, Loren A. Millen, Kathleen J. Mittleman, Guy Mosconi, Matthew W. Persico, Antonio M. Sweeney, John A. Webb, Sara J. Welsh, John P. TI Consensus Paper: Pathological Role of the Cerebellum in Autism SO CEREBELLUM LA English DT Review DE Cerebellum; Autism ID FRAGILE-X-SYNDROME; FUNCTIONAL MAGNETIC-RESONANCE; PERVASIVE DEVELOPMENTAL DISORDERS; LYMPHOCYTE CYTOKINE PROFILES; PURKINJE-CELL DEGENERATION; TUBEROUS SCLEROSIS COMPLEX; RECEPTOR TYROSINE KINASE; LHERMITTE-DUCLOS-DISEASE; GAMMA-AMINOBUTYRIC-ACID; MESSENGER-RNA LEVELS AB There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation. C1 [Fatemi, S. Hossein] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Aldinger, Kimberly A.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Ashwood, Paul] Univ Calif Davis, Dept Med Microbiol & Immunol, Med Invest Neurodev Disorders MIND Inst, Davis, CA 95616 USA. [Bauman, Margaret L.] Harvard Univ, Sch Med, Boston, MA USA. [Bauman, Margaret L.] Massachusetts Gen Hosp, Dept Pediat & Neurol, Boston, MA 02114 USA. [Blaha, Charles D.; Dickson, Price E.; Mittleman, Guy] Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. [Blatt, Gene J.; Kemper, Thomas L.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Chauhan, Abha; Chauhan, Ved] NYS Inst Basic Res Dev Disabil, Staten Isl, NY USA. [Dager, Stephen R.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Dager, Stephen R.] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Dager, Stephen R.; Estes, Annette M.] Univ Washington, Autism Ctr, Seattle, WA 98195 USA. [Goldowitz, Dan] Univ British Columbia, Dept Med Genet, Ctr Mol Med & Therapeut, Vancouver, BC, Canada. [Heck, Detlef H.] Univ Tennessee, Dept Anat & Neurobiol, Hlth Sci Ctr, Memphis, TN USA. [King, Bryan H.; Webb, Sara J.] Univ Washington, Dept Psychiat & Behav Sci, Seattle Childrens Autism Ctr, Seattle, WA 98195 USA. [Martin, Loren A.] Azusa Pacific Univ, Dept Psychol, Azusa, CA USA. [Mosconi, Matthew W.; Sweeney, John A.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Mosconi, Matthew W.; Sweeney, John A.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Persico, Antonio M.] Univ Campus Biomed, Child Neuropsychiat Unit, Lab Mol Psychiat & Neurogenet, Rome, Italy. [Persico, Antonio M.] IRCCS Fdn Santa Lucia, Dept Expt Neurosci, Rome, Italy. [Welsh, John P.] Univ Washington, Dept Pediat, Ctr Integrat Brain Res, Seattle Childrens Res Inst, Seattle, WA 98195 USA. RP Fatemi, SH (reprint author), Univ Minnesota, Sch Med, 420 Delaware St SE,MMC 392, Minneapolis, MN 55455 USA. EM fatem002@umn.edu OI Persico, Antonio/0000-0001-8910-4479; Blaha, Charles/0000-0001-5155-1505 FU Alfred and Ingrid Lenz Harrison Autism Initiative; Autism Speaks Foundation; Jane Botsford Johnson Foundation; National Alliance for Research on Schizophrenia and Depression; National Institute of Neurological Disorders and Stroke [R21HD065269]; Peter Emch Foundation; Nancy Lurie Marks Family Foundation; NINDS [NS38975-05]; NAAR/Autism Speaks; Autism Speaks [4853]; NIH/NINDS [R01 NS063009]; Hussman Foundation; Department of Defense [AS073224P2]; Autism Research Institute; Autism Collaboration (autism.org); NYS Office for People with Developmental Disabilities; Autism Centers of Excellence [NICHD P50-HD055782]; NICHD [HD35465 NICHD, RO1-HD055741]; ACE Network (NICHD) [HD05571]; American Recovery and Reinvestment Act [NICHD R01-HD065283]; National Institute for Neurological Disorders and Stroke [NINDS R01-NS31224-18, R01 NS31224-18]; Simons Foundation; NIH [RO1NS060887, R01NS063009]; Eunice Kennedy Shriver National Institute of Child Health & Human Development [P50 HD055782]; Autism Center of Excellence from the Eunice Kennedy Shriver NICHD [P50HD055751]; NIMH [1K23MH092696]; Janssen Foundation; Italian Ministry of University, Research and Technology [2006058195, 2008BACT54]; Italian Ministry of Health [RFPS-2007-5-640174]; Autism Research Institute (San Diego, CA); Autism Speaks (Princeton, NJ); Fondazione Gaetano e Mafalda Luce (Milan, Italy); Cure Autism now; Eunice Kennedy Shriver National Institute of Child Health and Human Development [5R01HD052074-05, 3R01HD05207403-S1] FX (1) Dr. S. Hossein Fatemi appreciates the excellent technical assistance by Rachel Elizabeth Kneeland in editing of this consensus paper, and the critical review of the manuscript by Mr. Timothy D. Folsom. Research support for Dr. Fatemi's work is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD052074-05 and 3R01HD05207403-S1 supplemental grant), as well as the Alfred and Ingrid Lenz Harrison Autism Initiative; (2) Research support for work by Drs. Kimberly A. Aldinger and Kathleen J. Millen is from the Autism Speaks Foundation; (3) Research support for work by Dr. Paul Ashwood is from Autism Speaks Foundation, the Jane Botsford Johnson Foundation, National Alliance for Research on Schizophrenia and Depression, and National Institute of Neurological Disorders and Stroke R21HD065269, and the Peter Emch Foundation is gratefully acknowledged; (4) Research support for work by Drs. Margaret L. Bauman and Thomas L. Kemper is from the Nancy Lurie Marks Family Foundation, by NINDS (NS38975-05) and by NAAR/Autism Speaks. We would also like to acknowledge and thank the many families whose generous donation of postmortem brain tissue has made this research possible; (5) Research support for work by Drs. Charles D. Blaha, Price E. Dickson, Dan Goldowitz, Loren A. Martin, and Guy Mittleman is from Cure Autism Now, Autism Speaks, and R01 NS063009 from NIH/NINDS; (6) Research support for work by Dr. Gene Blatt is from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD039459-06) and The Hussman Foundation; (7) Research support for work by Drs. Abha Chauhan and Ved Chauhan is from the Department of Defense Autism Spectrum Disorders Research Program AS073224P2, the Autism Research Institute, the Autism Collaboration (autism.org), and the NYS Office for People with Developmental Disabilities; (8) Drs. Stephen R. Dager, Annette M. Estes, and John P. Welsh would like to thank Elizabeth Kelly for assistance in preparing their manuscript. Research support for their work is from Autism Centers of Excellence (NICHD P50-HD055782), Collaborative Programs of Excellence in Autism (NICHD #HD35465 NICHD, RO1-HD055741), ACE Network (NICHD RO1 supplement HD05571), American Recovery and Reinvestment Act (NICHD R01-HD065283), and National Institute for Neurological Disorders and Stroke (NINDS R01-NS31224-18). Support from Autism Speaks and the Simons Foundation is also gratefully acknowledged; (9) Research support for Dr. Detlef H. Heck is from NIH grants RO1NS060887 and R01NS063009. The content of this publication is solely the responsibility of the author and does not necessarily represent the official views of the NIH; (10) Research support for Drs. Bryan H. King, Sara J. Webb, and John P. Welsh is from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (P50 HD055782; King/Webb) and the National Institute for Neurological Disorders and Stroke (R01 NS31224-18; Welsh). We want to thank the families of and individuals with autism who have participated in research; (11) Research support for work by Drs. Matthew W. Mosconi and John A. Sweeney is from the Autism Center of Excellence Award Number P50HD055751 from the Eunice Kennedy Shriver NICHD, NIMH Grant 1K23MH092696, and Autism Speaks Grant 4853. Dr. John Sweeney consults with Pfizer and Takeda and has received a grant from the Janssen Foundation.; The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding institutes; (12) Research support for work by Dr. Antonio M. Persico is from the Italian Ministry of University, Research and Technology (PRIN 2006058195 and 2008BACT54), the Italian Ministry of Health (RFPS-2007-5-640174), Autism Speaks (Princeton, NJ), the Autism Research Institute (San Diego, CA), and the Fondazione Gaetano e Mafalda Luce (Milan, Italy). NR 310 TC 172 Z9 173 U1 20 U2 83 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1473-4222 EI 1473-4230 J9 CEREBELLUM JI Cerebellum PD SEP PY 2012 VL 11 IS 3 BP 777 EP 807 DI 10.1007/s12311-012-0355-9 PG 31 WC Neurosciences SC Neurosciences & Neurology GA 985SX UT WOS:000307291500017 PM 22370873 ER PT J AU Zanni, MV Burdo, TH Makimura, H Williams, KC Grinspoon, SK AF Zanni, Markella V. Burdo, Tricia H. Makimura, Hideo Williams, Kenneth C. Grinspoon, Steven K. TI Relationship between monocyte/macrophage activation marker soluble CD163 and insulin resistance in obese and normal-weight subjects SO CLINICAL ENDOCRINOLOGY LA English DT Article ID SCAVENGER RECEPTOR CD163; NECROSIS-FACTOR-ALPHA; UP-REGULATION; RISK; ATHEROSCLEROSIS; IDENTIFICATION; INFLAMMATION; THERAPY; PLASMA; GAIN AB Context The relationship of monocyte/macrophage activation to insulin resistance in obesity is unknown. Objective To investigate a marker of macrophage activation, soluble CD163 (sCD163), in relationship to insulin resistance and metabolic parameters in obese and normal-weight subjects. Design and Participants Ninety-five healthy subjects (65 obese and 30 normal-weight) were studied. Plasma concentrations of sCD163 were assessed, as well as markers of glucose homeostasis, anthropometrics, cytokines and adipokines. The relationships between sCD163 and these parameters were investigated, and multiple regression modelling assessing the contribution of sCD163 to insulin resistance (HOMA-IR) was performed. Results Soluble CD163 was significantly increased in obese subjects compared with normal-weight controls [974 (657, 1272) ng/ml vs 599 (423, 892) ng/ml, median (IQR); P < 0.0001]. sCD163 was strongly associated with HOMA-IR (Spearmans ? = 0.37, P = 0.0003) and other metabolic parameters. In multiple regression modelling for log HOMA-IR, sCD163 remained significantly associated (P = 0.005) controlling for known mediators of insulin resistance including age, gender, visceral adiposity and inflammatory markers (model R2 = 0.54, P < 0.0001). Additional nested multiple regression models for log HOMA-IR showed that sCD163 added more than other adipokines and inflammatory markers to the prediction of HOMA-IR. Conclusions Monocyte/macrophage activation, as reflected by sCD163 levels, is strongly associated with HOMA-IR in normal-weight and obese subjects after controlling for known mediators of insulin resistance. Moreover, sCD163 adds to standard risk markers for predicting insulin resistance. These data suggest that monocyte/macrophage activation may be an important determinant of insulin resistance in obesity. C1 [Zanni, Markella V.; Makimura, Hideo; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Zanni, Markella V.; Makimura, Hideo; Grinspoon, Steven K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Burdo, Tricia H.; Williams, Kenneth C.] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, LON5-207,55 Fruit St, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIH [F32 DK085969, K23 DK087857, NS37654, NS40237, K24 DK064545, R01 HL085268] FX NIH funding was provided through F32 DK085969 to M.Z., K23 DK087857 to H. M, and NS37654 and NS40237 to K. W, and through K24 DK064545 and R01 HL085268 to S. G. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.Z., T.B., H.M., K.W. and S.G. have nothing to declare. NR 29 TC 34 Z9 35 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2012 VL 77 IS 3 BP 385 EP 390 DI 10.1111/j.1365-2265.2011.04284.x PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 989TL UT WOS:000307583300008 PM 22098563 ER PT J AU Lin, E Wexler, TL Nachtigall, L Tritos, N Swearingen, B Hemphill, L Loeffler, J Biller, BMK Klibanski, A Miller, KK AF Lin, E. Wexler, T. L. Nachtigall, L. Tritos, N. Swearingen, B. Hemphill, L. Loeffler, J. Biller, B. M. K. Klibanski, A. Miller, K. K. TI Effects of growth hormone deficiency on body composition and biomarkers of cardiovascular risk after definitive therapy for acromegaly SO CLINICAL ENDOCRINOLOGY LA English DT Article ID GH DEFICIENCY; IGF-I; ADULTS; REPLACEMENT; MORTALITY; MARKERS; TRIAL; HYPOPITUITARISM; METAANALYSIS; METABOLISM AB Background Both growth hormone (GH) excess and GH deficiency are associated with abnormalities in body composition and biomarkers of cardiovascular risk in patients with pituitary disorders. However, the effects of developing GH deficiency after definitive treatment of acromegaly are largely unknown. Objective To determine whether development of GH deficiency after definitive therapy for acromegaly is associated with increased visceral adiposity and biomarkers of cardiovascular risk compared with GH sufficiency after definitive therapy for acromegaly. Design Cross-sectional. Patients We studied three groups of subjects, all with a history of acromegaly (n=76): subjects with subsequent GH deficiency (GHD; n=31), subjects with subsequent GH sufficiency (GHS; n=25) and subjects with active acromegaly (AA; n=20). No study subjects were receiving somatostatin analogues, dopamine agonists or hGH. Measurements Body composition (by DXA), abdominal adipose tissue depots (by cross-sectional CT), total body water (by bioimpedance analysis) and carotid intima-media thickness (IMT) were measured. Fasting morning serum was collected for high-sensitivity C-reactive protein (hsCRP), lipids and lipoprotein levels. An oral glucose tolerance test was performed, and homoeostasis model of assessment-insulin resistance (HOMA-IR) was calculated. Results Abdominal visceral adipose tissue, total adipose tissue and total body fat were higher in subjects with GHD than GHS or AA (P<0.05). Subcutaneous abdominal fat was higher, and fibrinogen and IMT were lower in GHD (but not GHS) than AA (P<0.05). Patients with GHD had the highest hsCRP, followed by GHS, and hsCRP was lowest in AA (P<0.05). Fasting glucose, 120-min glucose, fasting insulin, HOMA-IR and per cent total body water were lower in GHD and GHS than AA (P<0.05). Triglycerides were higher in GHS than AA (P<0.05). Lean body mass, mean arterial pressure, total cholesterol, HDL and LDL were comparable among groups. Conclusions Development of GHD after definitive treatment of acromegaly may adversely affect body composition and inflammatory biomarkers of cardiovascular risk but does not appear to adversely affect glucose homoeostasis, lipids and lipoproteins, or other cardiovascular risk markers. C1 [Miller, K. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Neuroendocrine Unit, Boston, MA 02114 USA. [Swearingen, B.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Hemphill, L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Loeffler, J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Loeffler, J.] Harvard Univ, Sch Med, Boston, MA USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Dept Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM KKMiller@partners.org FU Pfizer; Guthart Family Foundation; NIH [MO1-RR-01066, ULI-RR-025758, T32-DK-007028-36] FX This work was supported in part by an investigator-initiated research grant from Pfizer, a grant from the Guthart Family Foundation, and NIH grants MO1-RR-01066, ULI-RR-025758, and T32-DK-007028-36. NR 38 TC 15 Z9 15 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 EI 1365-2265 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2012 VL 77 IS 3 BP 430 EP 438 DI 10.1111/j.1365-2265.2012.04361.x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 989TL UT WOS:000307583300014 PM 22315983 ER PT J AU Tsao, CK Small, AC Moshier, EL Gartrell, BA Wisnivesky, JP Sonpavde, G Godbold, JH Palese, MA Hall, SJ Oh, WK Galsky, MD AF Tsao, Che-Kai Small, Alexander C. Moshier, Erin L. Gartrell, Benjamin A. Wisnivesky, Juan P. Sonpavde, Guru Godbold, James H. Palese, Michael A. Hall, Simon J. Oh, William K. Galsky, Matthew D. TI Trends in the Use of Cytoreductive Nephrectomy in the United States SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Kidney cancer; Renal cell carcinoma; Socioeconomic differences; Tyrosine kinase inhibitor ID RENAL-CELL CARCINOMA; TARGETED THERAPY; SURVIVAL; CANCER; IMPACT; DISEASE AB Cytoreductive nephrectomy had been considered a standard in the treatment of metastatic renal cell carcinoma in the cytokine era, but with the introduction of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) an 'evidence void' for this approach has been created. In this study, we found that the use of cytoreductive nephrectomy (CyNx) has declined in the VEGFR TKI era, and in addition, potential racial and socioeconomic disparities exist. Background: Two randomized trials published in 2001 established CyNx for patients with metastatic renal carcinoma (mRCC) as a treatment standard in the cytokine era. However, first-line systemic therapy for mRCC changed in 2005 with FDA approval of VEGFR TKIs. We evaluated the patterns of use of CyNx from 2000 to 2008. Materials and Methods: The National Cancer Database was queried for patients diagnosed with mRCC. Patients who underwent CyNx were identified and were further categorized by pre-VEGFR versus VEGFR TKI era, race, insurance status, and hospital. For these subcategories, prevalence ratios (PRs) were generated using the proportion of patients with mRCC undergoing CyNx versus those not undergoing CyNx. Results: Of the 47,417 patients (pts) identified with mRCC, the prevalence of cytoreductive nephrectomy increased 3% each year from 2000 to 2005 (P < .0001), then decreased 3% each year from 2005 to 2008 (P = .0048), with a significant difference between the eras (0.97 vs. 1.025; P < .0001). Black and Hispanic pts were less likely than Caucasian pts to undergo CyNx. Pts with Medicaid, Medicare, and no insurance were less likely than pts with private insurance to undergo CyNx. Pts diagnosed at community hospitals were significantly less likely than pts at teaching hospitals to undergo CyNx. Conclusion: The use of CyNx has declined in the VEGFR-TKI era. In addition, racial and socioeconomic disparities exist in the use of CyNx. The results of pending randomized trials evaluating the role of CyNx in the VEGFR-TKI era are awaited to optimize use of this modality and address potential disparities. C1 [Tsao, Che-Kai; Small, Alexander C.; Moshier, Erin L.; Gartrell, Benjamin A.; Godbold, James H.; Oh, William K.; Galsky, Matthew D.] Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY 10029 USA. [Sonpavde, Guru] Texas Oncol, Houston, TX USA. [Sonpavde, Guru] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Med Oncol, Houston, TX 77030 USA. [Palese, Michael A.; Hall, Simon J.] Mt Sinai Sch Med, Dept Urol, New York, NY USA. RP Galsky, MD (reprint author), Tisch Canc Inst, Div Hematol & Med Oncol, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM matthew.galsky@mssm.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU NCI NIH HHS [R21 CA176551] NR 24 TC 13 Z9 13 U1 0 U2 2 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD SEP PY 2012 VL 10 IS 3 BP 159 EP 163 DI 10.1016/j.clgc.2012.03.008 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 992ZJ UT WOS:000307820600004 PM 22651971 ER PT J AU Butt, AA Umbleja, T Andersen, JW Sherman, KE Chung, RT AF Butt, Adeel A. Umbleja, Triin Andersen, Janet W. Sherman, Kenneth E. Chung, Raymond T. CA ACTG A5178 Study Team TI Impact of Peginterferon Alpha and Ribavirin Treatment on Lipid Profiles and Insulin Resistance in Hepatitis C Virus/HIV-Coinfected Persons: The AIDS Clinical Trials Group A5178 Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SUSTAINED VIROLOGICAL RESPONSE; INTERFERON PLUS RIBAVIRIN; TYPE-2 DIABETES-MELLITUS; PEGYLATED INTERFERON; COMBINATION THERAPY; INFECTED PATIENTS; SERUM-LIPIDS; HCV; CLEARANCE; RISK AB Background. The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. Methods. We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. Results. Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log10 IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR], 150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. Conclusions. Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. C1 [Butt, Adeel A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Butt, Adeel A.] Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates. [Umbleja, Triin; Andersen, Janet W.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Sherman, Kenneth E.] Univ Cincinnati, Cincinnati, OH 45221 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Butt, AA (reprint author), Univ Pittsburgh, Sch Med, 3520 5th Ave,Ste 510, Pittsburgh, PA 15213 USA. EM aabutt@pitt.edu FU National Institute of Allergy and Infectious Diseases [U01AI068636, U01AI068634]; National Institute of Mental Health; National Institute of Dental and Craniofacial Research; Gilead Sciences FX This study was supported by the National Institute of Allergy and Infectious Diseases (U01AI068636 and U01AI068634) and by the National Institute of Mental Health and the National Institute of Dental and Craniofacial Research.; A. A. B. has received consulting fees from Gilead Sciences. All other authors report no potential conflicts. NR 31 TC 6 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 631 EP 638 DI 10.1093/cid/cis463 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300004 PM 22563020 ER PT J AU Fishman, JA Greenwald, MA Grossi, PA AF Fishman, Jay A. Greenwald, Melissa A. Grossi, Paolo A. TI Transmission of Infection With Human Allografts: Essential Considerations in Donor Screening SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ORGAN TRANSPLANT RECIPIENTS; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; WEST-NILE-VIRUS; MUSCULOSKELETAL TISSUE DONORS; TRANSMITTED VIRAL-INFECTIONS; UNITED-STATES; LIVER-TRANSPLANTATION; DISEASE TRANSMISSION; BLOOD-DONORS AB Transmission of infection via transplantation of allografts including solid organs, eyes, and tissues are uncommon but potentially life-threatening events. Donor-derived infections have been documented following organ, tissue, and ocular transplants. Each year, more than 70 000 organs, 100 000 corneas, and 2 million human tissue allografts are implanted worldwide. Single donors may provide allografts for >100 organ and tissue recipients; each allograft carries some, largely unquantifiable, risk of disease transmission. Protocols for screening of organ or tissue donors for infectious risk are nonuniform, varying with the type of allograft, national standards, and availability of screening assays. In the absence of routine, active surveillance, coupled with the common failure to recognize or report transmission events, few data are available on the incidence of allograft-associated disease transmission. Research is needed to define the optimal screening assays and the transmissibility of infection with allografts. Approaches are reviewed that may contribute to safety in allograft transplantation. C1 [Fishman, Jay A.] Harvard Univ, Massachusetts Gen Hosp, MGH Transplantat Ctr,Med Sch, Transplant Infect Dis Program,Infect Dis Div, Boston, MA USA. [Greenwald, Melissa A.] US FDA, US PHS, Div Human Tissues,Ctr Biol Evaluat & Res, Reprod Branch Off Cellular Tissue & Gene Therapie, Rockville, MD 20857 USA. [Grossi, Paolo A.] Univ Insubria, Dept Infect Dis, Varese, Italy. [Grossi, Paolo A.] Natl Ctr Transplantat, Rome, Italy. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Transplant Infect Dis & Compromised Host Program, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jfishman@partners.org RI GROSSI, PAOLO/A-6158-2013; Snydman, David/O-3889-2014 OI Snydman, David/0000-0003-0119-3978 NR 62 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 720 EP 727 DI 10.1093/cid/cis519 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300017 PM 22670038 ER PT J AU Justice, AC Tate, JP Freiberg, MS Rodriguez-Barradas, MC Tracy, R AF Justice, Amy C. Tate, Janet P. Freiberg, Matthew S. Rodriguez-Barradas, Maria C. Tracy, Russ TI Role of the Veterans Aging Cohort Study Index in Assessing Total Atherosclerotic Burden Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID CARDIOVASCULAR-DISEASE; CALCIFICATION; ASSOCIATION; HIV C1 [Justice, Amy C.; Tate, Janet P.] Vet Affairs Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Justice, Amy C.; Tate, Janet P.] Yale Univ, Dept Med, Gen Internal Med Sect, New Haven, CT 06520 USA. [Freiberg, Matthew S.] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Pittsburgh, PA 15260 USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Infect Dis Sect, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Tracy, Russ] Univ Vermont, Coll Med, Burlington, VT 05405 USA. RP Justice, AC (reprint author), Vet Affairs Connecticut Healthcare Syst, 950 Campbell Ave,11 ACSLG, West Haven, CT 06516 USA. EM amy.justice2@va.gov NR 11 TC 8 Z9 8 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP 751 EP 752 DI 10.1093/cid/cis539 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300024 ER PT J AU Dransfield, MT Harnden, S Burton, RL Albert, RK Bailey, WC Casaburi, R Connett, J Cooper, JAD Criner, GJ Curtis, JL Han, MK Make, B Marchetti, N Martinez, FJ McEvoy, C Nahm, MH Niewoehner, DE Porszasz, J Reilly, J Scanlon, PD Scharf, SM Sciurba, FC Washko, GR Woodruff, PG Lazarus, SC AF Dransfield, Mark T. Harnden, Sarah Burton, Robert L. Albert, Richard K. Bailey, William C. Casaburi, Richard Connett, John Cooper, J. Allen D., Jr. Criner, Gerard J. Curtis, Jeffrey L. Han, MeiLan K. Make, Barry Marchetti, Nathaniel Martinez, Fernando J. McEvoy, Charlene Nahm, Moon H. Niewoehner, Dennis E. Porszasz, Janos Reilly, John Scanlon, Paul D. Scharf, Steven M. Sciurba, Frank C. Washko, George R. Woodruff, Prescott G. Lazarus, Stephen C. CA NIH COPD Clinical Res Network TI Long-term Comparative Immunogenicity of Protein Conjugate and Free Polysaccharide Pneumococcal Vaccines in Chronic Obstructive Pulmonary Disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID OLDER-ADULTS; STREPTOCOCCUS-PNEUMONIAE; ELDERLY ADULTS; VACCINATION; EFFICACY; ANTIBODY; RESPONSES; PROTECTION; INFLUENZA; SAFETY AB Background. Although the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years. Methods. One hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years. Results. Relative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed. Conclusions. PCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points. C1 [Dransfield, Mark T.; Bailey, William C.; Cooper, J. Allen D., Jr.] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL 35294 USA. [Dransfield, Mark T.; Cooper, J. Allen D., Jr.] Birmingham VA Med Ctr, Pulm Sect, Birmingham, AL USA. [Harnden, Sarah; Connett, John] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Burton, Robert L.; Nahm, Moon H.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Burton, Robert L.; Nahm, Moon H.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Albert, Richard K.] Denver Hlth Med Ctr, Dept Med, Denver, CO USA. [Casaburi, Richard; Porszasz, Janos] Harbor UCLA Med Ctr, Div Resp & Crit Care Physiol & Med, Torrance, CA 90509 USA. [Criner, Gerard J.; Marchetti, Nathaniel] Temple Univ, Div Pulm & Crit Care Med, Philadelphia, PA 19122 USA. [Curtis, Jeffrey L.; Han, MeiLan K.; Martinez, Fernando J.] Univ Michigan, Div Pulm & Crit Care Med, Ann Arbor, MI 48109 USA. [Make, Barry] Univ Colorado, Natl Jewish Hlth, Denver, CO 80202 USA. [McEvoy, Charlene; Niewoehner, Dennis E.] Univ Minnesota, VA Med Ctr, Pulm Sect, Minneapolis, MN USA. [Reilly, John; Sciurba, Frank C.] Univ Pittsburgh, Div Pulm & Crit Care Med, Pittsburgh, PA 15260 USA. [Scanlon, Paul D.] Mayo Clin, Div Pulm & Crit Care Med, Rochester, MN USA. [Scharf, Steven M.] Univ Maryland, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. [Washko, George R.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Woodruff, Prescott G.; Lazarus, Stephen C.] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Woodruff, Prescott G.; Lazarus, Stephen C.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Dransfield, MT (reprint author), Univ Alabama Birmingham, Div Pulm & Crit Care, 422 THT 1900 Univ Blvd, Birmingham, AL 35294 USA. EM mdransfield99@msn.com RI Reilly, John/H-8755-2012; OI Curtis, Jeffrey/0000-0001-5191-4847; Nahm, Moon/0000-0002-6922-1042; Porszasz, Janos/0000-0002-5823-0031 FU Division of Lung Diseases of the National Heart, Lung, and Blood Institute; GCRC [RR02635, RR00051, RR16500, RR00056]; UpToDate; ePocrates; Pfizer; Actelion; GSK; Forest; MPex; Nycomed; American Lung Association; Almirall; Altana/Nycomed; Astra Zeneca; Boehringer Ingelheim; CME Incite; France Foundation; MedEd; NACE; Potomac; Prescott; Sanofi Aventis; Vox Medic; WebMD; Associates in Medical Marketing; Castle Connolly; Merck; Genentech; [HL074428]; [HL074409]; [1U10-HL074416]; [HL074408]; [HL074418]; [1U10-HL074431]; [HL074441]; [HL074422]; [HL074439]; [1U10-HL074424] FX The COPD Clinical Research Network is supported by a Cooperative Agreement from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute.; Brigham and Women's Hospital: J. J. Reilly, Jr, G. Washko (PIs), S. Peterson (Coordinator). Grant HL074428, GCRC Grant RR02635.; Denver Health Medical Center: R. K. Albert (PI), B. Make (Co-PI), M. Schwarz, C. Welsh (Investigators), C. Verano, J. Binford, J. Herrell (Coordinators). Grant HL074409, GCRC Grant RR00051.; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center: R. Casaburi, (PI), G. Mason, J. Porszasz, (Investigators), K. Norulak, R. Kiledjian, L. Diaz, R. Love, P. Walker (Coordinators). Grant HL074407, GCRC Grant RR00425.; Minnesota Veterans Research Institute, Minneapolis (Affiliated Sites: HealthPartners Research Foundation, Mayo Clinic): D. E. Niewoehner (PI), C. McEvoy, K. R. Rice, P. D. Scanlon (Co-PIs). C. Andrist, J. Hart, K. Timm (Coordinators). Grant 1U10-HL074416.; Temple University: G. J. Criner (PI), W. Chatila, N. Marchetti, V. Kim, G. D'Alonzo, S. Krachman, F. Cordova, K. Brennan, N. Patel, J. Mamary (Investigators), C. Grabianowski, G. Jones, N. Krayger, A. M. Kuzma, H. Smith (Coordinators). Grant HL074408.; University of Alabama at Birmingham: M. T. Dransfield (PI), J. A. D. Cooper (Co-PI), W. C. Bailey, L. B. Gerald, P. O'Reilly (Investigators), S. Tidwell (Coordinator). Grant HL074418.; University of California, San Francisco: S. C. Lazarus (PI), H. A. Boushey, J. V. Fahy, P. G. Woodruff (Investigators), K. Schardein, C. Nguyen, R. Sakurai, M. Dyjak (Coordinators). 1U10-HL074431.; University of Maryland, Baltimore: S. M. Scharf (PI), M. Alattar, P. Amelung, M. Cowan, J. Hanson, J. Hasday, A. Iacono, C. Shanholtz, N. Todd, A. Verceles (Investigators), W. Bell-Farrell, T. Fitzgerald, P. Wood(Coordinators). Grant HL074441, GCRC Grant RR16500.; University of Michigan, Ann Arbor: F. J. Martinez (PI), J. L. Curtis, M. K. Han, S. E. Gay, T. H. Sisson, P. J. Christensen, M. Mendez (Investigators), D. Thompson (Project Manager), C. Flaherty, T. Felt, S. Smith, L. Husselman, D. White (Coordinators at UM), C. Getty, C. Jett, L. McCloskey, M. Christensen (Coordinators at VA). Grant HL074422.; University of Pittsburgh: F. Sciurba (PI), L. Kniolek, L. Lane, M. Pitaro (Coordinators). Grant HL074439, GCRC Grant RR00056.; University of Minnesota (Data Coordinating Center): J. E. Connett (PI), N. R. Anthonisen (Steering Committee Chair), C. Wendt (Co-PI), S. Harnden, W. Patrek, H. Voelker (Coordinators). Grant 1U10-HL074424.; M. T. D. has served as an advisory board member for GlaxoSmithKline and Boehringer Ingelheim and has received industry contracts for clinical trials from GlaxoSmithKline, Boehringer Ingelheim, Otsuka, Boston Scientific and Centocor. R. C. has served in the speakers' bureau for Pfizer Pharmaceuticals. M. K. H. has participated in advisory boards for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, Genentech, Novartis, and Medimmune; has participated on speaker's bureaus for Boehringer Ingelheim GmbH, Pfizer, GlaxoSmithKline, the National Association for Continuing Education, and WebMD; has consulted for Novartis and Nycomed; and has received royalties from UpToDate and ePocrates. B. M. has served on an advisory boards for Merck and Pfizer and has been the local principal investigator for multicenter trials sponsored by Pfizer. F. J. M. has participated in Advisory Boards in COPD development for Actelion, Astra Zeneca, Bayer, Boom-Comm, fbCommunications, Forest/Almirall, GSK, Ikaria, MedImmune, Merck, Novartis, Nycomed, Pearl, Pfizer, Roche, Schering, and Talecris; has been a member of Steering Committee for COPD studies sponsored by Actelion, GSK, Forest, MPex, and Nycomed; has participated in FDA Mock panels for Boehringer Ingelheim and Forest; has served on speaker's bureaus or in CME activities sponsored by American Lung Association, Almirall, Altana/Nycomed, Astra Zeneca, Boehringer Ingelheim, CME Incite, ePocrates, Forest, France Foundation, GSK, MedEd, NACE, Pfizer, Potomac, Prescott, Sanofi Aventis, Vox Medic, WebMD, and UpToDate; and has received royalties from Associates in Medical Marketing, Castle Connolly. D. E. N has received advisory fees from Merck and Pfizer. P. D, S. has participated in clinical trials funded by Pfizer and Boehringer Ingelheim, and his wife works for Merck Research Laboratories. P. G. W. has had a recent research grant with Genentech, recent consulting for Medimmune, and is co-inventor on a patent pending for asthma diagnostics. The University of Alabama at Birmingham owns the intellectual property rights to some of the reagents described in this work. M. H. N., R. L. B., W. C. B., J. A. D. C. and M. T. D. are employees of the University of Alabama at Birmingham, and M. H. N. has been a consultant to Merck regarding the diagnosis of pneumonia. All other authors report no potential conflicts. NR 32 TC 21 Z9 22 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 1 PY 2012 VL 55 IS 5 BP E35 EP E44 DI 10.1093/cid/cis513 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 988NR UT WOS:000307498300001 PM 22652582 ER PT J AU Suri, P Saunders, KW Von Korff, M AF Suri, Pradeep Saunders, Kathleen W. Von Korff, Michael TI Prevalence and Characteristics of Flare-ups of Chronic Nonspecific Back Pain in Primary Care A Telephone Survey SO CLINICAL JOURNAL OF PAIN LA English DT Article DE back pain; flare; flare-up; exacerbation; disability; coping ID ELECTRONIC DIARY ASSESSMENT; ANKYLOSING-SPONDYLITIS; NATURAL-HISTORY; DISABILITY; QUESTIONNAIRE; INTENSITY AB Objectives: To describe the prevalence and characteristics of flare-ups of chronic nonspecific back pain (CNSBP) among primary care patients, and to examine associations with measures of pain severity and psychosocial factors. Methods: Six hundred thirty-four participants with nonspecific back pain were interviewed by telephone 2 years after an initial primary care visit for back pain. Participants experiencing flare-ups in the last 6 months reported on frequency, duration, and other characteristics of flare-ups. Using bivariate and multivariate analyses, we compared individuals with and without CNSBP flare-ups with respect to demographic characteristics, measures of pain severity, and psychosocial factors. Results: Approximately 51% of the participants reported flare-ups. Physical activities, including lifting and bending, were the most common perceived triggers of flare-ups. Participants with flare-ups experienced greater levels of pain intensity, disability, opioid medication use, and psychosocial comorbidities. After adjustment for demographic factors, pain intensity, and pain frequency, participants with flare-ups were more disabled than those without [mean (95% confidence interval) disability score 4.2 (3.9-4.4) vs. 3.3 (2.9-3.6); P < 0.0001] and demonstrated higher levels of passive coping [mean passive coping score 4.1(3.8-4.3) vs. 3.4 (3.1-3.7); P = 0.0008]. Discussion: Flare-ups of CNSBP are common among primary care patients, and are independently associated with higher levels of pain intensity, disability, and passive coping. The presence of flare-ups and the perception of activity as a trigger may predispose patients with flare-ups to experience disability not explained by pain intensity alone. Further longitudinal studies are required to better characterize CNSBP flare-ups and determine their clinical implications. C1 [Suri, Pradeep] VA Boston Healthcare Syst, Div Phys Med & Rehabil, Boston, MA 02130 USA. [Suri, Pradeep] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, Pradeep] Spaulding Rehabil Hosp, Boston, MA USA. [Suri, Pradeep] New England Baptist Hosp, Div Res, Boston, MA USA. [Saunders, Kathleen W.; Von Korff, Michael] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. RP Suri, P (reprint author), VA Boston Healthcare Syst, Div Phys Med & Rehabil, 150 S Huntington Ave, Boston, MA 02130 USA. EM pradeep.suri@va.gov FU Rehabilitation Medicine Scientist Training Program (RMSTP), Pittsburgh, PA; National Institutes of Health, Bethesda, MD [K12 HD001097-12]; NIA, Bethesda, MD [R01 AG034181]; NIDCR, Bethesda, MD [P01 DE08773] FX P.S. is funded by the Rehabilitation Medicine Scientist Training Program (RMSTP), Pittsburgh, PA, and the National Institutes of Health (K12 HD001097-12), Bethesda, MD. K. W. S. and M. V. K. are funded by the NIA (R01 AG034181), Bethesda, MD. This research was supported by the NIDCR (P01 DE08773), Bethesda, MD. The authors declare no conflict of interest. NR 25 TC 3 Z9 3 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-8047 J9 CLIN J PAIN JI Clin. J. Pain PD SEP PY 2012 VL 28 IS 7 BP 573 EP 580 DI 10.1097/AJP.0b013e31823ae173 PG 8 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 990ON UT WOS:000307640500003 PM 22699128 ER PT J AU Krishna, V Lazaridis, C Ellegala, D Glazier, S Kindy, M Spampinato, M Chalela, JA AF Krishna, Vibhor Lazaridis, Christos Ellegala, Dilantha Glazier, Steven Kindy, Mark Spampinato, Maria Chalela, Julio A. TI Spinal cord infarction associated with subarachnoid hemorrhage SO CLINICAL NEUROLOGY AND NEUROSURGERY LA English DT Article DE Delayed ischemia; Subarachnoid hemorrhage; Spinal cord stroke C1 [Krishna, Vibhor; Lazaridis, Christos; Ellegala, Dilantha; Glazier, Steven; Chalela, Julio A.] Med Univ S Carolina, Div Neurosurg, Dept Neurosci, Charleston, SC 29407 USA. [Kindy, Mark] Med Univ S Carolina, Div Res, Dept Neurosci, Charleston, SC 29407 USA. [Kindy, Mark] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Spampinato, Maria] Med Univ S Carolina, Dept Radiol, Charleston, SC 29407 USA. [Lazaridis, Christos; Chalela, Julio A.] Med Univ S Carolina, Div Neurol, Dept Neurosci, Charleston, SC 29407 USA. RP Krishna, V (reprint author), Med Univ S Carolina, Div Neurosurg, Dept Neurosci, 96 Jonathan Lucas St, Charleston, SC 29407 USA. EM Krishna@musc.edu FU NCRR NIH HHS [P20 RR021949]; NIEHS NIH HHS [R01 ES016774]; NIGMS NIH HHS [P20 GM103444] NR 6 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0303-8467 J9 CLIN NEUROL NEUROSUR JI Clin. Neurol. Neurosurg. PD SEP PY 2012 VL 114 IS 7 BP 1030 EP 1032 DI 10.1016/j.clineuro.2012.01.037 PG 3 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 993JU UT WOS:000307855800042 PM 22386902 ER PT J AU Cheng, G Alavi, A Lim, E Akers, SR AF Cheng, Gang Alavi, Abass Lim, Esther Akers, Scott R. TI Superscan-like Hypermetabolic Lesions on Delayed FDG PET/CT Imaging in a Patient With Lung Cancer SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE FDG PET/CT; superscan; bone marrow metastasis; lung cancer ID BONE-SCINTIGRAPHY; PULMONARY NODULES; F-18-FDG PET; POINT AB A 69-year-oldman with a lung mass underwent multiple-time-point FDG PET/CT imaging for diagnostic evaluation. The initial PET imaging (performed at 1 hour after tracer injection) revealed equivocal bone marrow uptake in the right iliac bone and proximal femurs in addition to lung and mediastinal lesions. The 3-hour delayed PET imaging, however, demonstrated widespread bone marrow metastases. Biopsies of the right lung mass and right iliac bone marrow were later performed and revealed a poorly differentiated squamous cell carcinoma in both sites. This case indicates the value of delayed FDG PET in detecting superscan-like hypermetabolic bone marrow lesions in patients with lung cancer. C1 [Cheng, Gang; Lim, Esther; Akers, Scott R.] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA 19104 USA. [Alavi, Abass] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. RP Akers, SR (reprint author), Philadelphia VA Med Ctr, Dept Radiol, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM Scott.Akers@va.gov NR 9 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD SEP PY 2012 VL 37 IS 9 BP 912 EP 913 DI 10.1097/RLU.0b013e31825b23d5 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 992VL UT WOS:000307808000034 PM 22889790 ER PT J AU Tamez, H Thadhani, RI AF Tamez, Hector Thadhani, Ravi I. TI Vitamin D and hypertension: an update and review SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE activated vitamin D analogs; blood pressure; hypertension; vitamin D ID 25-HYDROXYVITAMIN D LEVELS; RANDOMIZED CONTROLLED-TRIAL; PARATHYROID-HORMONE LEVELS; RENIN-ANGIOTENSIN SYSTEM; CARDIOVASCULAR RISK-FACTORS; ARTERIAL-BLOOD PRESSURE; INCIDENT HYPERTENSION; D DEFICIENCY; APPARENTLY HEALTHY; D SUPPLEMENTATION AB Purpose of review Vitamin D deficiency and hypertension are highly prevalent. This review will discuss the association between vitamin D deficiency and blood pressure. Recent findings During the past several years multiple prospective cohorts and randomized studies have been published. Recent studies have focused mostly on 25-hydroxy vitamin D, but a small number of trials used active vitamin D analog compounds. Summary Data from cross-sectional studies report that low 25-hydroxy vitamin D is associated with higher systolic blood pressure and higher incidence of hypertension. Large observational studies show a weaker, yet similar association, but they have not largely accounted for the change in vitamin D levels over time. Randomized control trials conflict with observational data probably due to differences in populations studied, doses of vitamin D used, and unmeasured confounders. Further research is needed before clinical practice recommends vitamin D prescription as treatment for hypertension in the general population. C1 [Tamez, Hector; Thadhani, Ravi I.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Tamez, H (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 55 Fruit St,Bulfinch 127, Boston, MA 02114 USA. EM htamez@partners.org FU Abbott Laboratories FX Dr. Thadhani has a research grant from Abbott Laboratories. NR 60 TC 22 Z9 23 U1 0 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD SEP PY 2012 VL 21 IS 5 BP 492 EP 499 DI 10.1097/MNH.0b013e3283557bf0 PG 8 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 990RQ UT WOS:000307649300006 PM 22820371 ER PT J AU Krapf, D Ruan, YC Wertheimer, EV Battistone, MA Pawlak, JB Sanjay, A Pilder, SH Cuasnicu, P Breton, S Visconti, PE AF Krapf, Dario Ruan, Ye Chun Wertheimer, Eva V. Battistone, Maria A. Pawlak, John B. Sanjay, Archana Pilder, Stephen H. Cuasnicu, Patricia Breton, Sylvie Visconti, Pablo E. TI cSrc is necessary for epididymal development and is incorporated into sperm during epididymal transit SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Epididymal maturation; Extracellular trafficking; Src kinase; Sperm capacitation; Sperm motility ID TYROSINE PHOSPHORYLATION; MOUSE SPERMATOZOA; RAT EPIDIDYMIS; V-ATPASE; SRC; CAPACITATION; EXPRESSION; PROTEINS; TESTIS; CELLS AB Changes that occur to mammalian sperm upon epididymal transit and maturation render these cells capable of moving progressively and capacitating. Signaling events leading to mammalian sperm capacitation depend on the modulation of proteins by phosphorylation and dephosphorylation cascades. Recent experiments have demonstrated that the Src family of kinases plays an important role in the regulation of these events. However, sperm from cSrc null mice display normal tyrosine phosphorylation associated with capacitation. We report here that, despite normal phosphorylation, sperm from cSrc null mice display a severe reduction in forward motility, and are unable to fertilize in vitro. Histological analysis of seminiferous tubules in the testes, caput and corpus epididymis do not reveal obvious defects. However, the cauda epididymis is significantly smaller, and expression of key transport proteins in the epithelial cells lining this region is reduced in cSrc null mice compared to wild type littermates. Although previously, we and others have shown the presence of cSrc in mature sperm from cauda epididymis, a closer evaluation indicates that this tyrosine kinase is not present in sperm from the caput epididymis, suggesting that this protein is acquired by sperm later during epididymal maturation. Consistent with this observation, cSrc is enriched in vesicles released by the epididymal epithelium known as epididymosomes. Altogether, these observations indicate that cSrc is essential for cauda epididymal development and suggest an essential role of this kinase in epididymal sperm maturation involving cSrc extracellular trafficking. (c) 2012 Elsevier Inc. All rights reserved. C1 [Krapf, Dario; Wertheimer, Eva V.; Pawlak, John B.; Visconti, Pablo E.] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. [Krapf, Dario] CONICET UNR, Inst Mol & Cell Biol Rosario, Rosario, Argentina. [Ruan, Ye Chun; Breton, Sylvie] Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. [Ruan, Ye Chun; Breton, Sylvie] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ruan, Ye Chun; Breton, Sylvie] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Battistone, Maria A.; Cuasnicu, Patricia] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Buenos Aires, DF, Argentina. [Sanjay, Archana] Univ Connecticut, Ctr Hlth, New England Musculoskeletal Inst, Dept Orthopaed Surg, Farmington, CT 06030 USA. [Pilder, Stephen H.] Temple Univ, Sch Med, Dept Anat & Cell Biol, Philadelphia, PA 19140 USA. RP Visconti, PE (reprint author), Univ Massachusetts, Dept Vet & Anim Sci, 661 N Pleasant ST, Amherst, MA 01003 USA. EM pvisconti@vasci.umass.edu FU NIH [HD44044, HD038082, HD40793, HD45821, DK38452]; National Agency for Scientific and Technological Promotion of Argentina [PICT 633]; WHO [H9-TSA-037]; Lalor Foundation postdoctoral fellowship FX This work was supported by NIH: R01 HD44044 and HD038082 (to PEV), HD40793, HD45821 and DK38452 (to SB), National Agency for Scientific and Technological Promotion of Argentina PICT 633 and WHO H9-TSA-037 (to PSC) and by a Lalor Foundation postdoctoral fellowship (to YCR). We would also like to thank Dr. Paula Stein for her assistance in in vitro fertilization experiments. Authors declare no conflict of interests. NR 44 TC 25 Z9 25 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD SEP 1 PY 2012 VL 369 IS 1 BP 43 EP 53 DI 10.1016/j.ydbio.2012.06.017 PG 11 WC Developmental Biology SC Developmental Biology GA 986TN UT WOS:000307368600004 PM 22750823 ER PT J AU Singer, JR Palmas, W Teresi, J Weinstock, R Shea, S Luchsinger, JA AF Singer, Jessica R. Palmas, Walter Teresi, Jeanne Weinstock, Ruth Shea, Steven Luchsinger, Jose A. TI Adiponectin and All-Cause Mortality in Elderly People With Type 2 Diabetes SO DIABETES CARE LA English DT Article ID MOLECULAR-WEIGHT ADIPONECTIN; CORONARY-HEART-DISEASE; COLUMBIA-UNIVERSITY INFORMATICS; TELEMEDICINE IDEATEL PROJECT; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; METABOLIC SYNDROME; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; RISK AB OBJECTIVE To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality. RESEARCH DESIGN AND METHODS A total of 609 men and women aged 72 +/- 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications. RESULTS Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7-9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered. CONCLUSIONS Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss. C1 [Singer, Jessica R.; Palmas, Walter; Shea, Steven; Luchsinger, Jose A.] Columbia Univ, Dept Med, Div Gen Med, New York, NY 10027 USA. [Teresi, Jeanne] Hebrew Home Riverdale, Res Div, Bronx, NY USA. [Teresi, Jeanne] Columbia Univ, Stroud Ctr, New York, NY USA. [Teresi, Jeanne] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Weinstock, Ruth] SUNY Upstate Med Univ, Joslin Diabet Ctr, Syracuse, NY USA. [Weinstock, Ruth] SUNY Upstate Med Univ, Div Endocrinol Diabet & Metab, Syracuse, NY USA. [Weinstock, Ruth] VA Med Ctr, Dept Vet Affairs, Syracuse, NY USA. [Shea, Steven; Luchsinger, Jose A.] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Luchsinger, JA (reprint author), Columbia Univ, Dept Med, Div Gen Med, New York, NY 10027 USA. EM jal94@columbia.edu FU National Institute on Minority Health and Health Disparities [P60 MD 000206]; Alzheimer's Association [IIRG-05-15053]; Fidelity Foundation; Centers for Medicare and Medicaid Services [95-C-90998] FX This work is supported by National Institute on Minority Health and Health Disparities grant P60 MD 000206 (J.A.L., W.P., S.S., J.T.), Alzheimer's Association grant IIRG-05-15053 (J.A.L.), the Fidelity Foundation (J.A.L.), and Cooperative Agreement 95-C-90998 from the Centers for Medicare and Medicaid Services (R.W., S.S., J.T., W.P., J.A.L.). NR 34 TC 20 Z9 21 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1858 EP 1863 DI 10.2337/dc11-2215 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100010 PM 22773703 ER PT J AU Florez, JC Jablonski, KA Taylor, A Mather, K Horton, E White, NH Barrett-Connor, E Knowler, WC Shuldiner, AR Pollin, TI AF Florez, Jose C. Jablonski, Kathleen A. Taylor, Andrew Mather, Kieren Horton, Edward White, Neil H. Barrett-Connor, Elizabeth Knowler, William C. Shuldiner, Alan R. Pollin, Toni I. CA Diabet Prevention Program Res Grp TI The C Allele of ATM rs11212617 Does Not Associate With Metformin Response in the Diabetes Prevention Program SO DIABETES CARE LA English DT Article ID LIFE-STYLE INTERVENTION; EUROPEAN ASSOCIATION; CONSENSUS ALGORITHM; MEDICAL-MANAGEMENT; STATEMENT; GLUCOSE; HYPERGLYCEMIA; ADJUSTMENT; INITIATION; MELLITUS AB OBJECTIVE-The C allele at the rs11212617 polymorphism in the ataxia-telangiectasia-mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance. RESEARCH DESIGN AND METHODS-We genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits. RESULTS-Contrary to expectations, C carriers enjoyed no preventive advantage on metformin ; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96-1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin's effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index. CONCLUSIONS-The reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP. C1 [Florez, Jose C.; Taylor, Andrew] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; Taylor, Andrew] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.; Taylor, Andrew] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.; Horton, Edward] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Jablonski, Kathleen A.] George Washington Univ, Biostat Ctr, Dept Epidemiol & Biostat, Rockville, MD USA. [Mather, Kieren] Indiana Univ Sch Med, Div Endocrinol & Metab, Dept Med, Indianapolis, IN USA. [Horton, Edward] Joslin Diabet Ctr, Sect Clin Behav & Outcomes Res, Boston, MA 02215 USA. [White, Neil H.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [White, Neil H.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family Med, San Diego, CA 92103 USA. [Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Shuldiner, Alan R.; Pollin, Toni I.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.; Pollin, Toni I.] Univ Maryland, Sch Med, Program Genet & Genom Med, Baltimore, MD 21201 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org RI Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI Altshuler, David/0000-0002-7250-4107; de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Franks, Paul/0000-0002-0520-7604 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research on Women's Health; Centers for Disease Control and Prevention; American Diabetes Association; T.I.P. McKesson BioServices Corp.; Matthews Media Group, Inc.; Henry M. Jackson Foundation; National Institute on Aging; [R01-DK-072041] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the coordinating center for the design and conduct of the study, including collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Aging, the Office of Research on Women's Health, the Centers for Disease Control and Prevention, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK and Grant R01-DK-072041 to J.C.F., K.A.J., A.R.S., and T.I.P. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the coordinating center. NR 13 TC 22 Z9 22 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1864 EP 1867 DI 10.2337/dc11-2301 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100011 PM 22751958 ER PT J AU Rutter, MK Massaro, JM Hoffmann, U O'Donnell, CJ Fox, CS AF Rutter, Martin K. Massaro, Joseph M. Hoffmann, Udo O'Donnell, Christopher J. Fox, Caroline S. TI Fasting Glucose, Obesity, and Coronary Artery Calcification in Community-Based People Without Diabetes SO DIABETES CARE LA English DT Article ID INTIMA-MEDIA THICKNESS; SERVICES TASK-FORCE; RISK-FACTORS; METABOLIC SYNDROME; HEART-DISEASE; CARDIOVASCULAR-DISEASE; SCIENTIFIC STATEMENT; ASYMPTOMATIC ADULTS; VISCERAL ADIPOSITY; INSULIN-RESISTANCE AB OBJECTIVE-Our objective was to assess whether impaired fasting glucose (IFG) and obesity are independently related to coronary artery calcification (CAC) in a community-based population. RESEARCH DESIGN AND METHODS-We assessed CAC using multidetector computed tomography in 3,054 Framingham Heart Study participants (mean [SD] age was 50 [10] years, 49% were women, 29% had IFG, and 25% were obese) free from known vascular disease or diabetes. We tested the hypothesis that IFG (5.6-6.9 mmol/L) and obesity (BMI >= 30 kg/m(2)) were independently associated with high CAC (>90th percentile for age and sex) after adjusting for hypertension, lipids, smoking, and medication. RESULTS-High-CAC was significantly related to IFG in an age- and sex-adjusted model (odds ratio 1.4 [95% Cl 1.1-1.7], P = 0.002; referent: normal fasting glucose) and after further adjustment for obesity (1.3 [1.0-1.6], P = 0.045). However, IFG was not associated with high CAC in multivariable-adjusted models before (1.2 [0.9-1.4], P = 0.20) or after adjustment for obesity. Obesity was associated with high CAC in age- and sex-adjusted models (1.6 [1.3-2.0], P < 0.001) and in multivariable models that included IFG (1.4 [1.1-1.7], P = 0.005). Multivariableadjusted spline regression models suggested nonlinear relationships linking high CAC with BMI (J-shaped), waist circumference 0-shaped), and fasting glucose. CONCLUSIONS-In this community-based cohort, CAC was associated with obesity, but not IFG, after adjusting for important confounders. With the increasing worldwide prevalence of obesity and nondiabetic hyperglycemia, these data underscore the importance of obesity in the pathogenesis of CAC. C1 [Rutter, Martin K.] Univ Manchester, Sch Biomed, Cardiovasc Res Grp, Manchester, Lancs, England. [Rutter, Martin K.] Natl Hlth Serv Fdn Trust, Manchester Acad Hlth Sci Ctr, Natl Inst Hlth Res,Cent Manchester Biomed Res Ctr, Manchester Diabet Ctr,Cent Manchester Univ Hosp, Manchester, Lancs, England. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Div Biostat, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Boston, MA USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [O'Donnell, Christopher J.; Fox, Caroline S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. RP Rutter, MK (reprint author), Univ Manchester, Sch Biomed, Cardiovasc Res Grp, Manchester, Lancs, England. EM martin.rutter@manchester.ac.uk OI Massaro, Joseph/0000-0002-2682-4812; Rutter, Martin/0000-0001-6380-539X FU National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland) [N01-HC-25195]; Higher Education Funding Council for England (Clinical Senior Lecturer Award); Manchester National Institute for Health Research Biomedical Research Centre; Manchester Academic Health Science Centre FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Bethesda, Maryland; N01-HC-25195). M.K.R. was supported by the Higher Education Funding Council for England (Clinical Senior Lecturer Award). We also acknowledge support from the Manchester National Institute for Health Research Biomedical Research Centre and Manchester Academic Health Science Centre. NR 34 TC 18 Z9 18 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD SEP PY 2012 VL 35 IS 9 BP 1944 EP 1950 DI 10.2337/dc11-1950 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 998XG UT WOS:000308273100025 PM 22773705 ER PT J AU Munshi, MN Hayes, M Iwata, I Lee, Y Weinger, K AF Munshi, M. N. Hayes, M. Iwata, I. Lee, Y. Weinger, K. TI Which aspects of executive dysfunction influence ability to manage diabetes in older adults? SO DIABETIC MEDICINE LA English DT Article DE cognition; diabetes; elderly ID COGNITIVE IMPAIRMENT; DYSEXECUTIVE SYMPTOMS; MELLITUS; TRAIL; QUESTIONNAIRE; DECLINE; SAMPLE; WOMEN AB Diabet. Med. 29, 1171-1177 (2012) Abstract Aims To examine whether different aspects of executive function as measured by different assessment tools are associated with glycaemic control and other clinical characteristics in older adults with Type 2 diabetes. Methods We performed a cross-sectional study of older adults aged >= 70 years with Type 2 diabetes at a tertiary care diabetes centre. The Dysexecutive Questionnaire was used to measure self-reported executive dysfunction. Objective tests of executive functions included a modified clock drawing test (Clock-in-a-Box), Trail Making Tests (parts A and B) and verbal fluency. Demographic and clinical information was collected using questionnaires and surveys. Glycaemic control was measured by HbA1c. Results We evaluated 145 patients [average age 77 +/- 5 years, diabetes duration 15 +/- 11 years, mean HbA1c 56 +/- 11 mmol/mol (7.3 +/- 1.1%)]. Poor performances on objective tests (low scores on Clock-in-a-Box and verbal fluency; and high scores on Trail Making Tests A and B) but not on the subjective test (the Dysexecutive Questionnaire), were associated with poor glycaemic control (r = -0.23, P < 0.005; r = -0.17, P < 0.04; r = 0.20, P < 0.01, r = 0.22, P < 0.008, r = -0.07, P < 0.42, respectively). In a multiple regression model (r2 = 0.39), high Dysexecutive Questionnaire scores were associated with higher diabetes-related distress (P < 0.0004), depressive symptoms (P < 0.004), number of falls (P < 0.009), fear of falling (P < 0.01), less years of education (P < 0.0007) and fewer medications (P < 0.001). Conclusions On the one hand, in older adults, executive dysfunction detected by objective tests is associated with poor glycaemic control and may be considered before prescribing complex treatment regimens. On the other hand, self-reported executive dysfunction is associated with risk and fear of falls, and more affective symptoms, which may indicate higher awareness of subtle deficits. C1 [Munshi, M. N.; Lee, Y.; Weinger, K.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Munshi, M. N.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Munshi, M. N.; Weinger, K.] Harvard Univ, Sch Med, Boston, MA USA. [Hayes, M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Iwata, I.] Duke Univ, Med Ctr, Durham, NC USA. RP Munshi, MN (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. EM medha.munshi@joslin.harvard.edu FU American Diabetes Association [1-07-CR-40]; Department of Defense PRMRP of the Office of the Congressionally Directed Medical Research Programs [W81XWH-07-1-0282]; Joslin Diabetes Center Clinical Research Center FX The study was partly supported by a grant from a clinical research award from American Diabetes Association, 1-07-CR-40 (MM), Department of Defense PRMRP of the Office of the Congressionally Directed Medical Research Programs, W81XWH-07-1-0282 (MM), and the Joslin Diabetes Center Clinical Research Center. NR 29 TC 8 Z9 9 U1 6 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD SEP PY 2012 VL 29 IS 9 BP 1171 EP 1177 DI 10.1111/j.1464-5491.2012.03606.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 988EC UT WOS:000307470200029 PM 22340082 ER PT J AU Brodsky, MB Abbott, KV McNeil, MR Palmer, CV Grayhack, JP Martin-Harris, B AF Brodsky, Martin B. Abbott, Katherine Verdolini McNeil, Malcolm R. Palmer, Catherine V. Grayhack, Judith P. Martin-Harris, Bonnie TI Effects of Divided Attention on Swallowing in Persons with Idiopathic Parkinson's Disease SO DYSPHAGIA LA English DT Article DE Deglutition; Deglutition disorders; Attention; Reaction time; Cognition; Parkinson's disease ID COGNITIVE STATUS EXAMINATION; DUAL-TASK; CORTICAL REPRESENTATION; MOTOR; ACTIVATION; GAIT; DYSPHAGIA; VALIDITY; HUMANS; BOTTLENECK AB The purpose of this study was to determine whether attentional resources are involved in swallowing in persons with idiopathic Parkinson's disease, and if so, in which phase(s) of swallowing. The approach involved a dual-task, reaction time (RT) paradigm using ten participants with Parkinson's disease. Single-task baseline measures were obtained for durations of the anticipatory phase and oropharyngeal phase of swallowing and RTs were obtained for nonword auditory stimuli. A dual-task then required participants to swallow 5 ml of water from an 8-oz. cup while listening for a target nonword presented auditorily during the anticipatory or oropharyngeal phase. Target stimuli were randomized across baseline and dual-task trials. Durations of the anticipatory and oropharyngeal phases of swallowing and RTs during baseline and dual-task trials were determined. Results showed a nonsignificant change in speed of completion for both the anticipatory phase and the oropharyngeal phase of swallowing during dual-task trials. However, there was a statistically significant increase in RT during the anticipatory phase during the dual-task condition. RT during the oropharyngeal phase remained unaffected. Given a need for additional research using more complex competing tasks, these data on attention are consistent with earlier claims of an automatic, nonresource-demanding, oropharyngeal swallowing mechanism that is preserved for persons with early-to-mid-stage Parkinson's disease. Clinical implications of these data suggest that disruptive environmental stimuli to individuals with early-to-mid-stage Parkinson's disease may alter feeding but have little effect on the oropharyngeal swallow. C1 [Brodsky, Martin B.] Johns Hopkins Univ, Dept Phys Med & Rehabil, Baltimore, MD 21231 USA. [Abbott, Katherine Verdolini; McNeil, Malcolm R.; Palmer, Catherine V.; Grayhack, Judith P.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA USA. [McNeil, Malcolm R.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Washington, DC USA. [Martin-Harris, Bonnie] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Brodsky, MB (reprint author), Johns Hopkins Univ, Dept Phys Med & Rehabil, 98 N Broadway,Suite 403, Baltimore, MD 21231 USA. EM brodsky@jhmi.edu FU Mark and Evelyn Trammell Trust, Atlanta, Georgia; Evelyn Trammell Institute for Voice and Swallowing in the Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina; Trident Parkinson's Support Group FX The authors thank the Mark and Evelyn Trammell Trust, Atlanta, Georgia; the Evelyn Trammell Institute for Voice and Swallowing in the Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina; and the Trident Parkinson's Support Group for their support. The authors also thank Neil Szuminsky and Pete Arvenitis for their dedication, ingenuity, and technical expertise that lead to the design and creation of the hardware and programming necessary for this research. NR 50 TC 5 Z9 8 U1 2 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD SEP PY 2012 VL 27 IS 3 BP 390 EP 400 DI 10.1007/s00455-011-9381-x PG 11 WC Otorhinolaryngology SC Otorhinolaryngology GA 988VF UT WOS:000307518100011 PM 22197910 ER PT J AU Oudega, M Chao, OY Avison, DL Bronson, RT Buchser, WJ Hurtado, A Grimpe, B AF Oudega, Martin Chao, Owen Y. Avison, Donna L. Bronson, Roderick T. Buchser, William J. Hurtado, Andres Grimpe, Barbara TI Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Spinal cord injury; Glial scar; Chondroitin sulfate proteoglycans; DNA enzyme; Neurotherapeutics; Regeneration; Functional recovery ID CHONDROITIN SULFATE PROTEOGLYCANS; ADULT-RAT; GLIAL SCAR; CORTICOSPINAL TRACT; FUNCTIONAL RECOVERY; ARTICULAR-CARTILAGE; NERVOUS-SYSTEM; AXON GROWTH; REGENERATION; PLASTICITY AB After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury. (C) 2012 Elsevier Inc. All rights reserved. C1 [Grimpe, Barbara] Univ Dusseldorf, Dept Neurol, D-40225 Dusseldorf, Germany. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Oudega, Martin] Univ Pittsburgh, Sch Med, Dept Bioengn, Pittsburgh, PA 15213 USA. [Chao, Owen Y.] Univ Dusseldorf, Dept Expt Psychol, D-40225 Dusseldorf, Germany. [Avison, Donna L.] Univ Miami, Leonard M Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Bronson, Roderick T.] Dana Faber Harvard Canc Ctr, Boston, MA 02115 USA. [Buchser, William J.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. [Hurtado, Andres] Johns Hopkins Univ, Hugo W Moser Res Inst Kennedy Krieger, Int Ctr Spinal Cord Injury, Dept Neurol,Sch Med, Baltimore, MD 21205 USA. RP Grimpe, B (reprint author), Univ Dusseldorf, Dept Neurol, Moorenstr 5, D-40225 Dusseldorf, Germany. EM moudega@pitt.edu; owenchao@gmail.com; d.avison@miami.edu; Roderick_Bronson@hms.harvard.edu; buchserw@upmc.edu; hurtado@kennedykrieger.edu; Barbara.Grimpe@med.uni-duesseldorf.de OI Buchser, William/0000-0002-6675-6359 FU Department of Physical Medicine and Rehabilitation at the University of Pittsburgh; German Research Foundation (DFG); Forschungskommission of the HHU; Ralph Wilson Medical Research Foundation; Buoniconti Fund; Florida State Fund FX We thank the Animal/Behavioral and Histology Core Facilities, Dr. Alex Marcillo, and Dr. Beata Frydel of the Miami Project to Cure Paralysis, and Heidrun Podini and Julia Domke. This work was supported by the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh (MO); the German Research Foundation (DFG, BG); Forschungskommission of the HHU (BG); Ralph Wilson Medical Research Foundation (BG); Buoniconti Fund (BG); and the Florida State Fund (BG). The authors declare no conflict of interest. NR 56 TC 5 Z9 5 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD SEP PY 2012 VL 237 IS 1 BP 170 EP 179 DI 10.1016/j.expneurol.2012.06.006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 991JI UT WOS:000307696900021 PM 22721770 ER PT J AU van der Laan, AM Nahrendorf, M Piek, JJ AF van der Laan, Anja M. Nahrendorf, Matthias Piek, Jan J. TI Healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response SO HEART LA English DT Article ID PERIPHERAL-BLOOD; MONOCYTE SUBSETS; STEM-CELLS; INFLAMMATION; ANGIOPLASTY; INTRACORONARY; RECEPTOR; INJURY C1 [van der Laan, Anja M.; Piek, Jan J.] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1100 DD Amsterdam, Netherlands. [Nahrendorf, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. RP Piek, JJ (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Cardiol, POB 22660, NL-1100 DD Amsterdam, Netherlands. EM j.j.piek@amc.uva.nl FU Graduate School for Medical Sciences of the Academic Medical Centre, Amsterdam, The Netherlands; National Institutes of Health [R01HL096576] FX This work was supported by a grant by the Graduate School for Medical Sciences of the Academic Medical Centre, Amsterdam, The Netherlands to AML, and a grant from the National Institutes of Health (R01HL096576) to MN. NR 20 TC 23 Z9 23 U1 0 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD SEP PY 2012 VL 98 IS 18 BP 1384 EP 1390 DI 10.1136/heartjnl-2012-301623 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 990QV UT WOS:000307646800011 PM 22904145 ER PT J AU Cerliani, L Thomas, RM Jbabdi, S Siero, JCW Nanetti, L Crippa, A Gazzola, V D'Arceuil, H Keysers, C AF Cerliani, Leonardo Thomas, Rajat M. Jbabdi, Saad Siero, Jeroen C. W. Nanetti, Luca Crippa, Alessandro Gazzola, Valeria D'Arceuil, Helen Keysers, Christian TI Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex SO HUMAN BRAIN MAPPING LA English DT Review DE DTI; insula; laplacian eigenmaps; diffusion-weighted imaging; connectivity-based parcellation ID HUMAN CEREBRAL-CORTEX; OLD-WORLD MONKEY; COMPARATIVE CYTOARCHITECTONIC ANALYSIS; VENTROLATERAL PREFRONTAL CORTEX; SUPERIOR PARIETAL CORTEX; MACAQUE MONKEY; HUMAN BRAIN; RHESUS-MONKEY; CORTICOCORTICAL CONNECTIONS; CORTICAL CONNECTIONS AB The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions. Hum Brain Mapp 33:20052034, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Cerliani, Leonardo] Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, BCN NeuroImaging Ctr, NL-9713 AW Groningen, Netherlands. [Cerliani, Leonardo; Gazzola, Valeria; Keysers, Christian] Royal Netherlands Acad Arts & Sci, Social Brain Lab, Netherlands Inst Neurosci, Amsterdam, Netherlands. [Thomas, Rajat M.] Univ Groningen, Kapteyn Astron Inst, Fac Math & Nat Sci, NL-9700 AV Groningen, Netherlands. [Jbabdi, Saad] Univ Oxford, Oxford Ctr Funct Magnet Resonance Imaging Brain F, Dept Clin Neurol, Oxford OX1 2JD, England. [Siero, Jeroen C. W.] Univ Med Ctr Utrecht, Dept Radiol, Utrecht, Netherlands. [Crippa, Alessandro] Univ Groningen, Inst Math & Comp Sci, Sci Visualizat & Comp Graph Grp, NL-9700 AV Groningen, Netherlands. [D'Arceuil, Helen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. RP Cerliani, L (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Neurosci, BCN NeuroImaging Ctr, Antonius Deusinglaan 2, NL-9713 AW Groningen, Netherlands. EM leonardo.cerliani@gmail.com RI Thomas, Rajat/B-7105-2014; OI Thomas, Rajat/0000-0002-5362-4816; Gazzola, Valeria/0000-0003-0324-0619; Jbabdi, Saad/0000-0003-3234-5639; Keysers, Christian/0000-0002-2845-5467; cerliani, leonardo/0000-0002-2655-6133 FU Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Cognitive Pilot Project [051.07.003]; NWO VIDI [452-04-305]; NWO MaGW [400-08-089]; Marie Curie Excellence Grant [MEXT-CT-2005-023253] FX Contract grant sponsor: Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) Cognitive Pilot Project; Contract grant number: 051.07.003; Contract grant sponsor: NWO VIDI; Contract grant number: 452-04-305; Contract grant sponsor: NWO MaGW; Contract grant number: 400-08-089; Contract grant sponsor: Marie Curie Excellence Grant; Contract grant number: MEXT-CT-2005-023253. NR 177 TC 70 Z9 71 U1 3 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2012 VL 33 IS 9 BP 2005 EP 2034 DI 10.1002/hbm.21338 PG 30 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 989XB UT WOS:000307593400001 PM 21761507 ER PT J AU Ciesielski, KT Rauch, SL Ahlfors, SP Vangel, ME Wilhelm, S Rosen, BR Hamalainen, MS AF Ciesielski, Kristina T. Rauch, Scott L. Ahlfors, Seppo P. Vangel, Mark E. Wilhelm, Sabine Rosen, Bruce R. Haemaelaeinen, Matti S. TI Role of medial cortical networks for anticipatory processing in obsessive-compulsive disorder SO HUMAN BRAIN MAPPING LA English DT Article DE OCD; MEG; anticipatory top-down control; posterior medial self-regulatory networks; compensatory mechanism ID VISUAL-ATTENTION; DEFAULT-MODE; RETROSPLENIAL CORTEX; COGNITIVE CONTROL; NEURONAL-ACTIVITY; MACAQUE MONKEY; BRAIN-FUNCTION; MEMORY TASK; ACTIVATION; MEG AB Recurrent anticipation of ominous events is central to obsessions, the core symptom of obsessive-compulsive disorder (OCD), yet the neural basis of intrinsic anticipatory processing in OCD is unknown. We studied nonmedicated adults with OCD and case matched healthy controls in a visual-spatial working memory task with distractor. Magnetoencephalography was used to examine the medial cortex activity during anticipation of to-be-inhibited distractors and to-be-facilitated retrieval stimuli. In OCD anticipatory activation to distractors was abnormally reduced within the posterior cingulate and fusiform gyrus compared to prominent activation in controls. Conversely, OCD subjects displayed significantly increased activation to retrieval stimuli within the anterior cingulate and supplementary motor cortex. This previously unreported discordant pattern of medial anticipatory activation in OCD was accompanied by normal performance accuracy. While increased anterior cortex activation in OCD is commonly viewed as failure of inhibition, the current pattern of data implicates the operation of an anterior compensatory mechanism amending the posterior medial self-regulatory networks disrupted in OCD. Hum Brain Mapp 33:2125-2134, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Ciesielski, Kristina T.; Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ciesielski, Kristina T.; Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] Harvard Univ, McLean Hosp, Sch Med, Charlestown, MA USA. [Ciesielski, Kristina T.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Rauch, Scott L.; Wilhelm, Sabine] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Ahlfors, Seppo P.; Vangel, Mark E.; Rosen, Bruce R.; Haemaelaeinen, Matti S.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Ciesielski, KT (reprint author), Massachusetts Gen Hosp, Dept Radiol, MGH MIT HMS AA Martinos Ctr Biomed Imaging, Bldg 149,13th St, Charlestown, MA USA. EM ktc@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; Ahlfors, Seppo/P-3644-2016 FU National Center for Research Resources/National Institutes of Health [P41RR14075] FX Contract grant sponsor: National Center for Research Resources/National Institutes of Health; Contract grant number: P41RR14075. NR 52 TC 6 Z9 6 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2012 VL 33 IS 9 BP 2125 EP 2134 DI 10.1002/hbm.21341 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 989XB UT WOS:000307593400009 PM 21882299 ER PT J AU Al-Sukhni, W Joe, S Lionel, AC Zwingerman, N Zogopoulos, G Marshall, CR Borgida, A Holter, S Gropper, A Moore, S Bondy, M Klein, AP Petersen, GM Rabe, KG Schwartz, AG Syngal, S Scherer, SW Gallinger, S AF Al-Sukhni, Wigdan Joe, Sarah Lionel, Anath C. Zwingerman, Nora Zogopoulos, George Marshall, Christian R. Borgida, Ayelet Holter, Spring Gropper, Aaron Moore, Sara Bondy, Melissa Klein, Alison P. Petersen, Gloria M. Rabe, Kari G. Schwartz, Ann G. Syngal, Sapna Scherer, Stephen W. Gallinger, Steven TI Identification of germline genomic copy number variation in familial pancreatic cancer SO HUMAN GENETICS LA English DT Article ID COLORECTAL-CANCER; PROSTATE-CANCER; RISK; POPULATION; VARIANTS; GENE; ASSOCIATION; DELETIONS; ONSET; DISEASES AB Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer. C1 [Gallinger, Steven] Toronto Gen Hosp, Toronto, ON M5G 2C4, Canada. [Al-Sukhni, Wigdan; Zogopoulos, George; Gallinger, Steven] Univ Torontom, Div Gen Surg, Dept Surg, Toronto, ON, Canada. [Lionel, Anath C.; Marshall, Christian R.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada. [Lionel, Anath C.; Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, McLaughlin Ctr, Toronto, ON, Canada. [Bondy, Melissa] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Klein, Alison P.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sol Goldman Pancreat Res Ctr, Baltimore, MD USA. [Petersen, Gloria M.; Rabe, Kari G.] Mayo Clin, Coll Med, Rochester, MN USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Syngal, Sapna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Al-Sukhni, Wigdan; Joe, Sarah; Zwingerman, Nora; Zogopoulos, George; Borgida, Ayelet; Holter, Spring; Gropper, Aaron; Moore, Sara; Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Gallinger, S (reprint author), Toronto Gen Hosp, 10th Floor,Rm 10EN206,200 Elizabeth St, Toronto, ON M5G 2C4, Canada. EM wigdan.al.sukhni@utoronto.ca; steven.gallinger@uhn.on.ca RI Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Gallinger, Steven/E-4575-2013 OI Scherer, Stephen /0000-0002-8326-1999; FU National Institute of Health, Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE) [5R01CA097975-08]; Lustgarten Foundation; Princess Margaret Hospital Invest-in-Research Fund; Canadian Institute for Health Research; Canadian Society for Surgical Oncology; American Hepato-Pancreato-Biliary Association; Johnson & Johnson Medical Products/University of Toronto Surgeon Scientist Program Fellowship FX Sources of funding were from National Institute of Health, Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE) Grant#5R01CA097975-08; Lustgarten Foundation; Princess Margaret Hospital Invest-in-Research Fund; Canadian Institute for Health Research (Graduate Research Award; Vanier Doctoral Award); Canadian Society for Surgical Oncology; American Hepato-Pancreato-Biliary Association; Johnson & Johnson Medical Products/University of Toronto Surgeon Scientist Program Fellowship. We thank the following individuals for their contributions: A. Fiebig, A. Franke and S. Schreiber at POPGEN (University of Kiel, Kiel, Germany) and A. Stewart, R. McPherson and R. Roberts of the University of Ottawa Heart Institute (University of Ottawa, Ottawa, Canada) for generously providing population control microarray data; D. Merico and D. Pinto (The Centre for Applied Genomics, Toronto, Canada) for assistance with data review; G. Bader (University of Toronto, Toronto, Canada) and S. Narod (Women's College Hospital, Toronto, Canada) for review of the manuscript; H. Rothenmund (Samuel Lunenefeld Research Institute, Toronto, Canada) for her help with patient selection for the study; T. Selander of the Biospecimen Repository (Samuel Lunenfeld Research Institute, Toronto, Canada) for DNA extraction and storage. PACGENE coordinators (Mayo Clinic: J. Cogswell, T. Hammer, C. Wong; JHU: D. Echavarria; Karmanos: K. Sargent; MDA: P. Adatto, G. Armstrong; Dana Farber: M. Lenn, M. Perez, C. Ukaegbu). NR 52 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD SEP PY 2012 VL 131 IS 9 BP 1481 EP 1494 DI 10.1007/s00439-012-1183-1 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 988UG UT WOS:000307515600007 PM 22665139 ER PT J AU Usenovic, M Knight, AL Ray, A Wong, V Brown, KR Caldwell, GA Caldwell, KA Stagljar, I Krainc, D AF Usenovic, Marija Knight, Adam L. Ray, Arpita Wong, Victoria Brown, Kevin R. Caldwell, Guy A. Caldwell, Kim A. Stagljar, Igor Krainc, Dimitri TI Identification of novel ATP13A2 interactors and their role in alpha-synuclein misfolding and toxicity SO HUMAN MOLECULAR GENETICS LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; KUFOR-RAKEB SYNDROME; P-TYPE ATPASE; CAENORHABDITIS-ELEGANS; IN-VIVO; NEURODEGENERATIVE DISEASES; DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; SPLIT-UBIQUITIN; PROTEIN AB Lysosomes are responsible for degradation and recycling of bulky cell material, including accumulated misfolded proteins and dysfunctional organelles. Increasing evidence implicates lysosomal dysfunction in several neurodegenerative disorders, including Parkinson's disease and related synucleinopathies, which are characterized by the accumulation of alpha-synuclein (alpha-syn) in Lewy bodies. Studies of lysosomal proteins linked to neurodegenerative disorders present an opportunity to uncover specific molecular mechanisms and pathways that contribute to neurodegeneration. Loss-of-function mutations in a lysosomal protein, ATP13A2 (PARK9), cause Kufor-Rakeb syndrome that is characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While loss of ATP13A2 function plays a role in alpha-syn misfolding and toxicity, the normal function of ATP13A2 in the brain remains largely unknown. Here, we performed a screen to identify ATP13A2 interacting partners, as a first step toward elucidating its function. Utilizing a split-ubiquitin membrane yeast two-hybrid system that was developed to identify interacting partners of full-length integral membrane proteins, we identified 43 novel interactors that primarily implicate ATP13A2 in cellular processes such as endoplasmic reticulum (ER) translocation, ER-to-Golgi trafficking and vesicular transport and fusion. We showed that a subset of these interactors modified alpha-syn aggregation and alpha-syn-mediated degeneration of dopaminergic neurons in Caenorhabditis elegans, further suggesting that ATP13A2 and alpha-syn are functionally linked in neurodegeneration. These results implicate ATP13A2 in vesicular trafficking and provide a platform for further studies of ATP13A2 in neurodegeneration. C1 [Usenovic, Marija; Krainc, Dimitri] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Charlestown, MA 02129 USA. [Usenovic, Marija] Mediterranean Inst Life Sci, Split 21000, Croatia. [Knight, Adam L.; Ray, Arpita; Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama, Dept Biol Sci, Tuscaloosa, AL 35487 USA. [Wong, Victoria; Stagljar, Igor] Univ Toronto, Dept Biochem, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Wong, Victoria; Stagljar, Igor] Univ Toronto, Dept Mol Genet, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Brown, Kevin R.] Univ Toronto, Donnelly Ctr, Banting & Best Dept Med Res, Toronto, ON M5S 3E1, Canada. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurol, Birmingham, AL 35294 USA. [Caldwell, Guy A.; Caldwell, Kim A.] Univ Alabama Birmingham, Ctr Neurodegenerat & Expt Therapeut, Dept Neurobiol, Birmingham, AL 35294 USA. RP Krainc, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, 114 16th St,Room 2008, Charlestown, MA 02129 USA. EM krainc@helix.mgh.harvard.edu FU National Institutes of Health [R01NS051303, R15NS075684]; Canadian Foundation for Innovation (CFI); Canadian Institutes of Health Research (CIHR); Canadian Cancer Society Research Institute (CCSRI); Heart and Stroke Foundation; Cystic Fibrosis Foundation; Ontario Genomics Institute; Natural Sciences and Engineering Research Council of Canada (NSERC); Novartis FX This work was supported by National Institutes of Health (R01NS051303 to D. K. and R15NS075684 to G. A. C.). The research in the Stagljar lab is supported by grants from the Canadian Foundation for Innovation (CFI), the Canadian Institutes of Health Research (CIHR), the Canadian Cancer Society Research Institute (CCSRI), the Heart and Stroke Foundation, the Cystic Fibrosis Foundation, the Ontario Genomics Institute, Natural Sciences and Engineering Research Council of Canada (NSERC), and Novartis. NR 53 TC 32 Z9 33 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2012 VL 21 IS 17 BP 3785 EP 3794 DI 10.1093/hmg/dds206 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 988PX UT WOS:000307504100005 PM 22645275 ER PT J AU Fasching, PA Pharoah, PDP Cox, A Nevanlinna, H Bojesen, SE Karn, T Broeks, A van Leeuwen, FE van 't Veer, LJ Udo, R Dunning, AM Greco, D Aittomaki, K Blomqvist, C Shah, M Nordestgaard, BG Flyger, H Hopper, JL Southey, MC Apicella, C Garcia-Closas, M Sherman, M Lissowska, J Seynaeve, C Huijts, PEA Tollenaar, RAEM Ziogas, A Ekici, AB Rauh, C Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Andrulis, IL Ozcelik, H Mulligan, AM Glendon, G Hall, P Czene, K Liu, JJ Chang-Claude, J Wang-Gohrke, S Eilber, U Nickels, S Doerk, T Schiekel, M Bremer, M Park-Simon, TW Giles, GG Severi, G Baglietto, L Hooning, MJ Martens, JWM Jager, A Kriege, M Lindblom, A Margolin, S Couch, FJ Stevens, KN Olson, JE Kosei, M Cross, SS Balasubramanian, SP Reed, MWR Miron, A John, EM Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Burwinkel, B Marme, F Schneeweiss, A Sohn, C Chenevix-Trench, G Lambrechts, D Dieudonne, AS Hatse, S van Limbergen, E Benitez, J Milne, RL Zamora, MP Perez, JIA Bonanni, B Peissel, B Loris, B Peterlongo, P Rajaraman, P Schonfeld, SJ Anton-Culver, H Devilee, P Beckmann, MW Slamon, DJ Phillips, KA Figueroa, JD Humphreys, MK Easton, DF Schmidt, MK AF Fasching, Peter A. Pharoah, Paul D. P. Cox, Angela Nevanlinna, Heli Bojesen, Stig E. Karn, Thomas Broeks, Annegien van Leeuwen, Flora E. van 't Veer, Laura J. Udo, Renate Dunning, Alison M. Greco, Dario Aittomaki, Kristiina Blomqvist, Carl Shah, Mitul Nordestgaard, Borge G. Flyger, Henrik Hopper, John L. Southey, Melissa C. Apicella, Carmel Garcia-Closas, Montserrat Sherman, Mark Lissowska, Jolanta Seynaeve, Caroline Huijts, Petra E. A. Tollenaar, Rob A. E. M. Ziogas, Argyrios Ekici, Arif B. Rauh, Claudia Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Andrulis, Irene L. Ozcelik, Hilmi Mulligan, Anna-Marie Glendon, Gord Hall, Per Czene, Kamila Liu, Jianjun Chang-Claude, Jenny Wang-Gohrke, Shan Eilber, Ursula Nickels, Stefan Doerk, Thilo Schiekel, Maria Bremer, Michael Park-Simon, Tjoung-Won Giles, Graham G. Severi, Gianluca Baglietto, Laura Hooning, Maartje J. Martens, John W. M. Jager, Agnes Kriege, Mieke Lindblom, Annika Margolin, Sara Couch, Fergus J. Stevens, Kristen N. Olson, Janet E. Kosei, Matthew Cross, Simon S. Balasubramanian, Sabapathy P. Reed, Malcolm W. R. Miron, Alexander John, Esther M. Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Burwinkel, Barbara Marme, Frederik Schneeweiss, Andreas Sohn, Christof Chenevix-Trench, Georgia Lambrechts, Diether Dieudonne, Anne-Sophie Hatse, Sigrid van Limbergen, Erik Benitez, Javier Milne, Roger L. Pilar Zamora, M. Arias Perez, Jose Ignacio Bonanni, Bernardo Peissel, Bernard Loris, Bernard Peterlongo, Paolo Rajaraman, Preetha Schonfeld, Sara J. Anton-Culver, Hoda Devilee, Peter Beckmann, Matthias W. Slamon, Dennis J. Phillips, Kelly-Anne Figueroa, Jonine D. Humphreys, Manjeet K. Easton, Douglas F. Schmidt, Marjanka K. CA KConFab Investigators TI The role of genetic breast cancer susceptibility variants as prognostic factors SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CONFER SUSCEPTIBILITY; COMMON VARIANTS; ATM GENE; RISK; SURVIVAL; POLYMORPHISMS; LOCUS; WOMEN; CONSORTIUM AB Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers1.21; 95 CI: 1.091.35, P0.0002 and HR1.29; 95 CI: 1.121.47, P0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. C1 [Fasching, Peter A.; Rauh, Claudia; Beckmann, Matthias W.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr,Comprehens Canc Ctr Erlangen Nure, D-91054 Erlangen, Germany. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, D-91054 Erlangen, Germany. [Fasching, Peter A.; Slamon, Dennis J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA. [Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Cambridge, England. [Pharoah, Paul D. P.; Humphreys, Manjeet K.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Cox, Angela] Univ Sheffield, Inst Canc Studies, CRUK YCR Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield, S Yorkshire, England. [Balasubramanian, Sabapathy P.; Reed, Malcolm W. R.] Univ Sheffield, Acad Unit Surg Oncol, CRUK YCR Sheffield Canc Res Ctr, Dept Oncol, Sheffield, S Yorkshire, England. [Nevanlinna, Heli; Greco, Dario] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Blomqvist, Carl] Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Copenhagen, Denmark. [Bojesen, Stig E.; Nordestgaard, Borge G.] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Flyger, Henrik] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Copenhagen, Denmark. [Karn, Thomas] Goethe Univ Frankfurt, Univ Hosp, Dept Gynecol & Obstet, Frankfurt, Germany. [Broeks, Annegien; van 't Veer, Laura J.; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands. [van Leeuwen, Flora E.; Udo, Renate; Giles, Graham G.; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Southey, Melissa C.] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Hopper, John L.; Apicella, Carmel; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Enviromental Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England. [Sherman, Mark; Figueroa, Jonine D.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Seynaeve, Caroline; Jager, Agnes; Kriege, Mieke] Dr Daniel Den Hoed Canc Ctr, Erasmus Med Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. [Huijts, Petra E. A.; Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Tollenaar, Rob A. E. M.; Hooning, Maartje J.] Leiden Univ, Dept Surg Oncol, Med Ctr, Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Ziogas, Argyrios; Anton-Culver, Hoda] Univ Calif Irvine, Sch Med, UCI Ctr Canc Genet Res & Prevent, Irvine, CA 92717 USA. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.] Univ Eastern Finland, Canc Ctr Eastern Finland, Bioctr Kuopio, Kuopio, Finland. [Kataja, Vesa] Univ Eastern Finland, Inst Clin Med, Sch Med, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland. [Kataja, Vesa; Glendon, Gord] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland. [Andrulis, Irene L.] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna-Marie] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Andrulis, Irene L.; Ozcelik, Hilmi] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet,Dept Lab Med & Patho, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.; Mulligan, Anna-Marie] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet,Dept Mol Genet, Toronto, ON M5G 1X5, Canada. St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Dept Lab Med, Toronto, ON M5B 1W8, Canada. [Hall, Per; Czene, Kamila] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lindblom, Annika] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Margolin, Sara] Karolinska Inst, Dept Oncol & Pathol, Stockholm, Sweden. [Liu, Jianjun] Genome Inst Singapore, Human Genet Lab, Singapore, Singapore. [Chang-Claude, Jenny; Eilber, Ursula; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, Mol Epidemiol Unit, Heidelberg, Germany. [Wang-Gohrke, Shan] Univ Ulm, Univ Hosp Ulm, Dept Obstet & Gynecol, Ulm, Germany. [Doerk, Thilo; Schiekel, Maria; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Obstet, D-3000 Hannover, Germany. [Doerk, Thilo; Schiekel, Maria; Park-Simon, Tjoung-Won] Hannover Med Sch, Clin Gynaecol, D-3000 Hannover, Germany. [Bremer, Michael] Hannover Med Sch, Clin Radiat Oncol, D-3000 Hannover, Germany. [Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Martens, John W. M.] Erasmus Univ, Josephine Nefkens Inst, Dept Med Oncol, Med Ctr, Rotterdam, Netherlands. [Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Stevens, Kristen N.; Olson, Janet E.; Kosei, Matthew] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Miron, Alexander] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [John, Esther M.] Stanford Canc Inst, Stanford, CA USA. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Dept Clin Genet, Lab Canc Genet, Oulu, Finland. [Winqvist, Robert; Pylkas, Katri] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Jukkola-Vuorinen, Arja] Univ Oulu, Dept Oncol, Oulu Univ Hosp, Oulu, Finland. [Kauppila, Saila] Univ Oulu, Dept Pathol, Oulu Univ Hosp, Oulu, Finland. [Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof] Heidelberg Univ, Univ Heidelberg Hosp, Dept Obstet & Gynecol, Heidelberg, Germany. [Marme, Frederik; Schneeweiss, Andreas] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, Sect Gynecol Oncol, Heidelberg, Germany. [Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Lambrechts, Diether] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Louvain, Belgium. [Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik] Katholieke Univ Leuven, Univ Hosp, Leuven Multidisciplinary Breast Ctr, Louvain, Belgium. [Benitez, Javier] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Milne, Roger L.] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Genet & Mol Epidemiol Grp, Madrid, Spain. [Pilar Zamora, M.] Hosp Univ La Paz, Serv Oncol Med, Madrid, Spain. [Arias Perez, Jose Ignacio] Hosp Mt Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain. [Bonanni, Bernardo] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy. [Loris, Bernard] Ist Europeo Oncol, Dept Expt Oncol, Milan, Italy. [Peissel, Bernard] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy. [Peterlongo, Paolo] IFOM, Fdn Ist FIRC Oncol Mol, Milan, Italy. [Rajaraman, Preetha; Schonfeld, Sara J.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Div Canc Med, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Univ Melbourne, St Vincents Hosp, Dept Med, Melbourne, Vic 3010, Australia. RP Fasching, PA (reprint author), Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Univ Breast Ctr,Comprehens Canc Ctr Erlangen Nure, D-91054 Erlangen, Germany. EM peter.fasching@uk-erlangen.de RI Verdrengh, Evelien/H-4571-2012; Peissel, Bernard/E-8187-2017; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Dork, Thilo/J-8620-2012; karn, t/C-7452-2013; Garcia-Closas, Montserrat /F-3871-2015; Hartikainen, Jaana/E-6256-2015; OI Peissel, Bernard/0000-0001-9233-3571; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Phillips, Kelly-Anne/0000-0002-0475-1771; karn, t/0000-0002-3264-6573; Garcia-Closas, Montserrat /0000-0003-1033-2650; Greco, Dario/0000-0001-9195-9003; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Giles, Graham/0000-0003-4946-9099 FU European Community [223175 (HEALTH-F2-2009-223175) (COGS)]; CR-UK [C1287/A10118, C1287/A12014]; European Union COST programme [BM0606]; Cancer Research UK [C1287/A12014, C490/A10124, C490/A10119]; Cambridge Biomedical Research Centre; Dutch Cancer Society [NKI 2001-2423, NKI 2007-3839, DDHK 2004-3124, DDHK 2009-4318]; Dutch National Genomics Initiative; Dutch Biobanking and Biomolecular Resources Research Infrastructure; National Institutes of Health (NIH) National Cancer Institute (NCI) [CA122340]; NCI Recovery Act grant [CA122340Z]; NCI Specialized Program of Research Excellence (SPORE) in breast cancer [CA116201]; ELAN research program; University Hospital Erlangen; Deutsche Krebshilfe e. V. [70492]; state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P.685]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Associazione Italiana per la Ricerca sul Cancro [4017]; Fondazione IRCCS Istituto Nazionale Tumori; 'Stichting tegen Kanker' [232-2008, 196-2010]; Kuopio University Hospital; Cancer Fund of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Copenhagen University Hospital; Herlev Hospital; Rudolf Bartling Foundation; National Breast Cancer Foundation of Australia; Cancer Australia; National Health and Medical Research Council of Australia; Queensland Cancer Fund; Cancer Council of New South Wales; Cancer Council of Victoria; Cancer Council of Tasmania; Cancer Council of South Australia; Cancer Foundation of Western Australia; Victorian Health Promotion Foundation (Australia); Breast Cancer Campaign [2004Nov49]; Yorkshire Cancer Research [S295, S299]; Dietmar-Hopp Foundation; Helmholtz Society; German Cancer Research Center (DKFZ); Finnish Cancer Foundation; University of Oulu; Oulu University Hospital; Biocenter Oulu; Helsinki University Central Hospital Research Fund; Academy of Finland [132473]; Finnish Cancer Society; Nordic Cancer Union; Sigrid Juselius Foundation; Swedish Cancer Society; Stockholm Cancer Society; Gustav V Jubilee foundation; Bert von Kantzow foundation; Agency for Science; Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Marit and Hans Rausings Initiative Against Breast Cancer; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI081583, PI081120]; United States National Cancer Institute, National Institutes of Health (NIH) [RFA-CA-06-503] FX This work was supported by funding from the European Community's Seventh Framework Programme under grant agreement - 223175 (HEALTH-F2-2009-223175) (COGS). Co-ordination and genotyping in BCAC was funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). D. F. E. is a Principal Research Fellow of CR-UK. The genotyping was supported by Cancer Research UK (C490/A10124) and (C1287/A12014). Funding of the constituent studies and data analysis was supported by the Cambridge Biomedical Research Centre, Cancer Research UK (C490/A10119). Other studies have been funded by the Dutch Cancer Society (grants NKI 2001-2423; NKI 2007-3839), the Dutch National Genomics Initiative, the Dutch Biobanking and Biomolecular Resources Research Infrastructure, the National Institutes of Health (NIH) National Cancer Institute (NCI) grant CA122340, NCI Recovery Act grant CA122340Z, NCI Specialized Program of Research Excellence (SPORE) in breast cancer CA116201, the ELAN research program, University Hospital Erlangen, the Deutsche Krebshilfe e. V. (70492), the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm (P.685), the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, the Associazione Italiana per la Ricerca sul Cancro (4017) and funds from Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "5x1000"), the 'Stichting tegen Kanker' (232-2008 and 196-2010), the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland, the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Copenhagen University Hospital, Herlev Hospital, Rudolf Bartling Foundation, the National Breast Cancer Foundation of Australia, Cancer Australia, the National Health and Medical Research Council of Australia, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, the Cancer Foundation of Western Australia, the Victorian Health Promotion Foundation (Australia), the Breast Cancer Campaign (2004Nov49), Yorkshire Cancer Research (S295, S299 and core funding), the Dietmar-Hopp Foundation, the Helmholtz Society, the German Cancer Research Center (DKFZ), the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, the Oulu University Hospital, Biocenter Oulu; the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union and the Sigrid Juselius Foundation; the Dutch Cancer Society, grants DDHK 2004-3124 and DDHK 2009-4318, the Swedish Cancer Society, the Stockholm Cancer Society, the Gustav V Jubilee foundation, the Bert von Kantzow foundation, the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH), the Susan G. Komen Breast Cancer Foundation and Marit and Hans Rausings Initiative Against Breast Cancer, the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario (PI081583 and PI081120).; The ABCFS, NC-BCFR and OFBCR work was supported by the United States National Cancer Institute, National Institutes of Health (NIH) under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417) and University of Melbourne (U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. NR 61 TC 41 Z9 41 U1 0 U2 19 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 1 PY 2012 VL 21 IS 17 BP 3926 EP 3939 DI 10.1093/hmg/dds159 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 988PX UT WOS:000307504100018 PM 22532573 ER PT J AU de Jesus-Gonzalez, N Robinson, E Moslehi, J Humphreys, BD AF de Jesus-Gonzalez, Nilka Robinson, Emily Moslehi, Javid Humphreys, Benjamin D. TI Management of Antiangiogenic Therapy-Induced Hypertension SO HYPERTENSION LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; NITRIC-OXIDE SYNTHASE; ANGIOGENESIS INHIBITOR BEVACIZUMAB; ARTERIAL THROMBOEMBOLIC EVENTS; PREECLAMPSIA-LIKE SYNDROME; HIGH BLOOD-PRESSURE; CANCER-PATIENTS; KINASE INHIBITORS; PLUS BEVACIZUMAB C1 [de Jesus-Gonzalez, Nilka] Boston Childrens Hosp, Div Nephrol, Boston, MA USA. [Robinson, Emily; Humphreys, Benjamin D.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Moslehi, Javid] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Moslehi, Javid; Humphreys, Benjamin D.] Dana Farber Canc Inst, Lance Armstrong Fdn, Boston, MA 02115 USA. RP Humphreys, BD (reprint author), Harvard Inst Med, Room 554,4 Blackfan Cir, Boston, MA 02115 USA. EM bhumphreys@partners.org FU National Institutes of Health Training Grant [T32-DK007726-27S1, DK088923] FX This work was supported by the National Institutes of Health Training Grant T32-DK007726-27S1 (to N.D.G.) and DK088923 (to B.D.H.). NR 67 TC 21 Z9 21 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD SEP PY 2012 VL 60 IS 3 BP 607 EP 615 DI 10.1161/HYPERTENSIONAHA.112.196774 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 994SM UT WOS:000307951900015 PM 22851729 ER PT J AU Chiu, CY Gomolka, B Dierkes, C Huang, NR Schroeder, M Purschke, M Manstein, D Dangi, B Weylandt, KH AF Chiu, Cheng-Ying Gomolka, Beate Dierkes, Cordula Huang, Nora R. Schroeder, Maik Purschke, Martin Manstein, Dieter Dangi, Bindi Weylandt, Karsten H. TI Omega-6 docosapentaenoic acid-derived resolvins and 17-hydroxydocosahexaenoic acid modulate macrophage function and alleviate experimental colitis SO INFLAMMATION RESEARCH LA English DT Article DE PUFA; 17-HDHA; 17-HDPA; 10,17-HDPA; Colitis; Lipid mediators ID INFLAMMATORY-BOWEL-DISEASE; ASPIRIN-TRIGGERED LIPOXIN; ALTERNATIVE ACTIVATION; DOCOSAHEXAENOIC ACID; APOPTOTIC NEUTROPHILS; CROHNS-DISEASE; RESOLUTION; PHAGOCYTOSIS; MICE; E1 AB Enzymatically oxygenated lipid products derived from omega-3 and omega-6 fatty acids play an important role in inflammation dampening. This study examined the anti-inflammatory effects of n-6 docosapentaenoic acid-derived (17S)-hydroxy-docosapentaenoic acid (17-HDPAn-6) and (10,17S)-dihydroxy-docosapentaenoic acid (10,17-HDPAn-6) as well as n-3 docosahexaenoic acid-derived 17(R/S)-hydroxy-docosahexaenoic acid (17-HDHA). The effects of 17-HDPAn-6, 10,17-HDPAn-6 or 17-HDHA on activity and M1/M2 polarization of murine macrophage cell line RAW 264.7 were examined by phagocytosis assay and real-time PCR. To assess anti-inflammatory effects in vivo, dextran sodium sulfate (DSS) colitis was induced in mice treated with 17-HDPAn-6, 10,17-HDPAn-6, 17-HDHA or NaCl. Our results show that 17-HDPAn-6, 10,17-HDPAn-6 and 17-HDHA increase phagocytosis in macrophages in vitro and promote polarization towards the anti-inflammatory M2 phenotype with decreased gene expression of TNF-alpha and inducible Nitric oxide synthase and increased expression of the chemokine IL-1 receptor antagonist and the Scavenger receptor Type A. Intraperitoneal treatment with 17-HDPAn-6, 10,17-HDPAn-6, or 17-HDHA alleviated DSS-colitis and significantly improved body weight loss, colon epithelial damage, and macrophage infiltration. These results suggest that DPAn-6-derived 17-HDPAn-6 and 10,17-HDPAn-6 as well as the DHA-derived 17-HDHA have inflammation-dampening and resolution-promoting effects that could be used to treat inflammatory conditions such as inflammatory bowel disease. C1 [Weylandt, Karsten H.] Charite Campus Virchow Hosp, Med Klin MS Gastroenterol & Hepatol, D-13353 Berlin, Germany. [Chiu, Cheng-Ying; Gomolka, Beate; Dierkes, Cordula; Huang, Nora R.; Schroeder, Maik; Weylandt, Karsten H.] Charite, Campus Virchow Klinikum, Dept Hepatol Gastroenterol & Endocrinol, D-13353 Berlin, Germany. [Chiu, Cheng-Ying; Huang, Nora R.; Weylandt, Karsten H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lab Lipid Med & Technol, Boston, MA USA. [Purschke, Martin; Manstein, Dieter] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Dangi, Bindi] DSM Nutr Prod, Columbia, MD USA. RP Weylandt, KH (reprint author), Charite Campus Virchow Hosp, Med Klin MS Gastroenterol & Hepatol, Augustenburger Pl 1, D-13353 Berlin, Germany. EM karsten.weylandt@charite.de FU German Research Fund (DFG); Charite intramural research funds; Martek Biosciences; German Academic Exchange Service FX 17-HDPA and 10,17-HDPA were provided by Martek Biosciences (a division of DSM Nutritional Products). K.H.W. is supported by the German Research Fund (DFG) and Charite intramural research funds. Part of the research work presented here was funded by Martek Biosciences. C.Y.C. was supported by a grant from the German Academic Exchange Service (Biomedical Sciences Exchange Program). NR 53 TC 27 Z9 28 U1 0 U2 7 PU SPRINGER BASEL AG PI BASEL PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND SN 1023-3830 J9 INFLAMM RES JI Inflamm. Res. PD SEP PY 2012 VL 61 IS 9 BP 967 EP 976 DI 10.1007/s00011-012-0489-8 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 988UX UT WOS:000307517300007 PM 22618200 ER PT J AU Bandelow, B Sher, L Bunevicius, R Hollander, E Kasper, S Zohar, J Moller, HJ AF Bandelow, Borwin Sher, Leo Bunevicius, Robertas Hollander, Eric Kasper, Siegfried Zohar, Joseph Moeller, Hans-Juergen TI Guidelines for the pharmacological treatment of anxiety disorders, obsessive compulsive disorder and post-traumatic stress disorder in primary care (vol 16, pg 77, 2012) SO INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE LA English DT Correction C1 [Sher, Leo] Mt Sinai Sch Med, New York, NY USA. [Sher, Leo] James J Peters Vet Adm Med Ctr, New York, NY USA. RI Bandelow, Borwin/E-7295-2011 OI Bandelow, Borwin/0000-0003-2511-3768 NR 1 TC 0 Z9 0 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1365-1501 J9 INT J PSYCHIAT CLIN JI Int. J. Psychiat. Clin. PD SEP PY 2012 VL 16 IS 3 BP 242 EP 242 DI 10.3109/13651501.2012.700008 PG 1 WC Psychiatry SC Psychiatry GA 985WF UT WOS:000307300500013 ER PT J AU Zickmund, SL Campbell, SA Tirado, CF Zook, CL Weinrieb, RM AF Zickmund, Susan L. Campbell, Scott A. Tirado, Carlos F. Zook, Carolyn L. Weinrieb, Robert M. TI Perceived Barriers to Hepatitis C Therapy for Patients Receiving Opioid Agonist Treatment SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE barriers to antiviral therapy; hepatitis C; opioid agonist treatment; provider communication; stigmatization ID METHADONE-MAINTENANCE PATIENTS; VIRUS-INFECTION; DRUG-USERS; ANTIVIRAL TREATMENT; TREATMENT SERVICES; UNITED-STATES; KNOWLEDGE; EXPERIENCES; CLIENTS; MANAGEMENT AB Objectives: To explore attitudes toward hepatitis C antiviral therapy in a real-world setting, we asked patients in opioid agonist treatment who were offered antiviral therapy about perceived barriers to initiating therapy. Methods: We recruited patients in opioid agonist treatment who had previously been offered cost-free hepatitis C antiviral therapy in a clinical trial. We collected demographic and open-ended interview data. The semistructured interview guide included questions about attitudes toward hepatitis C therapy and barriers to initiating treatment. Each interview was audio recorded and transcribed verbatim. We used the qualitative editing method to analyze the interview transcripts. Results: We enrolled 19 patients who had been approached to initiate hepatitis C therapy in a clinical trial. All participants were low-income men, with one third self-identifying as racial minorities. When asked about possible barriers to treatment, multiple problems emerged, including the fear of treatment side effects, difficulties with health care providers, limited access to medical care and health information, and misperceptions about antiviral therapy. Conclusions: Despite intense educational efforts, concerns over antiviral therapy, relations with providers, and access to the health care system remain critical barriers. These factors should be addressed to improve antiviral therapy rates for patients receiving opioid agonist treatment. C1 [Zickmund, Susan L.; Zook, Carolyn L.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Zickmund, Susan L.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Campbell, Scott A.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Tirado, Carlos F.] Univ Texas SW Med Ctr, Dept Psychiat, Austin, TX USA. [Zook, Carolyn L.] Univ Pittsburgh, Dept Sociol, Pittsburgh, PA USA. [Weinrieb, Robert M.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Zickmund, SL (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr 151C-H, Pittsburgh, PA 15206 USA. EM Susan.Zickmund@va.gov FU Veterans Administration (VA) Health Services Research & Development (HSR&D) Merit Review Entry Program Career Development Award and Merit Review; VA VISN 4 Mental Illness Research, Education, and Clinical Center; VA HSRD; National Institutes of Health (NIH) FX Supported in part by the Veterans Administration (VA) Health Services Research & Development (HSR&D) Merit Review Entry Program Career Development Award and Merit Review and was also supported by pilot funds from the VA VISN 4 Mental Illness Research, Education, and Clinical Center. Dr Zickmund is currently receiving research support from the VA HSR&D. Dr Tirado has received honoraria from Rickett-Benckiser, Alkermes, and has received payments for educational presentations from the Texas Department of State Health Services. Dr Weinrieb is currently receiving research support from National Institutes of Health (NIH), has given legal testimony, and has given lectures to the University of Pennsylvania and received payment. The remaining authors have no conflicts of interest to declare. NR 39 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 J9 J ADDICT MED JI J. Addict. Med. PD SEP PY 2012 VL 6 IS 3 BP 233 EP 239 DI 10.1097/ADM.0b013e31825f491b PG 7 WC Substance Abuse SC Substance Abuse GA 993CS UT WOS:000307833400009 PM 22790464 ER PT J AU Tanner, ACR Sonis, AL Holgerson, PL Starr, JR Nunez, Y Kressirer, CA Paster, BJ Johansson, I AF Tanner, A. C. R. Sonis, A. L. Holgerson, P. Lif Starr, J. R. Nunez, Y. Kressirer, C. A. Paster, B. J. Johansson, I. TI White-spot Lesions and Gingivitis Microbiotas in Orthodontic Patients SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE orthodontic; adolescents; white-spot lesions; microbial ecology; Scardovia wiggsiae; HOMIM ID EARLY-CHILDHOOD CARIES; FIXED APPLIANCES; PERMANENT TEETH; CHILDREN; PCR; ADOLESCENTS; PREVALENCE; MICROFLORA; BRACKETS AB White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL. C1 [Tanner, A. C. R.; Kressirer, C. A.; Paster, B. J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Starr, J. R.] Forsyth Inst, Ctr Clin & Translat Res, Cambridge, MA USA. [Tanner, A. C. R.; Kressirer, C. A.; Paster, B. J.] Harvard Univ, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Sonis, A. L.] Harvard Univ, Dept Dev Biol, Boston, MA 02115 USA. [Starr, J. R.] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Holgerson, P. Lif; Johansson, I.] Umea Univ, Fac Med, Dept Odontol, Cariol Sect, Umea, Sweden. [Starr, J. R.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Nunez, Y.] Seton Hall Univ, S Orange, NJ 07079 USA. RP Tanner, ACR (reprint author), Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. EM annetanner@forsyth.org OI Starr, Jacqueline/0000-0002-3039-2311 FU USPHS from the NIDCR (NIH) [DE-015847, DE-021796, DE-007327]; Throne-Holst's Foundation; Bingham Trust; Harvard Catalyst [UL1 RR 025758, RC1 DE020549] FX We thank Winston Kuo and Alex Trachtenberg for assistance with qPCR assays, and Ralph Kent and Natalia Chalmers in project development. This work was conducted with support from USPHS grants DE-015847, DE-021796, and DE-007327 from the NIDCR (NIH), Throne-Holst's Foundation, the Bingham Trust, and Harvard Catalyst UL1 RR 025758, RC1 DE020549. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 26 TC 14 Z9 15 U1 7 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD SEP PY 2012 VL 91 IS 9 BP 853 EP 858 DI 10.1177/0022034512455031 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 989ES UT WOS:000307543700008 PM 22837552 ER PT J AU Beverly, EA Ritholz, MD Brooks, KM Hultgren, BA Lee, Y Abrahamson, MJ Weinger, K AF Beverly, Elizabeth A. Ritholz, Marilyn D. Brooks, Kelly M. Hultgren, Brittney A. Lee, Yishan Abrahamson, Martin J. Weinger, Katie TI A Qualitative Study of Perceived Responsibility and Self-Blame in Type 2 Diabetes: Reflections of Physicians and Patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE physician-patient relationship; type 2 diabetes; self-care behavior; qualitative methodology ID DIAGNOSED BREAST-CANCER; GLYCEMIC CONTROL; PSYCHOLOGICAL ADJUSTMENT; PSYCHOSOCIAL ISSUES; CHRONIC ILLNESS; GLUCOSE CONTROL; CHRONIC DISEASE; CARE; DEPRESSION; ADHERENCE AB Despite new treatment therapies and the emphasis on patient activation, nearly 50 % of diabetes patients have hemoglobin A(1c) levels above target. Understanding the impact of unmet treatment goals on the physician-patient relationship is important for maintaining quality care in clinical practice. To explore physicians' and type 2 diabetes patients' views of patients' difficulty achieving diabetes treatment goals. Qualitative study using in-depth interviews with a semi-structured interview guide. Nineteen endocrinologists and primary care physicians and 34 patients diagnosed with type 2 diabetes at least two years prior. In-depth interviews with physicians and patients. A multidisciplinary research team performed content and thematic analyses. Qualitative analysis revealed two main findings, organized by physician and patient perspectives. Physician Perspective: Physicians' Perceived Responsibility for Patients' Difficulty Achieving Treatment Goals: Physicians assumed responsibility for their patients not achieving goals and expressed concern that they may not be doing enough to help their patients achieve treatment goals. Physicians' Perceptions of Patients' Reactions: Most speculated that their patients may feel guilt, frustration, or disappointment when not reaching goals. Physicians also felt that many patients did not fully understand the consequences of diabetes. Patient Perspective: Patients' Self-Blame for Difficulty Achieving Treatment Goals: Patients attributed unmet treatment goals to their inability to carry out self-care recommendations. Most patients blamed themselves for their lack of progress and directed their frustration and disappointment inwardly through self-deprecating comments. Patients' Perceptions of Physicians' Reactions: Several patients did not know how their physician felt, while others speculated that their physicians might feel disappointed or frustrated. Physicians' perceived responsibility and patients' self-blame for difficulty achieving treatment goals may serve as barriers to an effective relationship. Physicians and patients may benefit from a greater understanding of each other's frustrations and challenges in diabetes management. C1 [Abrahamson, Martin J.; Weinger, Katie] Joslin Diabet Ctr, Joslin Clin, Boston, MA 02215 USA. [Beverly, Elizabeth A.; Ritholz, Marilyn D.; Abrahamson, Martin J.; Weinger, Katie] Harvard Univ, Sch Med, Boston, MA USA. [Ritholz, Marilyn D.] Childrens Hosp, Boston, MA 02115 USA. RP Weinger, K (reprint author), Joslin Diabet Ctr, Joslin Clin, 1 Joslin Pl, Boston, MA 02215 USA. EM Katie.Weinger@joslin.harvard.edu FU Kathleen P. Welsh Fund; NIDDK [RO1-060115]; NIH [P30 DK36836, T32 DK007260]; Diabetes and Endocrinology Research Core NIH [P30 DK36836] FX Funded by Kathleen P. Welsh Fund, NIDDK RO1-060115, NIH P30 DK36836, NIH Training Grant No. T32 DK007260; This work was supported by the Kathleen P. Welsh Fund, NIDDK RO1-060115, the Diabetes and Endocrinology Research Core NIH P30 DK36836, and the NIH Training Grant No. T32 DK007260. We thank the physicians and patients who shared their experiences and perceptions with us. We also thank Dr. Nadine Palermo, Nicholas Hebert, and Ross Markello for their useful comments on the manuscript. NR 68 TC 9 Z9 9 U1 12 U2 25 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1180 EP 1187 DI 10.1007/s11606-012-2070-0 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300018 PM 22549299 ER PT J AU Spelman, JF Hunt, SC Seal, KH Burgo-Black, AL AF Spelman, Juliette F. Hunt, Stephen C. Seal, Karen H. Burgo-Black, A. Lucile TI Post Deployment Care for Returning Combat Veterans SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE combat; post-deployment; OEF/OIF; veteran; Iraq; Afghanistan ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMATIC BRAIN-INJURY; MENTAL-HEALTH DIAGNOSES; PERSISTENT POSTCONCUSSIVE SYMPTOMS; CHRONIC PAIN; AFGHANISTAN VETERANS; WAR VETERANS; GULF-WAR; LONGITUDINAL ASSESSMENT; MILITARY COHORT AB Since September 11, 2001, 2.4 million military personnel have deployed to Iraq and Afghanistan. To date, roughly 1.44 million have separated from the military and approximately 772,000 of these veterans have used VA health care. Combat deployments impact the physical, psychological, and social health of veterans. Given that many veterans are receiving care from non-VA providers, it is important that all community health care workers be familiar with the unique health care needs of this patient population, which include injuries associated with blast exposures (including mild traumatic brain injury), as well as a variety of mental health conditions, such as post-traumatic stress disorder. Other important health concerns are chronic musculoskeletal pain, medically unexplained symptoms, sequelae of environmental exposures, depression, suicide, substance abuse, sleep disturbances, and impairments in family, occupational and social functioning. Elevated rates of hypertension and tobacco use remind us that deployment may result not only in immediate impacts on health, but also increase risk for chronic disease, contributing to a growing public health burden. This paper provides a comprehensive review of these health concerns and offers practical management guidelines for primary care providers. In light of relationships between physical, psychological and psychosocial concerns in this population, we recommend an interdisciplinary approach to care directed toward mitigating the long-term health impacts of combat. C1 [Spelman, Juliette F.; Burgo-Black, A. Lucile] VA Connecticut Hlth Care Syst, West Haven, CT 06511 USA. [Spelman, Juliette F.; Burgo-Black, A. Lucile] Yale Univ, Sch Med, West Haven, CT USA. [Hunt, Stephen C.] Puget Sound VA Med Ctr, Seattle, WA USA. [Hunt, Stephen C.] Univ Washington, Sch Med, Seattle, WA USA. [Seal, Karen H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Seal, Karen H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Seal, Karen H.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Spelman, JF (reprint author), VA Connecticut Hlth Care Syst, 950 Campbell Ave,11 ACSL, West Haven, CT 06511 USA. EM Juliette.spelman@va.gov FU Department of Veterans Affairs, (VA) Health Services Research and Development (HSR&D) Research Enhancement Award Program at the San Francisco VA Medical Center FX Dr. Seal was financially supported by the Department of Veterans Affairs, (VA) Health Services Research and Development (HSR&D) Research Enhancement Award Program at the San Francisco VA Medical Center. NR 53 TC 45 Z9 45 U1 4 U2 28 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1200 EP 1209 DI 10.1007/s11606-012-2061-1 PG 10 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300021 PM 22648608 ER PT J AU Ahluwalia, SC Gross, CP Chaudhry, SI Ning, YMM Leo-Summers, L Van Ness, PH Fried, TR AF Ahluwalia, Sangeeta C. Gross, Cary P. Chaudhry, Sarwat I. Ning, Yuming M. Leo-Summers, Linda Van Ness, Peter H. Fried, Terri R. TI Impact of Comorbidity on Mortality Among Older Persons with Advanced Heart Failure (vol 27, pg 513, 2012) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Correction C1 [Ahluwalia, Sangeeta C.] VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, Los Angeles, CA 90064 USA. [Gross, Cary P.; Chaudhry, Sarwat I.] Yale Univ, Sch Med, Dept Med, Sect Gen Internal Med, New Haven, CT 06510 USA. [Ning, Yuming M.; Leo-Summers, Linda; Van Ness, Peter H.] Yale Univ, Sch Med, Program Aging, New Haven, CT USA. [Van Ness, Peter H.; Fried, Terri R.] Yale Univ, Sch Med, Dept Internal Med, Sect Geriatr, New Haven, CT 06510 USA. [Fried, Terri R.] VA Connecticut Healthcare Syst, Clin Epidemiol Res Ctr, West Haven, CT USA. RP Ahluwalia, SC (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, 11301 Wilshire Blvd,111-G, Los Angeles, CA 90064 USA. EM sangeeta.ahluwalia@va.gov NR 1 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2012 VL 27 IS 9 BP 1228 EP 1230 DI 10.1007/s11606-012-2127-0 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 988SP UT WOS:000307511300029 ER PT J AU Fang, JC DeMarco, T Givertz, MM Borlaug, BA Lewis, GD Rame, JE Gomberg-Maitland, M Murali, S Frantz, RP McGlothlin, D Horn, EM Benza, RL AF Fang, James C. DeMarco, Teresa Givertz, Michael M. Borlaug, Barry A. Lewis, Gregory D. Rame, J. Eduardo Gomberg-Maitland, Mardi Murali, Srinivas Frantz, Robert P. McGlothlin, Dana Horn, Evelyn M. Benza, Raymond L. TI World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult-a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article DE Pulmonary hypertension; eft heart disease; heart failure; hight heart failure; left ventricular assist device; heart transplant ID INHALED NITRIC-OXIDE; MITRAL-VALVE-REPLACEMENT; VENTRICULAR EJECTION FRACTION; RANDOMIZED CONTROLLED-TRIAL; SOLUBLE GUANYLATE-CYCLASE; CARDIOVASCULAR MAGNETIC-RESONANCE; ARTERIAL WEDGE PRESSURE; RAPID VOLUME EXPANSION; COLLEGE-OF-CARDIOLOGY; 30 YEARS EXPERIENCE AB Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council. J Heart Lung Transplant 2012;31:913-33 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Fang, James C.] Univ Hosp, Case Med Ctr, Harrington Heart & Vasc Inst, Div Cardiovasc Med, Cleveland, OH USA. [DeMarco, Teresa; McGlothlin, Dana] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. [Givertz, Michael M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Borlaug, Barry A.] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN USA. [Lewis, Gregory D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Rame, J. Eduardo] Univ Penn, Cardiovasc Res Inst, Philadelphia, PA USA. [Gomberg-Maitland, Mardi] Univ Chicago, Med Ctr, Dept Med, Chicago, IL 60637 USA. [Murali, Srinivas; Benza, Raymond L.] Allegheny Gen Hosp, Gerald McGinnis Cardiovasc Inst, Pittsburgh, PA 15212 USA. [Frantz, Robert P.] Mayo Clin & Mayo Fdn, Div Cardiovasc Dis, Rochester, MN USA. [Horn, Evelyn M.] Weill Cornell Med Coll, Perkin Heart Failure Ctr, New York, NY USA. RP Fang, JC (reprint author), Case Western Reserve Univ, Div Cardiovasc, 11100 Euclid Ave,Lakeside 3001, Cleveland, OH 44120 USA. EM james.fang@uhhospitals.org FU National Heart, Lung and Blood Institute, National Institutes of Health [K23-HL091106, U01-HL084877] FX No primary funding sources supported this project. Gregory D. Lewis, MD, received support from National Heart, Lung and Blood Institute, National Institutes of Health Grants K23-HL091106 and U01-HL084877. NR 189 TC 74 Z9 75 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD SEP PY 2012 VL 31 IS 9 BP 913 EP 933 DI 10.1016/j.healun.2012.06.002 PG 21 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 996UL UT WOS:000308120200001 PM 22884380 ER PT J AU Polasek, M Fuchs, BC Uppal, R Schuhle, DT Alford, JK Loving, GS Yamada, S Wei, L Lauwers, GY Guimaraes, AR Tanabe, KK Caravan, P AF Polasek, Miloslav Fuchs, Bryan C. Uppal, Ritika Schuehle, Daniel T. Alford, Jamu K. Loving, Galen S. Yamada, Suguru Wei, Lan Lauwers, Gregory Y. Guimaraes, Alexander R. Tanabe, Kenneth K. Caravan, Peter TI Molecular MR imaging of liver fibrosis: A feasibility study using rat and mouse models SO JOURNAL OF HEPATOLOGY LA English DT Article DE Molecular imaging; Gadolinium; Type I collagen; Carbon tetrachloride; Diethylnitrosamine ID MAGNETIC-RESONANCE ELASTOGRAPHY; HEPATIC-FIBROSIS; TRANSIENT ELASTOGRAPHY; CONTRAST AGENT; DISEASE; BIOPSY; COMPLICATIONS; DIAGNOSIS; CIRRHOSIS; READY AB Background & Aims: Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment. Methods: Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results: EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39 +/- 0.04, fibrotic = 0.55 +/- 0.03, p <0.01) and slower signal washout in the fibrotic liver compared to controls (liver t(1/2) = 51.3 +/- 3.6 vs. 42.0 +/- 2.5 min, p <0.05 and 54.5 +/- 1.9 vs. 44.1 +/- 2.9 min, p <0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusions: Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved. C1 [Polasek, Miloslav; Uppal, Ritika; Schuehle, Daniel T.; Alford, Jamu K.; Loving, Galen S.; Guimaraes, Alexander R.; Caravan, Peter] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Polasek, Miloslav; Uppal, Ritika; Schuehle, Daniel T.; Alford, Jamu K.; Loving, Galen S.; Guimaraes, Alexander R.; Caravan, Peter] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Fuchs, Bryan C.; Yamada, Suguru; Wei, Lan; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Fuchs, Bryan C.; Yamada, Suguru; Wei, Lan; Lauwers, Gregory Y.; Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Caravan, P (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu RI Polasek, Miloslav/G-5949-2014 FU NIH Institutes of Health; National Cancer Institute [CA140861, CA009502, CA076183, EB009062]; National Institute of Biomedical Imaging and Bioengineering fund; Tucker Gosnell Research fund FX The underlying research reported in the study was funded by the NIH Institutes of Health.; Grant Nos. CA140861 (B. C. F.), CA009502 (G. S. L), CA076183 (K. K. T), and EB009062 (P. C.) from the National Cancer Institute and the National Institute of Biomedical Imaging and Bioengineering, and Tucker Gosnell Research funds (K.K.T.) NR 43 TC 28 Z9 28 U1 2 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD SEP PY 2012 VL 57 IS 3 BP 549 EP 555 DI 10.1016/j.jhep.2012.04.035 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 994LU UT WOS:000307933100014 PM 22634342 ER PT J AU Huang, JV Greyson, CR Schwartz, GG AF Huang, Janice V. Greyson, Clifford R. Schwartz, Gregory G. TI PPAR-gamma as a therapeutic target in cardiovascular disease: evidence and uncertainty SO JOURNAL OF LIPID RESEARCH LA English DT Review DE peroxisome proliferator-activated receptor gamma; diabetes; insulin resistance; fatty acids; atherosclerosis; randomized clinical trials ID ACTIVATED-RECEPTOR-GAMMA; TYPE-2 DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; ENDOTHELIAL PROGENITOR CELLS; RANDOMIZED-CONTROLLED-TRIAL; DENSITY-LIPOPROTEIN-CHOLESTEROL; CORONARY-ARTERY-DISEASE; INTIMA-MEDIA THICKNESS; K-ATP CHANNEL; ALL-CAUSE MORTALITY AB Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-gamma has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-gamma activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-gamma activation, or off-target effects of thiazolidinedione agents.(jlr) This review addresses these issues from a clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-gamma activators in cardiovascular disease.-Huang, J. V., C. R. Greyson, and G. G. Schwartz. PPAR-gamma as a therapeutic target in cardiovascular disease: evidence and uncertainty. J. Lipid Res. 2012. 53: 1738-1754. C1 [Schwartz, Gregory G.] US Dept Vet Affairs, Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. Univ Colorado, Sch Med, Denver, CO USA. RP Schwartz, GG (reprint author), US Dept Vet Affairs, Denver VA Med Ctr, Cardiol Sect, Denver, CO USA. EM Gregory.Schwartz@va.gov FU Medical Research Service, US Department of Veterans Affairs; National Institutes of Health Grant [5-R01-HL-049944]; Roche Laboratories FX This work was supported by the Medical Research Service, US Department of Veterans Affairs and by National Institutes of Health Grant 5-R01-HL-049944 (to G.G.S.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. G. G. Schwartz received research grant support from Roche Laboratories. NR 217 TC 29 Z9 30 U1 0 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD SEP PY 2012 VL 53 IS 9 BP 1738 EP 1754 DI 10.1194/jlr.R024505 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 991ZN UT WOS:000307743500003 PM 22685322 ER PT J AU Aronson, JP Mitha, AP Hoh, BL Auluck, PK Pomerantseva, I Vacanti, JP Ogilvy, CS AF Aronson, Joshua P. Mitha, Alim P. Hoh, Brian L. Auluck, Pavan K. Pomerantseva, Irina Vacanti, Joseph P. Ogilvy, Christopher S. TI A novel tissue engineering approach using an endothelial progenitor cell-seeded biopolymer to treat intracranial saccular aneurysms Laboratory investigation SO JOURNAL OF NEUROSURGERY LA English DT Article DE intracranial aneurysm; tissue engineering; rabbit endothelial progenitor cell; vascular disorders ID GUGLIELMI DETACHABLE COILS; ENDOVASCULAR TREATMENT; BIFURCATION ANEURYSMS; CEREBRAL ANEURYSMS; GROWTH-FACTOR; NATURAL-HISTORY; PLATINUM COILS; RABBIT MODEL; EMBOLIZATION; EXPERIENCE AB Object. Recurrence after endovascular coiling of intracranial aneurysms is reported in up to 42% of cases and is attributed to the lack of endothelialization across the neck. In this study the authors used a novel tissue engineering approach to promote endothelialization by seeding endothelial progenitor cells (EPCs) within a fibrin polymer injected endovascularly into the aneurysm. Methods. Experimental aneurysms were created in New Zealand White rabbits and were left untreated, surgically clipped, or embolized with platinum coils, fibrin biopolymer alone, or fibrin combined with autologous cultured EPCs. Results. In aneurysms treated with EPCs, a confluent monolayer of endothelial cells with underlying neointima was demonstrated across the neck at 16 weeks posttreatment, which was not observed with aneurysms treated using the other methods. Conclusions. This novel technique may address reasons for the limited durability of standard coil embolization and provides further avenues for the development of improved devices for the care of patients with aneurysms. (http://thejns.org/doi/abs/10.3171/2012.5.JNS091308) C1 [Aronson, Joshua P.; Mitha, Alim P.; Hoh, Brian L.; Ogilvy, Christopher S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Auluck, Pavan K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Pomerantseva, Irina; Vacanti, Joseph P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Lab Tissue Engn & Organ Fabricat, Boston, MA 02114 USA. [Mitha, Alim P.] Foothills Med Ctr, Div Neurosurg, Calgary, AB, Canada. [Hoh, Brian L.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. RP Ogilvy, CS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurosurg, 15 Parkman St,Wang Bldg,Room 745, Boston, MA 02114 USA. EM cogilvy@partners.org FU Alberta Heritage Fund for Medical Research Clinical Fellowship Award; AANS/CNS Resident Research Award in Cerebrovascular Disease; Centre for Integration of Medicine; Howard Hughes Medical Institute Medical Fellows Program FX This work was supported by an Alberta Heritage Fund for Medical Research Clinical Fellowship Award (A.P.M.), an AANS/CNS Resident Research Award in Cerebrovascular Disease (A.P.M.), a Centre for Integration of Medicine with Innovative Technologies New Concept Award (C.S.O.), and the Howard Hughes Medical Institute Medical Fellows Program (J.P.A.). NR 37 TC 11 Z9 11 U1 1 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2012 VL 117 IS 3 BP 546 EP 554 DI 10.3171/2012.5.JNS091308 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 990JP UT WOS:000307627100018 PM 22746379 ER PT J AU Song, JQ Finnerty, CC Herndon, DN Kraft, R Boehning, D Brooks, NC Tompkins, RG Jeschke, MG AF Song, Juquan Finnerty, Celeste C. Herndon, David N. Kraft, Robert Boehning, Darren Brooks, Natasha C. Tompkins, Ronald G. Jeschke, Marc G. TI Thermal Injury Activates the eEF2K-Dependent eEF2 Pathway in Pediatric Patients SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE burn; muscle; skin; protein synthesis; hypermeta-bolism ID SKELETAL-MUSCLE; BURN INJURY; TRANSLATION INITIATION; PROTEIN-METABOLISM; AMINO-ACIDS; KINASE; CATABOLISM; DYSFUNCTION; CHILDREN; STRESS AB Background: Burn induces a hypermetabolic state characterized by alterations in protein metabolism, which is associated with increased morbidity and mortality. Eukaryotic elongation factor 2 (eEF2) plays a crucial role in regulating protein synthesis in many diseases, but whether it participates in burn-induced hypermetabolism is unclear. The aim of this study was to determine the expression of eEF2 and the upstream eEF2-inactivating kinase, eEF2K, in severely burned pediatric patients. Methods: Eight pediatric patients (> 40% total body surface area) and 3 nonburned pediatric volunteers were enrolled. Muscle and skin biopsies were collected at early (0-10 days postburn [dpb]), middle (11-49 dpb), and late (50-365 dpb) time points. Resting energy expenditure (REE), body composition, and muscle protein fractional synthesis rate (FSR) were measured. Proteins were extracted and analyzed by Western blotting. To further investigate the protein synthesis pathway, microarray data from muscle and skin were examined from 22 nonburned and 20 burned children. Results: Burn patients exhibited a profound hypermetabolic response, as seen by a significant increase in REE (P < .05) and loss of lean body mass without altered muscle FSR, indicating a shift to catabolism after thermal injury. In muscle, the phosphorylation of eEF2K-dependent eEF2 was down regulated early and middle postburn. Similar changes in eEF2K and eEF2 levels occurred in skin at the early time point. Total amounts of eEF2 and eEF2K were not altered. Conclusion: Burn induces prolonged activation of eEF2K and eEF2. Alterations in these mediators may contribute to profound hypermetabolism in severely burned patients. (JPEN J Parenter Enteral Nutr. 2012;36:596-602) C1 [Jeschke, Marc G.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Surg & Plast Surg, Toronto, ON M4N 3M5, Canada. [Song, Juquan] Univ Texas Hlth Sci Ctr San Antonio, Dept Surg, San Antonio, TX 78229 USA. [Finnerty, Celeste C.; Boehning, Darren] Shriners Hosp Children, Galveston, TX 77550 USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Sealy Ctr Mol Med, Galveston, TX USA. [Finnerty, Celeste C.; Herndon, David N.; Kraft, Robert] Univ Texas Med Branch, Dept Surg, Galveston, TX USA. [Boehning, Darren] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX USA. [Brooks, Natasha C.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX USA. [Tompkins, Ronald G.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Jeschke, MG (reprint author), Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Surg & Plast Surg, 2075 Bayview Ave,Room D704, Toronto, ON M4N 3M5, Canada. EM Marc.Jeschke@sunnybrook.ca RI Boehning, Darren/I-8539-2015 OI Boehning, Darren/0000-0001-7920-6922 FU Shriners Hospitals for Children [8460, 8640, 8660, 8740, 8760, 8480, 8507]; Inflammation and the Host Response to Injury Glue Grant; NIGMS [U54 GM062119]; National Institutes of Health [GM056687, GM081685, GM087285, NIH T32-GM08256, NIH P50-GM60338, NIDRRH133A070026]; NIH [KL2RR029875, NIH UL1RR029876] FX This work was supported by grants from Shriners Hospitals for Children (8460, 8640, 8660, 8740, 8760, 8480, and 8507), the Inflammation and the Host Response to Injury Glue Grant funded by the NIGMS (U54 GM062119), and the National Institutes of Health (GM056687, GM081685, GM087285, NIH T32-GM08256, NIH P50-GM60338, NIDRRH133A070026). Celeste C. Finnerty is an Institute for Translational Sciences Career Development Scholar supported, in part, by NIH KL2RR029875 and NIH UL1RR029876. NR 37 TC 1 Z9 1 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD SEP PY 2012 VL 36 IS 5 BP 596 EP 602 DI 10.1177/0148607111422234 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 989CV UT WOS:000307538700017 PM 22269896 ER PT J AU Aversa, LH Stoddard, JA Doran, NM Au, S Chow, B McFall, M Saxon, A Baker, DG AF Aversa, Laura H. Stoddard, Jill A. Doran, Neal M. Au, Selwyn Chow, Bruce McFall, Miles Saxon, Andrew Baker, Dewleen G. TI PTSD and depression as predictors of physical health-related quality of life in tobacco-dependent veterans SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE Health-related quality of life; PTSD; Depression; Smoking; Tobacco; SF-36 ID POSTTRAUMATIC-STRESS-DISORDER; COMORBID ANXIETY DISORDERS; EXPOSURE THERAPY; PSYCHIATRIC-DISORDERS; SMOKING-CESSATION; PRIMARY-CARE; PSYCHOMETRIC PROPERTIES; RISK-FACTOR; PRIME-MD; MORTALITY AB Objective: Smoking, depression and PTSD are related to poor physical health outcomes and health-related quality of life (HRQoL). Previous studies examining the effects of quitting smoking on HRQoL have been mixed. This study aimed to examine the effects of PTSD, depressive symptoms and smoking cessation on HRQoL in a sample receiving treatment for PTSD. Method: This study utilized archival interview and self-report data from a clinical trial (VA Cooperative Study 519) that recruited tobacco dependent veterans with chronic FTSD (N=943). Results: Analyses were conducted using hierarchical linear modeling and indicated that PTSD and depressive symptoms differentially affected the various physical health status domains. Additionally, quitting smoking was associated with better self-perceived health status and social functioning. Conclusion: Our findings further explain the interrelationships of PTSD, depression, and smoking in the prediction of physical HRQoL and advocate the importance of integrated care. (C) 2012 Elsevier Inc. All rights reserved. C1 [Aversa, Laura H.; Baker, Dewleen G.] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Aversa, Laura H.; Stoddard, Jill A.] Alliant Int Univ, Calif Sch Profess Psychol, San Diego, CA USA. [Doran, Neal M.; Baker, Dewleen G.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Au, Selwyn; Chow, Bruce] Vet Affairs Palo Alto Hlth Care Syst, Cooperat Studies Program, Mountain View, CA USA. [McFall, Miles; Saxon, Andrew] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [McFall, Miles; Saxon, Andrew] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Baker, Dewleen G.] Vet Affairs Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. RP Aversa, LH (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr 151, San Diego, CA 92161 USA. EM laura.harder@gmail.com RI Doran, Neal/E-5653-2013 FU Cooperative Studies Program of the Clinical Science Research and Development Service, U.S. Department of Veterans Affairs (DVA) (CSP) [519, NCT00118534]; Tobacco-Related Disease Research Program [19DT-0003]; Department of Defense [PTO 090738]; DVA HSRD [SDR09-128]; VA Center of Excellence for Stress and Mental Health; VA Merit [821]; DVA; NIAAA [1 P20 AA017839-01]; NIDA [5 U10 DA013714-08]; VA HSRD [1 101 HX000616-01] FX Funding was provided by the Cooperative Studies Program of the Clinical Science Research and Development Service, U.S. Department of Veterans Affairs (DVA) (CSP #519, NCT00118534) and the Tobacco-Related Disease Research Program 19DT-0003. Dr. Baker receives research support from the Department of Defense (Navy BUMED and CDMRP) (PTO 090738) and the DVA HSR&D (SDR09-128) and is supported in part by the VA Center of Excellence for Stress and Mental Health. Dr. McFall receives research support from VA Merit #821 and DVA. Dr. Saxon receives research support from NIAAA (1 P20 AA017839-01), NIDA (5 U10 DA013714-08), and from VA HSR&D (1 101 HX000616-01). The views expressed herein are those of the authors and not necessarily those of the U.S. Department of Veterans Affairs. The authors have no competing interests to report. NR 82 TC 13 Z9 13 U1 7 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD SEP PY 2012 VL 73 IS 3 BP 185 EP 190 DI 10.1016/j.jpsychores.2012.06.010 PG 6 WC Psychiatry SC Psychiatry GA 986UW UT WOS:000307372100006 PM 22850258 ER PT J AU Bonawitz, SC Duvvuri, U AF Bonawitz, Steven C. Duvvuri, Umamaheswar TI Robot-Assisted Oropharyngeal Reconstruction with Free Tissue Transfer SO JOURNAL OF RECONSTRUCTIVE MICROSURGERY LA English DT Article DE robotic; TORS; free tissue transfer ID NECK-CANCER; SURGERY TORS; HEAD; CARCINOMA AB The surgical robot has been demonstrated to have useful applications in urologic, gynecologic, cardiac, general, and endocrine surgery. The development of robotic surgery has enhanced the precision and control of the surgeon in minimally invasive surgical situations specific to these specialties and, more recently, has been applied to the treatment of oropharyngeal tumors in the form of transoral robotic surgery (TORS). The elimination of the need for lip- and mandible-splitting approaches has allowed a reassessment of surgical options for the treatment of tumors that have until recently been primarily addressed nonoperatively with chemoradiation. The TORS approach has created the need to adapt current reconstructive options to robotic technology to manage the resultant tissue defects and to assess and compare the effectiveness of these procedures. This report details our early experience with the use of robot-assisted free tissue transfer for management of soft tissue defects of the oropharynx. C1 [Duvvuri, Umamaheswar] Univ Pittsburgh, Dept Otolaryngol, VA Pittsburgh Hlth Syst, Med Ctr,Eye & Ear Inst, Pittsburgh, PA 15213 USA. [Bonawitz, Steven C.] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Baltimore, MD USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Dept Otolaryngol, VA Pittsburgh Hlth Syst, Med Ctr,Eye & Ear Inst, Suite 500,200 Lothrop St, Pittsburgh, PA 15213 USA. EM duvvuriu@upmc.edu NR 12 TC 5 Z9 5 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0743-684X J9 J RECONSTR MICROSURG JI J. Reconstr. Microsurg. PD SEP PY 2012 VL 28 IS 7 BP 485 EP 490 DI 10.1055/s-0032-1313758 PG 6 WC Surgery SC Surgery GA 990KR UT WOS:000307630200010 PM 22638875 ER PT J AU Baibergenova, AT Weinstock, MA AF Baibergenova, A. T. Weinstock, M. A. CA VATTC Trial Grp TI Oral prednisone use and risk of keratinocyte carcinoma in non-transplant population. The VATTC trial SO JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY LA English DT Article ID TRETINOIN CHEMOPREVENTION TRIAL; SKIN-CANCER; TOPICAL TRETINOIN; IMMUNOSUPPRESSIVE THERAPY; GLUCOCORTICOID-RECEPTOR; TRANSPLANT RECIPIENTS; LYMPHOMA; CYCLOSPORINE; INFLAMMATION; ASSOCIATION AB Background Glucorticosteroids (GC) are potent anti-inflammatory medications with immunosuppressive property. Few retrospective studies have reported the increased risk of development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with GC use. Objective We aimed to assess the effect of oral GC use on the risk of BCC and SCC using prospective data. Methods We analysed data from the Veterans Affairs Topical Tretinoin Chemoprevention Trial, which followed up patients from 1998 to 2004. Exposure to oral GCs was defined as (1) use of any oral GCs at any point during follow-up and (2) use of GCs for a month or longer. Outcome was occurrence of new BCC or SCC. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results Among the 1051 study participants, 148 patients (14%) had prednisone prescription filled during study period, and 63 (6%) used prednisone for over a month. A total of 472 patients (45%) developed at least one BCC during study: 394 (44%) among non-users of prednisone and 78 (53%) among any time users. The total number of new SCC was 309 (29%): 258 (29%) among non-users of prednisone and 51 (34%) among users. Among any time prednisone users, the adjusted HR was 1.11 (95% CI, 0.871.42) for BCC, and 1.05 (95% CI, 0.761.45) for SCC. Among those who used prednisone for 30 or more days, the HR was 1.26 (95% CI, 0.901.78) for BCC, and 1.03 (95% CI, 0.661.60) for SCC. Conclusion This study does not support the existence of association between use of oral GCs and risk of BCC or SCC. C1 [Baibergenova, A. T.] Univ Toronto, Fac Med, Div Dermatol, Toronto, ON, Canada. [Weinstock, M. A.] Rhode Isl Hosp, Dept Dermatol, Providence, RI USA. [Weinstock, M. A.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [VATTC Trial Grp] US Dept Vet Affairs, Cooperat Studies Program, Washington, DC USA. [Weinstock, M. A.] VA Med Ctr Providence, Dermatoepidemiol Unit, Providence, RI USA. RP Baibergenova, AT (reprint author), Univ Toronto, Fac Med, Div Dermatol, Toronto, ON, Canada. EM akerke_b@yahoo.com FU Medical Dermatology Society FX We thank the Medical Dermatology Society for their mentorship program grant that allowed Dr A. Baibergenova to conduct this research under the mentorship of Dr M. Weinstock. NR 29 TC 7 Z9 7 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0926-9959 J9 J EUR ACAD DERMATOL JI J. Eur. Acad. Dermatol. Venereol. PD SEP PY 2012 VL 26 IS 9 BP 1109 EP 1115 DI 10.1111/j.1468-3083.2011.04226.x PG 7 WC Dermatology SC Dermatology GA 989JF UT WOS:000307555400008 PM 21923839 ER PT J AU Beuling, E Aronson, BE Tran, LMD Stapleton, KA ter Horst, EN Vissers, LATM Verzi, MP Krasinski, SD AF Beuling, Eva Aronson, Boaz E. Tran, Luc M. D. Stapleton, Kelly A. ter Horst, Ellis N. Vissers, Laurens A. T. M. Verzi, Michael P. Krasinski, Stephen D. TI GATA6 Is Required for Proliferation, Migration, Secretory Cell Maturation, and Gene Expression in the Mature Mouse Colon SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-6; HISTONE MODIFICATIONS; NA+/H+ EXCHANGER; SMALL-INTESTINE; PEPTIDE YY; MUCIN GENE; DIFFERENTIATION; MICE; HNF-1-ALPHA; ISOFORM AB Controlled renewal of the epithelium with precise cell distribution and gene expression patterns is essential for colonic function. GATA6 is expressed in the colonic epithelium, but its function in the colon is currently unknown. To define GATA6 function in the colon, we conditionally deleted Gata6 throughout the epithelium of small and large intestines of adult mice. In the colon, Gata6 deletion resulted in shorter, wider crypts, a decrease in proliferation, and a delayed crypt-to-surface epithelial migration rate. Staining techniques and electron microscopy indicated deficient maturation of goblet cells, and coimmunofluorescence demonstrated alterations in specific hormones produced by the endocrine L cells and serotonin-producing cells. Specific colonocyte genes were significantly downregulated. In LS174T, the colonic adenocarcinoma cell line, Gata6 knockdown resulted in a significant downregulation of a similar subset of goblet cell and colonocyte genes, and GATA6 was found to occupy active loci in enhancers and promoters of some of these genes, suggesting that they are direct targets of GATA6. These data demonstrate that GATA6 is necessary for proliferation, migration, lineage maturation, and gene expression in the mature colonic epithelium. C1 [Beuling, Eva; Aronson, Boaz E.; Tran, Luc M. D.; Stapleton, Kelly A.; ter Horst, Ellis N.; Vissers, Laurens A. T. M.; Krasinski, Stephen D.] Childrens Hosp Boston, Dept Med, Div Gastroenterol & Nutr, Boston, MA USA. [Aronson, Boaz E.] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands. [Verzi, Michael P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Verzi, Michael P.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Verzi, Michael P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Krasinski, Stephen D.] Tufts Univ, Gerald J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. RP Krasinski, SD (reprint author), Childrens Hosp Boston, Dept Med, Div Gastroenterol & Nutr, Boston, MA USA. EM stephen.krasinski@childrens.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [RO1-DK-061382, K01-DK-088868]; Crohn's and Colitis Foundation of America [1987]; Harvard Digestive Disease Center [5P30-DK-34854]; Nutricia Research Foundation; Foundation De Drie Lichten; Foundation Doctor Catharine van Tussenbroek; KWF Kankerbestrijding; Prins Bernhard Cultuurfonds in The Netherlands; European Society for Pediatric Research in Switzerland FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants RO1-DK-061382 (S. D. K.) and K01-DK-088868 (M. P. V.), fellowship no. 1987 from the Crohn's and Colitis Foundation of America (M. P. V.), the Harvard Digestive Disease Center (grant 5P30-DK-34854), the Nutricia Research Foundation (E. B. and B. E. A.), the Foundation De Drie Lichten (E. B.), the Foundation Doctor Catharine van Tussenbroek (E. B.), KWF Kankerbestrijding (B. E. A.), Prins Bernhard Cultuurfonds (B. E. A.) in The Netherlands, and the European Society for Pediatric Research (B. E. A.) in Switzerland. NR 38 TC 20 Z9 21 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2012 VL 32 IS 17 BP 3392 EP 3402 DI 10.1128/MCB.00070-12 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 992WM UT WOS:000307810900003 PM 22733991 ER PT J AU Janssens, T Keil, B Farivar, R Mcnab, JA Polimeni, JR Gerits, A Arsenault, JT Wald, LL Vanduffel, W AF Janssens, T. Keil, B. Farivar, R. McNab, J. A. Polimeni, J. R. Gerits, A. Arsenault, J. T. Wald, L. L. Vanduffel, W. TI An implanted 8-channel array coil for high-resolution macaque MRI at 3 T SO NEUROIMAGE LA English DT Article DE fMRI; Macaque; Parallel imaging; Implanted coil; High resolution ID VISUAL-CORTEX; BEHAVING MACAQUES; TEMPORAL CORTEX; CONTRAST AGENT; PHASED-ARRAY; HEAD COIL; MONKEYS; RESONANCE; BRAIN; FMRI AB An 8-channel receive coil array was constructed and implanted adjacent to the skull in a male rhesus monkey in order to improve the sensitivity of (functional) brain imaging. The permanent implant was part of an acrylic headpost assembly and only the coil element loop wires were implanted. The tuning, matching, and preamplifier circuitry was connected via a removable external assembly. Signal-to-noise ratio (SNR) and noise amplification for parallel imaging were compared to single-, 4-, and 8-channel external receive-only coils routinely used for macaque fMRI. In vivo measurements showed significantly improved SNR within the brain for the implanted versus the external coils. Within a region-of-interest covering the cerebral cortex, we observed a 5.4-, 3.6-fold, and 3.4-fold increase in SNR compared to the external single-, 4-, and 8-channel coils, respectively. In the center of the brain, the implanted array maintained a 2.4x, 2.5x, and 2.1x higher SNR, respectively compared to the external coils. The array performance was evaluated for anatomical, diffusion tensor and functional brain imaging. This study suggests that a stable implanted phased-array coil can be used in macaque MRI to substantially increase the spatial resolution for anatomical, diffusion tensor, and functional imaging. (C) 2012 Elsevier Inc. All rights reserved. C1 [Janssens, T.; Keil, B.; Farivar, R.; McNab, J. A.; Polimeni, J. R.; Gerits, A.; Arsenault, J. T.; Wald, L. L.; Vanduffel, W.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Keil, B.; Farivar, R.; McNab, J. A.; Polimeni, J. R.; Gerits, A.; Arsenault, J. T.; Wald, L. L.; Vanduffel, W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Keil, B.; Wald, L. L.] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Janssens, T.; Gerits, A.; Arsenault, J. T.; Vanduffel, W.] KU Leuven Med Sch, Lab Neuro & Psychophysiol, Louvain, Belgium. RP Vanduffel, W (reprint author), MGH, HMS, Dept Radiol, Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM wim@nmr.mgh.harvard.edu RI Keil, Boris/P-1411-2014; Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; FU Inter University Attraction Pole [6/29]; Program Financing [PFV/10/008]; Geconcerteerde Onderzoeks Actie [10/19]; Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen; Hercules funding; NSF [BCS-0745436]; National Center for Research Resources grant [P41RR14075]; [G062208N10]; [G083111N10]; [G043912N] FX The authors thank H. Deng for the technical support during the scans. This work received support from Inter University Attraction Pole 6/29, Program Financing PFV/10/008, Geconcerteerde Onderzoeks Actie 10/19, Hercules funding, Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen, G062208N10, G083111N10, and G043912N, and NSF grant BCS-0745436. TJ is an aspirant of the FWO-Vlaanderen. The Martinos Center is supported by National Center for Research Resources grant P41RR14075. NR 43 TC 9 Z9 10 U1 3 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1529 EP 1536 DI 10.1016/j.neuroimage.2012.05.028 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000021 PM 22609793 ER PT J AU Ganis, G Smith, D Schendan, HE AF Ganis, Giorgio Smith, Daniel Schendan, Haline E. TI The N170, not the P1, indexes the earliest time for categorical perception of faces, regardless of interstimulus variance SO NEUROIMAGE LA English DT Article DE Face perception; Object perception; Event-related potentials; N170; Interstimulus variance ID EVENT-RELATED POTENTIALS; HUMAN BRAIN; NEUROPHYSIOLOGICAL EVIDENCE; UNFAMILIAR FACES; NAME RECOGNITION; OBJECTS LEADS; REPETITION; MEMORY; EXPERTISE; RESPONSES AB A negative event-related potential (ERP) at occipito-temporal sites peaking around 150-170 ms after stimulus onset (N170) is typically larger for faces than other object categories. Most theories interpret this finding as due to face-selective processing in occipito-temporal and temporal cortex. However, a controversial account recently attributed the N170 effect to differences in interstimulus variance (ISV) among the images typically used for face and object conditions and proposed that the earlier P1 instead indexes the categorical processes generally attributed to the N170. This ERP study aimed to test this account definitively by using conditions in which the same face and object were shown repeatedly, eliminating both physical and perceptual ISV. Fourier amplitude spectra of faces and objects were matched to equate basic low-level visual properties that may affect early ERPs such as the P1. Results demonstrate that i) face selectivity of the N170 is largely preserved across many object categories after abolishing ISV, and ii) stimulus category does not modulate the P1. This conclusively refutes the ISV account while strongly supporting category as a critical factor driving N170 face selectivity. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ganis, Giorgio; Smith, Daniel; Schendan, Haline E.] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Ganis, Giorgio; Schendan, Haline E.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ganis, Giorgio] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Smith, Daniel] UCL, London WC1E 6BT, England. RP Ganis, G (reprint author), Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. EM giorgio.ganis@plymouth.ac.uk OI Ganis, Giorgio/0000-0001-6175-2618; Schendan, Haline/0000-0001-8925-5605 NR 55 TC 21 Z9 21 U1 1 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1563 EP 1574 DI 10.1016/j.neuroimage.2012.05.043 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000024 PM 22634853 ER PT J AU Wilcox, T Stubbs, J Hirshkowitz, A Boas, DA AF Wilcox, Teresa Stubbs, Jessica Hirshkowitz, Amy Boas, David A. TI Functional activation of the infant cortex during object processing SO NEUROIMAGE LA English DT Article DE Object processing; Temporal cortex; Parietal cortex; Infants; Near-infrared spectroscopy ID NEAR-INFRARED SPECTROSCOPY; SPATIOTEMPORAL INFORMATION; RECOGNITION; SHAPE; INDIVIDUATION; PERCEPTION; MONKEYS; HUMANS; COLOR; AREAS AB A great deal is known about the functional organization of the neural structures that mediate visual object processing in the adult observer. These findings have contributed significantly to our conceptual models of object recognition and identification and provided unique insight into the nature of object representations extracted from visual input. In contrast, little is known about the neural basis of object processing in the infant. The current research used near-infrared spectroscopy (NIRS) as a neuroimaging tool to investigate functional activation of the infant cortex during an object processing task that has been used extensively with infants. The neuroimaging data revealed that the infant cortex is functionally specialized for object processing (i.e., individuation-by-feature) early in the first year but that patterns of activation also change between 3 and 12 months. These changes may reflect functional reorganization of the immature cortex or age-related differences in the cognitive processes engaged during the task. (c) 2012 Elsevier Inc. All rights reserved. C1 [Wilcox, Teresa; Stubbs, Jessica; Hirshkowitz, Amy] Texas A&M Univ, Dept Psychol, College Stn, TX 77843 USA. [Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02129 USA. RP Wilcox, T (reprint author), Texas A&M Univ, Dept Psychol, 4235 TAMU, College Stn, TX 77843 USA. EM twilcox@tamu.edu FU [R21-HD048943]; [R01-HD057999]; [P41-RR14075] FX We thank Tracy Smith Brower, Lesley Wheeler, Kayla Boone Upshaw, Jennifer Moore Norvell, and the staff of the infant Cognition Lab at Texas A&M University for help with data collection and management, Lesley Wheeler and Mariam Massoud for preparation of figures, and the infants and parents who so graciously participated in the research. This work was support by grants R21-HD048943 and R01-HD057999 to TW and grant P41-RR14075 to DAB. NR 31 TC 14 Z9 15 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1833 EP 1840 DI 10.1016/j.neuroimage.2012.05.039 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000051 PM 22634218 ER PT J AU Lu, HB Chefer, S Kurup, PK Guillem, K Vaupel, DB Ross, TJ Moore, A Yang, YH Peoples, LL Stein, EA AF Lu, Hanbing Chefer, Svetlana Kurup, Pradeep K. Guillem, Karine Vaupel, D. Bruce Ross, Thomas J. Moore, Anna Yang, Yihong Peoples, Laura L. Stein, Elliot A. TI fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history SO NEUROIMAGE LA English DT Article DE Neuroadaptation; Self-administration; Abstinence; Pharmacological MRI ID CEREBRAL BLOOD-VOLUME; NUCLEUS-ACCUMBENS; DRUG-SEEKING; FUNCTIONAL CONNECTIVITY; GLUTAMATE TRANSMISSION; INDUCED REINSTATEMENT; MEDIODORSAL NUCLEUS; REWARD REGIONS; IN-VIVO; ADDICTION AB Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naive, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals. Published by Elsevier Inc. C1 [Lu, Hanbing; Chefer, Svetlana; Kurup, Pradeep K.; Vaupel, D. Bruce; Ross, Thomas J.; Yang, Yihong; Stein, Elliot A.] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Guillem, Karine; Peoples, Laura L.] Univ Penn, Dept Psychiat, TRL, Philadelphia, PA 19104 USA. [Moore, Anna] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Dept Radiol, Mol Imaging Lab, Boston, MA 02129 USA. [Peoples, Laura L.] Univ Penn, Neurosci Grad Grp, Philadelphia, PA 19104 USA. [Guillem, Karine] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. [Peoples, Laura L.] Drexel Univ, Dept Physiol & Pharmacol, Coll Med, Philadelphia, PA 19102 USA. [Guillem, Karine] CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,RM7A711, Baltimore, MD 21224 USA. EM estein@mail.nih.gov RI Ross, Thomas/B-7469-2008 OI Ross, Thomas/0000-0002-7745-3572 FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); NIH Director's Bench-to-Bedside grant; Institute for Translational Medicine and Therapeutics of the University of Pennsylvania; National Center for Research Resources [UL1RR024134]; [P50DA012756]; [R01 552981] FX We thank William Rea for his excellent technical assistance. This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA) and by an NIH Director's Bench-to-Bedside grant to L. L. Peoples and E. A Stein. It was also partially supported by P50DA012756, and R01 552981 (L.L.P.), Institute for Translational Medicine and Therapeutics of the University of Pennsylvania, and grant UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 70 TC 8 Z9 10 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1857 EP 1866 DI 10.1016/j.neuroimage.2012.05.076 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000054 PM 22664568 ER PT J AU Cooper, RJ Caffini, M Dubb, J Fang, QQ Custo, A Tsuzuki, D Fischl, B Wells, W Dan, I Boas, DA AF Cooper, Robert J. Caffini, Matteo Dubb, Jay Fang, Qianqian Custo, Anna Tsuzuki, Daisuke Fischl, Bruce Wells, William, III Dan, Ippeita Boas, David A. TI Validating atlas-guided DOT: A comparison of diffuse optical tomography informed by atlas and subject-specific anatomies SO NEUROIMAGE LA English DT Article DE Diffuse optical tomography; NIRS; MRI; Anatomical atlas; Registration ID SURFACE-BASED ANALYSIS; SPATIAL REGISTRATION; BRAIN-FUNCTION; MNI SPACE; MRI; RECONSTRUCTION; SEGMENTATION; SYSTEM; IMAGES; EEG AB We describe the validation of an anatomical brain atlas approach to the analysis of diffuse optical tomography (DOT). Using MRI data from 32 subjects, we compare the diffuse optical images of simulated cortical activation reconstructed using a registered atlas with those obtained using a subject's true anatomy. The error in localization of the simulated cortical activations when using a registered atlas is due to a combination of imperfect registration, anatomical differences between atlas and subject anatomies and the localization error associated with diffuse optical image reconstruction. When using a subject-specific MRI, any localization error is due to diffuse optical image reconstruction only. In this study we determine that using a registered anatomical brain atlas results in an average localization error of approximately 18 mm in Euclidean space. The corresponding error when the subject's own MRI is employed is 9.1 mm. In general, the cost of using atlas-guided DOT in place of subject-specific MRI-guided DOT is a doubling of the localization error. Our results show that despite this increase in error, reasonable anatomical localization is achievable even in cases where the subject-specific anatomy is unavailable. (C) 2012 Elsevier Inc. All rights reserved. C1 [Cooper, Robert J.; Dubb, Jay; Fang, Qianqian; Fischl, Bruce; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Caffini, Matteo] Univ Aquila, Dept Hlth Sci, I-67100 Laquila, Italy. [Custo, Anna] Univ Geneva, Funct Brain Mapping Lab, Ctr Med Univ, Geneva, Switzerland. [Tsuzuki, Daisuke; Dan, Ippeita] Jichi Med Univ, Ctr Dev Adv Med Technol, Funct Brain Sci Lab, Shimotsuke, Tochigi 3290498, Japan. [Wells, William, III] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wells, William, III] Brigham & Womens Hosp, Boston, MA 02115 USA. [Caffini, Matteo] Politecn Milan, Dipartimento Fis, Milan, Italy. RP Cooper, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. EM rcooper@nmr.mgh.harvard.edu OI Cooper, Robert/0000-0001-6696-8020 FU NIH [P41-RR14075, P41-RR13218, R01-EB006385, P41-RR-013218, P41-EB-015902]; Comprehensive Research on Disability, Health and Welfare from Health and Labour Sciences Research Grants; Japan Society for Promotion of Science [23390354, 23650217] FX This work was supported by NIH P41-RR14075, P41-RR13218, and R01-EB006385 (to D.A.B.), NIH P41-RR-013218 and P41-EB-015902 (to W.W.), Comprehensive Research on Disability, Health and Welfare from Health and Labour Sciences Research Grants (to I.D.), and the Grants-in-Aid for Scientific Research from the Japan Society for Promotion of Science (23390354, and 23650217 to I.D.). NR 30 TC 29 Z9 29 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 1999 EP 2006 DI 10.1016/j.neuroimage.2012.05.031 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000067 PM 22634215 ER PT J AU Oosterwijk, S Lindquist, KA Anderson, E Dautoff, R Moriguchi, Y Barrett, LF AF Oosterwijk, Suzanne Lindquist, Kristen A. Anderson, Eric Dautoff, Rebecca Moriguchi, Yoshiya Barrett, Lisa Feldman TI States of mind: Emotions, body feelings, and thoughts share distributed neural networks SO NEUROIMAGE LA English DT Article DE Constructionist; Emotion; Thought; Body feelings; Intrinsic networks ID TEMPORO-PARIETAL JUNCTION; MEDIAL PREFRONTAL CORTEX; INTRINSIC FUNCTIONAL CONNECTIVITY; NUCLEUS-ACCUMBENS DOPAMINE; BILATERAL AMYGDALA DAMAGE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; EVENT-RELATED FMRI; CORTICAL SURFACE; ANTERIOR INSULA AB Scientists have traditionally assumed that different kinds of mental states (e.g., fear, disgust, love, memory, planning, concentration, etc.) correspond to different psychological faculties that have domain-specific correlates in the brain. Yet, growing evidence points to the constructionist hypothesis that mental states emerge from the combination of domain-general psychological processes that map to large-scale distributed brain networks. In this paper, we report a novel study testing a constructionist model of the mind in which participants generated three kinds of mental states (emotions, body feelings, or thoughts) while we measured activity within large-scale distributed brain networks using fMRI. We examined the similarity and differences in the pattern of network activity across these three classes of mental states. Consistent with a constructionist hypothesis, a combination of large-scale distributed networks contributed to emotions, thoughts, and body feelings, although these mental states differed in the relative contribution of those networks. Implications for a constructionist functional architecture of diverse mental states are discussed. (c) 2012 Elsevier Inc. All rights reserved. C1 [Oosterwijk, Suzanne] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [Oosterwijk, Suzanne] Univ Amsterdam, Dept Psychol, NL-1018 XA Amsterdam, Netherlands. [Lindquist, Kristen A.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Dautoff, Rebecca; Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Moriguchi, Yoshiya] Natl Inst Mental Hlth Multimodal Neuroimaging Sec, Dept Psychophysiol, Natl Ctr Neurol & Psychiat, Kodaira, Tokyo 1878551, Japan. RP Oosterwijk, S (reprint author), Northeastern Univ, Dept Psychol, 114 Lake Hall, Boston, MA 02115 USA. EM s.oosterwijk@neu.edu OI Anderson, Eric/0000-0002-4215-6308 FU National Institutes of Health Director's Pioneer award [DP1OD003312]; Marie Curie International Outgoing Fellowship; Seventh Framework Program of the European Commission; Harvard University Mind/Brain/Behavior Postdoctoral Fellowship FX Many thanks to Thomas Yeo, Fenna Krienen, and the Buckner lab for making the Yeo et al. (2011) network parcellation available. This research was supported by a National Institutes of Health Director's Pioneer award (DP1OD003312) to Lisa Feldman Barrett. The writing of this manuscript was supported by a Marie Curie International Outgoing Fellowship awarded by the Seventh Framework Program of the European Commission to Suzanne Oosterwijk and a Harvard University Mind/Brain/Behavior Postdoctoral Fellowship to Kristen Lindquist. NR 153 TC 34 Z9 34 U1 2 U2 36 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2012 VL 62 IS 3 BP 2110 EP 2128 DI 10.1016/j.neuroimage.2012.05.079 PG 19 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 986TR UT WOS:000307369000076 PM 22677148 ER PT J AU Cleveland, RH Gordon, LB Kleinman, ME Miller, DT Gordon, CM Snyder, BD Nazarian, A Giobbie-Hurder, A Neuberg, D Kieran, MW AF Cleveland, Robert H. Gordon, Leslie B. Kleinman, Monica E. Miller, David T. Gordon, Catherine M. Snyder, Brian D. Nazarian, Ara Giobbie-Hurder, Anita Neuberg, Donna Kieran, Mark W. TI A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome SO PEDIATRIC RADIOLOGY LA English DT Article DE Progeria; Phenotype; Skeletal findings; Frequency; Children ID FIBROBLASTS; DYSPLASIA; PHENOTYPE AB Progeria is a rare segmental premature aging disease with significant skeletal abnormalities. Defining the full scope of radiologic abnormalities requires examination of a large proportion of the world's progeria population (estimated at 1 in 4 million). There has been no comprehensive prospective study describing the skeletal abnormalities associated with progeria. To define characteristic radiographic features of this syndrome. Thirty-nine children with classic progeria, ages 2-17 years, from 29 countries were studied at a single site. Comprehensive radiographic imaging studies were performed. Sample included 23 girls and 16 boys-the largest number of patients with progeria evaluated prospectively to date. Eight new and two little known progeria-associated radiologic findings were identified (frequencies of 3-36%). Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not encountered and 21 were present and ranked according to their frequency. Nine abnormalities were associated with increasing patient age (P = 0.02-0.0001). This study considerably expands the radiographic morphological spectrum of progeria. A better understanding of the radiologic abnormalities associated with progeria and improved understanding of the biology of progerin (the molecule responsible for this disease), will improve our ability to treat the spectrum of bony abnormalities. C1 [Cleveland, Robert H.] Harvard Univ, Sch Med, Dept Radiol, Childrens Hosp Boston, Boston, MA 02115 USA. [Gordon, Leslie B.; Kleinman, Monica E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Anesthesia, Boston, MA 02115 USA. [Gordon, Leslie B.] Brown Univ, Dept Pediat, Hasbro Childrens Hosp, Warren Alpert Med Sch, Providence, RI 02912 USA. [Miller, David T.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Genet, Boston, MA 02115 USA. [Gordon, Catherine M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Endocrinol & Adolescent Med, Boston, MA 02115 USA. [Snyder, Brian D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Orthoped Surg, Boston, MA 02115 USA. [Giobbie-Hurder, Anita; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Neuberg, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kieran, Mark W.] Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Kieran, Mark W.] Childrens Hosp, Boston, MA 02115 USA. RP Cleveland, RH (reprint author), Harvard Univ, Sch Med, Dept Radiol, Childrens Hosp Boston, 300 Longwood Ave, Boston, MA 02115 USA. EM robert.cleveland@childrens.harvard.edu OI Kieran, Mark/0000-0003-2184-7692 FU Progeria Research Foundation [PRFCLIN2007-01, PRFCLINTRIAL003-080109]; National Heart, Lung and Blood Institute [1RC2HL101631-01]; Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program; National Center for Research Resources [MO1-RR02172]; National Center for Research Resources, National Institutes of Health [UL1 RR025758-01] FX We are grateful to the children with progeria and their families for their participation in this study. We thank the Family Inn (Cambridge, MA) and Devon Nicole House (Boston, MA) for housing families; Susan Campbell, MS, Nancy Wolf-Jenssen, and Nancy Grossman for medical records coordination; and Kyra Johnson, Kelly Littlefield, Kiera McKendrick, Angela Kraybill, and William Fletcher for coordinator services. This project was funded by The Progeria Research Foundation (PRFCLIN2007-01 and Grant #PRFCLINTRIAL003-080109), the National Heart, Lung and Blood Institute (1RC2HL101631-01), the Dana-Farber Cancer Institute Stop&Shop Pediatric Brain Tumor Program, by a National Center for Research Resources to the Children's Hospital Boston General Clinical Research Center (MO1-RR02172), and a grant from the National Center for Research Resources, National Institutes of Health, to the Harvard Catalyst Clinical & Translational Science Center (Harvard Catalyst) (UL1 RR025758-01). NR 31 TC 6 Z9 7 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD SEP PY 2012 VL 42 IS 9 BP 1089 EP 1098 DI 10.1007/s00247-012-2423-1 PG 10 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 991RB UT WOS:000307717800007 PM 22752073 ER PT J AU Kogai, T Brent, GA AF Kogai, Takahiko Brent, Gregory A. TI The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE Sodium iodide symporter; Thyroid cancer; Breast cancer; Transcriptional regulation; Posttranslational regulation ID MCF-7 BREAST-CANCER; RAT-THYROID CELLS; TRANS-RETINOIC ACID; GROWTH-FACTOR-BETA; RECOMBINANT HUMAN THYROTROPIN; PAIRED-DOMAIN TRANSCRIPTION; PROTEIN-KINASE-A; ADENOSINE-3',5'-MONOPHOSPHATE SIGNAL ACTION; ACUTE PROMYELOCYTIC LEUKEMIA; SYSTEMIC NONVIRAL DELIVERY AB Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, beta-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS. Published by Elsevier Inc. C1 [Kogai, Takahiko] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Physiol, Los Angeles, CA 90073 USA. RP Kogai, T (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, David Geffen Sch Med,Dept Med, Bldg 114,Room 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM tkogai@ucla.edu; gbrent@ucla.edu FU NIH [R01 CA089364] FX We would like to thank Drs. Jerome Hershman, Masahiro Sugawara, and Yan-Yun Liu for helpful discussions. This study was supported by NIH R01 CA089364 and VA merit review funds. NR 208 TC 47 Z9 51 U1 1 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD SEP PY 2012 VL 135 IS 3 BP 355 EP 370 DI 10.1016/j.pharmthera.2012.06.007 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 988ZD UT WOS:000307529100007 PM 22750642 ER PT J AU Sneag, DB Krajewski, KM Howard, S Jagannathan, JP Star, KV Ramaiya, N AF Sneag, Darryl B. Krajewski, Katherine M. Howard, Stephanie Jagannathan, Jyothi P. Star, Kremena V. Ramaiya, Nikhil TI Sclerotic osseous metastases from renal cell carcinoma SO SKELETAL RADIOLOGY LA English DT Article DE Renal cell carcinoma; Sclerotic; Osseous; Metastases ID BONE METASTASES; OSTEOBLASTIC METASTASES; PROGNOSTIC IMPACT; TUMOR; MECHANISMS; FEATURES; SUBTYPE; PATTERN AB This case series describes and illustrates three cases of sclerotic osseous metastases from untreated renal cell carcinoma (RCC). RCC is commonly metastatic to the skeleton but almost always produces lytic metastases, with only three prior reports of sclerotic metastases identified in the literature. Sclerotic metastasis causing low back pain was the initial disease presentation in two of the three patients in this case series and the first manifestation of metastatic disease in one. The most common metastatic sites of RCC, i.e., retroperitoneal lymph nodes, lung, and liver, were not identified in any of the cases, and skeletal involvement with epidural extension was the only site of metastasis in two. Pathologic specimens from all three cases revealed RCC of high nuclear grade. C1 [Sneag, Darryl B.; Krajewski, Katherine M.; Howard, Stephanie; Jagannathan, Jyothi P.; Ramaiya, Nikhil] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02115 USA. [Sneag, Darryl B.; Krajewski, Katherine M.; Howard, Stephanie; Jagannathan, Jyothi P.; Star, Kremena V.; Ramaiya, Nikhil] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Star, Kremena V.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Sneag, DB (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM dsneag@partners.org; kmkrajewski@partners.org; sahoward@partners.org; jjagannathan@partners.org; kstar@partners.org; nramaiya@partners.org NR 19 TC 2 Z9 2 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 SEP PY 2012 VL 41 IS 9 BP 1169 EP 1175 DI 10.1007/s00256-012-1424-3 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 991SB UT WOS:000307720700021 PM 22576970 ER PT J AU Sharma, SM Fuchsluger, T Ahmad, S Katikireddy, KR Armant, M Dana, R Jurkunas, UV AF Sharma, Sandhya M. Fuchsluger, Thomas Ahmad, Sajjad Katikireddy, Kishore R. Armant, Myriam Dana, Reza Jurkunas, Ula V. TI Comparative Analysis of Human-Derived Feeder Layers with 3T3 Fibroblasts for the Ex Vivo Expansion of Human Limbal and Oral Epithelium SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Cornea; Limbal stem cells; Oral mucosa; Feeder layer; Human dermal fibroblasts; Human mesenchymal stem cells; 3T3; Ex vivo expansion; Xenobiotic-free corneal equivalents; Amniotic membrane ID OCULAR SURFACE RECONSTRUCTION; STEM-CELL DEFICIENCY; CULTIVATED CORNEAL EPITHELIUM; AMNIOTIC MEMBRANE; SUCCESSFUL TRANSPLANTATION; AUTOLOGOUS SERUM; BASAL CELLS; CULTURE; DISEASE; EQUIVALENTS AB Corneal transplantation with cultivated limbal or oral epithelium is a feasible treatment option for limbal stem cell deficiency (LSCD). Currently utilized co-culture of stem cells with murine 3T3 feeder layer renders the epithelial constructs as xenografts. To overcome the potential risks involved with xenotransplantation, we investigated the use of human-derived feeder layers for the ex vivo expansion of epithelial (stem) cells. Human limbal and oral epithelium was co-cultured with mouse 3T3 fibroblasts, human dermal fibroblasts (DF), human mesenchymal stem cells (MSC), and with no feeder cells (NF). Cell morphology was monitored with phase-contrast microscopy, and stem cell characteristics were assessed by immunohistochemistry, real-time PCR for p63 and ABCG2, (stem cell markers), and by colony-forming efficiency (CFE) assay. Immunohistochemical analysis detected positive staining for CK3 (cornea specific marker) and I beta 1 and p63 (putative stem cell markers) in all culture conditions. The level of I beta 1 and p63 was significantly higher in both limbal and oral cells cultured on the 3T3 feeder, as compared to the MSC or NF group (p < 0.01). This level was comparable to the cells cultured on DF. Expression of p63 and ABCG2 in limbal and oral epithelial cells in the 3T3 and DF groups was significantly higher than that in the MSC or NF group (p < 0.01). No statistical difference was detected between 3T3 and DF groups. The CFE of both limbal and oral cells co-cultured on 3T3 fibroblasts was comparable to cells grown on DF, and was significantly higher than that of cells co-cultured with MSC or NF (p < 0.01). Epithelial cells grown on a DF feeder layer maintained a stem cell-like phenotype, comparable to cells grown on a 3T3 feeder layer. In conclusion, DF provides a promising substitute for 3T3 feeder cells during cultivation of xenobiotic-free corneal equivalents. C1 [Sharma, Sandhya M.; Fuchsluger, Thomas; Katikireddy, Kishore R.; Dana, Reza; Jurkunas, Ula V.] Schepens Eye Res Inst, Boston, MA 02114 USA. [Dana, Reza; Jurkunas, Ula V.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Sharma, Sandhya M.; Fuchsluger, Thomas; Katikireddy, Kishore R.; Dana, Reza; Jurkunas, Ula V.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Ahmad, Sajjad] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Armant, Myriam] Immune Dis Inst, Ctr Human Cell Therapy, Boston, MA 02115 USA. RP Jurkunas, UV (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM ula.jurkunas@schepens.harvard.edu FU Center of Excellence in Women's Health Award; Harvard Medical School; New England Corneal Transplant Research Award; Massachusetts Lions Eye Research Fund; Cornea Donor Research Fund FX We thank Dr. Shigeru Kinoshita, Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan, for his mentorship in this project and allowing us to adopt his cell cultivation protocols. This work was supported by Center of Excellence in Women's Health Award, Harvard Medical School (UVJ), New England Corneal Transplant Research Award (UVJ), Massachusetts Lions Eye Research Fund (UVJ), Cornea Donor Research Fund (UVJ and RD). NR 45 TC 23 Z9 23 U1 2 U2 14 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1550-8943 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD SEP PY 2012 VL 8 IS 3 BP 696 EP 705 DI 10.1007/s12015-011-9319-6 PG 10 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 986HQ UT WOS:000307333100008 PM 21964568 ER PT J AU Kraft, S Mackler, E Schlickman, P Welch, K DePestel, DD AF Kraft, Shawna Mackler, Emily Schlickman, Peter Welch, Kathy DePestel, Daryl D. TI Outcomes of therapy vancomycin-resistant enterococcal bacteremia in hematology and bone marrow transplant patients SO SUPPORTIVE CARE IN CANCER LA English DT Letter C1 [Kraft, Shawna; DePestel, Daryl D.] Univ Michigan Hlth Syst, Ann Arbor, MI 48109 USA. [Mackler, Emily] Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA. [DePestel, Daryl D.] Univ Michigan, Coll Pharm, Ann Arbor, MI 48109 USA. [Schlickman, Peter] Denver VA Med Ctr, Eastern Colorado Hlth Care Syst, Denver, CO 80220 USA. [Welch, Kathy] Univ Michigan, Ctr Stat Consultat & Res, Ann Arbor, MI 48109 USA. RP Kraft, S (reprint author), Univ Michigan Hlth Syst, 1500 E Med Ctr Dr,UH B2D301,Box 0008, Ann Arbor, MI 48109 USA. EM svandeko@umich.edu NR 1 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2012 VL 20 IS 9 BP 1935 EP 1936 DI 10.1007/s00520-012-1440-9 PG 2 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 985RE UT WOS:000307285800002 PM 22447367 ER PT J AU Walling, AM Asch, SM Lorenz, KA Malin, J Roth, CP Barry, T Wenger, NS AF Walling, Anne M. Asch, Steven M. Lorenz, Karl A. Malin, Jennifer Roth, Carol P. Barry, Tod Wenger, Neil S. TI The quality of supportive care among inpatients dying with advanced cancer SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Quality of care; Supportive care; Advanced cancer ID PALLIATIVE CARE; LIFE; END; DEATH; PHYSICIANS; PROVIDERS; FAMILIES AB Managing symptoms and communicating effectively are essential aspects of providing high-quality cancer care, especially among patients with advanced cancer. The purpose of this study is to apply novel quality indicators to measure the quality of supportive care provided to patients with advanced cancer who died in a large university medical center. Cancer quality ASSIST is a comprehensive quality indicator (QI) set that includes 92 symptom and care planning indicators, of which we piloted 15 applicable to persons with advanced cancer who died in the hospital setting. We evaluated medical records of all adult terminal hospitalizations with lengths of stay a parts per thousand yen3 days at one university medical center between April 2005 and April 2006. Of 496 decedents, 118 had advanced cancer (mean age 60, 54 % male). Forty-five percent received chemotherapy or radiation in the month prior to or during admission. During the hospitalization, 56 % of the patients spent time in the ICU (median length of stay 8 days), one in five received first-time hemodialysis, and 23 % had a ventilator withdrawn anticipating death. The 118 patients triggered 596 quality indicators of which 476 passed (QI level pass rate 80 %, range 50-100 %). Pain assessment and management were consistently performed; however, other cancer supportive care needed improvement: 26 % of patients not receiving cancer therapy who had nausea and vomiting received inadequate follow-up, more than one quarter of patients with dyspnea had this symptom inadequately addressed, and 29 % of patients taking long-acting opioids were not prescribed a bowel regimen. Timely discussion of patient preferences upon admission to the ICU or initiation of mechanical ventilation occurred in 64 and 69 % of cases, respectively. This set of quality indicators can evaluate the quality of supportive and end-of-life care provided to inpatients dying with advanced cancer and identify aspects of care that need improvement. C1 [Walling, Anne M.; Wenger, Neil S.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Wenger, Neil S.] UCLA Hlth Syst Eth Ctr, Los Angeles, CA USA. [Walling, Anne M.; Lorenz, Karl A.; Malin, Jennifer] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Lorenz, Karl A.; Roth, Carol P.; Wenger, Neil S.] RAND Hlth, Santa Monica, CA USA. [Barry, Tod] UCLA Ctr Patient Safety & Qual, Los Angeles, CA USA. [Asch, Steven M.] VA Palo Alto Healthcare Syst, Palo Alto, CA 94304 USA. [Asch, Steven M.] Stanford Sch Med, Stanford, CA 94305 USA. RP Walling, AM (reprint author), Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, David Geffen Sch Med, 911 Broxton Plaza, Los Angeles, CA 90024 USA. EM awalling@mednet.ucla.edu FU National Research Service Award Training Grant [T32 PE19001]; UCLA; NIH; National Palliative Care Research Center FX This project was supported by a donation from Mary Kay Farley to RAND Health. Dr. Walling was supported by National Research Service Award Training Grant T32 PE19001, the UCLA Specialty Training & Advanced Research Program, the NIH Loan Repayment Program, and a National Palliative Care Research Center Career Development Award. NR 21 TC 11 Z9 11 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2012 VL 20 IS 9 BP 2189 EP 2194 DI 10.1007/s00520-012-1462-3 PG 6 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 985RE UT WOS:000307285800032 PM 22544290 ER PT J AU Offner, H Hurn, PD AF Offner, Halina Hurn, Patricia D. TI A Novel Hypothesis: Regulatory B Lymphocytes Shape Outcome from Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Experimental stroke; Bregs; IL-10; PD-1; Immunotherapy ID ACUTE ISCHEMIC-STROKE; MURINE EXPERIMENTAL STROKE; T-CELLS; INDUCED IMMUNODEPRESSION; NEUROLOGIC DEFICITS; IMMUNE PATHOLOGY; BRAIN ISCHEMIA; PD-1; AUTOIMMUNITY; INFLAMMATION AB Although inflammatory immune cells clearly contribute to the development of middle cerebral artery occlusion (MCAO) in mice, the failure to block neutrophil-associated injury in clinical stroke trials has discouraged further development of immunotherapeutic approaches. However, there is renewed interest in a possible protective role for regulatory T and B cells that can suppress inflammation and limit central nervous system damage induced by infiltrating pro-inflammatory cells. Our failure to implicate CD4(+)FoxP3(+) T cells in limiting brain lesion volume after MCAO turned our focus towards regulatory B cells known to mediate protection against other inflammatory CNS conditions. Our results clearly demonstrated that B cell-deficient mice developed larger infarct volumes, higher mortality, and more severe functional deficits compared to wild-type mice and had increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere. These MCAO-induced changes were completely prevented in B cell-restored mice after transfer of highly purified WT B cells but not IL-10-deficient B cells. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition. C1 [Offner, Halina] Portland VA Med Ctr, Neuroimmunol Res R&D 31, Portland, OR 97239 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Hurn, Patricia D.] Univ Texas Syst, Off Hlth Affairs, Austin, TX USA. RP Offner, H (reprint author), Portland VA Med Ctr, Neuroimmunol Res R&D 31, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH [NS075887, NR003521] FX The authors wish to thank Ms. Eva Niehaus for assistance with manuscript preparation. This work was supported by NIH grants NS075887 (HO) and NR003521 (PDH). This material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center, Portland, OR. The contents do not represent the views of the Department of Veterans Affairs or the US government. NR 48 TC 23 Z9 23 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD SEP PY 2012 VL 3 IS 3 SI SI BP 324 EP 330 DI 10.1007/s12975-012-0187-4 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 992FK UT WOS:000307760800005 PM 23175646 ER PT J AU Tang, XN Zheng, Z Yenari, MA AF Tang, Xian Nan Zheng, Zhen Yenari, Midori A. TI Bone Marrow Chimeras in the Study of Experimental Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Bone marrow; Chimera; Inflammation; Stroke ID FOCAL CEREBRAL-ISCHEMIA; BLOOD-BRAIN-BARRIER; PROTEIN-KINASE-C; NADPH OXIDASE; IN-VIVO; REPERFUSION INJURY; REACTIVE OXYGEN; ACTIVATION; MATRIX-METALLOPROTEINASE-9; CELLS AB Inflammation is known to contribute to stroke evolution, and poststroke immune responses have been documented to emanate from the brain via microglia. However, circulating immune cells are increasingly recognized to play a significant role as well. Recent work has demonstrated the importance of the peripheral circulation and stroke pathogenesis. Understanding how the peripheral circulation contributes to ischemic brain injury may reveal important therapeutic targets and strategies. The use of bone marrow chimeras can be a useful tool in understanding the relative contributions of brain resident and peripheral inflammatory responses. C1 [Zheng, Zhen; Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Tang, Xian Nan; Zheng, Zhen; Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Tang, Xian Nan] Stanford Univ, Dept Anesthesia, Sch Med, Stanford, CA 94305 USA. RP Yenari, MA (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM yenari@alum.mit.edu FU NIH [R01 NS40516, P50 NS014543]; VA Merit Award; Veterans Affairs Medical Center, San Francisco, California FX This work was supported by NIH grants R01 NS40516 (MAY), P50 NS014543 (MAY) and a VA Merit Award (MAY). Grants to MAY were administered by the Northern California Institute for Research and Education and supported by resources of the Veterans Affairs Medical Center, San Francisco, California. NR 58 TC 4 Z9 4 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD SEP PY 2012 VL 3 IS 3 SI SI BP 341 EP 347 DI 10.1007/s12975-012-0169-6 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 992FK UT WOS:000307760800007 PM 24323809 ER PT J AU Kim, MC Kim, KH Jang, JS Kwon, HC Kim, BG Rattner, DW AF Kim, Min-Chan Kim, Ki-Han Jang, Jin-Seok Kwon, Hyuk-Chan Kim, Byoung-Gwon Rattner, David W. TI Patient Perception of Natural Orifice Transluminal Endoscopic Surgery in an Endoscopy Screening Program in Korea SO YONSEI MEDICAL JOURNAL LA English DT Article DE NOTES; endoscopy; surgery; patient perception; survey ID CHOLECYSTECTOMY; SURVIVAL AB Purpose: Natural orifice transluminal endoscopic surgery (NOTES) is a new method of accessing intracavitary organs in order to minimize pain by avoiding incisions in the body wall. The aim of this study is to determine patients' acceptance of NOTES in Korea and to compare their views about laparoscopic surgery and NOTES for benign and malignant diseases. Materials and Methods: The target number of total subjects was calculated to be 540. The subjects were classified into 18 sub-groups based on age groups, gender, and history of prior surgery. The questionnaire elicited information about demographic characteristics, medical check-ups, diseases, endoscopic and surgical histories, marital status and childbirth, the acceptance of NOTES, and the preferred routes for NOTES. In addition, the subjects chose laparoscopic surgery or NOTES for a hypothetical cholecystectomy and rectal cancer surgery, and responded to questions regarding the acceptable complication rate of NOTES, the appropriate cost of NOTES, and the reason(s) why they did not select NOTES. Results: 486 of 540 patients (90.0%) who agreed to participate in this study completed the questionnaire. NOTES was preferred by the following patients: elderly; a history of treatment due to a disease; having regular cheek-ups; and a history of an endoscopic procedure (p<0.05). The most preferred route for NOTES was the stomach (67.1%). Eighty-four percent of the patients choosing NOTES responded that the complication rate of the new surgical method should be the same or lower than laparoscopic surgery. Vague anxiety over a new surgical method was the most common reason why NOTES was not selected in benign and malignant diseases (64% and 73%), respectively. Conclusion: Patients appear to be interested in the potential benefits of NOTES and would embrace it if their concerns about safety are met. We believe that qualified surgical endoscopists can meet these safety concerns, and that NOTES development has the potential to flourish. C1 [Rattner, David W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kim, Min-Chan; Kim, Ki-Han] Dong A Univ, Coll Med, Dept Surg, Pusan, South Korea. [Jang, Jin-Seok; Kwon, Hyuk-Chan] Dong A Univ, Coll Med, Dept Internal Med, Pusan, South Korea. [Kim, Byoung-Gwon] Dong A Univ, Coll Med, Dept Prevent Med, Pusan, South Korea. RP Rattner, DW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, 15 Parkman St, Boston, MA 02114 USA. EM drattner@partners.org FU Dong-A University research fund FX This work was supported by the Dong-A University research fund. NR 13 TC 6 Z9 6 U1 1 U2 2 PU YONSEI UNIV COLL MEDICINE PI SEOUL PA 50-1 YONSEI-RO, SEODAEMUN-GU, SEOUL 120-752, SOUTH KOREA SN 0513-5796 EI 1976-2437 J9 YONSEI MED J JI Yonsei Med. J. PD SEP 1 PY 2012 VL 53 IS 5 BP 960 EP 967 DI 10.3349/ymj.2012.53.5.960 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 995DA UT WOS:000307986900012 PM 22869479 ER PT J AU Masland, RH AF Masland, Richard H. TI The Retina: An Approachable Part of the Brain SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Book Review ID CELL C1 [Masland, Richard H.] Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Masland, RH (reprint author), Harvard Med Sch, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. NR 4 TC 0 Z9 0 U1 3 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD SEP-OCT PY 2012 VL 24 IS 5 BP 719 EP 719 DI 10.1002/ajhb.22305 PG 1 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 986WV UT WOS:000307377800022 ER PT J AU Rask-Madsen, C Kahn, CR AF Rask-Madsen, Christian Kahn, C. Ronald TI Tissue-Specific Insulin Signaling, Metabolic Syndrome, and Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE adhesion molecules; atherosclerosis; diabetes mellitus; endothelial function; insulin resistance ID SKELETAL-MUSCLE; ENDOTHELIAL-CELLS; GLUCOSE-UPTAKE; RECEPTOR SUBSTRATE-1; BETA-CELLS; BLOOD-FLOW; RESISTANCE; MICE; ATHEROSCLEROSIS; DYSFUNCTION AB Impaired insulin signaling is central to development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension, and a proinflammatory state. However, insulin's action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes mellitus. Recent advances in our understanding of the complex pathophysiology of insulin's effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders. (Arterioscler Thromb Vasc Biol. 2012;32:2052-2059.) C1 [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU National Institutes of Health (NIH) grant [EY018677]; NIH [DK31036, DK33201, DK55545, DK82659, R24DK085610] FX Dr Rask-Madsen is supported by National Institutes of Health (NIH) grant EY018677 and Dr Kahn by NIH grants DK31036, DK33201, DK55545, DK82659, and R24DK085610, as well as the Mary K. Iacocca Professorship. NR 55 TC 81 Z9 89 U1 2 U2 15 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 SEP PY 2012 VL 32 IS 9 BP 2052 EP 2059 DI 10.1161/ATVBAHA.111.241919 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 992JZ UT WOS:000307773100006 PM 22895666 ER PT J AU He, MA Wolpin, B Rexrode, K Manson, JE Rimm, E Hu, FB Qi, L AF He, Meian Wolpin, Brian Rexrode, Kathy Manson, JoAnn E. Rimm, Eric Hu, Frank B. Qi, Lu TI ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort Studies SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE ABO; coronary heart disease; cohort study; meta-analysis ID MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; PANCREATIC-CANCER; SELECTIN LEVELS; METAANALYSIS; ASSOCIATION; CYTOKINES; SYSTEM; FUTURE AB Objective-Epidemiological data regarding the association between ABO blood groups and risk of coronary heart disease (CHD) have been inconsistent. We sought to investigate the associations between ABO blood group and CHD risk in prospective cohort studies. Methods and Results-Two large, prospective cohort studies (the Nurses' Health Study [NHS] including 62 073 women and the Health Professionals Follow-up Study [HPFS] including 27 428 men) were conducted with more than 20 years of follow-up (26 years in NHS and 24 years in HPFS). A meta-analysis was performed to summarize the associations from the present study and previous studies. In NHS, during 1 567 144 person-years of follow-up, 2055 participants developed CHD; in HPFS, 2015 participants developed CHD during 517 312 person-years of follow-up. ABO blood group was significantly associated with the risk of developing CHD in both women and men (log-rank test; P=0.0048 and 0.0002, respectively). In the combined analysis adjusted for cardiovascular risk factors, compared with participants with blood group O, those with blood groups A, B, or AB were more likely to develop CHD (adjusted hazard ratios [95% CI] for incident CHD were 1.06 [0.99-1.15], 1.15 [1.04-1.26], and 1.23 [1.11-1.36], respectively). Overall, 6.27% of the CHD cases were attributable to inheriting a non-O blood group. Meta-analysis indicated that non-O blood group had higher risk of CHD (relative risk =1.11; 95% CI, 1.05-1.18; P=0.001) compared with O blood group. Conclusion-These data suggest that ABO blood group is significantly associated with CHD risk. Compared with other blood groups, those with the blood type O have moderately lower risk of developing CHD. (Arterioscler Thromb Vasc Biol. 2012;32:2314-2320.) C1 [He, Meian; Rimm, Eric; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [He, Meian] Huazhong Univ Sci & Technol, Inst Occupat Med, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [He, Meian] Huazhong Univ Sci & Technol, Dept Cardiol, Union Hosp, Tongji Med Coll, Wuhan 430074, Peoples R China. [Wolpin, Brian] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rimm, Eric; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Med, Channing Lab, Boston, MA 02115 USA. [Rexrode, Kathy; Manson, JoAnn E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu OI Rexrode, Kathryn/0000-0003-3387-8429 FU National Institutes of Health [R01 HL71981, HL034594, P01 HL34594, CA87969]; American Heart Association Scientist Development Award; Boston Obesity Nutrition Research Center [DK46200] FX This study was supported, in part, by National Institutes of Health grants R01 HL71981 and HL034594, P01 HL34594, and CA87969, an American Heart Association Scientist Development Award, and the Boston Obesity Nutrition Research Center (DK46200 to Dr Qi). NR 39 TC 58 Z9 63 U1 0 U2 10 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 SEP PY 2012 VL 32 IS 9 BP 2314 EP 2320 DI 10.1161/ATVBAHA.112.248757 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 992JZ UT WOS:000307773100035 PM 22895671 ER PT J AU McNeill, LH Stoddard, A Bennett, GG Wolin, KY Sorensen, GG AF McNeill, Lorna H. Stoddard, Anne Bennett, Gary G. Wolin, Kathleen Y. Sorensen, Glorian G. TI Influence of individual and social contextual factors on changes in leisure-time physical activity in working-class populations: results of the Healthy Directions-Small Businesses Study SO CANCER CAUSES & CONTROL LA English DT Article DE Health disparities; Multivitamin; Nutrition; Physical activity; Race/ethnicity; Social context ID AFRICAN-AMERICAN WOMEN; CAROLINA LATINA IMMIGRANTS; SOCIOECONOMIC-STATUS; CANCER PREVENTION; UNITED-STATES; MULTIETHNIC POPULATIONS; ACTIVITY QUESTIONNAIRE; COLLECTIVE EFFICACY; BUILT ENVIRONMENT; BEHAVIOR-CHANGE AB As part of the Harvard Cancer Prevention Program Project, we sought to address disparities reflected in social class and race/ethnicity by developing and testing a behavioral intervention model that targeted fruit and vegetable consumption, red meat consumption, multivitamin intake, and physical activity in working-class, multiethnic populations. This paper examined the associations between change in leisure-time physical activity and individual and social contextual factors in participants employed in small businesses (n = 850) at both baseline and at 18-month final. In bivariate analyses, age, language acculturation, social ties, and workplace social capital were significantly associated with physical activity at final. In multivariable analyses, being younger and having high language acculturation were significantly associated with greater leisure-time physical activity at final; high workplace social capital was significantly associated with a decline in physical activity at final. These findings have implications for understanding factors that are integral to promoting change in physical activity among working-class, multiethnic populations. C1 [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. [Stoddard, Anne] New England Res Inst, Watertown, MA 02172 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Wolin, Kathleen Y.] Washington Univ, Sch Med, Dept Surg, Div Canc Prevent & Control, St Louis, MO 63110 USA. [Sorensen, Glorian G.] Ctr Community Based Res, Dana Farber Canc Inst, Boston, MA USA. [Sorensen, Glorian G.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP McNeill, LH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Unit 125,1100 Holcombe Blvd, Houston, TX 77030 USA. EM lmcneill@mdanderson.org RI Wolin, Kathleen/I-2154-2014 OI Wolin, Kathleen/0000-0001-7950-9042 FU National Institutes of Health [5 POl CA75308]; Dana-Farber Cancer Institute by Liberty Mutual, National Grid; Patterson Fellowship Fund FX This research was supported by the National Institutes of Health (grant 5 POl CA75308) and the Dana-Farber Cancer Institute by Liberty Mutual, National Grid, and the Patterson Fellowship Fund. The authors thank the numerous investigators and staff members who contributed to this study, including Jennifer Dacey Allen, Elizabeth Alvarez, Jamie Baron, Joyce Gheatham, Tracy Liwen Ghen, Graham Golditz, Karen Ertel, Martha Fay, Robert Fletcher, Gaitlin Gutheil, Elizabeth Gonzalez Suarez, Elizabeth Harden, Laura Jay, Ichiro Kawachi, Kerry Kokkinogenis, Nancy Krieger, Karen Kuntz, Ruth Lederman, Nancy Lightman, Simone Pinheiro, Kathleen Scafidi, Tatyana Pinchuk, George Moseley, Lorraine Wallace, Jane Weeks, Milton Weinstein, and Richard Youngstrom. In addition, this work could not have been completed without the participation of 26 small manufacturing businesses and employees participating in the Healthy Directions-Small Business Study and the participation of Harvard Vanguard Medical Associates and members in the Healthy Directions-Health Centers Study. NR 99 TC 2 Z9 2 U1 4 U2 20 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2012 VL 23 IS 9 BP 1475 EP 1487 DI 10.1007/s10552-012-0021-z PG 13 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 987FD UT WOS:000307401400008 PM 22806257 ER PT J AU Van den Stock, J de Gelder, B De Winter, FL Van Laere, K Vandenbulcke, M AF Van den Stock, Jan de Gelder, Beatrice De Winter, Francois-Laurent Van Laere, Koen Vandenbulcke, Mathieu TI A strange face in the mirror. Face-selective self-misidentification in a patient with right lateralized occipito-temporal hypo-metabolism SO CORTEX LA English DT Letter ID DELUSIONAL BELIEF; RECOGNITION C1 [Van den Stock, Jan; de Gelder, Beatrice; De Winter, Francois-Laurent; Vandenbulcke, Mathieu] Katholieke Univ Leuven, Brain & Emot Lab Leuven BELL, Div Psychiat, Dept Neurosci, B-3000 Louvain, Belgium. [de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, Tilburg, Netherlands. [de Gelder, Beatrice] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Sch Med, Charlestown, MA USA. [Van Laere, Koen] Katholieke Univ Leuven, Div Nucl Med, UZ Gasthuisberg, B-3000 Louvain, Belgium. RP Van den Stock, J (reprint author), Katholieke Univ Leuven, Brain & Emot Lab Leuven BELL, Div Psychiat, Dept Neurosci, O&N 2,Herestr 49,Bus 1022, B-3000 Louvain, Belgium. EM jan.vandenstock@med.kuleuven.be RI Van den Stock, Jan/F-1906-2014 OI Van den Stock, Jan/0000-0001-5756-3195 NR 15 TC 14 Z9 14 U1 0 U2 8 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD SEP PY 2012 VL 48 IS 8 BP 1088 EP 1090 DI 10.1016/j.cortex.2012.03.003 PG 3 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 978EZ UT WOS:000306724700020 PM 22480403 ER PT J AU Langer, JE Lopes, MBS Fountain, NB Pranzatelli, MR Thiele, EA Rust, RS Goodkin, HP AF Langer, Jennifer E. Lopes, M. Beatriz S. Fountain, Nathan B. Pranzatelli, Michael R. Thiele, Elizabeth A. Rust, Robert S. Goodkin, Howard P. TI An unusual presentation of anti-Hu-associated paraneoplastic limbic encephalitis SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID ENCEPHALOMYELITIS SENSORY NEURONOPATHY; LUNG-CANCER; NEUROBLASTOMA; ANTIBODIES; TUMOR AB Paraneoplastic limbic encephalitis is a rare disorder characterized by personality changes, seizures, memory loss, and psychiatric symptoms often associated with antineuronal antibodies. It is well described in the adult literature but is still underreported in the pediatric literature. Symptoms are usually multifocal and subacute in presentation, occurring over days to weeks; however, in rare cases, symptom onset can be more gradual. We report the case of a 9-year-old male with anti-Hu-associated paraneoplastic limbic encephalitis that presented as episodic ataxia and behavioral changes evolving to intractable epilepsy and worsening behavioral changes over the course of a year. This case highlights the importance of considering a paraneoplastic disorder in the differential diagnosis for unexplained multifocal neurological symptoms of subacute or chronic onset as earlier detection and treatment may result in an improved outcome. C1 [Langer, Jennifer E.; Fountain, Nathan B.; Rust, Robert S.; Goodkin, Howard P.] Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA 22908 USA. [Lopes, M. Beatriz S.] Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA 22908 USA. [Pranzatelli, Michael R.] So Illinois Univ, Sch Med, Dept Neurol, Springfield, IL USA. [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rust, Robert S.; Goodkin, Howard P.] Univ Virginia Hlth Syst, Dept Pediat, Charlottesville, VA 22908 USA. RP Goodkin, HP (reprint author), Univ Virginia Hlth Syst, Dept Neurol, POB 800394, Charlottesville, VA 22908 USA. EM hpg9v@virginia.edu NR 11 TC 5 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD SEP PY 2012 VL 54 IS 9 BP 863 EP 866 DI 10.1111/j.1469-8749.2012.04221.x PG 4 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 988DP UT WOS:000307468700020 PM 22320677 ER PT J AU Bledsoe, JR Sadow, PM Stephen, A Nielsen, GP Faquin, WC AF Bledsoe, Jacob R. Sadow, Peter M. Stephen, Antonia Nielsen, G. Petur Faquin, William C. TI Fine Needle Aspiration Biopsy of an Unusual Follicular Adenoma with Sebaceous-Like Features SO ENDOCRINE PATHOLOGY LA English DT Article ID CLEAR-CELL-CHANGE; THYROID-GLAND; CARCINOMA; CYTOLOGY C1 [Bledsoe, Jacob R.; Sadow, Peter M.; Nielsen, G. Petur; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stephen, Antonia] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Bledsoe, Jacob R.; Sadow, Peter M.; Stephen, Antonia; Nielsen, G. Petur; Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. RP Faquin, WC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 219,55 Fruit St, Boston, MA 02114 USA. EM wfaquin@partners.org NR 19 TC 0 Z9 0 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD SEP PY 2012 VL 23 IS 3 BP 177 EP 180 DI 10.1007/s12022-012-9205-z PG 4 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 988VI UT WOS:000307518400008 PM 22527948 ER PT J AU Bosak, T Liang, B Wu, TD Templer, SP Evans, A Vali, H Guerquin-Kern, JL Klepac-Ceraj, V Sim, MS Mui, J AF Bosak, T. Liang, B. Wu, T. -D. Templer, S. P. Evans, A. Vali, H. Guerquin-Kern, J. -L. Klepac-Ceraj, V. Sim, M. S. Mui, J. TI Cyanobacterial diversity and activity in modern conical microbialites SO GEOBIOLOGY LA English DT Article ID YELLOWSTONE-NATIONAL-PARK; RIBOSOMAL-RNA GENES; BACTERIAL STROMATOLITES; OXYGENIC PHOTOSYNTHESIS; SPATIAL-RESOLUTION; MAT COMMUNITY; NORTH-ISLAND; HOT-SPRINGS; NEW-ZEALAND; SP-NOV AB Modern conical microbialites are similar to some ancient conical stromatolites, but growth, behavior and diversity of cyanobacteria in modern conical microbialites remain poorly characterized. Here, we analyze the diversity of cyanobacterial 16S rRNA gene sequences in conical microbialites from 14 ponds fed by four thermal sources in Yellowstone National Park and compare cyanobacterial activity in the tips of cones and in the surrounding topographic lows (mats), respectively, by high-resolution mapping of labeled carbon. Cones and adjacent mats contain similar 16S rRNA gene sequences from genetically distinct clusters of filamentous, non-heterocystous cyanobacteria from Subsection III and unicellular cyanobacteria from Subsection I. These sequences vary among different ponds and between two sampling years, suggesting that coniform mats through time and space contain a number of cyanobacteria capable of vertical aggregation, filamentous cyanobacteria incapable of initiating cone formation and unicellular cyanobacteria. Unicellular cyanobacteria are more diverse in topographic lows, where some of these organisms respond to nutrient pulses more rapidly than thin filamentous cyanobacteria. The densest active cyanobacteria are found below the upper 50 similar to mu m of the cone tip, whereas cyanobacterial cells in mats are less dense, and are more commonly degraded or encrusted by silica. These spatial differences in cellular activity and density within macroscopic coniform mats imply a strong role for diffusion limitation in the development and the persistence of the conical shape. Similar mechanisms may have controlled the growth, morphology and persistence of small coniform stromatolites in shallow, quiet environments throughout geologic history. C1 [Bosak, T.; Liang, B.; Templer, S. P.; Evans, A.; Sim, M. S.] MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA. [Liang, B.] Acad Sinica, Inst Earth Sci, Taipei 115, Taiwan. [Wu, T. -D.; Guerquin-Kern, J. -L.] Univ Paris 11, INSERM, F-91405 Orsay, France. [Wu, T. -D.; Guerquin-Kern, J. -L.] Inst Curie, Lab Microscopie Ion, F-91405 Orsay, France. [Templer, S. P.] Roche Mol Diagnost, Basel, Switzerland. [Vali, H.; Mui, J.] McGill Univ, Facil Electron Microscopy Res, Montreal, PQ, Canada. [Vali, H.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada. [Klepac-Ceraj, V.] Forsyth Inst, Cambridge, MA USA. [Klepac-Ceraj, V.] Wellesley Coll, Dept Biol Sci, Wellesley, MA 02181 USA. RP Bosak, T (reprint author), MIT, Dept Earth Atmospher & Planetary Sci, Cambridge, MA 02139 USA. EM tbosak@mit.edu RI Liang, Biqing/J-2799-2012; Vali, Hojatollah/F-3511-2012; Templer, Stefanie/D-6515-2012; OI Sim, Min Sub/0000-0002-3491-9002; Liang, Biqing/0000-0003-3634-5556; Vali, Hojatollah/0000-0003-3464-9943; Templer, Stefanie/0000-0003-2134-0699; Klepac-Ceraj, Vanja/0000-0001-5387-5706 FU Natural Sciences and Engineering Research Council (NSERC) of Canada FX We thank G. Geesey (U. Montana), S. Gunther (NPS), J. Thompson (MIT), L. Casillas (Univ. PR), D. Newman Lab (MIT), J. Holz and N. Watson (Keck Biological Imaging Facility, Whitehead Institute, MIT), members of the MIT Laboratory for Geomicrobiology and Microbial Sedimentology and Dr. S. K. Sears (McGill Univ.). H. V. acknowledges financial support from the Natural Sciences and Engineering Research Council (NSERC) of Canada. We also thank the PICT-IBiSA imaging facility in the Institut Curie for NanoSIMS analyses. Thoughtful comments by three anonymous reviewers improved the manuscript. NR 76 TC 17 Z9 17 U1 2 U2 28 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1472-4677 J9 GEOBIOLOGY JI Geobiology PD SEP PY 2012 VL 10 IS 5 BP 384 EP 401 DI 10.1111/j.1472-4669.2012.00334.x PG 18 WC Biology; Environmental Sciences; Geosciences, Multidisciplinary SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Geology GA 989FK UT WOS:000307545500002 PM 22713108 ER PT J AU Oh, S Go, GW Mylonakis, E Kim, Y AF Oh, S. Go, G. W. Mylonakis, E. Kim, Y. TI The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans SO JOURNAL OF APPLIED MICROBIOLOGY LA English DT Article DE biofilms; C; albicans; C; elegans; indole signalling; virulence ID ENTERICA SEROVAR TYPHIMURIUM; ESCHERICHIA-COLI; CAENORHABDITIS-ELEGANS; BIOFILM FORMATION; GENE-EXPRESSION; MUTANTS; SYSTEM; HOST; NRG1; PCR AB Aims Indole is a signalling molecule, produced by a number of Gram-positive and Gram-negative bacteria both in nature as well as clinical environments. Here, we explored the effect of bacterial indole and one of its main derivatives on the virulence of the fungal pathogen Candida albicans. Methods and Results We found that indole and its derivate indole-3-acetonitrile (IAN) did not affect the viability of C. albicans. Interestingly, indole and IAN repressed C. albicans biofilm formation as well as the attachment of C. albicans to intestinal epithelial HT-29 cells and inhibited the ability of the yeast to make filaments that are the main virulence factor of C. albicans. In addition, we used the heterologous model host Caenorhabditis elegans to demonstrate in vivo that the presence of indole or IAN attenuates C. albicans infection (P = 0.0188 and P < 0.0001 for indole and IAN, respectively, compared to worms exposed to C. albicans DAY185 alone) and decreases fungal colonization in the nematode gut. Importantly, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that in C. albicans, indole and IAN strongly stimulated the transcription of NRG1. Conclusions Indole and IAN attenuates fungal virulence by regulating the transcription of NRG1, a transcriptional factor that influences filamentation and biofilm formation in C. albicans. Significance and Impact of the Study Our findings indicate that the bacterial signalling molecules indole and its derivatives play an inter-kingdom role in dynamic network of microbiota and directly modulate the virulence of fungal C. albicans via NRG1. C1 [Oh, S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Gastroenterol, Boston, MA USA. [Go, G. W.] Yale Univ, Sch Med, Cardiovasc Res Ctr, New Haven, CT USA. [Mylonakis, E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Kim, Y.] Chonbuk Natl Univ, Dept Anim Sci, Jeonju, South Korea. RP Kim, Y (reprint author), 567 Baekje Daero, Jeonju 561756, South Korea. EM ykeys2584@jbnu.ac.kr RI Go, Gwang-woong/H-2733-2013 FU Chonbuk National University FX This study was supported by research funds of Chonbuk National University in 2012. NR 39 TC 16 Z9 18 U1 4 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1364-5072 J9 J APPL MICROBIOL JI J. Appl. Microbiol. PD SEP PY 2012 VL 113 IS 3 BP 622 EP 628 DI 10.1111/j.1365-2672.2012.05372.x PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 989KN UT WOS:000307558800016 PM 22726313 ER PT J AU Hollak, CEM Kuter, D Giraldo, P Hughes, D Belmatoug, N Brand, M Muller, A Schaaf, B Giorgino, R Zimran, A AF Hollak, C. E. M. Kuter, D. Giraldo, P. Hughes, D. Belmatoug, N. Brand, M. Muller, A. Schaaf, B. Giorgino, R. Zimran, A. TI MIGLUSTAT THERAPY IN TYPE 1 GAUCHER DISEASE: LONG-TERM TREATMENT EXPERIENCE FROM A MULTICENTER, RETROSPECTIVE COHORT STUDY SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Hollak, C. E. M.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Kuter, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Giraldo, P.] Hosp Univ Miguel Servet, CIBERER, Zaragoza, Spain. [Hughes, D.] Royal Free Hosp, London NW3 2QG, England. [Hughes, D.] Univ Coll Med Sch, London, England. [Belmatoug, N.] Hop Beaujon, Clichy, France. [Brand, M.; Muller, A.; Giorgino, R.] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Schaaf, B.] Factum, Offenbach, Germany. [Zimran, A.] Shaare Zedek Med Ctr, Jerusalem, Israel. RI Hughes, Derralynn/J-8012-2013 OI Hughes, Derralynn/0000-0003-4531-9173 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD SEP PY 2012 VL 35 SU 1 BP S97 EP S97 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 988TH UT WOS:000307513100341 ER PT J AU Watanabe, R Tawa, M Fisher, DC Kupper, T Clark, RA AF Watanabe, R. Tawa, M. Fisher, D. C. Kupper, T. Clark, R. A. TI Human skin lesion morphology reflects and predicts the recirculation patterns of pathogenic T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 42nd Annual Meeting of the European-Society-for-Dermatological-Research (ESDR) CY SEP 07-10, 2012 CL Venice, ITALY SP European Soc Dermatol Res (ESDR) C1 [Watanabe, R.; Tawa, M.; Fisher, D. C.; Kupper, T.; Clark, R. A.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2012 VL 132 SU 2 MA 141 BP S25 EP S25 PG 1 WC Dermatology SC Dermatology GA 992XM UT WOS:000307814000142 ER PT J AU Hawkins, EJ Malte, CA Baer, JS Kivlahan, DR AF Hawkins, Eric J. Malte, Carol A. Baer, John S. Kivlahan, Daniel R. TI Prevalence, predictors, and service utilization of patients with recurrent use of Veterans Affairs substance use disorder specialty care SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE Chronic; Recurrent; Prevalence; Predictors; Utilization ID ABUSE TREATMENT; ADDICTION TREATMENT; FOLLOW-UP; MANAGEMENT CHECKUPS; ALCOHOL DEPENDENCE; COLLABORATIVE CARE; TREATMENT REENTRY; MENTAL-HEALTH; DRUG; RECOVERY AB Although substance use disorders (SUDs) are chronic conditions for many patients, the prevalence, predictors, and health care utilization patterns of those who reenter SUD specialty care are understudied. We identified 1,640 patients who initiated SUD specialty care at 1 Veterans Affairs (VA) medical center and categorized them, using their subsequent 24 and prior 60 months receipt of VA SUD care, as index episode only (35.7%, 33.5-38.1), index and prior episode(s) (24.6%, 22.5-22.7), and index and postindex episodes (39.6%, 37.3-42.0). Compared with the index episode-only group, the postindex episode(s) group had modestly higher percentages of men, divorced/separated, and alcohol use, cocaine use, bipolar disorder, and psychotic disorders. Patients with postindex episodes averaged 2 times more postindex emergency visits and mental health hospitalizations than patients with an index only episode. Results document the prevalence, overall health care utilization, and limited predictability of SUD treatment reentry and support development of new models of care for these complex patients. Published by Elsevier Inc. C1 [Hawkins, Eric J.; Malte, Carol A.; Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Hawkins, Eric J.; Malte, Carol A.; Baer, John S.; Kivlahan, Daniel R.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98108 USA. [Baer, John S.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Hawkins, Eric J.; Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Hawkins, EJ (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div S116ATC, Hlth Serv Res & Dev, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Eric.Hawkins@va.gov NR 41 TC 7 Z9 7 U1 3 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD SEP PY 2012 VL 43 IS 2 BP 221 EP 230 DI 10.1016/j.jsat.2011.11.002 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 984QV UT WOS:000307207100009 PM 22197302 ER PT J AU Santa-Maria, I Diaz-Ruiz, C Ksiezak-Reding, H Chen, A Ho, L Wang, J Pasinetti, GM AF Santa-Maria, Ismael Diaz-Ruiz, Carmen Ksiezak-Reding, Hanna Chen, Alice Ho, Lap Wang, Jun Pasinetti, Giulio Maria TI GSPE interferes with tau aggregation in vivo: implication for treating tauopathy SO NEUROBIOLOGY OF AGING LA English DT Article DE GSPE; JNPL3 mouse model; tauopathy; hyperphosphorylation ID NANOELECTROSPRAY MASS-SPECTROMETRY; P301L HUMAN-TAU; ALZHEIMERS-DISEASE; FILAMENT FORMATION; TRANSGENIC MICE; NEURODEGENERATIVE DISEASES; PHOSPHORYLATION SITES; MOUSE MODEL; INHIBITION; PROTEIN AB Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation of hyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine-month-old JNPL3 mice were treated with GSPE delivered through their drinking water for 6 months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylated and conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8, and Alz50 tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motor function assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans. (C) 2012 Elsevier Inc. All rights reserved. C1 [Santa-Maria, Ismael; Diaz-Ruiz, Carmen; Ksiezak-Reding, Hanna; Chen, Alice; Ho, Lap; Wang, Jun; Pasinetti, Giulio Maria] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Santa-Maria, Ismael] Queen Sofia Fdn, CIEN Fdn, Alzheimer Dis Res Unit, Madrid, Spain. [Ksiezak-Reding, Hanna; Chen, Alice; Ho, Lap; Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu OI Diaz-Ruiz, Carmen/0000-0002-0112-0595 FU Polyphenolics Inc.; Division of Constellation Wine U.S. Inc.; Society for Progressive Supranuclear Palsy; NIH [PO1 AT004511]; Veterans Administration FX This work is supported by Polyphenolics Inc., Division of Constellation Wine U.S. Inc., the Society for Progressive Supranuclear Palsy, NIH PO1 AT004511, and in part from a MERIT Review grant from Veterans Administration to G.M.P. NR 36 TC 11 Z9 11 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2012 VL 33 IS 9 BP 2072 EP 2081 DI 10.1016/j.neurobiolaging.2011.09.027 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 981TW UT WOS:000306994600020 PM 22054871 ER PT J AU Bekris, LM Lutz, F Li, G Galasko, DR Farlow, MR Quinn, JF Kaye, JA Leverenz, JB Tsuang, DW Montine, TJ Peskind, ER Yu, CE AF Bekris, Lynn M. Lutz, Franziska Li, Gail Galasko, Douglas R. Farlow, Martin R. Quinn, Joseph F. Kaye, Jeffrey A. Leverenz, James B. Tsuang, Debby W. Montine, Thomas J. Peskind, Elaine R. Yu, Chang-En TI ADAM10 expression and promoter haplotype in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article DE ADAM10; Haplotype; sAPP alpha; Alzheimer's disease; Reporter assay; Neuritic plaques; Brain; Hippocampus; Cerebrospinal fluid ID AMYLOID PRECURSOR PROTEIN; ALPHA-SECRETASE ADAM10; UP-REGULATION; MOUSE MODEL; ADAM-10; MUTATIONS; BACE AB Alzheimer's disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain amyloid-beta (A beta) and lower levels of A beta correspond to an increase in ADAM10 alpha-secretase activity. ADAM10 alpha-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPP alpha) product and negates the pathological production of A beta. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPP alpha levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPP alpha levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3' UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region-and cell type-specific manner. (C) 2012 Elsevier Inc. All rights reserved. C1 [Bekris, Lynn M.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98108 USA. [Bekris, Lynn M.; Lutz, Franziska; Tsuang, Debby W.; Yu, Chang-En] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Galasko, Douglas R.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Galasko, Douglas R.] VA Med Ctr San Diego, San Diego, CA USA. [Farlow, Martin R.] Indiana Univ Sch Med, Dept Neurol, Indianapolis, IN USA. [Quinn, Joseph F.; Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Quinn, Joseph F.; Kaye, Jeffrey A.] Portland VA Med Ctr, Portland, OR USA. [Leverenz, James B.] VA Puget Sound Hlth Care Syst, MIRECC, NW Network VISN 20, Seattle, WA USA. [Leverenz, James B.] Parkinsons Dis Res Educ & Clin Ctr PADRECC, NW Network VISN 20, Philadelphia, PA USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. RP Bekris, LM (reprint author), Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Box 358280,VAPSHCS GRECC S182,1660 S Columbian Wa, Seattle, WA 98108 USA. EM lbekris@u.washington.edu RI Tsuang, Debby/L-7234-2016; OI Tsuang, Debby/0000-0002-4716-1894; Kaye, Jeffrey/0000-0002-9971-3478 FU U.S. Department of Veterans Affairs, Office of Research and Development; Biomedical Laboratory; NIH [2P50AG005136-27, 1P50NS062684-01A1, K99AG034214-02] FX This work is supported in part by the U.S. Department of Veterans Affairs, Office of Research and Development Clinical Research and Development Program, the Biomedical Laboratory Research Program, and NIH Grants 2P50AG005136-27, 1P50NS062684-01A1, and K99AG034214-02. Additional support includes University of Washington Alzheimer's Disease Research Center NIH P50-AB005136 and University of California San Diego Alzheimer's Disease Research Center AGO 5131. NR 32 TC 4 Z9 4 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2012 VL 33 IS 9 AR 2229.e1 DI 10.1016/j.neurobiolaging.2012.03.013 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 981TW UT WOS:000306994600036 PM 22572541 ER PT J AU Sanna-Cherchi, S Burgess, KE Nees, SN Papeta, N Choi, M Sampogna, RV Bodria, M Perry, BJ Weng, PL Lozanovski, VJ Materna-Kiryluk, A Ristoska-Bojkovska, N Gesualdo, L Gucev, Z Allegri, L Latos-Bielenska, A Scolari, F Ravazzolo, R Kiryluk, K Drummond, I Al-Awqati, Q D'Agati, VD Tasic, V Lifton, RP Ghiggeri, GM Gharavi, AG AF Sanna-Cherchi, Simone Burgess, Katelyn E. Nees, Shannon N. Papeta, Natalia Choi, Murim Sampogna, Rosemary V. Bodria, Monica Perry, Brittany J. Weng, Patricia L. Lozanovski, Vladimir J. Materna-Kiryluk, Anna Ristoska-Bojkovska, Nadica Gesualdo, Loreto Gucev, Zoran Allegri, Landino Latos-Bielenska, Anna Scolari, Francesco Ravazzolo, Roberto Kiryluk, Krzysztof Drummond, Iain Al-Awqati, Qais D'Agati, Vivette D. Tasic, Velibor Lifton, Richard P. Ghiggeri, Gian Marco Gharavi, Ali G. TI Exome sequencing identifies dominant alleles causing obstructive uropathy and other congenital anomalies SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Sanna-Cherchi, Simone; Burgess, Katelyn E.; Nees, Shannon N.; Papeta, Natalia; Sampogna, Rosemary V.; Perry, Brittany J.; Weng, Patricia L.; Kiryluk, Krzysztof; Al-Awqati, Qais; Gharavi, Ali G.] Columbia Univ, Div Nephrol, New York, NY USA. [Choi, Murim; Lifton, Richard P.] Yale Univ, Dept Genet, New Haven, CT USA. [Bodria, Monica; Ghiggeri, Gian Marco] G Gaslini Inst Children, Div Pediat Nephrol, Genoa, Italy. [Lozanovski, Vladimir J.; Ristoska-Bojkovska, Nadica; Gucev, Zoran; Tasic, Velibor] Univ Childrens Hosp, Div Pediat Nephrol, Skopje, Macedonia. [Materna-Kiryluk, Anna; Latos-Bielenska, Anna] Polish Registry Congenital Malformat, Poznan, Poland. [Gesualdo, Loreto] Univ Foggia, Dept Biomed Sci, Foggia, Italy. [Allegri, Landino] Univ Parma, Div Nephrol, I-43100 Parma, Italy. [Ravazzolo, Roberto] G Gaslini Inst Children, Mol Genet Lab, Genoa, Italy. [Drummond, Iain] Massachusetts Gen Hosp, Dept Genet, Boston, MA 02114 USA. [D'Agati, Vivette D.] Columbia Univ, Dept Pathol, New York, NY USA. RI Ghiggeri, Gian Marco/N-4712-2015; bodria, monica/K-2115-2016 OI Ghiggeri, Gian Marco/0000-0003-3659-9062; bodria, monica/0000-0001-9690-9945 NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2012 VL 27 IS 9 BP 1623 EP 1624 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 985NT UT WOS:000307274100061 ER PT J AU Aparici, CM Seo, Y AF Aparici, Carina Mari Seo, Youngho TI Functional Imaging for Prostate Cancer: Therapeutic Implications SO SEMINARS IN NUCLEAR MEDICINE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; LYMPH-NODE DISSECTION; ANDROGEN-DEPRIVATION THERAPY; MODULATED RADIATION-THERAPY; MEMBRANE ANTIGEN-EXPRESSION; RADICAL RETROPUBIC PROSTATECTOMY; DOMINANT INTRAPROSTATIC LESIONS; EXTERNAL-BEAM RADIOTHERAPY; MONOCLONAL-ANTIBODY J591; WHOLE-PELVIC IRRADIATION AB Functional radionuclide imaging modalities, now commonly combined with anatomical imaging modalities computed tomography (CT) or magnetic resonance imaging (single photon emission computed tomography [SPECT]/CT, positron emission tomography [PET]/CT, and PET/magnetic resonance imaging), are promising tools for the management of prostate cancer, particularly for therapeutic implications. Sensitive detection capability of prostate cancer using these imaging modalities is one issue; however, the treatment of prostate cancer using the information that can be obtained from functional radionuclide imaging techniques is another challenging area. There are not many SPECT or PET radiotracers that can cover the full spectrum of the management of prostate cancer from initial detection to staging, prognosis predictor, and all the way to treatment response assessment. However, when used appropriately, the information from functional radionuclide imaging improves, and sometimes significantly changes, the whole course of the cancer management. The limitations of using SPECT and PET radiotracers with regard to therapeutic implications are not so much different from their limitations solely for the task of detecting prostate cancer; however, the specific imaging target and how this target is reliably imaged by SPECT and PET can potentially make significant impact in the treatment of prostate cancer. Finally, although the localized prostate cancer is considered manageable, there is still significant need for improvement in noninvasive imaging of metastatic prostate cancer, in treatment guidance, and in response assessment from functional imaging, including radionuclide-based techniques. In this review article, we present the rationale of using functional radionuclide imaging and the therapeutic implications for each of radionuclide imaging agent that have been studied in human subjects. Semin Nucl Med 42:328-342 (c) 2012 Elsevier Inc. All rights reserved. C1 [Seo, Youngho] UCSF, Phys Res Lab, Dept Radiol & Biomed Imaging, San Francisco, CA 94107 USA. [Aparici, Carina Mari] San Francisco VA Med Ctr, Nucl Med Serv, San Francisco, CA USA. [Seo, Youngho] Univ Calif San Francisco, Dept Radiat Oncol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94107 USA. [Seo, Youngho] Univ Calif San Francisco, UCSF Grad Program Bioengn, UC Berkeley, San Francisco, CA 94107 USA. RP Seo, Y (reprint author), UCSF, Phys Res Lab, Dept Radiol & Biomed Imaging, 185 Berry St,Suite 350, San Francisco, CA 94107 USA. EM youngho.seo@ucsf.edu FU National Institutes of Health (NIH) [K25 CA114254]; American Recovery and Reinvestment Act (ARRA) through NIH [K25 CA114254-04S1]; UCSF Research Evaluation and Allocation Committee; UCSF Department of Radiation Oncology FX This work was supported by grants K25 CA114254 from the National Institutes of Health (NIH); K25 CA114254-04S1 American Recovery and Reinvestment Act (ARRA) of 2009 through NIH; and from UCSF Research Evaluation and Allocation Committee and UCSF Department of Radiation Oncology. NR 214 TC 13 Z9 13 U1 1 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0001-2998 EI 1558-4623 J9 SEMIN NUCL MED JI Semin. Nucl. Med. PD SEP PY 2012 VL 42 IS 5 BP 328 EP 342 DI 10.1053/j.semnuclmed.2012.04.004 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 986TO UT WOS:000307368700006 ER PT J AU Lehavot, K Molina, Y Simoni, JM AF Lehavot, Keren Molina, Yamile Simoni, Jane M. TI Childhood Trauma, Adult Sexual Assault, and Adult Gender Expression among Lesbian and Bisexual Women SO SEX ROLES LA English DT Article DE Childhood abuse; Sexual assault; Lesbian; Bisexual; Gender expression; Gender identity; Butch/femme ID PHYSICAL ABUSE; SUBSTANCE USE; BUTCH/FEMME DIFFERENCES; IDENTITY DEVELOPMENT; INITIAL RELIABILITY; ATYPICAL BEHAVIOR; EATING-DISORDER; MENTAL-HEALTH; UNITED-STATES; VICTIMIZATION AB Several studies have demonstrated that lesbian and bisexual women are more likely than heterosexual women to report childhood abuse and adult sexual assault. It is unknown, however, which sexual minority women are most likely to experience such abuse. We recruited adult sexual minority women living in the US through electronic fliers sent to listservs and website groups inviting them to complete an online survey (N = 1,243). We examined differences in both childhood abuse and adult sexual assault by women's current gender identity (i.e., butch, femme, androgynous, or other) and a continuous measure of gender expression (from butch/masculine to femme/feminine), adjusting for sexual orientation identity, age, education, and income. Results indicated that a more butch/masculine current self-assessment of gender expression, but not gender identity, was associated with more overall reported childhood trauma. Although one aspect of gender expression, a more butch/masculine gender role, was associated with adult sexual assault, feminine appearance and a femme gender identity also significantly predicted adult sexual assault. These findings highlight the significance of gender identity and expression in identifying women at greater risk for various abuse experiences. C1 [Lehavot, Keren] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Lehavot, Keren] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Molina, Yamile] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Simoni, Jane M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. RP Lehavot, K (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM klehavot@u.washington.edu OI Simoni, Jane/0000-0002-8711-1576 FU NCI NIH HHS [P50 CA148143]; NIMH NIH HHS [K24 MH093243]; ODCDC CDC HHS [R36 CD000996] NR 58 TC 10 Z9 10 U1 1 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-0025 J9 SEX ROLES JI Sex Roles PD SEP PY 2012 VL 67 IS 5-6 BP 272 EP 284 DI 10.1007/s11199-012-0171-1 PG 13 WC Psychology, Developmental; Psychology, Social; Women's Studies SC Psychology; Women's Studies GA 985LU UT WOS:000307268800002 PM 24003263 ER PT J AU de Silva, PSA Nguyen, DD Sauk, J Korzenik, J Yajnik, V Ananthakrishnan, AN AF de Silva, P. S. A. Nguyen, D. D. Sauk, J. Korzenik, J. Yajnik, V. Ananthakrishnan, A. N. TI Long-term outcome of a third anti-TNF monoclonal antibody after the failure of two prior anti-TNFs in inflammatory bowel disease SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CROHNS-DISEASE; RANDOMIZED-TRIAL; MAINTENANCE INFLIXIMAB; DOSE INTENSIFICATION; CERTOLIZUMAB PEGOL; ADALIMUMAB; THERAPY; IMMUNOMODULATORS; NATALIZUMAB; INDUCTION AB Background A significant proportion of patients with IBD lose response to anti-TNF therapies. There is limited knowledge of the long-term outcomes of those who have failed two anti-TNF agents and commenced a third. Aim To examine the safety and efficacy of third anti-TNF treatment after failure of two prior anti-TNF agents in patients with inflammatory bowel disease. Methods This was a retrospective study of all IBD patients [Crohn's disease (CD), ulcerative colitis (UC)] treated with a third anti-TNF agent after loss of response or intolerance to two prior anti-TNF agents at a single tertiary North American centre. Disease activity, drug therapy and Montreal phenotypes were noted at disease onset and commencement of the third anti-TNF agent. KaplanMeier estimates were used to calculate the probability of remaining on the third anti-TNF agent and to identify predictors of long-term clinical response. Results A total of 63 patients (64% women, 57 CD and 6 UC) were included in the analysis. The mean disease duration at initiation of third anti-TNF was 12 years. Thirty-five (55.6%) patients discontinued the third anti-TNF after a mean of 13.2 months. Probability of remaining on the third anti-TNF was 0.69, 0.55, 0.37 and 0.25 at 6, 12, 24 and 36 months respectively. Prior primary nonresponders to the first anti-TNF agent [hazard ratio (HR) 6.4, 95% CI 2.516.1] and persistent disease activity at 3 months after commencement of a third anti-TNF (HR 3.2, 95% CI 1.37.8) predicted poorer response. Conclusions Over half of patients with inflammatory bowel disease, initiated on a third anti-TNF agent after failure of two prior anti-TNF drugs, are able to remain on the third anti-TNF at 1 year. C1 [Ananthakrishnan, A. N.] Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org NR 19 TC 24 Z9 24 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP PY 2012 VL 36 IS 5 BP 459 EP 466 DI 10.1111/j.1365-2036.2012.05214.x PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 984BV UT WOS:000307164600006 PM 22784296 ER PT J AU Novara, G Ficarra, V Mocellin, S Ahlering, TE Carroll, PR Graefen, M Guazzoni, G Menon, M Patel, VR Shariat, SF Tewari, AK Van Poppel, H Zattoni, F Montorsi, F Mottrie, A Rosen, RC Wilson, TG AF Novara, Giacomo Ficarra, Vincenzo Mocellin, Simone Ahlering, Thomas E. Carroll, Peter R. Graefen, Markus Guazzoni, Giorgio Menon, Mani Patel, Vipul R. Shariat, Shahrokh F. Tewari, Ashutosh K. Van Poppel, Hendrik Zattoni, Filiberto Montorsi, Francesco Mottrie, Alexandre Rosen, Raymond C. Wilson, Timothy G. TI Systematic Review and Meta-analysis of Studies Reporting Oncologic Outcome After Robot-assisted Radical Prostatectomy SO EUROPEAN UROLOGY LA English DT Review DE Prostatic neoplasms; Prostatectomy; Laparoscopy; Robotics ID POSITIVE SURGICAL MARGINS; LEARNING-CURVE; LAPAROSCOPIC PROSTATECTOMY; FUNCTIONAL OUTCOMES; PERIOPERATIVE OUTCOMES; CANCER CONTROL; RETROPUBIC PROSTATECTOMY; SINGLE-SURGEON; CONTINENCE OUTCOMES; FOLLOW-UP AB Context: Despite the large diffusion of robot-assisted radical prostatectomy (RARP), literature and data on the oncologic outcome of RARP are limited. Objective: Evaluate lymph node yield, positive surgical margins (PSMs), use of adjuvant therapy, and biochemical recurrence (BCR)-free survival following RARP and perform a cumulative analysis of all studies comparing the oncologic outcomes of RARP and retropubic radical prostatectomy (RRP) or laparoscopic radical prostatectomy (LRP). Evidence acquisition: A systematic review of the literature was performed in August 2011, searching Medline, Embase, and Web of Science databases. A free-text protocol using the term radical prostatectomy was applied. The following limits were used: humans; gender (male); and publications dating from January 1, 2008. A cumulative analysis was conducted using Review Manager software v. 4.2 (Cochrane Collaboration, Oxford, UK) and Stata 11.0 SE software (StataCorp, College Station, TX, USA). Evidence synthesis: We retrieved 79 papers evaluating oncologic outcomes following RARP. The mean PSM rate was 15% in all comers and 9% in pathologically localized cancers, with some tumor characteristics being the most relevant predictors of PSMs. Several surgeon-related characteristics or procedure-related issues may play a major role in PSM rates. With regard to BCR, the very few papers with a follow-up duration >5 yr demonstrated 7-yr BCR-free survival estimates of approximately 80%. Finally, all the cumulative analyses comparing RARP with RRP and comparing RARP with LRP demonstrated similar overall PSM rates (RARP vs RRP: odds ratio [OR]: 1.21; p = 0.19; RARP vs LRP: OR: 1.12; p = 0.47), pT2 PSM rates (RARP vs RRP: OR: 1.25; p = 0.31; RARP vs LRP: OR: 0.99; p = 0.97), and BCR-free survival estimates (RARP vs RRP: hazard ratio [ HR]: 0.9; p = 0.526; RARP vs LRP: HR: 0.5; p = 0.141), regardless of the surgical approach. Conclusions: PSM rates are similar following RARP, RRP, and LRP. The few data available on BCR from high-volume centers are promising, but definitive comparisons with RRP or LRP are not currently possible. Finally, significant data on cancer-specific mortality are not currently available. (C) 2012 Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Novara, Giacomo] Univ Padua, Dept Surg & Oncol Sci, Urol Unit, I-35100 Padua, Italy. [Ficarra, Vincenzo; Mottrie, Alexandre] OLV Robot Surg Inst, Aalst, Belgium. [Ahlering, Thomas E.] Univ Calif Irvine, Orange, CA 92668 USA. [Carroll, Peter R.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco Helen Diller Family Comprehens Canc, San Francisco, CA 94143 USA. [Graefen, Markus] Univ Hamburg Eppendorf, Prostate Canc Ctr, Martini Clin, Hamburg, Germany. [Guazzoni, Giorgio; Montorsi, Francesco] Univ Vita Salute San Raffaele, Milan, Italy. [Menon, Mani] Henry Ford Hosp, Vattikuti Urol Inst, Detroit, MI 48202 USA. [Patel, Vipul R.] Florida Hosp Celebrat Hlth, Global Robot Inst, Celebration, FL USA. [Shariat, Shahrokh F.; Tewari, Ashutosh K.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Van Poppel, Hendrik] Katholieke Univ Leuven, Univ Hosp, Louvain, Belgium. [Rosen, Raymond C.] New England Res Inst Inc, Watertown, MA USA. [Wilson, Timothy G.] City Hope Natl Canc Ctr, Duarte, CA USA. RP Novara, G (reprint author), Univ Padua, Dept Surg & Oncol Sci, Urol Unit, Via Giustiniani 2, I-35100 Padua, Italy. EM giacomonovara@gmail.com OI Ahlering, Thomas/0000-0002-6492-4910; Guazzoni, Giorgio Ferruccio/0000-0002-5713-8313 FU Astellas; Eli Lilly; Pierre Fabre; Provenge; Recordati Int.; Takeda; Intuitive Surgical, Sunnyvale, CA, USA FX Giacomo Novara certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Giacomo Novara was lecturer/advisory board member for Astellas, Eli Lilly, Pierre Fabre, Provenge, Recordati Int., Takeda. Vincenzo Ficarra was speaker for Intuitive Surgical, Sunnyvale, CA, USA. Giorgio Guazzoni, Francesco Montorsi, and Alexandre Mottrie acknowledge receiving research grants from Intuitive Surgical, Sunnyvale, CA, USA. NR 104 TC 159 Z9 165 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD SEP PY 2012 VL 62 IS 3 BP 382 EP 404 DI 10.1016/j.eururo.2012.05.047 PG 23 WC Urology & Nephrology SC Urology & Nephrology GA 981VM UT WOS:000306999400013 PM 22749851 ER PT J AU McMillan, GP Konrad-Martin, D Dille, MF AF McMillan, Garnett P. Konrad-Martin, Dawn Dille, Marilyn F. TI Accuracy of distortion-product otoacoustic emissions-based ototoxicity monitoring using various primary frequency step-sizes SO INTERNATIONAL JOURNAL OF AUDIOLOGY LA English DT Article DE Distortion-product otoacoustic emissions; ototoxicity monitoring; cisplatin; fine structure ID FINE-STRUCTURE; MODEL AB Objective: A cisplatin ototoxicity monitoring protocol was recently proposed using distortion-product otoacoustic emissions (DPOAEs) measured in 1/48th octave steps over the highest obtainable quarter octave (Dille et al, 2010). This protocol can take up to 40 minutes to complete in both ears among seriously ill patients in a potentially noisy test environment. The goal of the current study was to contrast the diagnostic accuracy of ototoxicity monitoring protocols based on changes in DPOAE levels at wider, more rapidly tested, primary frequency step sizes. Design: Measure DPOAE levels in 1/48th octave steps over the highest half-octave of obtainable DPOAEs prior to treatment and at each ototoxicity monitoring session during the course of treatment with cisplatin. Study sample: Nineteen cancer patients being treated with cisplatin at the Portland Veterans Affairs Medical Center were observed over 56 monitoring appointments. Hearing thresholds in the sensitive region for ototoxicity (SRO) were measured concurrently with DPOAE levels. Results: DPOAE levels measured in 1/24th octave steps provided comparable accuracy, and half the testing time, to the 1/48th octave step protocol previously described. Conclusions: DPOAE level shifts measured in 1/24th octave steps may provide a basis for rapid ototoxicity monitoring among adult cancer patients treated with cisplatin. C1 [McMillan, Garnett P.; Konrad-Martin, Dawn; Dille, Marilyn F.] Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res, Portland, OR 97239 USA. [Konrad-Martin, Dawn; Dille, Marilyn F.] Oregon Hlth & Sci Univ, Dept Otolaryngol HNS, Portland, OR 97201 USA. RP McMillan, GP (reprint author), Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM garnett.mcmillan@va.gov FU Department of Veterans Affairs RRD Service [C4183R, C7113N]; VA RR&D National Center for Rehabilitative Auditory Research, Portland, Oregon, USA FX Work supported by the Department of Veterans Affairs RR&D Service (grants C4183R and C7113N) and the VA RR&D National Center for Rehabilitative Auditory Research, Portland, Oregon, USA. Helpful comments were provided by an anonymous reviewer to an early draft of this paper. NR 15 TC 3 Z9 3 U1 1 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1499-2027 J9 INT J AUDIOL JI Int. J. Audiol. PD SEP PY 2012 VL 51 IS 9 BP 689 EP 696 DI 10.3109/14992027.2012.688143 PG 8 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 986QY UT WOS:000307360500006 PM 22676700 ER PT J AU Brito, LCN Sobrinho, APR Teles, RP Socransky, SS Haffajee, AD Vieira, LQ Teles, FRF AF Brito, L. C. N. Ribeiro Sobrinho, A. P. Teles, R. P. Socransky, S. S. Haffajee, A. D. Vieira, L. Q. Teles, F. R. F. TI Microbiologic profile of endodontic infections from HIV- and HIV plus patients using Multiple-Displacement Amplification and Checkerboard DNA-DNA Hybridization SO ORAL DISEASES LA English DT Article DE endodontic infections; HIV-positive patients; MDA; checkerboard ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUBGINGIVAL MICROBIAL PROFILES; HELICOBACTER-PYLORI INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; CHRONIC PERIODONTITIS; RESPIRATORY PATHOGENS; APICAL PERIODONTITIS; ORAL COLONIZATION; POSITIVE PATIENTS; PLAQUE AB Oral Diseases (2012) 18, 558567 Objective: To compare the microbiota of endodontic infections in necrotic pulp from HIV-negative and HIV-positive subjects. Materials and Methods: Root canal samples from necrotic pulp were collected from 40 HIV- and 20 HIV+ subjects. Pulps were amplified using multiple displacement amplification (MDA). Then, checkerboard DNADNA hybridization was employed to assess the levels of 107 microbial taxa. The percentage of DNA probe count and the percentage of teeth colonized by each test species were investigated. Significant differences between groups regarding proportions of taxa and prevalence of the test species were sought using the MannWhitney test and the Chi-square analysis, respectively. Results: The most prevalent taxa detected were Dialister pneumosintes, Stenotrophomonas maltophilia, Streptococcus sobrinus, Corynebacterium diphteriae, and Helicobacter pylori among HIV- subjects and D. pneumosintes, Prevotella tannerae, Porphyromonas gingivalis, Parvimonas micra, Prevotella nigrescens, and Corynebacterium diphtheriae among HIV+ individuals. D. pneumosintes, C. diphtheria, and C. albicans were the most abundant species in the HIV- group, whereas the predominant taxa in HIV+ samples were P. tannerae, D. pneumosintes and Olsenella uli. P. tannerae, O. uli, Veilonella dispar, Bacteroides fragilis, and Actinomyces meyeri were significantly more abundant in HIV+ samples. Conclusions: There were significant differences in the prevalence and proportions of specific microbial taxa between HIV- and HIV+ individuals. The root canal microbiota may represent a reservoir of important oral and medical pathogens, mainly in HIV+ individuals. C1 [Brito, L. C. N.; Ribeiro Sobrinho, A. P.] Univ Fed Minas Gerais, Dept Operat Dent, Sch Dent, BR-31270901 Belo Horizonte, MG, Brazil. [Teles, R. P.; Socransky, S. S.; Haffajee, A. D.; Teles, F. R. F.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. [Teles, R. P.; Teles, F. R. F.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Vieira, L. Q.] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil. RP Sobrinho, APR (reprint author), Univ Fed Minas Gerais, Fac Odontol, Dept Odontol Restauradora, BR-31270901 Belo Horizonte, MG, Brazil. EM sobrinho.bhz@terra.com.br RI Sobrinho, Antonio/H-3245-2012; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; Vieira, Leda/G-7487-2014 FU NIH/NIDCR [R03 DE021742, U01-DE021127]; Eleanor and Miles Shore Fellowship Program for Scholars in Medicine (The Forsyth Institute/Harvard Medical School) FX This work was supported in part by NIH/NIDCR grants R03 DE021742 (FRFT), U01-DE021127 (RPT), the Eleanor and Miles Shore Fellowship Program for Scholars in Medicine (The Forsyth Institute/Harvard Medical School) (FRFT). The authors wish to thank the postgraduate program at the School of Dentistry of UFMG. LCNB is a CAPES fellow; APRS and LQV are CNPq fellows. NR 66 TC 4 Z9 4 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X EI 1601-0825 J9 ORAL DIS JI Oral Dis. PD SEP PY 2012 VL 18 IS 6 BP 558 EP 567 DI 10.1111/j.1601-0825.2012.01908.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 986KM UT WOS:000307340500004 PM 22335194 ER PT J AU Luo, AH Yang, DQ Xin, BC Paster, BJ Qin, J AF Luo, A. H. Yang, D. Q. Xin, B. C. Paster, B. J. Qin, J. TI Microbial profiles in saliva from children with and without caries in mixed dentition SO ORAL DISEASES LA English DT Article DE dental caries; saliva; HOMIM; bacteria; isolated population ID BACTERIAL DIVERSITY; ORAL-CAVITY; DENTAL-CARIES; ROOT CARIES; HEALTH; LEPTOTRICHIA; POPULATIONS; MICROFLORA; CREVICE; ADULTS AB Oral Diseases (2012) 18, 595601 Objective: The purpose of this study was to determine the bacterial profiles in saliva of the isolated children for studying caries etiology. Materials and methods: Samples were collected from isolated children from 6 to 8 years old including 20 caries-free (dmfs = 0) (healthy) and 30 caries-active individuals (dmfs > 8) (patients). 16S rRNA genes were amplified by PCR from bacterial DNA of saliva sample and labeled via incorporation of Cy3-dCTP in second nested PCR. After hybridization of labeled amplicons on HOMIM, the microarray slides were scanned and original data acquired from professional software. Results: Collectively, 94 bacterial species or clusters representing six bacterial phyla and 30 genera were detected. A higher bacterial diversity was observed in patients than in healthy samples. Statistical analyses revealed eight species or clusters were detected more frequently in diseased patients than in healthy samples, while six different species were detected more frequently in healthy as compared to diseased patients. Conclusion: The diversity of microbe within saliva derived from isolated population increased in caries-active status, and there are some bacteria in salivary flora can be as candidate biomarkers for caries prognosis in mixed dentition. The imbalances in the resident microflora may be the ultimate mechanism of dental caries. C1 [Yang, D. Q.; Qin, J.] Chongqing Med Univ, Affiliated Stomatol Hosp, Chongqing 401147, Peoples R China. [Luo, A. H.; Xin, B. C.; Qin, J.] Zunyi Med Coll, Affiliated Stomatol Hosp, Zunyi, Guizhou, Peoples R China. [Yang, D. Q.] Chongqing Med Univ, Res Ctr Oral Dis & Biomed Sci, Coll Stomatol, Chongqing 401147, Peoples R China. [Paster, B. J.] Forsyth Inst, Cambridge, MA 02142 USA. [Paster, B. J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Yang, DQ (reprint author), Chongqing Med Univ, Affiliated Stomatol Hosp, Chongqing 401147, Peoples R China. EM yangdeqin@gmail.com FU National Natural Science Foundation of China [30960419, 81170950, S (2007)1044, 2008037] FX We acknowledge the assistance of Sean Cotton in microbial analyses, and that of Di-Cong Wu and Wen-Ming Huang in subject recruitment. This study was supported by the National Natural Science Foundation of China grants 30960419 and 81170950, Guizhou Qian-Ke-He [S (2007)1044], Qian-Jiao-Ke grant 2008037. NR 35 TC 30 Z9 32 U1 1 U2 23 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2012 VL 18 IS 6 BP 595 EP 601 DI 10.1111/j.1601-0825.2012.01915.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 986KM UT WOS:000307340500009 PM 22458262 ER PT J AU Zanni, MV Grinspoon, SK AF Zanni, Markella V. Grinspoon, Steven K. TI HIV-Specific Immune Dysregulation and Atherosclerosis SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; Atherosclerosis; Immune dysregulation; Inflammation AB HIV + patients face a heightened risk of cardiovascular disease (CVD), which cannot be fully explained by traditional risk factors or antiretroviral therapy (ART)related cardiotoxicity. Increasing evidence suggests a significant contribution of HIV-specific immune dysregulation to atherosclerosis. HIV-specific immune dysregulation may have the following atherogenic effects: 1) activation of endothelial and immune cells; 2) enhancement of the percentage of circulating atherogenic immune cell subsets; and 3) modification of lipid function. Efforts are underway to link immune dysregulation markers with validated CVD endpoints and to identify genetic predispositions for HIVinduced atherogenesis. Moreover, immune suppressants are under evaluation in HIV + patients to attempt modification of immune-mediated CVD risk. Taken together, these studies will enhance understanding of CVD risk stratification and reduction strategies in HIV. C1 [Zanni, Markella V.; Grinspoon, Steven K.] Massachusetts Gen Hosp, Div Endocrine, Program Nutr Metab, Boston, MA 02114 USA. RP Zanni, MV (reprint author), Massachusetts Gen Hosp, Div Endocrine, Program Nutr Metab, 55 Fruit St 5LON 207, Boston, MA 02114 USA. EM mzanni@partners.org; sgrinspoon@partners.org NR 63 TC 17 Z9 17 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1548-3568 EI 1548-3576 J9 CURR HIV-AIDS REP JI Curr. Hiv/Aids Rep. PD SEP PY 2012 VL 9 IS 3 BP 200 EP 205 DI 10.1007/s11904-012-0123-y PG 6 WC Infectious Diseases SC Infectious Diseases GA V32TU UT WOS:000208974300002 PM 22638983 ER PT J AU Faje, A Klibanski, A AF Faje, Alexander Klibanski, Anne TI Body Composition and Skeletal Health: Too Heavy? Too Thin? SO CURRENT OSTEOPOROSIS REPORTS LA English DT Article DE Obesity; Anorexia nervosa; Osteoporosis; Bone density; Growth hormone; IGF-1; Estrogen; Adipokines; Body composition; Skeletal health AB The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity. C1 [Faje, Alexander; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, Boston, MA 02114 USA. [Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457, 55 Fruit St, Boston, MA 02114 USA. EM afaje@partners.org; aklibanski@partners.org FU NIDDK NIH HHS [R01 DK052625] NR 160 TC 11 Z9 12 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA EI 1544-2241 J9 CURR OSTEOPOROS REP JI Curr. Osteoporos. Rep. PD SEP PY 2012 VL 10 IS 3 BP 208 EP 216 DI 10.1007/s11914-012-0106-3 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V35YT UT WOS:000209181700004 PM 22644889 ER PT J AU Barton, SE Najita, J Ginsburg, ES Diller, LR AF Barton, S. E. Najita, J. Ginsburg, E. S. Diller, L. R. TI INFERTILITY AND THE UTILIZATION OF INFERTILITY TREATMENT IN FEMALE SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Barton, S. E.; Ginsburg, E. S.] Brigham & Womens Hosp, Div Reprod Med, Boston, MA 02115 USA. [Barton, S. E.; Ginsburg, E. S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Najita, J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Diller, L. R.] Dana Farber Childrens Hosp, Dept Pediat Oncol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-25 BP S8 EP S8 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700026 ER PT J AU Colaci, DS Gaskins, AJ Wright, D Petrozza, JC Hauser, R Chavarro, JE AF Colaci, D. S. Gaskins, A. J. Wright, D. Petrozza, J. C. Hauser, R. Chavarro, J. E. TI PROTEIN INTAKE AND EARLY IN-VITRO FERTILIZATION OUTCOMES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Colaci, D. S.; Gaskins, A. J.; Hauser, R.; Chavarro, J. E.] Harvard Sch Publ Hlth, Boston, MA USA. [Wright, D.; Petrozza, J. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-411 BP S234 EP S234 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700775 ER PT J AU Gaskins, AJ Colaci, DS Wright, DL Toth, TL Hauser, R Chavarro, JE AF Gaskins, A. J. Colaci, D. S. Wright, D. L. Toth, T. L. Hauser, R. Chavarro, J. E. TI DIETARY FOLATE INTAKE AND EARLY ASSISTED REPRODUCTIVE TECHNOLOGY OUTCOMES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Gaskins, A. J.; Colaci, D. S.; Hauser, R.; Chavarro, J. E.] Harvard Sch Publ Hlth, Boston, MA USA. [Wright, D. L.; Toth, T. L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-154 BP S47 EP S47 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700154 ER PT J AU Gray, KE Schiff, MA Fitzpatrick, AL Starr, JR AF Gray, K. E. Schiff, M. A. Fitzpatrick, A. L. Starr, J. R. TI LEUKOCYTE TELOMERE LENGTH AND AGE AT MENOPAUSE SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Gray, K. E.; Schiff, M. A.; Fitzpatrick, A. L.] Univ Washington, Epidemiol, Seattle, WA 98195 USA. [Starr, J. R.] Forsyth Inst, Ctr Clin & Translat Res, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-144 BP S44 EP S44 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700144 ER PT J AU Iager, AE Kocabas, AM Otu, HH Fernandez, E Cibelli, JB Crosby, JA AF Iager, A. E. Kocabas, A. M. Otu, H. H. Fernandez, E. Cibelli, J. B. Crosby, J. A. TI PREGNANCY OUTCOME FOLLOWING IVF CAN BE PREDICTED BY A GENE EXPRESSION SIGNATURE IN HUMAN CUMULUS CELLS. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Iager, A. E.; Cibelli, J. B.; Crosby, J. A.] Gema Diagnost, Ann Arbor, MI USA. [Iager, A. E.; Cibelli, J. B.; Crosby, J. A.] Rockefeller Univ, Lab Dev Neurobiol, 1230 York Ave, New York, NY 10021 USA. [Otu, H. H.] Istanbul Bilgi Univ, Dept Bioengn, Istanbul, Turkey. [Otu, H. H.] Harvard Med Sch, BIDMC Genom Ctr, Dept Med, Boston, MA USA. [Fernandez, E.; Crosby, J. A.] Clin Las Condes, Unidad Med Reprod, Santiago, Chile. [Cibelli, J. B.] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA. [Cibelli, J. B.] Michigan State Univ, Dept Anim Sci, E Lansing, MI 48824 USA. [Cibelli, J. B.] Consejeria Salud, Lab Andaluz Reprogramac Celular LARCEL, Seville, Andalucia, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-341 BP S101 EP S101 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700337 ER PT J AU Imudia, AN Awonuga, AO Kaimal, AJ Wright, DL Styer, AK Toth, TL AF Imudia, A. N. Awonuga, A. O. Kaimal, A. J. Wright, D. L. Styer, A. K. Toth, T. L. TI ELECTIVE CRYOPRESERVATION OF ALL EMBRYOS WITH INTERVAL CRYOTHAW TRANSFER IN PATIENTS AT RISK FOR OHSS REDUCES THE RISK OF SGA AND PREECLAMPSIA COMPARED TO SIMILAR GROUP OF PATIENTS WITH FRESH TRANSFER. SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Imudia, A. N.; Wright, D. L.; Styer, A. K.; Toth, T. L.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Awonuga, A. O.] Wayne State Univ, Sch Med, Div Reprod Endocrinol & Infertil, Detroit, MI USA. [Kaimal, A. J.] Vincent Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-246 BP S184 EP S184 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700614 ER PT J AU Imudia, AN Dimitriadis, I Petrozza, JC Souter, I AF Imudia, A. N. Dimitriadis, I. Petrozza, J. C. Souter, I. TI A SHORTER FOLLICULAR PHASE DOES NOT HAVE A DELETERIOUS EFFECT ON THE OUTCOME OF OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI) CYCLES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Imudia, A. N.; Dimitriadis, I.; Petrozza, J. C.; Souter, I.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-12 BP S4 EP S4 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700013 ER PT J AU Souter, I Smith, KW Dimitriadis, I Williams, PL Ford, JB Hauser, R AF Souter, I. Smith, K. W. Dimitriadis, I. Williams, P. L. Ford, J. B. Hauser, R. TI ASSOCIATION OF URINARY PHTHALATE (P) METABOLITE CONCENTRATIONS WITH OVARIAN RESPONSE AMONG PATIENTS UNDERGOING OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Society-for-Reproductive-Medicine (ASRM) CY OCT 20-24, 2012 CL San Diego, CA SP Amer Soc Reprod Med C1 [Souter, I.; Dimitriadis, I.; Ford, J. B.; Hauser, R.] Harvard Med Sch, Massachusetts Gen Hosp, Obstet Gynecol Reprod Endocrinol & Infertil Div, Boston, MA USA. [Smith, K. W.; Dimitriadis, I.; Ford, J. B.; Hauser, R.] Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA. [Williams, P. L.] Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA O-108 BP S33 EP S34 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700109 ER PT J AU Thakur, M Imudia, AN Shavell, VI Singh, M Diamond, MP Awonuga, AO AF Thakur, M. Imudia, A. N. Shavell, V. I. Singh, M. Diamond, M. P. Awonuga, A. O. TI SHOULD BODY MASS INDEX INFLUENCE THE DOSE OF hCG FOR OVULATION INDUCTION AFTER SUPEROVULATION IN IVF/ICSI CYCLES? SO FERTILITY AND STERILITY LA English DT Meeting Abstract C1 [Thakur, M.; Shavell, V. I.; Singh, M.; Diamond, M. P.; Awonuga, A. O.] Wayne State Univ, Div Reprod Endocrinol & Infertil, Detroit, MI USA. [Imudia, A. N.] Massachusetts Gen Hosp, Fertil Ctr, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2012 VL 98 IS 3 SU S MA P-542 BP S271 EP S272 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA V45UY UT WOS:000209842700899 ER PT J AU Caspi, CE Sorensen, G Subramanian, SV Kawachi, I AF Caspi, Caitlin E. Sorensen, Glorian Subramanian, S. V. Kawachi, Ichiro TI The local food environment and diet: A systematic review SO HEALTH & PLACE LA English DT Review DE Food environment; Diet; Measurement; GIS; Survey; Neighborhood ID VEGETABLE CONSUMPTION; NUTRITION ENVIRONMENTS; ATHEROSCLEROSIS RISK; INFORMATION-SYSTEMS; NEIGHBORHOOD ACCESS; STORE AVAILABILITY; BUILT ENVIRONMENTS; AFRICAN-AMERICANS; FRUIT; OBESITY AB Despite growing attention to the problem of obesogenic environments, there has not been a comprehensive review evaluating the food environment-diet relationship. This study aims to evaluate this relationship in the current literature, focusing specifically on the method of exposure assessment (GIS, survey, or store audit). This study also explores 5 dimensions of "food access" (availability, accessibility, affordability, accommodation, acceptability) using a conceptual definition proposed by Penchansky and Thomas (1981). Articles were retrieved through a systematic keyword search in Web of Science and supplemented by the reference lists of included studies. Thirty-eight studies were reviewed and categorized by the exposure assessment method and the conceptual dimensions of access it captured. GIS-based measures were the most common measures, but were less consistently associated with diet than other measures. Few studies examined dimensions of affordability, accommodation, and acceptability. Because GIS-based measures on their own may not capture important non-geographic dimensions of access, a set of recommendations for future researchers is outlined. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Caspi, Caitlin E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02114 USA. [Caspi, Caitlin E.; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Caspi, CE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Kresge 7th Floor,677 Huntington Ave, Boston, MA 02114 USA. EM caitlincaspi@gmail.com FU NCI NIH HHS [K05 CA108663] NR 67 TC 170 Z9 172 U1 16 U2 85 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8292 EI 1873-2054 J9 HEALTH PLACE JI Health Place PD SEP PY 2012 VL 18 IS 5 BP 1172 EP 1187 DI 10.1016/j.healthplace.2012.05.006 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 991VH UT WOS:000307730300030 PM 22717379 ER PT J AU Emmons, KM Puleo, E Viswanath, V Gillman, MW Bennett, GG Haines, J Sprunck-Harrild, K Greaney, M AF Emmons, K. M. Puleo, E. Viswanath, V. Gillman, M. W. Bennett, G. G. Haines, J. Sprunck-Harrild, K. Greaney, M. TI COMPARATIVE EFFECTIVENESS OF HEALTHY DIRECTIONS-2, A MULTIPLE RISK FACTOR INTERVENTION FOR PRIMARY CARE SETTINGS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Cancer; Health Behavior Change C1 [Emmons, K. M.; Viswanath, V.; Sprunck-Harrild, K.; Greaney, M.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Puleo, E.] Univ Massachusetts, Sch Publ Hlth, Amherst, MA 01003 USA. [Gillman, M. W.] Harvard Sch Publ Hlth, SPH Nutr, Boston, MA USA. [Gillman, M. W.] HMS Populat, Boston, MA USA. [Bennett, G. G.] Duke Univ, Psychol & Neurosci, Durham, NC 27706 USA. [Haines, J.] Univ Guelph, Family Relat & Appl Nutr, Guelph, ON, Canada. EM karen_m_emmons@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O208 BP S83 EP S84 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000203 ER PT J AU Freedland, KE Burg, MM Chait, S Steinmeyer, BC AF Freedland, K. E. Burg, M. M. Chait, S. Steinmeyer, B. C. TI EFFECTS OF DEPRESSION AND LOW PERCEIVED SOCIAL SUPPORT ON MEDICATION ADHERENCE AFTER ACUTE MYOCARDIAL INFARCTION SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Adherence; Coronary heart disease; Depression; Social support C1 [Freedland, K. E.; Steinmeyer, B. C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. [Burg, M. M.] Yale Univ, Sch Med, Sect Cardiovasc Med, New Haven, CT USA. [Chait, S.] VA Boston Healthcare Syst, Boston, MA USA. EM freedlak@bmc.wustl.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA O235 BP S94 EP S95 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000230 ER PT J AU Okvat, HA Okun, MA Davis, MC Zautra, AJ Knopf, RC AF Okvat, H. A. Okun, M. A. Davis, M. C. Zautra, A. J. Knopf, R. C. TI A PILOT STUDY OF THE BENEFITS OF TRADITIONAL AND MINDFUL COMMUNITY GARDENING FOR HEALTHY AGING AMONG URBAN OLDER ADULTS SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE aging; community intervention; health promotion; mindfulness; mood; older adults; quality of life; resilience; social support C1 [Okvat, H. A.] VA Boston Healthcare Syst, Behav Med, Boston, MA USA. [Okun, M. A.; Davis, M. C.; Zautra, A. J.] Arizona State Univ, Dept Psychol, Tempe, AZ 85287 USA. [Knopf, R. C.] Arizona State Univ, Osher Lifelong Learning Inst, Sch Community Resources & Dev, Phoenix, AZ USA. EM heather.okvat@asu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA P23 BP S13 EP S13 PG 1 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000033 ER PT J AU Tercyak, K Patenaude, A AF Tercyak, K. Patenaude, A. TI PRELIMINARY OUTCOMES OF A RANDOMIZED CONTROLLED TRIAL TO INFORM MATERNAL DECISIONS ABOUT COMMUNICATING CANCER GENETIC TEST RESULTS TO CHILDREN SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Meeting Abstract DE Decision making; Genetics; Children; Family C1 [Tercyak, K.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Patenaude, A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM tercyakk@georgetown.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 EI 1532-7558 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD SEP PY 2012 VL 19 SU 1 MA S252 BP S101 EP S102 PG 2 WC Psychology, Clinical SC Psychology GA V45KR UT WOS:000209816000246 ER PT J AU Anaya, HD Bokhour, B Feld, J Golden, JF Asch, SM Knapp, H AF Anaya, Henry D. Bokhour, Barbara Feld, Jamie Golden, Joya F. Asch, Steven M. Knapp, Herschel TI Implementation of Routine Rapid HIV Testing Within the US Department of Veterans Affairs Healthcare System SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE rapid HIV testing; nurse-initiated health interventions; implementation; evaluation AB Current HIV testing methods can be ineffective; patients often do not return for results. HIV rapid testing (RT) provides accurate results in 20 min. Patients find nurse-initiated HIV rapid testing (NRT) more acceptable than current testing methods and increases receipt of test results. Translating research findings into sustainable practice poses widely recognized implementation challenges. To ascertain effectiveness of NRT implementation, formative and process evaluations were conducted within the U. S. Department of Veterans Affairs Healthcare System (VA). Nurses and physicians at 2 VA medical centers were trained to administer RT. A preimplementation formative evaluation was conducted at Site 1. Process evaluations of ongoing RT activities were conducted at Site 2. Interviews were conducted with key informants. Content and thematic analysis was conducted on the field notes. A variety of barriers and facilitators were discovered that impacted the implementation of NRT. Findings indicate concerns regarding training and incorporating NRT into workflow. Process interviews indicated that training concerns could be alleviated through various means. Finally, interviewees highlighted that other clinic settings might be a more preferred setting for NRT than primary care. Findings are currently being used for the implementation of additional NRT interventions, and can also guide NRT adoption in other facilities. C1 [Anaya, Henry D.] US Dept Vet Affairs VA, West Los Angeles, CA USA. [Anaya, Henry D.] Univ Calif Los Angeles, Dept Biobehav Sci, Neuropsychiat Inst, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Ctr HIV Prevent & Treatment Serv, Los Angeles, CA 90024 USA. [Anaya, Henry D.; Golden, Joya F.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bokhour, Barbara] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Bokhour, Barbara] US Dept Vet Affairs, Ctr Hlth Qual, Bedford, MA USA. [Feld, Jamie; Golden, Joya F.; Asch, Steven M.] US Dept Vet Affairs, West Los Angeles, CA USA. [Feld, Jamie] United Nations Observ Urbano, Cordoba, Argentina. [Asch, Steven M.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Asch, Steven M.] Robert Wood Johnson Clin Scholars Program, Chapel Hill, NC USA. RP Anaya, HD (reprint author), US Dept Vet Affairs VA, West Los Angeles, CA USA. EM henry.anaya@va.gov OI Bokhour, Barbara/0000-0001-8238-0745 FU VHA FX The authors would like to thank B. Lane Turzan, Brenda Rue, Rebecca Jones, and Alicia Alcantara for their assistance on this project. We would also like to acknowledge Jaimi Butler for her substantive review and editorial suggestions and comments. The views and opinions expressed in this article are those of the author(s) and do not necessarily represent the views of the U.S. Department of Veterans Affairs. The VHA supported this study but had no input in the design or reporting, or decision to submit this paper for publication. This study was reviewed and sanctioned by a U.S. Department of Veterans Affairs Internal Review Board (IRB) process. NR 18 TC 11 Z9 11 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1062-2551 EI 1945-1474 J9 J HEALTHC QUAL JI J. Healthc. Qual. PD SEP-OCT PY 2012 VL 34 IS 5 BP 7 EP 14 DI 10.1111/j.1945-1474.2011.00151.x PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OP UT WOS:000209221300001 PM 22060061 ER PT J AU Keuthen, NJ Rothbaum, BO Fama, J Altenburger, E Falkenstein, MJ Sprich, SE Kearns, M Meunier, S Jenike, MA Welch, SS AF Keuthen, Nancy J. Rothbaum, Barbara O. Fama, Jeanne Altenburger, Erin Falkenstein, Martha J. Sprich, Susan E. Kearns, Megan Meunier, Suzanne Jenike, Michael A. Welch, Stacy S. TI DBT-enhanced cognitive-behavioral treatment for trichotillomania: A randomized controlled trial SO JOURNAL OF BEHAVIORAL ADDICTIONS LA English DT Article DE trichotillomania; hair pulling; cognitive-behavioral treatment; dialectical behavior therapy AB Background and aims: Limited treatment options are available for trichotillomania (TTM) and most have modest outcomes. Suboptimal treatment results may be due to the failure of existing approaches to address all TTM styles. Methods: Thirty-eight DSM-IV TTM participants were randomly assigned across two study sites to Dialectical Behavior Therapy (DBT) -enhanced cognitive-behavioral treatment (consisting of an 11-week acute treatment and 3-month maintenance treatment) or a minimal attention control (MAC) condition. MAC participants had active treatment after the 11-week control condition. Follow-up study assessments were conducted three and six months after the maintenance period. Results: Open trial treatment resulted in significant improvement in TTM severity, emotion regulation (ER) capacity, experiential avoidance, anxiety and depression with changes generally maintained over time. In the randomized controlled trial, those with active treatment had greater improvement than those in the MAC condition for both TTM severity and ER capacity. Correlations between changes in TTM severity and ER capacity were not reported at post-treatment but did occur in maintenance and follow-up indicating reduced TTM severity with improved ER capacity. Conclusions: DBT-enhanced cognitive-behavioral treatment is a promising treatment for TTM. Future studies should compare this approach to other credible treatment interventions and investigate the efficacy of this approach in more naturalistic samples with greater comorbidity. C1 [Keuthen, Nancy J.; Fama, Jeanne; Altenburger, Erin; Sprich, Susan E.; Jenike, Michael A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Rothbaum, Barbara O.; Kearns, Megan] Emory Univ, Sch Med, Atlanta, GA USA. [Falkenstein, Martha J.] Amer Univ, Washington, DC 20016 USA. [Meunier, Suzanne] Anxiety Treatment Ctr Northwest Arkansas, Fayetteville, AR USA. [Welch, Stacy S.] Univ Washington, Anxiety & Stress Reduct Ctr, Seattle, WA 98195 USA. RP Keuthen, NJ (reprint author), Massachusetts Gen Hosp, Trichotillomania Clin & Res Unit, Simches Res Bldg,Fl 2,185 Cambridge St, Boston, MA 02114 USA. EM nkeuthen@partners.org OI Falkenstein, Martha/0000-0001-5074-3409 FU David Judah Fund FX We gratefully acknowledge the David Judah Fund for its financial support of this research. We wish to recognize study staff including Michelle Hammond-Susten and Mary Heekin who assisted with clinical assessments and Amanda Allen, Mark Burton, Elizabeth Loerke, Lillian Reuman, Anne Wilson, as well as Cole Youngner, who helped with data collection and entry. We greatly appreciate the helpful comments of Dr. Martin Franklin in the early stages of study development. Lastly, we express our heartfelt thanks to all study participants and to Christina Pearson, Jennifer Raikes, Leslie Lee and other staff at the Trichotillomania Learning Center for their assistance with study recruitment. NR 27 TC 22 Z9 22 U1 1 U2 7 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 2062-5871 EI 2063-5303 J9 J BEHAV ADDICT JI J. Behav. Addict. PD SEP PY 2012 VL 1 IS 3 BP 106 EP 114 DI 10.1556/JBA.1.2012.003 PG 9 WC Psychiatry SC Psychiatry GA V32YJ UT WOS:000208986200003 PM 26165460 ER PT J AU Burney, BO Garcia, JM AF Burney, Basil O. Garcia, Jose M. TI Hypogonadism in male cancer patients SO JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE LA English DT Review DE Inflammation; Leptin; Ghrelin; Cachexia; Sarcopenia ID GONADOTROPIN-RELEASING-HORMONE; ANDROGEN REPLACEMENT THERAPY; QUALITY-OF-LIFE; LUTEINIZING-HORMONE; SEXUAL FUNCTION; TESTOSTERONE LEVELS; BODY-COMPOSITION; ORAL OPIOIDS; AGING MALES; HEALTHY-MEN AB Prevalence of hypogonadism in men with cancer has been reported between 40% and 90%, which is significantly higher than in the general population. Hypogonadism is likely to affect the quality of life in these patients by contributing to non-specific symptoms, including decreased energy, anorexia, sarcopenia, weight loss, depression, insomnia, fatigue, weakness, and sexual dysfunction. Pathogenesis of hypogonadism in cancer patients is thought to be multi-factorial. Inflammation may play an important role, but leptin, opioids, ghrelin, and high-dose chemotherapy through different mechanisms have all been implicated as the cause. Hypogonadism is also associated with poor survival in cancer patients. Data looking into the treatment of hypogonadal male cancer patients with testosterone are limited. However, improvements in body weight, muscle strength, lean body mass, and quality of life have been shown in hypogonadal men with other chronic diseases on testosterone replacement therapy. Prospective and interventional trials are needed to test the efficacy and safety of testosterone treatment in improving quality of life of these patients. C1 [Burney, Basil O.; Garcia, Jose M.] Baylor Coll Med, Div Endocrinol Diabet & Metab, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Garcia, JM (reprint author), Baylor Coll Med, Div Endocrinol Diabet & Metab, Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd,Bldg 109,Rm 210, Houston, TX 77030 USA. EM jgarcia1@bcm.edu FU Abbott FX JMG receives research support from and is a consultant with Abbott. NR 60 TC 12 Z9 12 U1 0 U2 1 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-5991 J9 J CACHEXIA SARCOPENI JI J. Caxhexia Sarcopenia Muscle PD SEP PY 2012 VL 3 IS 3 BP 149 EP 155 DI 10.1007/s13539-012-0065-7 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 218WO UT WOS:000324463400002 PM 22528986 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI DECOLONIZING INDIGENOUS HISTORIES: Exploring Prehistoric/Colonial Transitions in Archaeology SO JOURNAL OF THE WEST LA English DT Book Review C1 [Mifflin, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mifflin, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ABC-CLIO PI SANTA BARBARA PA 130 CREMONA DR, SANTA BARBARA, CA 93117 USA SN 0022-5169 EI 1930-0115 J9 J WEST JI J. West PD FAL PY 2012 VL 51 IS 4 BP 92 EP 92 PG 1 WC History SC History GA V35UY UT WOS:000209174600026 ER PT J AU Ratcliffe, TA Durning, SJ Jena, AB Grau, T Artino, AR Arora, VM Hauer, KE Borges, N Oriol, N Elnicki, DM Fagan, MJ Harrell, HE Torre, DM Prochaska, M Meltzer, DO Reddy, S AF Ratcliffe, Temple A. Durning, Steven J. Jena, Anupam B. Grau, Thomas Artino, Anthony R., Jr. Arora, Vineet M. Hauer, Karen E. Borges, Nicole Oriol, Nancy Elnicki, D. Michael Fagan, Mark J. Harrell, Heather E. Torre, Dario M. Prochaska, Meryl Meltzer, David O. Reddy, Shalini TI Postinterview Communication Between Military Residency Applicants and Training Programs SO MILITARY MEDICINE LA English DT Article AB Purpose: Each year military medical students participate in a separate, military match culminating with the Joint Services Graduate Medical Education Selection Board (JSGMESB). Prior studies have explored postinterview communication that occurs during the National Resident Matching Program (NRMP), but not during the JSGMESB. examined the frequency and nature of communication during the JSGMESB and compared it with the NRMP. Methods: Cross-sectional survey study of senior students conducted at Uniformed Services University of the Health Sciences (USU) and seven civilian U.S. medical schools during March to May 2010. Respondents answered questions regarding communication with residency programs during the match. Results: Significantly fewer USU respondents communicated with programs compared with the civilian cohort (54.1% vs. 86.4%, p < 0.01). Specific inquiries regarding rank order were more commonly experienced by USU respondents compared with civilians (17.5% vs. 4.8%, p = 0.02). USU respondents found postinterview communication both helpful (41.3%) and stressful (41.3%). 11.1% of USU respondents indicated that they moved a program higher on their final rank lists because of further communication with these programs. Conclusions: Postinterview communication during the JSGMESB process is less common and less stressful than that reported in the NRMP. USU respondents are more likely to be asked directly about their rank list and occasionally do change their lists. Uniform guidance mirroring the NRMP's dealing with direct inquiries about rank lists could potentially improve the process. C1 [Ratcliffe, Temple A.; Durning, Steven J.; Grau, Thomas; Artino, Anthony R., Jr.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Jena, Anupam B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Arora, Vineet M.; Prochaska, Meryl; Meltzer, David O.; Reddy, Shalini] Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA. [Hauer, Karen E.] Univ San Francisco, Sch Med, San Francisco, CA 94122 USA. [Borges, Nicole] Wright State Univ, Acad Affairs, Boonshoft Sch Med, Dept Community Hlth, Dayton, OH 45435 USA. [Oriol, Nancy] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Elnicki, D. Michael; Torre, Dario M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15261 USA. [Fagan, Mark J.] Brown Univ, Warren Alpert Sch Med, Dept Med, Providence, RI 02912 USA. [Harrell, Heather E.] Univ Florida, Coll Med, Dept Med, Gainesville, FL 32603 USA. RP Ratcliffe, TA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RI Meltzer, David/C-2926-2009; OI Meltzer, David/0000-0003-2790-7393; Artino, Anthony/0000-0003-2661-7853 FU Department of Medicine at the University of Chicago FX This study was funded by the Department of Medicine at the University of Chicago. NR 5 TC 3 Z9 3 U1 0 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2012 VL 177 IS 9 SU S SI SI BP 54 EP 60 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA V33OD UT WOS:000209027200013 PM 23029863 ER PT J AU Gadermann, AM Gilman, SE McLaughlin, KA Nock, MK Petukhova, M Sampson, NA Kessler, RC AF Gadermann, Anne M. Gilman, Stephen E. McLaughlin, Katie A. Nock, Matthew K. Petukhova, Maria Sampson, Nancy A. Kessler, Ronald C. TI Projected Rates of Psychological Disorders and Suicidality Among Soldiers Based on Simulations of Matched General Population Data SO MILITARY MEDICINE LA English DT Article AB Limited data are available on lifetime prevalence and age-of-onset distributions of psychological disorders and suicidal behaviors among Army personnel. We used simulation methods to approximate such estimates based on analysis of data from a U.S. national general population survey with the sociodemographic profile of U.S. Army personnel. Estimated lifetime prevalence of any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) anxiety, mood, behavior, or substance disorder in this sample was 53.1% (17.7% for mood disorders, 27.2% for anxiety disorders, 22.7% for behavior disorders, and 14.4% for substance disorders). The vast majority of cases had onsets before the expected age of enlistment if they were in the Army (91.6%). Lifetime prevalence was 14.2% for suicidal ideation, 5.4% for suicide plans, and 4.5% for suicide attempts. The proportion of estimated pre-enlistment onsets was between 68.4% (suicide plans) and 82.4% (suicidal ideation). Externalizing disorders with onsets before expected age of enlistment and internalizing disorders with onsets after expected age of enlistment significantly predicted postenlistment suicide attempts, with population attributable risk proportions of 41.8% and 38.8%, respectively. Implications of these findings are discussed for interventions designed to screen, detect, and treat psychological disorders and suicidality in the Army. C1 [Gadermann, Anne M.] Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, Vancouver, BC V6Z 1Y6, Canada. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [McLaughlin, Katie A.] Childrens Hosp Boston, Div Gen Pediat, Boston, MA 02115 USA. [McLaughlin, Katie A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Nock, Matthew K.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Petukhova, Maria; Sampson, Nancy A.; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Gadermann, AM (reprint author), Univ British Columbia, St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, 620B-1081 Burrard St, Vancouver, BC V6Z 1Y6, Canada. RI Gilman, Stephen/E-7632-2010; OI Gilman, Stephen/0000-0002-8331-6419; McLaughlin, Katie/0000-0002-1362-2410 FU Department of the Army [U01MH087981]; U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH) FX This study was supported by the Department of the Army and funded under cooperative agreement number U01MH087981 with the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health (NIH/NIMH). NR 30 TC 9 Z9 9 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2012 VL 177 IS 9 BP 1002 EP 1010 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA V33OC UT WOS:000209027100002 PM 23025127 ER PT J AU Sheth, RA Kunin, A Stangenberg, L Sinnamon, M Hung, KE Kucherlapati, R Mahmood, U AF Sheth, Rahul A. Kunin, Alexandra Stangenberg, Lars Sinnamon, Mark Hung, Kenneth E. Kucherlapati, Raju Mahmood, Umar TI In Vivo Optical Molecular Imaging of Matrix Metalloproteinase Activity following Celecoxib Therapy for Colorectal Cancer SO MOLECULAR IMAGING LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MULTIPLE INTESTINAL NEOPLASIA; COLON-CARCINOMA CELLS; MIN MOUSE MODEL; CYCLOOXYGENASE-2 INHIBITOR; ADENOMATOUS POLYPOSIS; ASPIRIN USE; PREVENTION; GROWTH; CHEMOPREVENTION AB We present an optical molecular imaging approach to measure the efficacy of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumor growth rate through its effect on matrix metalloproteinase (MMP) activity. A xenograft model of colorectal cancer was generated in nude mice, which were then randomized to receive celecoxib versus vehicle. MMP activity was measured by an enzyme-activatable optical molecular probe. A novel genetically engineered mouse (GEM) model of colorectal cancer was also used to assess celecoxib's effect on MMP activity, which was measured by quantitative fluorescence colonoscopy. Subcutaneously implanted xenograft tumors were 84% (SD 20.2%) smaller in volume in the treatment group versus the control group. Moreover, treated animals exhibited only a 7.6% (SEM 9%) increase in MMP activity versus 106% (SEM 8%) for untreated animals. There was an apparent linear relationship (r = .91) between measured MMP activity and tumor growth rate. Finally, in the GEM model experiment, treated murine tumors remained relatively unchanged in volume and MMP activity; however, untreated tumors grew significantly and showed an increase in MMP activity. This method may provide for the improved identification of patients for whom COX-2 inhibition therapy is indicated by allowing one to balance the patient's cardiovascular risk with the cancer's responsiveness to celecoxib. C1 [Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Tufts Med Sch, Dept Gastroenterol, Boston, MA USA. RP Mahmood, U (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, 55 Fruit St,White 427, Boston, MA 02114 USA. EM mahmood@helix.mgh.harvard.edu FU National Institute of Health [P50CA127003, U01CA084301] FX This work was supported by National Institute of Health Grants P50CA127003 and U01CA084301. NR 42 TC 7 Z9 7 U1 0 U2 4 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD SEP-OCT PY 2012 VL 11 IS 5 BP 417 EP 425 DI 10.2310/7290.2012.00003 PG 9 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA 220JT UT WOS:000324579900008 PM 22954186 ER PT J AU Erickson, JI Ditomassi, M Adams, JM AF Erickson, Jeanette Ives Ditomassi, Marianne Adams, Jeffrey M. TI Attending Registered Nurse: An Innovative Role to Manage Between the Spaces SO NURSING ECONOMICS LA English DT Article AB Massachusetts General Hospital embarked on the implementation of a new model that redesigned the role of selected staff nurses, advanced standardized processes, improved workflow, and introduced technology to enhance communication. These efforts included selecting 12 inpatient units to function as "Innovation Units." These units were specifically designated to support rapid change and test initiatives that would reduce costs and improve quality. The work of the Innovation Units allows nurse leaders to understand if the goals for improvement could be adopted by all inpatient units and beyond the walls of the hospital. The high-leverage intervention of introducing the role of the "Attending Nurse" in coordinating the work of the interdisciplinary team in addressing overuse, underuse, and misuse of services has been a significant staffing innovation. The Attending Nurse, while just one strategy, has placed the nurse at the center of the care team. C1 [Erickson, Jeanette Ives; Ditomassi, Marianne; Adams, Jeffrey M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Erickson, JI (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 9 TC 4 Z9 4 U1 0 U2 0 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD SEP-OCT PY 2012 VL 30 IS 5 BP 282 EP 287 PG 6 WC Nursing SC Nursing GA V35RQ UT WOS:000209166400008 PM 23198611 ER PT J AU Sayegh, RR Pineda, R AF Sayegh, Rony R. Pineda, Roberto, II TI Practical Applications of Anterior Segment Optical Coherence Tomography Imaging Following Corneal Surgery SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Corneal surgery; Cornea; Ocular imaging; Optical coherence tomography ID IN-SITU KERATOMILEUSIS; COLLAGEN CROSS-LINKING; DESCEMET MEMBRANE DETACHMENT; SWEPT SOURCE OCT; PENETRATING KERATOPLASTY; LAMELLAR KERATOPLASTY; LASIK FLAP; ENDOTHELIAL KERATOPLASTY; SECONDARY GLAUCOMA; INTERFACE FLUID AB Anterior segment optical coherence tomography (AS-OCT) has recently emerged as an important modality for imaging of the cornea. Since its introduction less than a decade ago, it has been clinically used for the diagnosis and management of an expanding number of corneal conditions. In this review, we will discuss the applications of anterior segment optical coherence tomography after corneal surgery, focusing on penetrating and lamellar keratoplasty, keratoprosthesis, intracorneal ring segments, collagen cross-linking and refractive surgery. Anterior segment optical coherence tomography is useful in evaluating outcomes, detecting adverse events, determining prognosis, guiding management decisions, and surgical planning. C1 [Sayegh, Rony R.; Pineda, Roberto, II] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Pineda, R (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Roberto_Pineda@meei.harvard.edu RI Sayegh, Rony/G-8777-2013 OI Sayegh, Rony/0000-0002-0119-4201 NR 82 TC 7 Z9 7 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 125 EP 132 DI 10.3109/08820538.2012.707274 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600007 PM 23163266 ER PT J AU Luo, ZHK Jacobs, DS AF Luo, Zhonghui K. Jacobs, Deborah S. TI Current and Potential Applications of Anterior Segment Optical Coherence Tomography in Contact Lens Fitting SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment OCT; Topography; Scleral lens; Contact lens; Ocular surface ID DOMAIN MODE-LOCKING; VERSUS-HOST-DISEASE; BOSTON SCLERAL LENS; SWEPT SOURCE OCT; CORNEAL TOPOGRAPHY; IN-VIVO; LASER; EYE; GLAUCOMA; REFLECTOMETRY AB Optical coherence tomography (OCT) is a non-invasive, high-resolution and high-speed imaging modality that has enjoyed rapid growth in ophthalmology since its development 20 years ago. Contact lens fitting is traditionally based on trial lenses, which is expensive and time-consuming. Modern anterior segment OCT is capable of generating three-dimensional ocular surface maps of the cornea and sclera with potential application in contact lens fitting. This paper reviewed the history, the ophthalmic applications, and the most recent advancement in three-dimensional anterior segment OCT. There is very limited literature of OCT in contact lens fitting to date. This review anticipates an increase in this application in the near future. C1 [Jacobs, Deborah S.] Boston Fdn Sight, Needham, MA 02494 USA. [Luo, Zhonghui K.; Jacobs, Deborah S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Jacobs, DS (reprint author), Boston Fdn Sight, 464 Hillside Ave,Suite 205, Needham, MA 02494 USA. EM djacobs@bostonsight.org NR 59 TC 4 Z9 4 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 133 EP 137 DI 10.3109/08820538.2012.708814 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600008 PM 23163267 ER PT J AU Alhatem, A Cavalcanti, B Hamrah, P AF Alhatem, Albert Cavalcanti, Bernardo Hamrah, Pedram TI In Vivo Confocal Microscopy in Dry Eye Disease and Related Conditions SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Ocular surface; Meibomian gland; Nerves; Dry eye disease; In vivo confocal microscopy ID MEIBOMIAN GLAND DYSFUNCTION; PRIMARY SJOGRENS-SYNDROME; CORNEAL NERVES; DIABETIC-PATIENTS; MORPHOLOGY; LASIK; REGENERATION; SENSITIVITY; INVOLVEMENT; DIAGNOSIS AB A new era of ocular imaging has recently begun with the advent of in vivo confocal microscopy (IVCM), shedding more light on the pathophysiology, diagnosis, and potential treatment strategies for dry eye disease. IVCM is a noninvasive and powerful tool that allows detection of changes in ocular surface epithelium, immune and inflammatory cells, corneal nerves, keratocytes, and meibomian gland structures on a cellular level. Ocular surface structures in dry eye-related conditions have been assessed and alterations have been quantified using IVCM. IVCM may aid in the assessment of dry eye disease prognosis and treatment, as well as lead to improved understanding of the pathophysiological mechanisms in this complex disease. Further, due to visualization of subclinical findings, IVCM may allow detection of disease at much earlier stages and allow stratification of patients for clinical trials. Finally, by providing an objective methodology to monitor treatment efficacy, image-guided therapy may allow the possibility of tailoring treatment based on cellular changes, rather than on clinical changes alone. C1 [Alhatem, Albert; Cavalcanti, Bernardo; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, Boston, MA USA. RP Hamrah, P (reprint author), Massachusetts Eye & Ear Infirm, Ocular Surface Imaging Ctr, Cornea Serv, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu FU NEI NIH HHS [L30 EY021919, K08 EY020575] NR 36 TC 29 Z9 29 U1 0 U2 6 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 138 EP 148 DI 10.3109/08820538.2012.711416 PG 11 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600009 PM 23163268 ER PT J AU Kronberg, BP Rhee, DJ AF Kronberg, Benjamin P. Rhee, Douglas J. TI Anterior Segment Imaging and the Intraocular Pressure Lowering Effect of Cataract Surgery for Open and Narrow Angle Glaucoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment optical coherence tomography (OCT); Cataract extraction; Intraocular pressure; Narrow angle glaucoma; Open angle glaucoma; Plateau iris syndrome; Ultrasound biomicroscopy (UBM) ID OPTICAL COHERENCE TOMOGRAPHY; CLEAR CORNEAL PHACOEMULSIFICATION; CHAMBER LENS IMPLANTATION; PLATEAU IRIS SYNDROME; ULTRASOUND BIOMICROSCOPY; NONGLAUCOMATOUS EYES; PSEUDOEXFOLIATION SYNDROME; CLOSURE GLAUCOMA; FOLLOW-UP; EXTRACTION AB Anterior segment imaging modalities including anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) are increasingly widespread, and can quantify several parameters of the anterior segment, such as anterior chamber depth and angle anatomy. These parameters are important to assess, particularly in patients with forms of narrow angle glaucoma. In many cases of open and narrow angle glaucoma, cataract extraction has been shown to result in favorable modification of these parameters, and a lasting decrease in intraocular pressure. Anterior segment imaging has the ability to enable the development of predictive models regarding the potential intraocular pressure lowering effect of cataract extraction in a given individual. C1 [Kronberg, Benjamin P.; Rhee, Douglas J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. RP Kronberg, BP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02115 USA. EM bkronberg@gmail.com NR 55 TC 2 Z9 2 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 149 EP 154 DI 10.3109/08820538.2012.708810 PG 6 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600010 PM 23163269 ER PT J AU Golez, E Latina, M AF Golez, Ernesto, III Latina, Mark TI The Use of Anterior Segment Imaging after Trabeculectomy SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Anterior segment optical coherence tomography; Eye; Glaucoma; Ultrasound biomicroscopy ID OPTICAL COHERENCE TOMOGRAPHY; ANGLE-CLOSURE GLAUCOMA; LASER SUTURE LYSIS; ULTRASOUND BIOMICROSCOPY; FILTERING BLEBS; SUPRACILIOCHOROIDAL FLUID; INTRAOCULAR-PRESSURE; MALIGNANT GLAUCOMA; EYES; SURGERY AB Evaluation of patients after trabeculectomy can be aided by the use of anterior segment imaging. Two commonly used forms of imaging are ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT). Both modalities can be used to assess bleb morphology and how it affects treatment outcome, measure anterior chamber biometry, identify the presence of supraciliochoroidal fluid, cyclodialysis clefts and malignant glaucoma, and evaluate treatment modalities after trabeculectomy such as in laser suture lysis and needling. OCT, with its finer resolution, is able to view the bleb wall anatomy in detail and because of its non-contact nature can examine the eye sooner after trabeculectomy. UBM, on the other hand, is superior for the visualization of deeper structures such as the ciliary body and posterior chamber essential to identify malignant glaucoma. C1 [Golez, Ernesto, III; Latina, Mark] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Golez, E (reprint author), Massachusetts Eye & Ear Infirm, 20 Pondmeadow Dr,Suite 203, Reading, MA 01867 USA. EM docernie3g@hotmail.com NR 50 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 155 EP 159 DI 10.3109/08820538.2012.707275 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600011 PM 23163270 ER PT J AU Wong, JJ Chen, TC Shen, LQ Pasquale, LR AF Wong, Jessica J. Chen, Teresa C. Shen, Lucy Q. Pasquale, Louis R. TI Macular Imaging for Glaucoma Using Spectral-domain Optical Coherence Tomography: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Glaucoma; Optical Coherence Tomography; Macula; Imaging; Spectral-Domain ID NERVE-FIBER LAYER; GANGLION-CELL COMPLEX; VISUAL-FIELD SENSITIVITY; OPEN-ANGLE GLAUCOMA; RETINAL-THICKNESS; EYES; OCT; DIAGNOSIS; VOLUME AB Since its introduction, optical coherence tomography (OCT) has become widely used and accepted as an imaging modality to detect and follow glaucoma, with measurement of the peripapillary retinal nerve fiber layer (pRNFL) being the most utilized parameter. Up until recently, macular thickness parameters have not been commonly used in glaucoma due to results of earlier studies with time-domain OCT (TD-OCT) that revealed macular imaging to be inferior to pRNFL in the diagnosis of glaucoma. The recent advent of spectral-domain OCT (SD-OCT) has renewed interest in the potential uses of macular imaging in glaucoma due to its ability to better segment and measure individual retinal layers. Multiple studies have been performed in the last few years to investigate the diagnostic ability, reproducibility, and limitations of these new SD-OCT macular parameters. The purpose of this paper is to review the findings of those studies to assess the current utility of macular SD-OCT in glaucoma. Overall, SD-OCT has been shown to have higher reproducibility than TD-OCT, and though there have been some conflicting reports, the majority of studies seem to concur that the diagnostic sensitivity of SD-OCT macular parameters is at least comparable to TD-OCT and other SD-OCT parameters. C1 [Wong, Jessica J.; Chen, Teresa C.; Shen, Lucy Q.; Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Glaucoma Serv, Boston, MA USA. RP Wong, JJ (reprint author), 808 Greenridge Dr, La Canada Flintridge, CA 91011 USA. EM Jessica.J.Wong@gmail.com NR 45 TC 12 Z9 12 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 160 EP 166 DI 10.3109/08820538.2012.712734 PG 7 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600012 PM 23163271 ER PT J AU De Castro, DK Hadlock, T Fay, A AF De Castro, Dawn K. Hadlock, Tessa Fay, Aaron TI Dynamic Imaging of Paralytic Eyelid Disorders SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Blink; Cranial nerve palsy; Eyelid imaging; Eyelid kinematics; Facial paralysis; Ptosis ID SPONTANEOUS BLINKING; SURFACE COIL; SEARCH COIL; MOVEMENTS; SACCADES; HUMANS; REFLEX; RETRACTION; EYEBLINK; ANATOMY AB Purpose: Eyelid dysmotility may result from trauma, tumors, inflammation, infection, and a variety of other conditions. In these cases, a mechanical effect is disrupting a normal neuromuscular apparatus. Dysmotility can also be caused by paralytic eyelid disorders; included in this broad category are neurologic and myogenic disorders of eyelid opening and/or closure. Secondary effects include spastic eyelid closure and synkinesis syndromes. These conditions, by definition, are disorders of movement, and can only be studied adequately using dynamic imaging techniques. Methods: A comprehensive literature search was performed on PubMed. Ninety abstracts were reviewed. Results: Dynamic eyelid imaging has evolved dramatically over the past two decades, at least partially due to the rise of inexpensive digital technology. Magnetic search coil imaging, high-and low-speed videography, electromyography, and high-resolution microscopy coil magnetic resonance imaging each has its advantages and disadvantages, an understanding of which will guide appropriate selection of technology in any given clinical situation. Conclusions: Dynamic eyelid imaging is useful to study dysmotility. The optimal technique depends upon the clinical setting and the physiologic or pathologic topic of interest. To our knowledge, a report of this type has not been previously summarized. C1 [De Castro, Dawn K.; Fay, Aaron] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Hadlock, Tessa] Massachusetts Eye & Ear Infirm, Facial Nerve Ctr, Boston, MA 02114 USA. [Hadlock, Tessa] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Fay, A (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Aaron_Fay@meei.harvard.edu NR 40 TC 0 Z9 0 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 167 EP 174 DI 10.3109/08820538.2012.708804 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600013 PM 23163272 ER PT J AU Lefebvre, DR Freitag, SK AF Lefebvre, Daniel R. Freitag, Suzanne K. TI Update on Imaging of the Lacrimal Drainage System SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Dacryocystography; Dacryoendoscopy; Dacryoscintigraphy; Lacrimal drainage system imaging; Lacrimal ultrasound ID COMPUTED TOMOGRAPHIC DACRYOCYSTOGRAPHY; NASOLACRIMAL DUCT OBSTRUCTION; INFERIOR MEATAL DACRYORHINOTOMY; CONGENITAL DACRYOCYSTOCELE; MR DACRYOCYSTOGRAPHY; ENDONASAL DACRYOCYSTORHINOSTOMY; RESPIRATORY-DISTRESS; MALIGNANT-MELANOMA; CONTRAST-MEDIA; CLINICAL-VALUE AB Epiphora is a common problem seen by the ophthalmologist. There are numerous etiologies of a watering eye, and the underlying diagnosis is not always clear. A variety of in-office examination techniques and procedures exist to aid with diagnosis and determination of appropriate therapy, but sometimes the diagnosis remains elusive, or an instituted therapy fails. Lacrimal imaging, particularly in these cases, can be helpful in assessing the function and anatomy of the lacrimal drainage system. This review serves to examine the literature of the last 10 years concerning imaging of the lacrimal drainage system. C1 [Lefebvre, Daniel R.; Freitag, Suzanne K.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Div Ophthalm Plast Surg, Boston, MA 02114 USA. [Lefebvre, Daniel R.; Freitag, Suzanne K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Lefebvre, DR (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Div Ophthalm Plast Surg, 243 Charles St,10th Floor, Boston, MA 02114 USA. EM daniel_lefebvre@meei.harvard.edu NR 106 TC 5 Z9 7 U1 2 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 175 EP 186 DI 10.3109/08820538.2012.711413 PG 12 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600014 PM 23163273 ER PT J AU Oliveira, C Cestari, DM Rizzo, JF AF Oliveira, Cristiano Cestari, Dean M. Rizzo, Joseph F., III TI The Use of Fourth-generation Optical Coherence Tomography in Multiple Sclerosis: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Axonal loss; Fourier domain; Multiple sclerosis; Optic neuritis; Optical coherence tomography; Retinal nerve fiber layer ID NERVE-FIBER LAYER; CIRRUS-HD-OCT; AXONAL LOSS; VISUAL DYSFUNCTION; NEURITIS; THICKNESS; ATROPHY; REPRODUCIBILITY; DISABILITY; LESIONS AB Optical coherence tomography (OCT) has been routinely used to obtain high spatial resolution images of the retina and choroid non-invasively. Within the past decade, a fourth-generation OCT device using Fourier domain (FD) analysis has been developed that provides higher velocity and higher axial resolution images with better reproducibility than the previous generation time domain (TD) OCT technology. This review addresses the use of fourth-generation, FD ocular OCT in patients with multiple sclerosis. C1 [Oliveira, Cristiano; Cestari, Dean M.; Rizzo, Joseph F., III] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Neuroophthalmol Serv, Boston, MA 02114 USA. RP Rizzo, JF (reprint author), 243 Charles St, Boston, MA 02114 USA. EM Joseph_Rizzo@meei.harvard.edu NR 35 TC 3 Z9 3 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 187 EP 191 DI 10.3109/08820538.2012.708808 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600015 PM 23163274 ER PT J AU Kruger, JM Lessell, S Cestari, DM AF Kruger, Joshua M. Lessell, Simmons Cestari, Dean M. TI Neuro-imaging: A Review for the General Ophthalmologist SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Neuro-ophthalmology; Neuro-imaging; MRI; CT ID ISCHEMIC OPTIC NEUROPATHY; MAGNETIC-RESONANCE; NERVE PALSY; ANEURYSMS; NEURITIS; ANGIOGRAPHY; TOMOGRAPHY; ADULTS; ARTERY AB The diagnosis of many neuro-ophthalmic conditions is facilitated with neuro-imaging. The two main modalities are Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Clinicians who refer patients for either of these techniques must not only know which of them to choose, but also where the imaging should be performed (e. g. brain, orbit), whether or not contrast is indicated, and if angiography should be supplemented. These complexities often result in imaging studies that are either unneeded or unhelpful. The goal of this manuscript is to provide a practical set of guidelines for the general ophthalmologist of how to choose the correct parameters for neuro-imaging studies. C1 [Cestari, Dean M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Neuroophthalmol Serv, Boston, MA USA. RP Cestari, DM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Dean_Cestari@meei.harvard.edu NR 31 TC 0 Z9 0 U1 4 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 192 EP 196 DI 10.3109/08820538.2012.708815 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600016 PM 23163275 ER PT J AU Nandakumar, N Buzney, S Weiter, JJ AF Nandakumar, Namrata Buzney, Sheldon Weiter, John J. TI Lipofuscin and the Principles of Fundus Autofluorescence: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Fundus autofluorescence; Age-related macular degeneration; Geographic atrophy; Lipofuscin ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; HUMAN RPE; GEOGRAPHIC ATROPHY; CONE PHOTOPIGMENT; OUTER SEGMENTS; MELANIN; PHAGOCYTOSIS; PHAGOSOME; CELLS AB Fundus autofluorescence is a non-invasive imaging modality that measures lipofuscin that has accumulated in the retinal pigment epithelium (RPE). Excessive lipofuscin in the RPE is a common pathway found in several diseases including Stargardt's disease and age-related macular degeneration. This review discusses the role of photooxidative damage in the development of lipofuscin and the principles of fundus autofluorescence. C1 [Nandakumar, Namrata; Buzney, Sheldon; Weiter, John J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Nandakumar, N (reprint author), 243 Charles St, Boston, MA 02114 USA. NR 41 TC 8 Z9 10 U1 1 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 197 EP 201 DI 10.3109/08820538.2012.711415 PG 5 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600017 PM 23163276 ER PT J AU Skondra, D Papakostas, TD Hunter, R Vavvas, DG AF Skondra, Dimitra Papakostas, Thanos D. Hunter, Rebecca Vavvas, Demetrios G. TI Near Infrared Autofluorescence Imaging of Retinal Diseases SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Enhanced imaging chorioretinal melanin ID KOYANAGI-HARADA-DISEASE; CENTRAL SEROUS CHORIORETINOPATHY; INDOCYANINE GREEN ANGIOGRAPHY; FUNDUS AUTOFLUORESCENCE; PSEUDOXANTHOMA ELASTICUM; MACULAR DEGENERATION; FLUORESCENCE; LIPOFUSCIN; MELANIN; ABNORMALITIES AB Near infrared autofluorescence (excitation 787 nm, emission > 800 nm) is a non-invasive imaging technology that provides information on the distribution of melanin within the retinal pigment epithelial cell/choroid complex. This review contains an introduction to near infrared autofluorescence imaging methods. Characteristics of near infrared imaging in a variety of retinal diseases, including age-related macular degeneration, choroidal nevus, retinal degenerations, retinal dystrophies, central serous chorioretinopathy, pseudoxanthoma elasticum and chloroquine retinopathy, are summarized. C1 [Skondra, Dimitra; Papakostas, Thanos D.; Hunter, Rebecca; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 40 TC 2 Z9 3 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 202 EP 208 DI 10.3109/08820538.2012.708806 PG 7 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600018 PM 23163277 ER PT J AU Skondra, D Papakostas, T Vavvas, DG AF Skondra, Dimitra Papakostas, Thanos Vavvas, Demetrios G. TI Enhanced Depth Imaging Optical Coherence Tomography in Age-related Macular Degeneration SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE AMD; Choroidal thickness; Imaging ID POLYPOIDAL CHOROIDAL VASCULOPATHY; RETICULAR PSEUDODRUSEN; MORPHOMETRIC-ANALYSIS; BRUCHS MEMBRANE; IN-VIVO; THICKNESS; FREQUENCY; THERAPY; RETINA; EDEMA AB Imaging of the choroidal layer has been limited with the conventional commercial SD-OCTs. Enhanced depth imaging optical coherence tomography (EDI-OCT) is a modification of the standard spectral-domain OCT (SD-OCT) technique that enables better non-invasive imaging of the choroid. This review contains an introduction of EDI imaging technique and principles and summarizes the findings of EDI-OCT imaging in age-related macular degeneration. C1 [Skondra, Dimitra; Papakostas, Thanos; Vavvas, Demetrios G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02114 USA. RP Vavvas, DG (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 27 TC 3 Z9 3 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 209 EP 212 DI 10.3109/08820538.2012.708807 PG 4 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600019 PM 23163278 ER PT J AU Huang, LL Hirose, T AF Huang, Lynn L. Hirose, Tatsuo TI Portable Optical Coherence Tomography in Management of Vitreoretinal Diseases: Current Developments, Indications, and Implications SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Hand-held; Intraoperative; Pediatric; Portable; Optical coherence tomography; OCT; Vitreoretinal diseases ID THICKNESS MACULAR HOLE; SURGERY; PREMATURITY; RETINOPATHY; MORPHOLOGY; INFANTS; EDEMA; OCT AB The advent of optical coherence tomography (OCT) technology has greatly enhanced our understanding of vitreoretinal diseases; it has become a routine diagnostic imaging method for the evaluation of vitreoretinal abnormalities and injuries in adult and pediatric patients. The use of OCT has recently been extended beyond the offices and clinics to perioperative and intraoperative settings. The new development in high-resolution and high-speed spectral domain OCT, along with the improvement in portability, has made the device more valuable than ever before. Our article summarizes the current development of the portable OCT devices in clinical, perioperative, and intraoperative settings in the management of vitreoretinal diseases. C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA USA. RP Huang, LL (reprint author), 1101 Beacon St, Brookline, MA 02446 USA. EM Lynn.huang05@post.harvard.edu NR 28 TC 5 Z9 7 U1 1 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 213 EP 220 DI 10.3109/08820538.2012.708811 PG 8 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600020 PM 23163279 ER PT J AU Hunter, RS Skondra, D Papaliodis, G Sobrin, L AF Hunter, Rebecca S. Skondra, Dimitra Papaliodis, George Sobrin, Lucia TI Role of OCT in the Diagnosis and Management of Macular Edema from Uveitis SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE Optical coherence tomography; Uveitis; Macular edema ID OPTICAL COHERENCE TOMOGRAPHY; FLUORESCEIN ANGIOGRAPHY; QUANTITATIVE ASSESSMENT; EPIRETINAL MEMBRANES; VISUAL-ACUITY; TIME-DOMAIN; PATTERNS; RETINITIS; THERAPY AB Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world. 1 The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME). 1 The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis. 2 In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema. C1 [Hunter, Rebecca S.; Skondra, Dimitra; Papaliodis, George; Sobrin, Lucia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Hunter, RS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM rebecca_hunter@meei.harvard.edu NR 38 TC 6 Z9 6 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 236 EP 241 DI 10.3109/08820538.2012.708813 PG 6 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600023 PM 23163282 ER PT J AU Kohanim, S Daniels, AB Huynh, N Eliott, D Chodosh, J AF Kohanim, Sahar Daniels, Anthony B. Huynh, Nancy Eliott, Dean Chodosh, James TI Utility of Ocular Ultrasonography in Diagnosing Infectious Endophthalmitis in Patients with Media Opacities SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE B-scan; Ocular ultrasound; Infectious endophthalmitis; Diagnostic utility ID BACTERIAL ENDOPHTHALMITIS AB Assessment of patients with infectious endophthalmitis is frequently limited by media opacities, and ocular ultrasonography is routinely performed in this setting. We examined the literature to assess the level of evidence for the utility of ocular ultrasonography in these patients. Common ultrasonographic findings reported include low amplitude mobile echoes, vitreous membranes, and thickening of the retina and choroid. Based on the available evidence, we conclude that ocular ultrasound may be a useful adjunct in guiding treatment and minimizing complications. While positive findings may be confirmatory in cases in which the clinical suspicion is high, ocular ultrasound alone cannot be used to prove or to exclude the diagnosis of infectious endophthalmitis. C1 [Chodosh, James] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, Boston, MA 02114 USA. RP Chodosh, J (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM james_chodosh@meei.harvard.edu NR 18 TC 1 Z9 1 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2012 VL 27 IS 5-6 BP 242 EP 245 DI 10.3109/08820538.2012.711417 PG 4 WC Ophthalmology SC Ophthalmology GA 041SD UT WOS:000311420600024 PM 23163283 ER PT J AU Huang, YW Chung, RT AF Huang, Yi-Wen Chung, Raymond T. TI Management of hepatitis B reactivation in patients receiving cancer chemotherapy SO THERAPEUTIC ADVANCES IN GASTROENTEROLOGY LA English DT Review DE cancer; chemotherapy; HBV reactivation; hepatitis B virus; lamivudine; prophylaxis AB Hepatitis B virus (HBV) reactivation is well documented in previously resolved or inactive HBV carriers who receive cancer chemotherapy. The consequences of HBV reactivation range from self-limited conditions to fulminant hepatic failure and death. HBV reactivation also leads to premature termination of chemotherapy or delay in treatment schedules. This review summarizes current knowledge of management of HBV reactivation in patients receiving cancer chemotherapy. HBV surface antigen (HBsAg) testing should be performed in patients who require cancer chemotherapy. Four meta-analyses support lamivudine prophylaxis for HBV reactivation during chemotherapy in HBsAg-positive patients. Randomized controlled trials to compare different HBV antiviral agents are needed to define optimal regimens for the prevention and treatment of HBV reactivation in patients receiving cancer chemotherapy. C1 [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Boston, MA 02114 USA. [Huang, Yi-Wen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA USA. [Huang, Yi-Wen] Cathay Gen Hosp, Med Ctr, Ctr Liver, Taipei, Taiwan. [Huang, Yi-Wen] Taipei Med Univ, Sch Med, Taipei, Taiwan. [Huang, Yi-Wen] Natl Taiwan Univ Coll Med & Hosp, Dept Internal Med, Div Gastroenterol, Taipei, Taiwan. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Warren 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org OI Huang, Yi-Wen/0000-0002-5196-7030 FU National Science Council of Taiwan, Republic of China; Cathay General Hospital Medical Center, Taipei, Taiwan; NIH [DK078772, DK082919] FX Yi-Wen Huang is a research fellow at Massachusetts General Hospital and Harvard Medical School sponsored by National Science Council of Taiwan, Republic of China and Cathay General Hospital Medical Center, Taipei, Taiwan. Dr. Chung was supported by NIH DK078772 and DK082919. NR 79 TC 7 Z9 8 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1756-283X EI 1756-2848 J9 THER ADV GASTROENTER JI Ther. Adv. Gastroenterol. PD SEP PY 2012 VL 5 IS 5 BP 359 EP 370 DI 10.1177/1756283X12450245 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V31ZQ UT WOS:000208921900006 PM 22973419 ER PT J AU Hussain, M Corn, P Michaelson, D Hammers, H Alumkal, J Ryan, C Bruce, J Moran, S Lee, S Borgstein, N Webb, I Mortimer, P George, D AF Hussain, M. Corn, P. Michaelson, D. Hammers, H. Alumkal, J. Ryan, C. Bruce, J. Moran, S. Lee, S. Borgstein, N. Webb, I Mortimer, P. George, D. TI Safety and Efficacy of the Investigational Agent Orteronel (TAK-700) Without Prednisone in Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) Patients with Rising Prostate-Specific Antigen (PSA): Updated Results from a Phase 2 Study SO UROLOGY LA English DT Meeting Abstract C1 [Hussain, M.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Corn, P.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Michaelson, D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Hammers, H.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alumkal, J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Ryan, C.] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bruce, J.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53706 USA. [Moran, S.; Lee, S.; Borgstein, N.; Webb, I] Millennium Pharmaceut Inc, Cambridge, MA USA. [Mortimer, P.] Takeda Global Res & Dev Ctr Europe Ltd, London, England. [George, D.] Duke Univ, Med Ctr, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.01 BP S29 EP S29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800063 ER PT J AU Mulders, P Scher, H Fizazi, K Saad, F Taplin, M Sternberg, C Miller, K De Wit, R Hirmand, M Selby, B De Bono, J AF Mulders, P. Scher, H. Fizazi, K. Saad, F. Taplin, M. Sternberg, C. Miller, K. De Wit, R. Hirmand, M. Selby, B. De Bono, J. CA AFFIRM Investigators TI MDV3100, an Androgen Receptor Signaling Inhibitor, Improves Overall Survival in Patients with Prostate Cancer Post Docetaxel: Results from the Phase 3 AFFIRM Study SO UROLOGY LA English DT Meeting Abstract C1 [Mulders, P.] Radboud Univ Nijmegen, Nijmegen Med Ctr, Nijmegen, Netherlands. [Scher, H.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Saad, F.] Univ Montreal, Ctr Hosp, Montreal, PQ, Canada. [Taplin, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Sternberg, C.] San Camillo Forlanini Hosp, Rome, Italy. [Miller, K.] Charite Univ Med Berlin, Berlin, Germany. [Hirmand, M.; Selby, B.] Medivat Inc, San Francisco, CA USA. [Fizazi, K.] Univ Paris Sud, Villejuif, France. [De Wit, R.] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [De Bono, J.] Inst Canc Res, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.04 BP S30 EP S30 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800066 ER PT J AU Santiago-Lastra, Y Talab, SS Bachmann, A Muir, G Choi, B Tabatabaei, S AF Santiago-Lastra, Y. Talab, Shafaat S. Bachmann, A. Muir, G. Choi, B. Tabatabaei, S. TI Ejaculation Preserving Photoselective Vaporization of the Prostate SO UROLOGY LA English DT Meeting Abstract C1 [Santiago-Lastra, Y.; Talab, Shafaat S.; Tabatabaei, S.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Bachmann, A.] Univ Hosp, Dept Urol, Basel, Switzerland. [Muir, G.] Kings Coll Hosp London, Dept Urol, London, England. [Choi, B.] Weill Cornell Univ, Dept Urol, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA VID-04 BP S179 EP S179 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800433 ER PT J AU Zareba, P Fiorentino, M Flavin, R Martin, N Andersson, S Andren, O Fall, K Rider, J Mucci, L AF Zareba, P. Fiorentino, M. Flavin, R. Martin, N. Andersson, S. Andren, O. Fall, K. Rider, J. Mucci, L. TI Perineural Invasion and Lethal Prostate Cancer SO UROLOGY LA English DT Meeting Abstract C1 [Zareba, P.] McMaster Univ, Div Urol, Hamilton, ON, Canada. [Fiorentino, M.; Flavin, R.; Rider, J.] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Fiorentino, M.] St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, Bologna, Italy. [Martin, N.; Mucci, L.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Martin, N.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Andersson, S.; Andren, O.; Fall, K.; Rider, J.] Orebro Univ Hosp, Dept Urol, Orebro, Sweden. [Fall, K.] Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. [Rider, J.; Mucci, L.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA MP-07.16 BP S84 EP S84 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800199 ER PT J AU Zareba, P Pettersson, A Gerke, T Fiorentino, M Flavin, R Rider, J Giovannucci, E Finn, S Loda, M Mucci, L AF Zareba, P. Pettersson, A. Gerke, T. Fiorentino, M. Flavin, R. Rider, J. Giovannucci, E. Finn, S. Loda, M. Mucci, L. TI Immunohistochemical Expression of BRCA1 and Prostate Cancer Progression in a Large Radical Prostatectomy Cohort SO UROLOGY LA English DT Meeting Abstract C1 [Zareba, P.] McMaster Univ, Div Urol, Hamilton, ON, Canada. [Pettersson, A.; Gerke, T.; Giovannucci, E.; Mucci, L.] Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Fiorentino, M.; Flavin, R.; Rider, J.; Finn, S.; Loda, M.] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Fiorentino, M.] St Orsola Marcello Malpighi Hosp, Addarii Inst, Patbol Unit, Bologna, Italy. [Rider, J.; Giovannucci, E.; Mucci, L.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Giovannucci, E.] Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA. [Loda, M.] Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD SEP PY 2012 VL 80 IS 3 SU S MA POD-09.02 BP S29 EP S29 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V45WN UT WOS:000209846800064 ER PT J AU Cohen, BE Maguen, S Bertenthal, D Shi, Y Jacoby, V Seal, KH AF Cohen, Beth E. Maguen, Shira Bertenthal, Daniel Shi, Ying Jacoby, Vanessa Seal, Karen H. TI Reproductive and Other Health Outcomes in Iraq and Afghanistan Women Veterans Using VA Health Care: Association with Mental Health Diagnoses SO WOMENS HEALTH ISSUES LA English DT Article AB Background: An increasing number of women serve in the military and are exposed to trauma during service that can lead to mental health problems. Understanding how these mental health problems affect reproductive and physical health outcomes will inform interventions to improve care for women veterans. Methods: We analyzed national Department of Veterans Affairs (VA) data from women Iraq and Afghanistan veterans who were new users of VA healthcare from October 7, 2001, through December 31, 2010 (n = 71,504). We used ICD-9 codes to categorize veterans into five groups by mental health diagnoses (MH Dx): Those with no MH Dx, posttraumatic stress disorder (PTSD), depression, comorbid PTSD and depression, and a MH Dx other than PTSD and depression. We determined the association between mental health category and reproductive and other physical health outcomes defined by ICD-9 codes. Categories included sexually transmitted infections, other infections (e. g., urinary tract infections), pain-related conditions (e. g., dysmenorrhea and dsypareunia), and other conditions (e. g., polycystic ovarian syndrome, infertility, sexual dysfunction). Models were adjusted for sociodemographic and military service factors. Results: There were 31,481 patients (44%) who received at least one mental health diagnosis. Women veterans with any mental health diagnosis had significantly higher prevalences of nearly all categories of reproductive and physical disease diagnoses (p < .0001 for adjusted prevalences). There was a trend of increasing prevalence of disease outcomes in women with PTSD, depression, and comorbid PTSD and depression (p for trend <.0001 for all outcomes). Conclusions: Iraq and Afghanistan women veterans with mental health diagnoses had significantly greater prevalences of several important reproductive and physical health diagnoses. These results provide support for VA initiatives to address mental and physical health concerns and improve comprehensive care for women veterans. Published by Elsevier Inc. C1 [Cohen, Beth E.; Maguen, Shira; Bertenthal, Daniel; Shi, Ying; Seal, Karen H.] San Francisco VA Med Ctr, San Francisco, CA USA. [Cohen, Beth E.; Maguen, Shira; Bertenthal, Daniel; Jacoby, Vanessa; Seal, Karen H.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Jacoby, Vanessa] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bertenthal, Daniel; Seal, Karen H.] San Francisco VA Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, San Francisco, CA USA. RP Cohen, BE (reprint author), 4150 Clement St, San Francisco, CA 94121 USA. EM beth.cohen@va.gov FU NHLBI NIH HHS [K23 HL 094765-01, K23 HL094765] NR 63 TC 17 Z9 17 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2012 VL 22 IS 5 BP E461 EP E471 DI 10.1016/j.whi.2012.06.005 PG 11 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33ST UT WOS:000209039200007 PM 22944901 ER PT J AU Katon, J Maynard, C Reiber, G AF Katon, Jodie Maynard, Charles Reiber, Gayle TI Attempts at Weight Loss in US Women with and without a History of Gestational Diabetes Mellitus SO WOMENS HEALTH ISSUES LA English DT Article AB Background and Objective: Gestational diabetes mellitus (GDM) is a risk factor for type 2 diabetes. Relatively modest weight loss can delay or prevent the onset of type 2 diabetes. The objective of this study was to determine, using a nationally representative survey, whether among women without diabetes, those with a history of GDM (hGDM) were more likely than those without hGDM to be currently attempting weight loss. Methods: This study used data from the 2003 Behavioral Risk Factor Surveillance System, a national, population-based, random-sample telephone survey. Women aged 18 to 44 years without diabetes who answered questions related to current weight loss activity were included in the analysis. The primary outcome was currently attempting weight loss. Logistic regression was used to analyze the association between hGDM and currently attempting weight loss. Results: We included 53,608 women without diabetes: 1,260 (2%) with hGDM, and 52,348 (98%) without hGDM. Among women with hGDM, 53% were currently attempting weight loss compared with 47% of women without hGDM. Overall, after adjusting for age, race/ethnicity, education, marital status, and medical insurance, compared with women without hGDM, those with hGDM had 20% higher odds of currently attempting weight loss (95% confidence interval [CI], 0.97-1.49); however, among obese women (body mass index >= 30 kg/m(2)), compared with women without hGDM, those with hGDM had 46% lower odds of currently attempting weight loss (95% CI, 0.35-0.82). Conclusions: Obese women with hGDM are less likely to be currently attempting weight loss compared with those without hGDM. Effective interventions for obese women with hGDM are needed. Published by Elsevier Inc. C1 [Katon, Jodie; Reiber, Gayle] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Maynard, Charles; Reiber, Gayle] VA Puget Sound Hlth Care Syst, HSR&D, Seattle, WA USA. [Maynard, Charles; Reiber, Gayle] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. RP Katon, J (reprint author), Univ Washington, Sch Publ Hlth, Dept Epidemiol, Box 357236, Seattle, WA 98195 USA. EM jkaton@u.washington.edu RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU NICHD NIH HHS [T32 HD052462] NR 23 TC 2 Z9 2 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 EI 1878-4321 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2012 VL 22 IS 5 BP E447 EP E453 DI 10.1016/j.whi.2012.07.004 PG 7 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33ST UT WOS:000209039200005 PM 22944900 ER PT J AU Bromley, E AF Bromley, Elizabeth TI Building patient-centeredness: Hospital design as an interpretive act SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Patient-centeredness; Hospital design; USA; Medical professionalism; Consumerism; Patienthood ID HEALTH-CARE; MEDICAL PROFESSIONALISM; THERAPEUTIC LANDSCAPES; SATISFACTION; TECHNOLOGY; COMMUNICATION; PHYSICIAN; ENCOUNTER; ILLNESS; ISSUES AB Hospital designs reflect the sociocultural, economic, professional, and aesthetic priorities prevalent at a given time. As such, hospital buildings concretize assumptions about illness, care and healing, patienthood, and medical providers' roles. Trends in hospital design have been attributed to the increasing influence of consumerism on healthcare, the influx of business-oriented managers, and technological changes. This paper describes the impact of the concept of patient-centeredness on the design of a new hospital in the USA. Data come from 35 interviews with planners, administrators, and designers of the new hospital, as well as from public documents about the hospital design. Thematic content analysis was used to identify salient design principles and intents. For these designers, administrators, and planners, an interpretation of patient-centeredness served as a heuristic, guiding the most basic decisions about space, people, and processes in the hospital. 1 detail the particular interpretation of patient-centeredness used to build and manage the new hospital space and the roles and responsibilities of providers working within it. Three strategies were central to the implementation of patient-centeredness: an onstage/offstage layout; a concierge approach to patients; and the scripting of communication. I discuss that this interpretation of patient-centeredness may challenge medical professionals' roles, may construct medical care as a product that should sate the patient's desire, and may distance patients from the realities of medical care. By describing the ways in which hospital designs reflect and reinforce contemporary concepts of patienthood and caring, this paper raises questions about the implementation of patient-centeredness that deserve further empirical study by medical social scientists. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Bromley, Elizabeth] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. [Bromley, Elizabeth] W Los Angeles VA Healthcare Ctr, VA Desert Pacific Mental Illness Res Educ & Clin, Los Angeles, CA USA. RP Bromley, E (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. EM ebromley@ucla.edu FU UniHealth Foundation FX This study was funded by the UniHealth Foundation. An earlier version of this paper was presented to the American Anthropological Association annual meeting November 2010 in New Orleans, LA. The author wishes to thank Lisa Mikesell, Marian Katz, Susan Stockdale, Joseph Mango, Elizabeth O'Toole, Stefan Timmermans, Kenneth B. Wells, Peter Whybrow, Joel T. Braslow, Neil Wenger, and James B. Atkinson for invaluable contributions to this research. The author also gratefully acknowledges anonymous reviewers for their insightful comments. NR 101 TC 16 Z9 16 U1 6 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD SEP PY 2012 VL 75 IS 6 BP 1057 EP 1066 DI 10.1016/j.socscimed.2012.04.037 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 979LQ UT WOS:000306821900013 PM 22703887 ER PT J AU Vogt, DS Shipherd, JC Resick, PA AF Vogt, Dawne S. Shipherd, Jillian C. Resick, Patricia A. TI Posttraumatic Maladaptive Beliefs Scale: Evolution of the Personal Beliefs and Reactions Scale SO ASSESSMENT LA English DT Article DE cognition; PTSD; measurement; maladaptive beliefs; coping; trauma ID COGNITIVE-PROCESSING THERAPY; ADMINISTERED PTSD SCALE; SEXUAL-ABUSE SURVIVORS; STRESS-DISORDER; ASSUMPTIONS SCALE; QUICK TEST; VICTIMS; TRAUMA; CLINICIAN; VICTIMIZATION AB The Posttraumatic Maladaptive Beliefs Scale (PMBS) was developed to measure maladaptive beliefs about current life circumstances that may occur following trauma exposure. This scale assesses maladaptive beliefs within three domains: (a) Threat of Harm, (b) Self-Worth and Judgment, and (c) Reliability and Trustworthiness of Others. Items for the PMBS were drawn from a larger preexisting measure that assesses a wide range of personal beliefs and reactions associated with trauma exposure. The construct validity of the PMBS was assessed in two independent samples of interpersonal trauma survivors. This article provides data to support the reliability and validity of the PMBS as an instrument to assess general, rather than trauma-specific, maladaptive beliefs that have relevance for functioning in the aftermath of a traumatic event. Moreover, the measure is sensitive to changes that occur in treatment, and the length of the measure (15 items) is practical for use in clinical settings. C1 [Vogt, Dawne S.; Shipherd, Jillian C.; Resick, Patricia A.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Vogt, Dawne S.; Shipherd, Jillian C.; Resick, Patricia A.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. RP Vogt, DS (reprint author), VA Boston Healthcare Syst 116B 3, Womens Hlth Sci Div, 150 S Huntington Ave, Boston, MA 02130 USA. EM Dawne.Vogt@va.gov NR 57 TC 7 Z9 7 U1 1 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD SEP PY 2012 VL 19 IS 3 BP 308 EP 317 DI 10.1177/1073191110376161 PG 10 WC Psychology, Clinical SC Psychology GA 978HS UT WOS:000306732000005 PM 20660470 ER PT J AU Yang, JA Kim, ES Kwon, JH Kim, H Shin, JH Yun, SH Choi, KY Hahn, SK AF Yang, Jeong-A Kim, Eung-Sam Kwon, Jung Hee Kim, Hyemin Shin, Ji Hye Yun, Seok Hyun Choi, Kwan Yong Hahn, Sei Kwang TI Transdermal delivery of hyaluronic acid - Human growth hormone conjugate SO BIOMATERIALS LA English DT Article DE Hyaluronic acid; Human growth hormone; Conjugate; Receptors; Transdermal delivery ID DRUG-DELIVERY; HUMAN SKIN; CELL-PROLIFERATION; PENETRATION ENHANCERS; RECEPTOR; CD44; FIBROBLASTS; MICRONEEDLES; ADHESION; CULTURE AB Hyaluronic acid (HA) is one of the major components of extracellular matrix (ECM). Keratinocyte and fibroblast are known to have HA receptors in the skin. Fibroblast also has human growth hormone (hGH) receptors. In this work, HA hGH conjugate was developed as a receptor mediated transdermal delivery system of protein drugs. HA hGH conjugate was synthesized by specific coupling reaction between aldehyde modified HA and the N-terminal amine group of hGH. We could confirm the proliferative effect of HA on keratinocyte and fibroblast, and the biological activity of HA hGH conjugate in fibroblast with an elevated expression level of phosphorylated Janus kinase 2 (p-JAK2). Interestingly, fluorescence microscopy clearly visualized the dramatically enhanced penetration of HA hGH conjugate through the dorsal skin of mice after topical treatment with FITC labeled HA hGH conjugate. According to pharmacokinetic analysis, HA hGH conjugate appeared to be delivered through the skin into the blood stream possibly by the receptor mediated transdermal delivery. This work confirms the feasibility of using the HA hGH conjugate as a model system for the receptor mediated transdermal delivery of protein drugs and their further exploitation for various cosmetic and tissue engineering applications. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Yang, Jeong-A; Kim, Hyemin; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, Pohang 790784, Kyungbuk, South Korea. [Kim, Eung-Sam; Choi, Kwan Yong; Hahn, Sei Kwang] Pohang Univ Sci & Technol POSTECH, Sch Interdisciplinary Biosci & Bioengn, Pohang 790784, Kyungbuk, South Korea. [Kwon, Jung Hee; Shin, Ji Hye; Choi, Kwan Yong] Pohang Univ Sci & Technol POSTECH, Div Mol & Life Sci, Dept Life Sci, Pohang 790784, Kyungbuk, South Korea. [Yun, Seok Hyun; Hahn, Sei Kwang] Harvard Univ, Sch Med, Wellman Ctr Photomed, Cambridge, MA 02139 USA. [Yun, Seok Hyun; Hahn, Sei Kwang] Massachusetts Gen Hosp, Cambridge, MA 02139 USA. RP Hahn, SK (reprint author), Pohang Univ Sci & Technol POSTECH, Dept Mat Sci & Engn, San 31, Pohang 790784, Kyungbuk, South Korea. EM kchoi@postech.ac.kr; skhanb@postech.ac.kr FU Converging Research Center through National Research Foundation of Korea (NRF); Ministry of Education. Science and Technology [2009-0081871, 2011K000801]; Ministry of Health & Welfare, Republic of Korea [A080711]; Rural Development Administration, Republic of Korea [PJ007974] FX This research was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education. Science and Technology (2009-0081871 and 2011K000801). This study was also supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A080711). This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ007974), Rural Development Administration, Republic of Korea. We also thank Yong Ryoul Yang for embedding the skin tissue into OCT compound and Hyuntae Jung for fluorescence microscopic images. NR 30 TC 34 Z9 35 U1 5 U2 51 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 SEP PY 2012 VL 33 IS 25 BP 5947 EP 5954 DI 10.1016/j.biomaterials.2012.05.003 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 979KY UT WOS:000306820100007 PM 22632765 ER PT J AU Lillis, KP Kramer, MA Mertz, J Staley, KJ White, JA AF Lillis, Kyle P. Kramer, Mark A. Mertz, Jerome Staley, Kevin J. White, John A. TI Pyramidal cells accumulate chloride at seizure onset SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Epilepsy; Ictogenesis; Chloride accumulation; Ion imaging; Calcium; Seizure; GABA; Chloride transport; Interneuron; Targeted path scanning ID TEMPORAL-LOBE EPILEPSY; GAMMA-AMINOBUTYRIC-ACID; GABA-MEDIATED POTENTIALS; ENTORHINAL CORTEX; IN-VITRO; EXTRACELLULAR POTASSIUM; FLUORESCENT INDICATORS; GABAERGIC INTERNEURONS; EPILEPTIFORM ACTIVITY; HIPPOCAMPAL-NEURONS AB Seizures are thought to originate from a failure of inhibition to quell hyperactive neural circuits, but the nature of this failure remains unknown. Here we combine high-speed two-photon imaging with electrophysiological recordings to directly evaluate the interaction between populations of interneurons and principal cells during the onset of seizure-like activity in mouse hippocampal slices. Both calcium imaging and dual patch clamp recordings reveal that in vitro seizure-like events (SLEs) are preceded by pre-ictal bursts of activity in which interneurons predominate. Corresponding changes in intracellular chloride concentration were observed in pyramidal cells using the chloride indicator Clomeleon. These changes were measurable at SLE onset and became very large during the SLE. Pharmacological manipulation of GABAergic transmission, either by blocking GABA(A) receptors or by hyperpolarizing the GABA(A) reversal potential, converted SLEs to short interictal-like bursts. Together, our results support a model in which pre-ictal GABA(A) receptor-mediated chloride influx shifts E-GABA to produce a positive feedback loop that contributes to the initiation of seizure activity. (C) 2012 Elsevier Inc. All rights reserved. C1 [White, John A.] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. [Lillis, Kyle P.; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Lillis, Kyle P.; Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Mertz, Jerome] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP White, JA (reprint author), Univ Utah, Dept Bioengn, 20 S 2030 E, Salt Lake City, UT 84112 USA. EM lillis.kyle@mgh.harvard.edu; mak@bu.edu; jmertz@bu.edu; staley.kevin@mgh.harvard.edu; john.white@utah.edu RI Kramer, Mark/A-1291-2014; OI White, John/0000-0003-1073-2638 FU NIH; Epilepsy Foundation; Burroughs Wellcome Fund FX This work was supported by grants from the NIH, the Epilepsy Foundation and the Burroughs Wellcome Fund. We thank G. Feng, T. Kuner, and G.J. Augustine for generously providing us with the Clomeleon mice. NR 62 TC 31 Z9 31 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD SEP PY 2012 VL 47 IS 3 BP 358 EP 366 DI 10.1016/j.nbd.2012.05.016 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 976YC UT WOS:000306622300007 PM 22677032 ER PT J AU Mai, CL Young, MJ Quraishi, SA AF Mai, Christine L. Young, Mark J. Quraishi, Sadeq A. TI Clinical implications of the transversus abdominis plane block in pediatric anesthesia SO PEDIATRIC ANESTHESIA LA English DT Review DE transversus abdominis plane; TAP; nerve block; regional anesthesia; pediatric ID PROSPECTIVE RANDOMIZED-TRIAL; POSTOPERATIVE ANALGESIA; TAP BLOCK; LIVER TRAUMA; CHILDREN; SURGERY; INFANTS; NERVES; AUDIT; WALL AB Optimal perioperative analgesia for infants and children after major abdominal surgery poses a challenge when central neuraxial techniques are contraindicated. As a regional anesthesia technique, the transversus abdominis plane (TAP) block has been shown to reduce opioid consumption and improve pain scores compared to traditional perioperative pain strategies. Accordingly, TAP blocks may be considered as an alternative to central neuraxial analgesia to optimize perioperative pain control. Advancements in ultrasound technology have further improved the reliability and safety profile of this technique. Despite growing recognition of the diverse clinical scenarios where TAP blocks may be of benefit, its use among pediatric anesthesiologists remains limited. This article describes the history, anatomy, and a review of the current literature on TAP blocks with an emphasis on outcomes in pediatric patients. C1 [Quraishi, Sadeq A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Quraishi, SA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRJ 402, Boston, MA 02114 USA. EM squraishi@partners.org FU Harvard Anaesthesia Center [5T32GM007592-33] FX Harvard Anaesthesia Center (5T32GM007592-33) supported SAQ. NR 46 TC 12 Z9 12 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1155-5645 J9 PEDIATR ANESTH JI Pediatr. Anesth. PD SEP PY 2012 VL 22 IS 9 BP 831 EP 840 DI 10.1111/j.1460-9592.2012.03916.x PG 10 WC Anesthesiology; Pediatrics SC Anesthesiology; Pediatrics GA 980NP UT WOS:000306900400001 PM 22834467 ER PT J AU Smith, KA Tong, X Abu-Yousif, AO Mikulec, CC Gottardi, CJ Fischer, SM Pelling, JC AF Smith, Kimberly A. Tong, Xin Abu-Yousif, Adnan O. Mikulec, Carol C. Gottardi, Cara J. Fischer, Susan M. Pelling, Jill C. TI UVB radiation-induced beta-catenin signaling is enhanced by COX-2 expression in keratinocytes SO MOLECULAR CARCINOGENESIS LA English DT Article DE UVB; ss-catenin; COX-2; PGE2 ID SQUAMOUS-CELL CARCINOMA; NONMELANOMA SKIN-CANCER; GROWTH-FACTOR RECEPTOR; CYCLOOXYGENASE-2 EXPRESSION; ULTRAVIOLET-RADIATION; INDUCED APOPTOSIS; MOUSE SKIN; E-CADHERIN; ACTIVATION; CARCINOGENESIS AB UVB radiation is the major carcinogen responsible for skin carcinogenesis, thus elucidation of the molecular pathways altered in skin in response to UVB would reveal novel targets for therapeutic intervention. It is well established that UVB leads to upregulation of cyclooxygenase 2 (COX-2) in the skin which contributes to skin carcinogenesis. Overexpression of COX-2 has been shown to promote colon cancer cell growth through beta-catenin signaling, however, little is known about the connection between UVB, COX-2, and beta-catenin in the skin. In the present study, we have identified a novel pathway in which UVB induces beta-catenin signaling in keratinocytes, which is modulated by COX-2 expression. Exposure of the mouse 308 keratinocyte cell line (308 cells) and primary normal human epidermal keratinocytes (NHEKs) to UVB resulted in increased protein levels of both N-terminally unphosphorylated and total beta-catenin. In addition, we found that UVB-enhanced beta-catenin-dependent TOPflash reporter activity and expression of a downstream beta-catenin target gene. We demonstrated that UVB-induced beta-catenin signaling is modulated by COX-2, as treatment of keratinocytes with the specific COX-2 inhibitor NS398 blocked UVB induction of beta-catenin. Additionally, beta-catenin target gene expression was reduced in UVB-treated COX-2 knockout (KO) MEFs compared to wild-type (WT) MEFs. Furthermore, epidermis from UVB-exposed SKH-1 mice exhibited increased N-terminally unphosphorylated and total beta-catenin protein levels and increased staining for total beta-catenin, and both responses were reduced in COX-2 heterozygous mice. Taken together, these results suggest a novel pathway in which UVB induces beta-catenin signaling in keratinocytes which is enhanced by COX-2 expression. (c) 2011 Wiley Periodicals, Inc. C1 [Smith, Kimberly A.; Tong, Xin; Pelling, Jill C.] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. [Smith, Kimberly A.; Tong, Xin; Pelling, Jill C.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Gottardi, Cara J.] Northwestern Univ, Feinberg Sch Med, Dept Med, Div Pulm & Crit Care, Chicago, IL 60611 USA. [Abu-Yousif, Adnan O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Mikulec, Carol C.; Fischer, Susan M.] Univ Texas Dallas, MD Anderson Canc Ctr, Sci Pk Res Div, Smithville, TX USA. RP Pelling, JC (reprint author), Northwestern Univ, Dept Pathol, Feinberg Sch Med, 303 E Super St,Lurie Bldg 3-115, Chicago, IL 60611 USA. OI Smith, Kimberly/0000-0002-2621-0052 FU NIH [CA104768, AR057579, CA09560]; Zell Foundation; Malkin Scholars Award; Robert H. Lurie Comprehensive Cancer Center; Northwestern Skin Disease Research Center, Chicago, IL [5P30AR057216]; NIH/NIAMS FX This work was supported by NIH grant CA104768 and AR057579 to J.C.P., the Zell Foundation (J.C.P was a Zell Scholar), NIH T32 grant CA09560 to K. A. S., a Malkin Scholars Award to K. A. S, in part by the Robert H. Lurie Comprehensive Cancer Center and in part by resources provided by the Northwestern Skin Disease Research Center 5P30AR057216, Chicago, IL with support from the NIH/NIAMS. NR 44 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2012 VL 51 IS 9 BP 734 EP 745 DI 10.1002/mc.20840 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 976GU UT WOS:000306569700005 PM 21853475 ER PT J AU Liu, XH Joshi, SK Samagh, SP Dang, YX Laron, D Lovett, DH Bodine, SC Kim, HT Feeley, BT AF Liu, Xuhui Joshi, Sunil K. Samagh, Sanjum P. Dang, Yu-Xuan Laron, Dominique Lovett, David H. Bodine, Sue C. Kim, Hubert T. Feeley, Brian T. TI Evaluation of Akt/mTOR activity in muscle atrophy after rotator cuff tears in a rat model SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE muscle atrophy; rotator cuff tear; Akt; mTOR; denervation ID FOXO TRANSCRIPTION FACTORS; SKELETAL-MUSCLE; UBIQUITIN LIGASES; FATTY INFILTRATION; EXPRESSION; PATHWAY; SUPRASPINATUS; HYPERTROPHY; ATROGIN-1; REVEALS AB Atrophy of the rotator cuff muscles is a factor that complicates the treatment of a massive rotator cuff tear (RCT). However, the molecular mechanisms that govern the development of muscle atrophy after RCTs have not been well defined. The Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role in maintaining muscle mass in response to mechanical loading. The role of this pathway in the development of muscle atrophy after a massive RCT remains unknown. The purpose of this study was to investigate the regulation of the Akt/mTOR pathway in the development of muscle atrophy after a RCT and suprascapular nerve (SSN) injury. We evaluated the activity of the Akt/mTOR signaling pathway and how this pathway interacts with two atrophy-related genes, MuRF-1 and MAFbx, in supraspinatus muscles of rats that underwent unilateral complete rotator cuff tendon transection or SSN transection. Akt/mTOR activity was significantly reduced after tendon rupture, but increased after nerve injury. MuRF-1 and MAFbx were only up-regulated following denervation. These results suggest that tendon transection leads to a decrease in protein synthesis with down-regulation of the Akt/mTOR signaling pathway, whereas denervation leads to an increase in protein degradation via up-regulation of expression of MuRF-1 and MAFbx. (C) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:14401446, 2012 C1 [Liu, Xuhui; Joshi, Sunil K.; Dang, Yu-Xuan; Lovett, David H.; Kim, Hubert T.; Feeley, Brian T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Liu, Xuhui; Samagh, Sanjum P.; Laron, Dominique; Kim, Hubert T.; Feeley, Brian T.] Univ Calif San Francisco, Dept Orthoped Surg, San Francisco, CA 94143 USA. [Lovett, David H.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Bodine, Sue C.] Univ Calif Davis, Dept Physiol & Membrane Biol, Davis, CA 95616 USA. RP Feeley, BT (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. EM feeleyb@orthosurg.ucsf.edu FU Orthopaedic Research & Education Foundation (OREF); VA RRD [RX000195] FX This work was supported by the Orthopaedic Research & Education Foundation (OREF) and VA RR&D (grant #: RX000195). NR 24 TC 15 Z9 15 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD SEP PY 2012 VL 30 IS 9 BP 1440 EP 1446 DI 10.1002/jor.22096 PG 7 WC Orthopedics SC Orthopedics GA 972WH UT WOS:000306311400013 PM 22378614 ER PT J AU Hasserjian, RP Preffer, FI AF Hasserjian, Robert P. Preffer, Frederic I. TI Flow cytometry to distinguish myelodysplastic syndromes from non-neoplastic causes of cytopenia: Ready for prime time? SO LEUKEMIA RESEARCH LA English DT Editorial Material DE Myelodysplastic syndrome; Therapy-related; Flow cytometry; Cytopenia; Chemotherapy ID BONE-MARROW; MUTATIONS; DYSPLASIA; CELLS C1 [Hasserjian, Robert P.; Preffer, Frederic I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hasserjian, RP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM rhasserjian@partners.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2012 VL 36 IS 9 BP 1089 EP 1090 DI 10.1016/j.leukres.2012.03.029 PG 2 WC Oncology; Hematology SC Oncology; Hematology GA 975PP UT WOS:000306523600010 PM 22727507 ER PT J AU George, RE Perez-Atayde, AR Yao, XP London, WB Shamberger, RC Neuberg, D Diller, L AF George, Rani E. Perez-Atayde, Antonio R. Yao, Xiaopan London, Wendy B. Shamberger, Robert C. Neuberg, Donna Diller, Lisa TI Tumor histology during induction therapy in patients with high-risk neuroblastoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE histology; induction; mitosis; neuroblastoma; persistent neuroblastic cells ID BONE-MARROW-TRANSPLANTATION; SCHWANNIAN STROMA-POOR; STAGE-IV NEUROBLASTOMA; HIGH-DOSE THERAPY; PATHOLOGY CLASSIFICATION; PROGNOSTIC-FACTORS; UNSELECTED GROUP; SURVIVAL; CHEMOTHERAPY; DIAGNOSIS AB Background In high-risk neuroblastoma patients, response to induction chemotherapy is emerging as an important determinant of overall survival. We sought to determine whether histological changes in the primary tumor following induction therapy could be used as a marker of response. Procedure Second-look primary tumor specimens from 43 patients were reviewed according to specific morphological features. Results In the majority, induction therapy resulted in a shift from an intermediate/high to low mitosis-karyorrhexis index (MKI) (P?=?0.0009) and from undifferentiated/poorly differentiated to differentiating tumors (P? C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-kappa B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenstrom's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced I kappa B alpha and NF-kappa B p65 phosphorylation, as well as NF-kappa B nuclear staining, in Waldenstrom's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2. CONCLUSIONS MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom's macroglobulinemia that can be useful in differentiating Waldenstrom's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.) C1 [Treon, Steven P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Pinkus, Geraldine S.; Rodig, Scott J.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. [Sohani, Aliyah R.; Harris, Nancy Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Hunter, Zachary R.] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. [Arcaini, Luca] Univ Pavia, Sch Med, Dept Hematol Oncol, I-27100 Pavia, Italy. [Arcaini, Luca] Policlin San Matteo, Fdn Ist Ricovero & Cura Carattere Sci IRCCS, I-27100 Pavia, Italy. [Laramie, Jason M.; Skifter, Donald A.; Lincoln, Stephen E.] Complete Genom, Mountain View, CA USA. RP Treon, SP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,450 Brookline Ave, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013; Arcaini, Luca/P-8913-2015 OI Hunter, Zachary/0000-0002-1689-1691; Arcaini, Luca/0000-0002-9504-991X FU Peter and Helen Bing Foundation; International Waldenstrom's Macroglobulinemia Foundation; Coyote Fund for Waldenstrom's Macroglobulinemia; Waldenstrom's Cancer Fund; Bailey Family Fund for Waldenstrom's Macroglobulinemia; D'Amato Family Fund for Genomic Discovery; Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research; Bauman Family Trust; Tannenhauser Family Foundation FX Funded by the Peter and Helen Bing Foundation and others.; Supported by the Peter and Helen Bing Foundation, the International Waldenstrom's Macroglobulinemia Foundation, the Coyote Fund for Waldenstrom's Macroglobulinemia, the Waldenstrom's Cancer Fund, the Bailey Family Fund for Waldenstrom's Macroglobulinemia, the D'Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for Waldenstrom's Macroglobulinemia Research, the Bauman Family Trust, and the Tannenhauser Family Foundation. NR 35 TC 327 Z9 344 U1 1 U2 21 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 AUG 30 PY 2012 VL 367 IS 9 BP 826 EP 833 DI 10.1056/NEJMoa1200710 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 996EN UT WOS:000308067400004 PM 22931316 ER PT J AU Byrne, TN Isakoff, SJ Rincon, SP Gudewicz, TM AF Byrne, Thomas N. Isakoff, Steven Jay Rincon, Sandra P. Gudewicz, Thomas M. TI Case 27-2012: A 60-Year-Old Woman with Painful Muscle Spasms and Hyperreflexia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STIFF-PERSON SYNDROME; PRIMARY BREAST-CANCER; AMPHIPHYSIN; CARCINOMA; METASTASES; ANTIBODIES C1 [Byrne, Thomas N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Isakoff, Steven Jay] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Rincon, Sandra P.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Gudewicz, Thomas M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Byrne, Thomas N.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Isakoff, Steven Jay] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Rincon, Sandra P.] Harvard Univ, Sch Med, Dept Neuroradiol, Boston, MA 02115 USA. [Gudewicz, Thomas M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Byrne, TN (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 21 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 30 PY 2012 VL 367 IS 9 BP 851 EP 861 DI 10.1056/NEJMcpc1114036 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 996EN UT WOS:000308067400009 PM 22931320 ER PT J AU Barth, RF Vicente, MGH Harling, OK Kiger, WS Riley, KJ Binns, PJ Wagner, FM Suzuki, M Aihara, T Kato, I Kawabata, S AF Barth, Rolf F. Vicente, M. Graca H. Harling, Otto K. Kiger, W. S., III Riley, Kent J. Binns, Peter J. Wagner, Franz M. Suzuki, Minoru Aihara, Teruhito Kato, Itsuro Kawabata, Shinji TI Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer SO RADIATION ONCOLOGY LA English DT Review DE Boron neutron capture therapy; Gliomas; Head and neck cancer; Radiation therapy ID NEWLY-DIAGNOSED GLIOBLASTOMA; INTERNATIONAL DOSIMETRY EXCHANGE; EPIDERMAL-GROWTH-FACTOR; CERVICAL LYMPH-NODE; TSUKUBA BNCT TRIAL; I CLINICAL-TRIAL; EPITHERMAL NEUTRON; BRAIN-TUMORS; AMINO-ACIDS; COMPUTATIONAL DOSIMETRY AB Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 mu g/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options. C1 [Barth, Rolf F.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Vicente, M. Graca H.] Louisiana State Univ, Dept Chem, Baton Rouge, LA 70803 USA. [Harling, Otto K.] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. [Kiger, W. S., III] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Riley, Kent J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Binns, Peter J.] Mt Auburn Hosp, Dept Radiat Oncol, Cambridge, MA 02138 USA. [Wagner, Franz M.] Tech Univ Munich, Forsch Neutronenquelle Heinz Maier Leibnitz FRM 2, D-8046 Garching, Germany. [Suzuki, Minoru] Kyoto Univ, Particle Radiat Oncol Res Ctr, Osaka, Japan. [Aihara, Teruhito] Kawasaki Med Univ, Dept Otolaryngol & Head & Neck Surg, Okayama, Japan. [Kato, Itsuro] Osaka Univ, Grad Sch Dent, Dept Oral & Maxillofacial Surg 2, Osaka, Japan. [Kawabata, Shinji] Osaka Med Coll, Dept Neurosurg, Takatsuki, Osaka 569, Japan. RP Barth, RF (reprint author), Ohio State Univ, Dept Pathol, 165 Hamilton Hall,1645 Neil Ave, Columbus, OH 43210 USA. EM rolf.barth@osumc.edu FU United States Department of Energy; National Institutes of Health; Ministry of Health, Labor and Welfare (MONBUSHO) from the government of Japan; BNCT Committee of Kyoto University Research Reactor Institute, Japan Atomic Energy Agency FX This paper is dedicated to Professor Emeritus Albert H. Soloway in celebration of his 87th birthday. Dr. Barth thanks Mrs. Heidi Bosworth for expert secretarial assistance in the preparation of this manuscript. Research of Drs. Barth, Binns, Harling, Kiger, Riley and Vicente has been supported by numerous grants from the United States Department of Energy and the National Institutes of Health. Animal studies described in this review were carried out under protocols approved by the respective Institutional Animal Care and Use Committees and in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Dr. Kawabata's clinical studies have been supported by grants from the Ministry of Health, Labor and Welfare (MONBUSHO) from the government of Japan and were approved by the Ethical Committee of Osaka Medical College (No. 98, 218, 260) and by the BNCT Committee of Kyoto University Research Reactor Institute, Japan Atomic Energy Agency. Clinical studies that were carried out at Osaka University, Department of Oral and Maxillofacial Surgery II, were approved by the Ethics Committee of Osaka University Dental Hospital under approved Protocol H19-C1. Clinical studies carried out at Kawasaki Medical School, Okayama, Japan, were approved by the Institutional Ethical Committee. NR 127 TC 64 Z9 66 U1 4 U2 71 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD AUG 29 PY 2012 VL 7 AR 146 DI 10.1186/1748-717X-7-146 PG 21 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 007UN UT WOS:000308914000001 PM 22929110 ER PT J AU Karmacharya, D Yu, DM Dixit, S Rajbhandari, R Subedi, B Shrestha, S Manandhar, S Santangelo, SL AF Karmacharya, Dibesh Yu, Dongmei Dixit, Sameer Rajbhandari, Rajesh Subedi, Bhawana Shrestha, Sonu Manandhar, Sulochana Santangelo, Susan L. TI A study of the prevalence and risk factors leading to HIV infection among a sample of street children and youth of Kathmandu SO AIDS RESEARCH AND THERAPY LA English DT Article DE HIV prevalence; Behavioural risk factors; Intravenous drug use; Street children; Kathmandu; Nepal ID SEROPREVALENCE; DRUG; SEX AB Background: The true prevalence of HIV and other sexually transmitted diseases among street children in Nepal is virtually unknown while information on related behavioural risk factors in this population is non-existent. The risk of HIV infection among street children and adolescents may be especially high due to their marginalized social and economic conditions. This study was conducted to determine the prevalence of HIV infection among a sample of street children and youth of Kathmandu and to identify risk factors associated with HIV infection in this group. A sample of street children and youth was recruited based on the purposive sampling of ten streets in Kathmandu, Nepal, known to have a high density of street children and youth. A total of 251 street children (aged 11-16 years) and youth (aged 17-24 years) were enrolled, with informed consent, from November, 2008 through June, 2009. Most of the participants (95%) were male. Case status was determined by serological assessment of HIV status; data on risk factors were obtained using structured survey interviews. HIV prevalence and rates of a number of behavioural risk factors suspected to play a role in HIV transmission among street children and youth were determined, including unprotected sex, intravenous drug use, and other risky sex and substance use behaviours. Results: Among the 251 children and youth, we found an overall HIV prevalence of 7.6%. As the sample size of females was small (n = 13) and the behavioural risk factors are likely to be quite different for boys and girls, we conducted separate analyses by gender. As our small sample of females is unlikely to be representative and lacks power for statistical testing, our report focuses on the results for the males surveyed. The strongest behavioural risk factor to emerge from this study was intravenous drug use; 30% of the male subjects were injecting drug users and 20% of those were HIV positive. Furthermore, frequency of drug injection was a highly significant predictor with a dose-response relationship; males reporting occasional injection drug use were nearly 9 times more likely to be HIV positive than never users, while weekly drug injectors had over 46 times the risk of non-users, controlling for exposure to group sex, the only other significant risk factor in the multivariate model. Conclusions: This sample of street children and youth of Kathmandu has a nearly 20-fold higher prevalence of HIV infection than the general population of Nepal (0.39%). The children and youth engage in number of high risk behaviours, including intravenous drug use, putting them at significant risk of contracting HIV and other sexually transmitted infections. C1 [Karmacharya, Dibesh; Dixit, Sameer; Rajbhandari, Rajesh; Subedi, Bhawana; Shrestha, Sonu; Manandhar, Sulochana] Ctr Mol Dynam Nepal, Kathmandu, Nepal. [Yu, Dongmei; Santangelo, Susan L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Santangelo, Susan L.] Harvard Univ, Sch Publ Hlth, Sch Med, Boston, MA 02115 USA. RP Karmacharya, D (reprint author), Ctr Mol Dynam Nepal, Thapathali 11, Kathmandu, Nepal. EM dibesh@cmdn.org FU NRN (Non-Nepalese Residents) Community of North America; Friends of Nepal-Los Angeles, Friends of Nepal-New Jersey; UNICEF/Nepal; District AIDS Coordination Committee (DACC) of Kathmandu City FX This study was supported by financial contributions from the NRN (Non-Nepalese Residents) Community of North America, Friends of Nepal-Los Angeles, Friends of Nepal-New Jersey and UNICEF/Nepal. We will be forever grateful for their support, and for the participation of the street children and youth of Kathmandu, without which this study would not have been possible. We would also like to thank the District AIDS Coordination Committee (DACC) of Kathmandu City for their support, the National Center for AIDS and STD Control (NCASC) for technical and logistical support and all the stakeholders that are involved in the fight against HIV/AIDS in Nepal. We would also like to thank Ms. Rupa Sharma of the Arkansas Department of Health (USA) and Mr. Ganesh Sharma for their valuable input on the study design and analysis. NR 15 TC 4 Z9 4 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD AUG 28 PY 2012 VL 9 AR 25 DI 10.1186/1742-6405-9-25 PG 7 WC Infectious Diseases SC Infectious Diseases GA 072UX UT WOS:000313699800001 PM 22929124 ER PT J AU Campos, F Perez-Mato, M Agulla, J Blanco, M Barral, D Almeida, A Brea, D Waeber, C Castillo, J Ramos-Cabrer, P AF Campos, Francisco Perez-Mato, Maria Agulla, Jesus Blanco, Miguel Barral, David Almeida, Angeles Brea, David Waeber, Christian Castillo, Jose Ramos-Cabrer, Pedro TI Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke SO PLOS ONE LA English DT Article ID ACUTE ISCHEMIC-STROKE; FOCAL CEREBRAL-ISCHEMIA; MILD HYPOTHERMIA; BLOOD-FLOW; RAT-BRAIN; OXALOACETATE; METABOLISM; LACTATE; SPECTROSCOPY; COMBINATION AB Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33 degrees C, normothermia at 37 degrees C and hyperthermia at 39 degrees C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke. C1 [Campos, Francisco; Perez-Mato, Maria; Agulla, Jesus; Blanco, Miguel; Barral, David; Brea, David; Castillo, Jose; Ramos-Cabrer, Pedro] Univ Santiago de Compostela, IDIS, Hosp Univ Santiago, Clin Neurosci Res Lab,Dept Neurol, Santiago De Compostela, Spain. [Almeida, Angeles] Hosp Univ Salamanca, Res Unit, Salamanca, Spain. [Almeida, Angeles] Inst Hlth Sci Castilla & Leon, Salamanca, Spain. [Almeida, Angeles] Univ Salamanca, Dept Biochem & Mol Biol, E-37008 Salamanca, Spain. [Waeber, Christian] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. RP Campos, F (reprint author), Univ Santiago de Compostela, IDIS, Hosp Univ Santiago, Clin Neurosci Res Lab,Dept Neurol, Santiago De Compostela, Spain. EM francampos@linc-stg.eu; pedro.ramos@usc.es RI Waeber, Christian/A-8333-2009; Brea Lopez, David/M-1128-2015; Ramos-Cabrer, Pedro/J-5306-2014; OI Waeber, Christian/0000-0001-6078-0027; Brea Lopez, David/0000-0003-2365-7374; Ramos-Cabrer, Pedro/0000-0003-0368-7031; Castillo, Jose/0000-0002-6685-3001 FU Spanish Ministry of Science and Innovation [SAF2011-30517]; Fondo de Investigaciones Sanitarias, Instituto Salud Carlos III [RETICS-RD06/0026]; Xunta de Galicia (Conselleria de Innovacion, Industria e Comercio) [09CSA057918PR]; Xunta de Galicia (Conselleria de Sanidade) [PS09/32]; Xunta de Galicia (Fundacion Mutua Madrilena); Red de Investigacion Cooperativa Neurovascular FX This project has been partially supported by grants from the Spanish Ministry of Science and Innovation SAF2011-30517 and Fondo de Investigaciones Sanitarias, Instituto Salud Carlos III, RETICS-RD06/0026; Xunta de Galicia (Conselleria de Innovacion, Industria e Comercio: 09CSA057918PR; Conselleria de Sanidade: PS09/32 and; Fundacion Mutua Madrilena and by Red de Investigacion Cooperativa Neurovascular. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 18 Z9 20 U1 1 U2 7 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 AUG 28 PY 2012 VL 7 IS 8 AR e44191 DI 10.1371/journal.pone.0044191 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600090 PM 22952923 ER PT J AU Huang, S Belliveau, JW Tengshe, C Ahveninen, J AF Huang, Samantha Belliveau, John W. Tengshe, Chinmayi Ahveninen, Jyrki TI Brain Networks of Novelty-Driven Involuntary and Cued Voluntary Auditory Attention Shifting SO PLOS ONE LA English DT Article ID EVENT-RELATED FMRI; MEDIAL FRONTAL-CORTEX; SCALE NEURAL-NETWORK; SPATIAL ATTENTION; MISMATCH NEGATIVITY; CORTICAL NETWORK; PREFRONTAL CORTEX; PARIETAL CORTEX; ACOUSTIC NOISE; INCREASED DISTRACTIBILITY AB In everyday life, we need a capacity to flexibly shift attention between alternative sound sources. However, relatively little work has been done to elucidate the mechanisms of attention shifting in the auditory domain. Here, we used a mixed event-related/sparse-sampling fMRI approach to investigate this essential cognitive function. In each 10-sec trial, subjects were instructed to wait for an auditory "cue" signaling the location where a subsequent "target" sound was likely to be presented. The target was occasionally replaced by an unexpected "novel" sound in the uncued ear, to trigger involuntary attention shifting. To maximize the attention effects, cues, targets, and novels were embedded within dichotic 800-Hz vs. 1500-Hz pure-tone "standard" trains. The sound of clustered fMRI acquisition (starting at t = 7.82 sec) served as a controlled trial-end signal. Our approach revealed notable activation differences between the conditions. Cued voluntary attention shifting activated the superior intra-parietal sulcus (IPS), whereas novelty-triggered involuntary orienting activated the inferior IPS and certain subareas of the precuneus. Clearly more widespread activations were observed during voluntary than involuntary orienting in the premotor cortex, including the frontal eye fields. Moreover, we found -evidence for a frontoinsular-cingular attentional control network, consisting of the anterior insula, inferior frontal cortex, and medial frontal cortices, which were activated during both target discrimination and voluntary attention shifting. Finally, novels and targets activated much wider areas of superior temporal auditory cortices than shifting cues. C1 [Huang, Samantha; Belliveau, John W.; Tengshe, Chinmayi; Ahveninen, Jyrki] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Belliveau, John W.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Huang, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM samhuang@nmr.mgh.harvard.edu FU National Institutes of Health [R01MH083744, R21DC010060, R01HD040712, R01NS037462, P41RR14075]; [S10RR014978]; [S10RR021110]; [S10RR019307]; [S10RR023401] FX This work was supported by National Institutes of Health awards R01MH083744, R21DC010060, R01HD040712, R01NS037462, and P41RR14075. The research environment was supported by Shared Instrumentation grants S10RR014978, S10RR021110, S10RR019307, and S10RR023401. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 115 TC 24 Z9 24 U1 2 U2 17 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 AUG 28 PY 2012 VL 7 IS 8 AR e44062 DI 10.1371/journal.pone.0044062 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998CA UT WOS:000308213600073 PM 22937153 ER PT J AU Lage, K Greenway, SC Rosenfeld, JA Wakimoto, H Gorham, JM Segre, AV Roberts, AE Smoot, LB Pu, WT Pereira, AC Mesquita, SM Tommerup, N Brunak, S Ballif, BC Shaffer, LG Donahoe, PK Daly, MJ Seidman, JG Seidman, CE Larsen, LA AF Lage, Kasper Greenway, Steven C. Rosenfeld, Jill A. Wakimoto, Hiroko Gorham, Joshua M. Segre, Ayellet V. Roberts, Amy E. Smoot, Leslie B. Pu, William T. Pereira, Alexandre C. Mesquita, Sonia M. Tommerup, Niels Brunak, Soren Ballif, Blake C. Shaffer, Lisa G. Donahoe, Patricia K. Daly, Mark J. Seidman, Jonathan G. Seidman, Christine E. Larsen, Lars A. TI Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetics; transcriptional profiles; systems biology; developmental biology ID DE-NOVO MUTATIONS; EXPRESSION; DISORDERS; MORPHOGENESIS; COMPLEXES; SPECTRUM; DEFECTS; MODEL; GATA4 AB Congenital heart disease (CHD) occurs in similar to 1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development. C1 [Lage, Kasper; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Roberts, Amy E.; Smoot, Leslie B.; Pu, William T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Lage, Kasper; Donahoe, Patricia K.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Greenway, Steven C.; Wakimoto, Hiroko; Gorham, Joshua M.; Seidman, Jonathan G.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Daly, Mark J.; Seidman, Christine E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Seidman, Christine E.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Lage, Kasper; Segre, Ayellet V.; Donahoe, Patricia K.; Daly, Mark J.] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA. [Lage, Kasper; Brunak, Soren] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Lage, Kasper; Segre, Ayellet V.; Donahoe, Patricia K.; Daly, Mark J.] Univ Copenhagen, Ctr Prot Res, Fac Hlth Sci, DK-2200 Copenhagen, Denmark. [Rosenfeld, Jill A.; Ballif, Blake C.; Shaffer, Lisa G.] PerkinElmer Inc, Signature Genom Labs, Spokane, WA 99207 USA. [Wakimoto, Hiroko; Segre, Ayellet V.] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Roberts, Amy E.] Partners HealthCare Ctr Genet & Genom, Boston, MA 02139 USA. [Pu, William T.; Donahoe, Patricia K.] Harvard Stem Cell Inst, Boston, MA 02138 USA. [Smoot, Leslie B.; Pereira, Alexandre C.; Mesquita, Sonia M.] Univ Sao Paulo, Sch Med, Heart Inst InCor, Lab Genet & Mol Cardiol, BR-05403000 Sao Paulo, Brazil. [Tommerup, Niels; Larsen, Lars A.] Univ Copenhagen, Dept Cellular & Mol Med, Wilhelm Johannsen Ctr Funct Genome Res, DK-2200 Copenhagen, Denmark. RP Lage, K (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. EM lage.kasper@mgh.harvard.edu; cseidman@genetics.med.harvard.edu; larsal@sund.ku.dk FU Danish Heart Foundation; Forskningsradet for Sundhed og Sygdom; Eleanor and Miles Shore Fellowship; Pediatric Scientist Developmental Program; National Institutes of Health [NICHD HD055150-03, 1P01HD068250-01, NHLBI UO1 HL098166, U01 HL098147]; Howard Hughes Medical Institute FX This work was supported by grants from the Danish Heart Foundation (L.A.L.), Forskningsradet for Sundhed og Sygdom and the Eleanor and Miles Shore Fellowship (K.L.), the Pediatric Scientist Developmental Program (S.C.G.), the National Institutes of Health (NICHD HD055150-03 and 1P01HD068250-01 to K.L. and P.K.D. and NHLBI UO1 HL098166 and U01 HL098147 to A.E.R., W.T.P., H.W., J.M.G., C.E.S. and J.G.S.), and the Howard Hughes Medical Institute (C.E.S). NR 28 TC 32 Z9 33 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 AUG 28 PY 2012 VL 109 IS 35 BP 14035 EP 14040 DI 10.1073/pnas.1210730109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300038 PM 22904188 ER PT J AU Larman, TC DePalma, SR Hadjipanayis, AG Protopopov, A Zhang, JH Gabriel, SB Chin, L Seidman, CE Kucherlapati, R Seidman, JG AF Larman, Tatianna C. DePalma, Steven R. Hadjipanayis, Angela G. Protopopov, Alexei Zhang, Jianhua Gabriel, Stacey B. Chin, Lynda Seidman, Christine E. Kucherlapati, Raju Seidman, J. G. CA Canc Genome Atlas Res Network TI Spectrum of somatic mitochondrial mutations in five cancers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deleterious mutations; colon adenocarcinoma; rectal adenomcarcinoma; acute myeloid leukemia; ovarian serous cystadenocarcinoma ID DNA MUTATIONS; CELL-METABOLISM; GENOME; SELECTION; DISEASE; TUMORS; MTDNA; DEHYDROGENASE; GENERATION; PROSTATE AB Somatic mtDNA mutations have been reported in some human tumors, but their spectrum in different malignancies and their role in cancer development remain incompletely understood. Here, we describe the breadth of somatic and inherited mutations across the mitochondrial genome by sequence analyses of paired tumor and normal tissue samples from 226 individuals with five types of cancer using whole-genome data generated by The Cancer Genome Atlas Research Network. The frequencies of deleterious tumor-specific somatic mutations found in mtDNA varied across tumor types, ranging from 13% of glioblastomas to 63% of rectal adenocarcinomas. Compared with inherited mtDNA variants, somatic mtDNA mutations were enriched for nonsynonymous vs. synonymous changes (93 vs. 15; P < 2.2E-16) and were predicted to functionally impact the encoded protein. Somatic missense mutations in tumors were distributed uniformly among the mitochondrial protein genes, but 65% of somatic truncating mutations occurred in NADH dehydrogenase 5. Analysis of staging data in colon and rectal cancers revealed that the frequency of damaging mitochondrial mutations is the same in stages I and IV tumors. In summary, these data suggest that damaging somatic mtDNA mutations occur frequently (13-63%) in these five tumor types and likely confer a selective advantage in oncogenesis. C1 [Larman, Tatianna C.; DePalma, Steven R.; Hadjipanayis, Angela G.; Seidman, Christine E.; Kucherlapati, Raju; Seidman, J. G.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Larman, Tatianna C.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Larman, Tatianna C.; DePalma, Steven R.; Seidman, Christine E.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Gabriel, Stacey B.] Broad Inst, Cambridge, MA 02142 USA. [Protopopov, Alexei; Zhang, Jianhua; Chin, Lynda] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Seidman, Christine E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Seidman, JG (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM seidman@genetics.med.harvard.edu FU Howard Hughes Medical Institute; National Cancer Institute, National Institutes of Health; LeDucq Foundation; National Heart, Lung and Blood Institute, National Institutes of Health; SysCODE FX We thank the genome sequencing centers at the Broad Institute, Washington University, and Baylor College of Medicine for sequencing data production. We also thank Kai Wang (Children's Hospital, Philadelphia) and Yevgeniy Antipin (Memorial Sloan-Kettering Cancer Center) for assistance with variant calling and computational analyses. Studies were supported by The Howard Hughes Medical Institute (T.C.L. and C.E.S.), National Cancer Institute, National Institutes of Health (T.C.L., R.K., and J.G.S.), LeDucq Foundation (C.E.S. and J.G.S.), National Heart, Lung and Blood Institute, National Institutes of Health (J.G.S.), and SysCODE (J.G.S.). NR 42 TC 63 Z9 64 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 AUG 28 PY 2012 VL 109 IS 35 BP 14087 EP 14091 DI 10.1073/pnas.1211502109 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300047 PM 22891333 ER PT J AU Fenton, TR Nathanson, D de Albuquerque, CP Kuga, D Iwanami, A Dang, J Yang, HJ Tanaka, K Oba-Shinjo, SM Uno, M Inda, MD Wykosky, J Bachoo, RM James, CD DePinho, RA Vandenberg, SR Zhou, HL Marie, SKN Mischel, PS Cavenee, WK Furnari, FB AF Fenton, Tim R. Nathanson, David de Albuquerque, Claudio Ponte Kuga, Daisuke Iwanami, Akio Dang, Julie Yang, Huijun Tanaka, Kazuhiro Oba-Shinjo, Sueli Mieko Uno, Miyuki Inda, Maria del Mar Wykosky, Jill Bachoo, Robert M. James, C. David DePinho, Ronald A. Vandenberg, Scott R. Zhou, Huilin Marie, Suely K. N. Mischel, Paul S. Cavenee, Webster K. Furnari, Frank B. TI Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glioma; phosphatase; erlotinib; gefitinib ID PROTEIN PHOSPHATASE-ACTIVITY; GROWTH-FACTOR RECEPTOR; TRASTUZUMAB RESISTANCE; FUNCTIONAL-ANALYSIS; CRYSTAL-STRUCTURE; MEK/ERK PATHWAY; NUCLEAR PTEN; IN-VIVO; GLIOMA; SRC AB Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM. C1 [Fenton, Tim R.; de Albuquerque, Claudio Ponte; Inda, Maria del Mar; Wykosky, Jill; Zhou, Huilin; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Cavenee, Webster K.; Furnari, Frank B.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Vandenberg, Scott R.; Furnari, Frank B.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Zhou, Huilin] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Nathanson, David; Mischel, Paul S.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Kuga, Daisuke; Iwanami, Akio; Dang, Julie; Yang, Huijun; Tanaka, Kazuhiro; Mischel, Paul S.] Univ Calif Los Angeles, Dept Pathol, Los Angeles, CA 90095 USA. [Oba-Shinjo, Sueli Mieko; Uno, Miyuki; Marie, Suely K. N.] Univ Sao Paulo, Sch Med, Dept Neurol, Sao Paulo, Brazil. [Bachoo, Robert M.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Bachoo, Robert M.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [James, C. David] Univ Calif San Francisco, Brain Tumor Res Ctr, Dept Neurol Surg, San Francisco, CA 94143 USA. [DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. RP Cavenee, WK (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM wcavenee@ucsd.edu; ffurnari@ucsd.edu RI Oba-Shinjo, Sueli /C-4017-2012; Marie, Suely/D-1870-2012; OI Fenton, Tim/0000-0002-4737-8233 FU Goldhirsh Foundation; National Institutes of Health [P01-CA95616, P50-CA097257]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Grant [04/12433-6] FX We thank Cameron Brennan (Memorial Sloan-Kettering Cancer Center) for the TS543 GBM tumor sphere line, Daniel Donoghue (University of California, San Diego) for the plasmid encoding FGFR3 K650E, Richard Kolodner (University of California, San Diego) and Rob de Bruin [Medical Research Council (MRC) Laboratory for Molecular Cell Biology, United Kingdom] for yeast reagents, and Stephen Henderson (University College London, United Kingdom) for assistance with bioinformatics. This work was supported by an award from the Goldhirsh Foundation (to F.B.F.), National Institutes of Health Grants P01-CA95616 (to R.A.D., W.K.C., and F.B.F.) and P50-CA097257 (to C.D.J. and P.S.M.), and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Grant 04/12433-6 (to S.K.N.M). W.K.C. is a fellow of the National Foundation for Cancer Research. NR 45 TC 47 Z9 49 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 AUG 28 PY 2012 VL 109 IS 35 BP 14164 EP 14169 DI 10.1073/pnas.1211962109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300060 PM 22891331 ER PT J AU Baker, BM Shah, RP Silverstein, AM Esterhai, JL Burdick, JA Mauck, RL AF Baker, Brendon M. Shah, Roshan P. Silverstein, Amy M. Esterhai, John L. Burdick, Jason A. Mauck, Robert L. TI Sacrificial nanofibrous composites provide instruction without impediment and enable functional tissue formation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anisotropy; electrospinning; nanofiber; tissue engineering; meniscus fibrocartilage ID ENGINEERING SCAFFOLDS; ELECTROSPUN SCAFFOLDS; CELLULAR INFILTRATION; MENISCUS; ANISOTROPY; CELLS; ALIGNMENT; FIBERS; MATRIX; REPAIR AB The fibrous tissues prevalent throughout the body possess an ordered structure that underlies their refined and robust mechanical properties. Engineered replacements will require recapitulation of this exquisite architecture in three dimensions. Aligned nanofibrous scaffolds can dictate cell and matrix organization; however, their widespread application has been hindered by poor cell infiltration due to the tight packing of fibers during fabrication. Here, we develop and validate an enabling technology in which tunable composite nanofibrous scaffolds are produced to provide instruction without impediment. Composites were formed containing two distinct fiber fractions: slow-degrading poly(e-caprolactone) and water-soluble, sacrificial poly(ethylene oxide), which can be selectively removed to increase pore size. Increasing the initial fraction of sacrificial poly(ethylene oxide) fibers enhanced cell infiltration and improved matrix distribution. Despite the removal of >50% of the initial fibers, the remaining scaffold provided sufficient instruction to align cells and direct the formation of a highly organized ECM across multiple length scales, which in turn led to pronounced increases in the tensile properties of the engineered constructs (nearly matching native tissue). This approach transforms what is an interesting surface phenomenon (cells on top of nanofibrous mats) into a method by which functional, 3D tissues (>1 mm thick) can be formed, both in vitro and in vivo. As such, this work represents a marked advance in the engineering of load-bearing fibrous tissues, and will find widespread applications in regenerative medicine. C1 [Baker, Brendon M.; Shah, Roshan P.; Silverstein, Amy M.; Esterhai, John L.; Mauck, Robert L.] Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. [Baker, Brendon M.; Silverstein, Amy M.; Burdick, Jason A.; Mauck, Robert L.] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Esterhai, John L.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Mauck, RL (reprint author), Univ Penn, McKay Orthopaed Res Lab, Dept Orthopaed Surg, Perelman Sch Med, Philadelphia, PA 19104 USA. EM lemauck@mail.med.upenn.edu FU National Institutes of Health [R01 AR056624]; Department of Veterans Affairs [I01 RX000174]; National Science Foundation FX This work was supported by National Institutes of Health Grant R01 AR056624 and Department of Veterans Affairs Grant I01 RX000174. 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. Additional support was provided by the Penn Center for Musculoskeletal Disorders and a National Science Foundation Graduate Research Fellowship (to B.M.B.). NR 33 TC 55 Z9 55 U1 4 U2 56 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 AUG 28 PY 2012 VL 109 IS 35 BP 14176 EP 14181 DI 10.1073/pnas.1206962109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 002VP UT WOS:000308565300062 PM 22872864 ER PT J AU Wu, SM Milan, DJ AF Wu, Sean M. Milan, David J. TI Reprogramming the Beat Kicking It Up a Notch SO CIRCULATION LA English DT Editorial Material ID CARDIAC CONDUCTION SYSTEM; PURKINJE-FIBER DIFFERENTIATION; ENDOTHELIN-CONVERTING ENZYME-1; CONGENITAL HEART-DISEASE; EMBRYONIC STEM-CELLS; IN-VIVO; DEFINED FACTORS; DIRECT CONVERSION; HUMAN FIBROBLASTS; CARDIOMYOCYTES C1 [Milan, David J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Cambridge, MA USA. [Wu, Sean M.] Harvard Stem Cell Inst, Cambridge, MA USA. [Wu, Sean M.; Milan, David J.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Cardiovasc Res Ctr, Cambridge, MA USA. RP Milan, DJ (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Dept Med, 55 Fruit St, Boston, MA 02115 USA. EM DMilan@Partners.org FU NHLBI NIH HHS [U01 HL100408, HL109004, U01 HL099776, R01 HL109004, HL100408]; NIDA NIH HHS [R21 DA026982, DA026982]; NIH HHS [OD004411, DP2 OD004411] NR 38 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP 1009 EP 1011 DI 10.1161/CIRCULATIONAHA.112.126482 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100008 PM 22837161 ER PT J AU Kiefer, FW Cohen, P Plutzky, J AF Kiefer, Florian W. Cohen, Paul Plutzky, Jorge TI Fifty Shades of Brown Perivascular Fat, Thermogenesis, and Atherosclerosis SO CIRCULATION LA English DT Editorial Material DE Editorials; adipose tissue, brown; muscle, smooth; obesity; peroxisome proliferator-activated receptors; thermogenesis; atherosclerosis; adipose tissue, white ID ADIPOSE-TISSUE; CARDIOVASCULAR-DISEASE; INFLAMMATION; COLD; ADIPOCYTES; HUMANS; MOUSE; MEN C1 [Kiefer, Florian W.; Cohen, Paul; Plutzky, Jorge] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kiefer, Florian W.; Cohen, Paul; Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiovasc, Vasc Dis Prevent Program, Boston, MA 02115 USA. [Cohen, Paul] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Plutzky, J (reprint author), Harvard Univ, Sch Med, 77 Ave Louis Pasteur,NRB 742, Boston, MA 02115 USA. EM jplutzky@rics.bwh.harvard.edu FU Austrian Science Fund FWF [J 3107]; NHLBI NIH HHS [P01 HL048743, HL048743,]; NIAMS NIH HHS [AR0546040351]; NIDDK NIH HHS [5P30DK057521] NR 22 TC 7 Z9 7 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP 1012 EP 1015 DI 10.1161/CIRCULATIONAHA.112.123521 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100009 PM 22927471 ER PT J AU Bonaca, MP Wiviott, SD Braunwald, E Murphy, SA Ruff, CT Antman, EM Morrow, DA AF Bonaca, Marc P. Wiviott, Stephen D. Braunwald, Eugene Murphy, Sabina A. Ruff, Christian T. Antman, Elliott M. Morrow, David A. TI Response to Letter Regarding Articles, "Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II, ICTUS, and RITA-3 Trials (FIR)" and "American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation Universal Definition of Myocardial Infarction Classification System and the Risk of Cardiovascular Death: Observations From the TRITON-TIMI 38 Trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38)" SO CIRCULATION LA English DT Letter C1 [Bonaca, Marc P.; Wiviott, Stephen D.; Braunwald, Eugene; Murphy, Sabina A.; Ruff, Christian T.; Antman, Elliott M.; Morrow, David A.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Bonaca, MP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 28 PY 2012 VL 126 IS 9 BP E138 EP E138 DI 10.1161/CIRCULATIONAHA.112.114496 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 999ZK UT WOS:000308355100005 ER PT J AU Fellin, T Ellenbogen, JM De Pitta, M Ben-Jacob, E Halassa, MM AF Fellin, Tommaso Ellenbogen, Jeffery M. De Pitta, Maurizio Ben-Jacob, Eshel Halassa, Michael M. TI Astrocyte regulation of sleep circuits: experimental and modeling perspectives SO FRONTIERS IN COMPUTATIONAL NEUROSCIENCE LA English DT Review DE glia; astrocytes; sleep; ATP; adenosine; neuronal networks; slow oscillations; computational models ID SLOW-WAVE SLEEP; GLIAL TNF-ALPHA; IN-VIVO; D-SERINE; SYNAPTIC PLASTICITY; NMDA RECEPTORS; LOCAL SLEEP; NEURONAL EXCITABILITY; NETWORK MECHANISMS; THALAMIC NETWORKS AB Integrated within neural circuits, astrocytes have recently been shown to modulate brain rhythms thought to mediate sleep function. Experimental evidence suggests that local impact of astrocytes on single synapses translates into global modulation of neuronal networks and behavior. We discuss these findings in the context of current conceptual models of sleep generation and function, each of which have historically focused on neural mechanisms. We highlight the implications and the challenges introduced by these results from a conceptual and computational perspective. We further provide modeling directions on how these data might extend our knowledge of astrocytic properties and sleep function. Given our evolving understanding of how local cellular activities during sleep lead to functional outcomes for the brain, further mechanistic and theoretical understanding of astrocytic contribution to these dynamics will undoubtedly be of great basic and translational benefit. C1 [Fellin, Tommaso] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Ellenbogen, Jeffery M.] Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. [Ellenbogen, Jeffery M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [De Pitta, Maurizio; Ben-Jacob, Eshel] Tel Aviv Univ, Sch Phys & Astron, Ramat Aviv, Israel. [Ben-Jacob, Eshel] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA. [Halassa, Michael M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Halassa, Michael M.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Fellin, T (reprint author), Ist Italiano Tecnol, Dept Neurosci & Brain Technol, Via Morego 30, I-16163 Genoa, Italy. EM tommaso.fellin@iit.it; mhalassa@partners.org FU National Institute of Neurological Disorders and Stroke (NINDS) [K99 NS078115]; Telethon-Italy [GGP10138]; San Paolo "Programma in Neuroscienze"; FIRB [RBAP11X42L]; Tauber Family Fund; Maguy-Glass Chair in Physics of Complex Systems at Tel Aviv University FX We thank R. Beltramo and A. M. De Stasi for the pictures shown in Figure 1, and members of the Tommaso Fellin laboratory for helpful discussion. Maurizio De Pitta and Eshel Ben-Jacob are also grateful to H. Berry for insightful comments on modeling aspects discussed in this paper. This work was supported by K99 NS078115 from National Institute of Neurological Disorders and Stroke (NINDS) to Michael M. Halassa, Telethon-Italy (GGP10138), San Paolo "Programma in Neuroscienze" and FIRB (RBAP11X42L) to Tommaso Fellin, and the Tauber Family Fund and the Maguy-Glass Chair in Physics of Complex Systems at Tel Aviv University to Maurizio De Pitta and Eshel Ben-Jacob. NR 109 TC 10 Z9 10 U1 1 U2 17 PU FRONTIERS RES FOUND PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5188 J9 FRONT COMPUT NEUROSC JI Front. Comput. Neurosci. PD AUG 28 PY 2012 VL 6 AR 65 DI 10.3389/fncom.2012.00065 PG 10 WC Mathematical & Computational Biology; Neurosciences SC Mathematical & Computational Biology; Neurosciences & Neurology GA 995AK UT WOS:000307977700002 PM 22973222 ER PT J AU Ahmed, MI Aban, I Lloyd, SG Gupta, H Howard, G Inusah, S Peri, K Robinson, J Smith, P McGiffin, DC Schiros, CG Denney, T Dell'Italia, LJ AF Ahmed, Mustafa I. Aban, Inmaculada Lloyd, Steven G. Gupta, Himanshu Howard, George Inusah, Seidu Peri, Kalyani Robinson, Jessica Smith, Patty McGiffin, David C. Schiros, Chun G. Denney, Thomas, Jr. Dell'Italia, Louis J. TI A Randomized Controlled Phase IIb Trial of Beta(1)-Receptor Blockade for Chronic Degenerative Mitral Regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE beta blockade; medical therapy; mitral regurgitation; mitral valve disease ID CARDIAC-HYPERTROPHY; VOLUME-OVERLOAD; CARDIOCYTE; FRACTION; EJECTION; DOG AB Objectives The purpose of the study was to evaluate the effect of long-term beta(1)-aderergic receptor (AR) blockade on left ventricular (LV) remodeling and function in patients with chronic, isolated, degenerative mitral regurgitation (MR). Background Isolated MR currently has no proven therapy that attenuates LV remodeling or preserves systolic function. Methods Thirty-eight asymptomatic subjects with moderate to severe, isolated MR were randomized either to placebo or beta(1)-AR blockade (Toprol-XL, AstraZeneca, London, United Kingdom) for 2 years. Magnetic resonance imaging with tissue tagging and 3-dimensional analysis was performed at baseline and at 6-month intervals for 2 years. Rate of progression analysis was performed for endpoint variables for primary outcomes: LV end-diastolic volume/body surface area, LV ejection fraction, LV end-diastolic (ED) mass/ED volume ratio, LV ED 3-dimensional radius/wall thickness; LV end-systolic volume/body surface area, LV longitudinal strain rate, and LV early diastolic filling rate. Results Baseline LV magnetic resonance imaging or demographic variables did not differ between the 2 groups. Significant treatment effects were found on LV ejection fraction (p = 0.006) and LV early diastolic filling rate (p = 0.001), which decreased over time in untreated patients on an intention-to-treat analysis and remained significant after sensitivity analysis. There were no significant treatment effects found on LV ED or LV end-systolic volumes, LV ED mass/LV ED volume or LV ED 3-dimensional radius/wall thickness, or LV longitudinal strain rate. Over 2 years, 6 patients treated in the placebo group and 2 patients in the beta(1)-AR blockade group required mitral valve surgery (p = 0.23). Conclusions beta(1)-AR blockade improves LV function over a 2-year follow-up in isolated MR and provides the impetus for a large-scale clinical trial with clinical outcomes. (Molecular Mechanisms of Volume Overload-Aim 1 [SCCOR in Cardiac Dysfunction and Disease]; NCT01052428) (J Am Coll Cardiol 2012;60:833-8) (C) 2012 by the American College of Cardiology Foundation C1 [Dell'Italia, Louis J.] Univ Alabama Birmingham, Dept Med & Cardiovasc Dis, Div Cardiol, Birmingham, AL 35294 USA. [Aban, Inmaculada; Howard, George; Inusah, Seidu; Peri, Kalyani] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Lloyd, Steven G.; Gupta, Himanshu; Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [McGiffin, David C.] Univ Alabama Birmingham, Dept Cardiovasc Surg, Birmingham, AL 35294 USA. [Schiros, Chun G.; Denney, Thomas, Jr.] Auburn Univ, Samuel Ginn Coll Engn, Auburn, AL 36849 USA. RP Dell'Italia, LJ (reprint author), Univ Alabama Birmingham, Dept Med & Cardiovasc Dis, Div Cardiol, 901 19th St S,434 BMR2, Birmingham, AL 35294 USA. EM loudell@uab.edu FU National Heart, Lung and Blood Institute Specialized Center for Clinically Oriented Research (SCCOR) in Cardiac Dysfunction; National Institutes of Health, Bethesda, Maryland [P50HL077100] FX From the Department of Medicine and Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama; Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; Birmingham Veteran Affairs Medical Center, Birmingham, Alabama; Department of Cardiovascular Surgery, University of Alabama at Birmingham, Birmingham, Alabama; and the Samuel Ginn College of Engineering, Auburn University, Auburn, Alabama. This study was funded by the National Heart, Lung and Blood Institute Specialized Center for Clinically Oriented Research (SCCOR) in Cardiac Dysfunction, National Institutes of Health, Bethesda, Maryland (grant no.: P50HL077100). Drugs and placebos were supplied by AstraZeneca. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 19 TC 28 Z9 28 U1 1 U2 5 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 AUG 28 PY 2012 VL 60 IS 9 BP 833 EP 838 DI 10.1016/j.jacc.2012.04.029 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 997AY UT WOS:000308137600008 PM 22818065 ER PT J AU Abu-Yousif, AO Moor, ACE Zheng, X Savellano, MD Yu, WP Selbo, PK Hasan, T AF Abu-Yousif, Adnan O. Moor, Anne C. E. Zheng, Xiang Savellano, Mark D. Yu, Weiping Selbo, Pal K. Hasan, Tayyaba TI Epidermal growth factor receptor-targeted photosensitizer selectively inhibits EGFR signaling and induces targeted phototoxicity in ovarian cancer cells SO CANCER LETTERS LA English DT Article DE Ovarian cancer; Photodynamic therapy; Cetuximab; Verteporfin; Immunoconjugate ID DISSEMINATED INTRAPERITONEAL TUMORS; PHASE-II TRIAL; PHOTODYNAMIC THERAPY; IN-VIVO; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; DEBULKING SURGERY; MALIGNANT GLIOMA; CARCINOMA-CELLS; EX-VIVO AB Targeted photosensitizer delivery to EGFR-expressing cells was achieved in the present study using a high purity, targeted photoimmunoconjugate (PIC). When the PDT agent, benzoporphyrin derivative monoacid ring A (BPD) was coupled to an EGFR-targeting antibody (cetuximab), we observed altered cellular localization and selective phototoxicity of EGFR-positive cells, but no phototoxicity of EGFR-negative cells. Cetuximab in the PIC formulation blocked EGF-induced activation of the EGFR and downstream signaling pathways. Our results suggest that photoimmunotargeting is a useful dual strategy for the selective destruction of cancer cells and also exerts the receptor-blocking biological function of the antibody. (c) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Abu-Yousif, Adnan O.; Moor, Anne C. E.; Zheng, Xiang; Savellano, Mark D.; Yu, Weiping; Selbo, Pal K.; Hasan, Tayyaba] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. RP Hasan, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Bartlett Hall 314,40 Blossom St, Boston, MA 02114 USA. EM thasan@partners.org OI Selbo, Pal/0000-0002-5310-057X FU National Institutes of Health [RO1AR40352, 5R01CA160998, PO1CA84203]; Massachusetts Department of Public Health [34081126112]; Whitaker Foundation FX This study was supported by the National Institutes of Health Grant RO1AR40352, 5R01CA160998, PO1CA84203, a Grant from the Massachusetts Department of Public Health, (34081126112), and the Whitaker Foundation (MS). We thank Drs. Tara Heitner and James Marks (UCSF) for providing the transfected cell lines, and Drs. Jonathan P. Celli, Imran Rizvi, Klaas W. Mulder, Mr. Nathaniel Sznycer-Taub, and Ms. Divya Errabelli for superb technical advice. NR 58 TC 31 Z9 31 U1 0 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD AUG 28 PY 2012 VL 321 IS 2 BP 120 EP 127 DI 10.1016/j.canlet.2012.01.014 PG 8 WC Oncology SC Oncology GA 953UV UT WOS:000304899600003 PM 22266098 ER PT J AU Gaber, AO Matas, AJ Henry, ML Brennan, DC Stevens, RB Kapur, S Ilsley, JN Kistler, KD Cosimi, AB AF Gaber, A. Osama Matas, Arthur J. Henry, Mitchell L. Brennan, Daniel C. Stevens, R. Brian Kapur, Sandip Ilsley, Jillian N. Kistler, Kristen D. Cosimi, A. Benedict CA Thymoglobulin Antibody TI Antithymocyte Globulin Induction in Living Donor Renal Transplant Recipients: Final Report of the TAILOR Registry SO TRANSPLANTATION LA English DT Article DE Antithymocyte globulin; Immunosuppression; Live donor transplantation; Renal transplantation ID FREE MAINTENANCE IMMUNOSUPPRESSION; RANDOMIZED-TRIAL; CORTICOSTEROID CESSATION; KIDNEY-TRANSPLANTATION; ACUTE REJECTION; UNITED-STATES; THERAPY; THYMOGLOBULIN; CYCLOSPORINE; TACROLIMUS AB Background. The Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry was established to assess clinical experience with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant recipients. Methods. From 2003 to 2008, US transplant centers prospectively entered information on patients who received rATG induction. In addition to standard United Network for Organ Sharing registry data elements, information was collected regarding immunosuppression, viral prophylaxis, acute rejection, and adverse events. Results. Data on 2322 patients from 49 transplant centers were enrolled and met inclusion criteria for analysis. Patient and graft survival were 99.3% and 99.0% at 6 months and 98.4% and 98.2% at 12 months as recorded in Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry and were 91.5% and 83.2% at 5 years by Kaplan-Meier estimates based on linked United Network for Organ Sharing registry records. Freedom from rejection was 93.6% through 5 years. Mean rATG cumulative dose was 5.29 mg/kg. More than one-third of patients (37.6%) were steroid-free at discharge, and nearly half of patients (48%) were steroid-free at 12 months. Before discharge, 3.2% experienced serious adverse events, with 11 events (0.005%) reported as possibly or probably related to rATG. Incidence of cytomegalovirus infection was 4.2% at 12 months, and 99.1% of patients were posttransplant lymphoproliferative disorder-free through 5 years. Conclusions. rATG induction in living donor renal transplantation is safe and associated with a low incidence of acute rejection and posttransplantation complications. C1 [Gaber, A. Osama] Methodist Hosp Syst, Methodist Hosp Phys Org, Dept Surg, Weill Cornell Med Coll, Houston, TX 77030 USA. [Matas, Arthur J.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Henry, Mitchell L.] Ohio State Univ, Wexner Med Ctr, Div Transplantat, Columbus, OH 43210 USA. [Brennan, Daniel C.] Washington Univ, Sch Med, Dept Med, Barnes Jewish Hosp,Renal Div, St Louis, MO 63110 USA. [Stevens, R. Brian] Univ Nebraska Med Ctr, Dept Surg, Omaha, NE USA. [Kapur, Sandip] NewYork Presbyterian Hosp, Weill Cornell Med Ctr, Div Transplant Surg, New York, NY USA. [Ilsley, Jillian N.] Sanofi Rech, Med Affairs, Cambridge, MA USA. [Kistler, Kristen D.] United BioSource Corp, Lexington, MA USA. [Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. RP Gaber, AO (reprint author), Methodist Hosp Syst, Methodist Hosp Phys Org, Dept Surg, Weill Cornell Med Coll, 6550 Fannin St,Suite SM1661, Houston, TX 77030 USA. EM aogaber@tmhs.org FU Genzyme Corporation; Novartis; Wyeth; Astellas; Roche FX The authors did not receive financial support for their participation in article development. Enrolling centers received per patient funds to offset the costs associated with additional data entry beyond the requirements of the United Network for Organ Sharing. J.N.I. is an employee of Sanofi (formerly Genzyme Corporation). K. D. K. is an employee of United BioSource Corporation (formerly Prosanos Corporation), which has received research support and/or consulting fees from Genzyme Corporation. Authors declare receiving research support and consulting fees from Genzyme Corporation (A.J.M, M. L. H., D. C. B., R. B. S, and S. K.), Novartis (A.J.M, D. C. B, R. B. S, and M. L. H), Wyeth (A.O.G, A.J.M, D. C. B, R. B. S, and M. L. H.), Astellas (A.J.M and D. C. B.), and Roche (A.J.M, D. C. B, M. L. H). A. B. C. has no conflicts of interest to declare. NR 31 TC 13 Z9 14 U1 1 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 AUG 27 PY 2012 VL 94 IS 4 BP 331 EP 337 DI 10.1097/TP.0b013e31825a7d1f PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 997CE UT WOS:000308141000006 PM 22850297 ER PT J AU Schlenner, SM Weigmann, B Ruan, QG Chen, YH von Boehmer, H AF Schlenner, Susan M. Weigmann, Benno Ruan, Qingguo Chen, Youhai von Boehmer, Harald TI Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TGF-BETA; MEDIATED REGULATION; RETINOIC-ACID; EXPRESSION; MECHANISMS; GENE; DNA; GENERATION AB Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-beta-Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3(CNS1mut)). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut. C1 [Schlenner, Susan M.; von Boehmer, Harald] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Lab Lymphocyte Biol, Boston, MA 02115 USA. [Schlenner, Susan M.; von Boehmer, Harald] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Schlenner, Susan M.] Univ Leuven VIB, Dept Microbiol & Immunol, B-3000 Louvain, Belgium. [Weigmann, Benno] Univ Erlangen Nurnberg, Med Clin 1, D-91052 Erlangen, Germany. [Ruan, Qingguo; Chen, Youhai] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [von Boehmer, Harald] Harvard Univ, Harvard Fac Arts & Sci, Cambridge, MA 02138 USA. RP von Boehmer, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Lab Lymphocyte Biol, Boston, MA 02115 USA. EM harald_von_boehmer@dfci.harvard.edu FU National Institutes of Health [NIH-5R37AI053102-09]; German Research Foundation (DFG) [Schl 1897/1-1] FX This paper was supported by the National Institutes of Health (NIH-5R37AI053102-09 to H. von Boehmer) and the German Research Foundation (DFG, Schl 1897/1-1 to S.M. Schlenner). NR 26 TC 43 Z9 47 U1 2 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 27 PY 2012 VL 209 IS 9 BP 1529 EP 1535 DI 10.1084/jem.20112646 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 000XK UT WOS:000308423900002 PM 22908322 ER PT J AU Gupta, VA Kawahara, G Myers, JA Chen, AT Hall, TE Manzini, MC Currie, PD Zhou, Y Zon, LI Kunkel, LM Beggs, AH AF Gupta, Vandana A. Kawahara, Genri Myers, Jennifer A. Chen, Aye T. Hall, Thomas E. Manzini, M. Chiara Currie, Peter D. Zhou, Yi Zon, Leonard I. Kunkel, Louis M. Beggs, Alan H. TI A Splice Site Mutation in Laminin-alpha 2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish SO PLOS ONE LA English DT Article ID LAMININ ALPHA-2; LAMA2 GENE; MEROSIN; MODEL; MUTANT; POPULATION; PHENOTYPE; MICE AB Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-alpha 2 gene (LAMA2). Laminin-alpha 2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501), exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-alpha 2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha 2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD. C1 [Gupta, Vandana A.; Kawahara, Genri; Myers, Jennifer A.; Manzini, M. Chiara; Kunkel, Louis M.; Beggs, Alan H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Genom Program,Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Gupta, Vandana A.; Kawahara, Genri; Myers, Jennifer A.; Manzini, M. Chiara; Kunkel, Louis M.; Beggs, Alan H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Genet,Manton Ctr Orphan Dis Res, Boston, MA USA. [Chen, Aye T.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Chen, Aye T.; Zhou, Yi; Zon, Leonard I.] Harvard Univ, Sch Med, Boston Childrens Hosp, Stem Cell Program, Boston, MA USA. [Currie, Peter D.] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. [Zon, Leonard I.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA. RP Gupta, VA (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Genom Program,Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. EM beggs@enders.tch.harvard.edu RI Hall, Thomas/J-2125-2014 OI Hall, Thomas/0000-0002-7718-7614 FU Muscular Dystrophy Association [MDA201302]; National Institute of Health (NIH) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR044345]; Lee and Penny Anderson Family Foundation; William Randolph Hearst Fund; NIH from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [K01 AR062601-01]; National Institute of Child Health and Human Development [P30HD18655] FX This work was supported by the Muscular Dystrophy Association (MDA201302); National Institute of Health (NIH) grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR044345); by the Lee and Penny Anderson Family Foundation; and the William Randolph Hearst Fund. VAG was supported by NIH K01 AR062601-01 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. DNA sequencing was performed by the Children's Hospital Boston Genomics Program Molecular Genetics Core supported in part by National Institute of Child Health and Human Development grant (P30HD18655). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 15 Z9 15 U1 0 U2 9 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 AUG 27 PY 2012 VL 7 IS 8 AR e43794 DI 10.1371/journal.pone.0043794 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800060 PM 22952766 ER PT J AU Hulgan, T Robbins, GK Kalams, SA Samuels, DC Grady, B Shafer, R Murdock, DG Selph, D Haas, DW Pollard, RB AF Hulgan, Todd Robbins, Gregory K. Kalams, Spyros A. Samuels, David C. Grady, Benjamin Shafer, Robert Murdock, Deborah G. Selph, Doug Haas, David W. Pollard, Richard B. CA AIDS Clinical Trials Grp TI T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384 SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; BLOOD MONONUCLEAR-CELLS; SEQUENTIAL 3-DRUG REGIMENS; HIV-INFECTED PATIENTS; IMMUNE ACTIVATION; COUNT RECOVERY; IMMUNOLOGICAL SYNAPSE; PERIPHERAL NEUROPATHY; VIROLOGICAL RESPONSE; INITIAL THERAPY AB Introduction: Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup. Methods: ACTG 384 randomized ART-naive subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression. Results: Data from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (-4% vs. -11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naive-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells. Conclusions: Among ART-naive non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms. C1 [Hulgan, Todd; Kalams, Spyros A.; Samuels, David C.; Grady, Benjamin; Murdock, Deborah G.; Selph, Doug; Haas, David W.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Robbins, Gregory K.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shafer, Robert] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Pollard, Richard B.] Univ Calif Davis, Sacramento, CA 95817 USA. RP Hulgan, T (reprint author), Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. EM todd.hulgan@vanderbilt.edu RI Samuels, David/A-5393-2008; Murdock, Deborah/C-3483-2012; Samuels, David/C-1365-2012; Hulgan, Todd/B-3947-2014; Vella, Stefano/D-4912-2015 OI Samuels, David/0000-0003-3529-7791; Hulgan, Todd/0000-0002-3339-067X; Vella, Stefano/0000-0003-2347-5984 FU National Institutes of Health (NIH)/National Institute of Neurological Diseases and Stroke [NS059330]; National Institute of Allergy and Infectious Diseases [U01AI068636]; National Institute of Mental Health (NIMH); National Institute of Dental and Craniofacial Research (NIDCR); Agouron/Pfizer; Bristol Myers Squibb; GlaxoSmithKline; NIH [AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, AI32782, AI27661, AI25859, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853]; National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000445]; Merck; Gilead Sciences; Schering-Plough; Boehringer-Ingelheim; National Institutes of Health [AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI069502, AI069419, AI077505, AI54999, HL087726, AI69495, 5T32GM80178, AI062435]; [AI38858] FX Funding for the genomic sequencing was provided by the National Institutes of Health (NIH)/National Institute of Neurological Diseases and Stroke grant NS059330. The project described was also supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), and National Institute of Dental and Craniofacial Research (NIDCR). AIDS Clinical Trials Group (ACTG) Study 384 was also supported by grant AI38858, and by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. The ACTG sites contributing DNA for these analyses were funded by NIH grants AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, AI32782, AI27661, AI25859, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI069502, and AI069419. The ACTG Human DNA Repository is also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR000445. Additional NIH grant support included: AI077505, AI54999, HL087726, AI69495, 5T32GM80178 and AI062435. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have read the journal's policy and have the following conflicts: TH has received research support from Merck. GKR has received research support from Gilead Sciences, Schering-Plough. DWH has received research grants from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and Merck, and has served as a consultant for Boehringer-Ingelheim. AIDS Clinical Trials Group (ACTG) Study 384 was also supported in part by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 61 TC 2 Z9 2 U1 2 U2 11 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 AUG 27 PY 2012 VL 7 IS 8 AR e43803 DI 10.1371/journal.pone.0043803 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800061 PM 22970105 ER PT J AU Lechene, CP Lee, GY Poczatek, JC Toner, M Biggers, JD AF Lechene, Claude P. Lee, Gloria Y. Poczatek, J. Collin Toner, Mehmet Biggers, John D. TI 3D Multi-isotope Imaging Mass Spectrometry Reveals Penetration of O-18-Trehalose in Mouse Sperm Nucleus SO PLOS ONE LA English DT Article ID SPERMATOZOA; PORE; CELLS AB The prevalence of genetically engineered mice in medical research has led to ever increasing storage costs. Trehalose has a significant beneficial effect in preserving the developmental potential of mouse sperm following partial desiccation and storage at temperatures above freezing. Using multi-isotope imaging mass spectrometry, we are able to image and measure trehalose in individual spermatozoa. We provide the first evidence that trehalose penetrates the nucleus of a mammalian cell, permitting tolerance to desiccation. These results have broad implications for long-term storage of mammalian cells. C1 [Lechene, Claude P.; Poczatek, J. Collin] Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Lee, Gloria Y.; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Biggers, John D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Lechene, CP (reprint author), Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Cambridge, MA 02138 USA. EM cpl@harvard.edu FU NIH/NIBIB [5P41 EB001974-10]; NIH/NIA [1R21AG034641-01]; NIH/NCRR [5 R24 RR018934] FX This work was funded through the following grants: NIH/NIBIB 5P41 EB001974-10, NIH/NIA 1R21AG034641-01 and NIH/NCRR 5 R24 RR018934. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 8 Z9 8 U1 0 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 AUG 27 PY 2012 VL 7 IS 8 AR e42267 DI 10.1371/journal.pone.0042267 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 995WH UT WOS:000308044800006 PM 22952592 ER PT J AU Danzer, KM Kranich, LR Ruf, WP Cagsal-Getkin, O Winslow, AR Zhu, LY Vanderburg, CR McLean, PJ AF Danzer, Karin M. Kranich, Lisa R. Ruf, Wolfgang P. Cagsal-Getkin, Ozge Winslow, Ashley R. Zhu, Liya Vanderburg, Charles R. McLean, Pamela J. TI Exosomal cell-to-cell transmission of alpha synuclein oligomers SO MOLECULAR NEURODEGENERATION LA English DT Article DE Alpha synuclein; Oligomers; Exosomes; Parkinson's disease; Aggregation; Secretion ID CHAPERONE-MEDIATED AUTOPHAGY; PARKINSONS-DISEASE; NEURODEGENERATIVE DISORDERS; TRANSCRIPTION FACTOR; INCLUSION FORMATION; HUMAN MICRORNAS; EXPRESSION; PROTEIN; BODY; IDENTIFICATION AB Background: Aggregation of alpha-synuclein (asyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson's disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of asyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted asyn across membranes. The aim of this study is to characterize the transcellular spread of asyn oligomers and determine their extracellular location. Results: Using a novel protein fragment complementation assay where asyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that asyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated asyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free asyn oligomers. Specifically, we determine that asyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of asyn oligomers is strongly influenced by autophagic activity. Conclusions: Our data suggest that asyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of asyn oligomers is a mechanism whereby cells clear toxic asyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in asyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies. C1 [Danzer, Karin M.; Kranich, Lisa R.; Ruf, Wolfgang P.; Cagsal-Getkin, Ozge; Winslow, Ashley R.; Zhu, Liya; Vanderburg, Charles R.; McLean, Pamela J.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA USA. [Cagsal-Getkin, Ozge; Vanderburg, Charles R.] Harvard Univ, Sch Med, Harvard NeuroDiscovery Ctr, Adv Tissue Resource Ctr, Boston, MA USA. RP McLean, PJ (reprint author), Mayo Clin, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM mclean.pamela@mayo.edu FU NIH [NS063963] FX This work was supported by NIH NS063963 to PJM. We thank Harvard Medical School EM core for electron microscopy assistance. NR 105 TC 174 Z9 174 U1 6 U2 61 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 AUG 24 PY 2012 VL 7 AR 42 DI 10.1186/1750-1326-7-42 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 028ZI UT WOS:000310464100001 PM 22920859 ER PT J AU Carroll, MC Isenman, DE AF Carroll, Michael C. Isenman, David E. TI Regulation of Humoral Immunity by Complement SO IMMUNITY LA English DT Review ID FOLLICULAR DENDRITIC CELLS; SUBCAPSULAR SINUS MACROPHAGES; EPSTEIN-BARR-VIRUS; RECEPTOR 2; B-CELLS; STAPHYLOCOCCUS-AUREUS; GERMINAL-CENTERS; LYMPH-NODES; AFFINITY MATURATION; ACQUIRED-IMMUNITY AB The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity. C1 [Carroll, Michael C.] Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Childrens Hosp, Sch Med, Program Mol & Cellular Med, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Dept Pediat, Sch Med, Boston, MA 02115 USA. [Isenman, David E.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Isenman, David E.] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Carroll, MC (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM carroll@idi.harvard.edu FU NIAID NIH HHS [R01 AI039246] NR 73 TC 86 Z9 88 U1 1 U2 29 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 199 EP 207 DI 10.1016/j.immuni.2012.08.002 PG 9 WC Immunology SC Immunology GA 998SX UT WOS:000308261800006 PM 22921118 ER PT J AU Acton, SE Astarita, JL Malhotra, D Lukacs-Kornek, V Franz, B Hess, PR Jakus, Z Kuligowski, M Fletcher, AL Elpek, KG Bellemare-Pelletier, A Sceats, L Reynoso, ED Gonzalez, SF Graham, DB Chang, J Peters, A Woodruff, M Kim, YA Swat, W Morita, T Kuchroo, V Carroll, MC Kahn, ML Wucherpfennig, KW Turley, SJ AF Acton, Sophie E. Astarita, Jillian L. Malhotra, Deepali Lukacs-Kornek, Veronika Franz, Bettina Hess, Paul R. Jakus, Zoltan Kuligowski, Michael Fletcher, Anne L. Elpek, Kutlu G. Bellemare-Pelletier, Angelique Sceats, Lindsay Reynoso, Erika D. Gonzalez, Santiago F. Graham, Daniel B. Chang, Jonathan Peters, Anneli Woodruff, Matthew Kim, Young-A. Swat, Wojciech Morita, Takashi Kuchroo, Vijay Carroll, Michael C. Kahn, Mark L. Wucherpfennig, Kai W. Turley, Shannon J. TI Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2 SO IMMUNITY LA English DT Article ID SECONDARY LYMPHOID ORGANS; IN-VIVO; LYMPHATIC VESSELS; RHO; MIGRATION; RAC; NEUTROPHILS; INVASION; GTPASES; ROLES AB To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces. C1 [Acton, Sophie E.; Astarita, Jillian L.; Malhotra, Deepali; Lukacs-Kornek, Veronika; Franz, Bettina; Fletcher, Anne L.; Elpek, Kutlu G.; Bellemare-Pelletier, Angelique; Sceats, Lindsay; Reynoso, Erika D.; Chang, Jonathan; Wucherpfennig, Kai W.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Acton, Sophie E.] UCL, Dept Cell & Dev Biol, London WC1E 6BT, England. [Astarita, Jillian L.; Malhotra, Deepali; Chang, Jonathan; Woodruff, Matthew] Harvard Univ, Sch Med, Div Med Sci, Boston, MA 02115 USA. [Hess, Paul R.; Jakus, Zoltan; Kahn, Mark L.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Hess, Paul R.; Jakus, Zoltan; Kahn, Mark L.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Immune Dis Inst, Sch Med, Boston, MA 02115 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Program Cellular & Mol Med, Sch Med, Childrens Hosp,Dept Pediat, Boston, MA 02115 USA. [Kuligowski, Michael; Gonzalez, Santiago F.; Kim, Young-A.; Carroll, Michael C.] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp,Dept Pathol, Boston, MA 02115 USA. [Graham, Daniel B.; Swat, Wojciech] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Peters, Anneli; Kuchroo, Vijay] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Morita, Takashi] Meiji Pharmaceut Univ, Dept Biochem, Kiyose, Tokyo 2048588, Japan. [Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. RP Turley, SJ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM shannon_turley@dfci.harvard.edu RI Acton, Sophie/G-9784-2012; Jakus, Zoltan/O-1762-2015; OI Acton, Sophie/0000-0003-2704-716X; Jakus, Zoltan/0000-0002-6304-2369; Malhotra, Deepali/0000-0002-8215-7639 FU National Institutes of Health [R01 DK074500, P01 AI045757, R01AI073718, AI061077]; LLS; Wellcome Trust; National Science Foundation; Benacerraf Postdoctoral Fellowship; National Health Medical Research Council; European Union [220044] FX The authors are grateful to J. Campbell and B. Vander Lugt for CCR7 knockout mice; to L.-H. Ang, Y. Zheng, and S. Hagen for assistance with microscopy; and to R. Gelman for assistance with statistical analysis. They are also grateful to E. Sahai for critical reading of the manuscript. This work was supported by National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), R01AI073718 and AI061077 (W.S.), and LLS (W.S., D.B.G.); a Wellcome Trust Henry Wellcome Postdoctoral Fellowship (to S.E.A.); a National Science Foundation Graduate Research Fellowship (to J.L.A.); a Benacerraf Postdoctoral Fellowship (to V.L.K.); a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.); and a Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044, to S.F.G.). NR 31 TC 86 Z9 94 U1 2 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 24 PY 2012 VL 37 IS 2 BP 276 EP 289 DI 10.1016/j.immuni.2012.05.022 PG 14 WC Immunology SC Immunology GA 998SX UT WOS:000308261800012 PM 22884313 ER PT J AU Miller, E Yang, JY DeRan, M Wu, CL Su, AI Bonamy, GMC Liu, J Peters, EC Wu, X AF Miller, Eric Yang, Jiayi DeRan, Michael Wu, Chunlei Su, Andrew I. Bonamy, Ghislain M. C. Liu, Jun Peters, Eric C. Wu, Xu TI Identification of Serum-Derived Sphingosine-1-Phosphate as a Small Molecule Regulator of YAP SO CHEMISTRY & BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR PATHWAY; HIPPO SIGNALING PATHWAY; ORGAN SIZE CONTROL; CELL SELF-RENEWAL; SPHINGOSINE 1-PHOSPHATE; TISSUE-GROWTH; PROMOTES APOPTOSIS; CONTACT INHIBITION; TEAD/TEF FAMILY; CYCLE EXIT AB Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that Si P and LPA might modulate cell proliferation and tumorigenesis through YAP activation. C1 [DeRan, Michael; Wu, Xu] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Miller, Eric; Yang, Jiayi; Bonamy, Ghislain M. C.; Liu, Jun; Peters, Eric C.] Genom Inst Novartis Res Fdn, San Diego, CA 92121 USA. [Wu, Chunlei; Su, Andrew I.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Wu, X (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM xwu@cbrc2.mgh.harvard.edu OI Su, Andrew I./0000-0002-9859-4104 FU Genomics Institute of the Novartis Research Foundation; Massachusetts General Hospital institutional fund; Harvard Stem Cell Institute; Children's Tumor Foundation; Novartis Research Foundation FX This work is supported by the Genomics Institute of the Novartis Research Foundation postdoctoral program (EM, and J.Y.), Massachusetts General Hospital institutional fund, Harvard Stem Cell Institute, and Children's Tumor Foundation (X.W.). We thank Drs. Charles Cho, Kun-Liang Guan, and Nabeel Bardeesy for discussions and reagents; Daniel Mason for assistance with mass spectrometry; and Richard Brusch III for assistance with imaging analyses and confocal microscopy. J.Y., E.M., and X.W. conceived the concepts and designed the experiments; E.M. performed isolation and analytical experiments; J.Y., M.D., and E.M. performed the cell biology and biochemistry experiments; C.W. performed bioinformatics analysis and G.B. performed imaging analysis; all authors analyzed the data; and E.M. and X.W. wrote the manuscript. E.M., J.Y., G.B., J.L. and E.P. are employees of Novartis. Part of this work was supported by the Novartis Research Foundation postdoctoral program (E.M. and J.Y.). NR 52 TC 86 Z9 88 U1 4 U2 32 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 AUG 24 PY 2012 VL 19 IS 8 BP 955 EP 962 DI 10.1016/j.chembiol.2012.07.005 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 011GH UT WOS:000309152500007 PM 22884261 ER PT J AU Tolstorukov, MY Goldman, JA Gilbert, C Ogryzko, V Kingston, RE Park, PJ AF Tolstorukov, Michael Y. Goldman, Joseph A. Gilbert, Cristele Ogryzko, Vasily Kingston, Robert E. Park, Peter J. TI Histone Variant H2A.Bbd Is Associated with Active Transcription and mRNA Processing in Human Cells SO MOLECULAR CELL LA English DT Article ID HUMAN GENOME; U2 SNRNP; NUCLEOSOME; CHROMATIN; RECOGNITION; DEPOSITION; RESOLUTION; REGULATOR; BINDING; PROTEIN AB Variation in chromatin composition and organization often reflects differences in genome function. Histone variants, for example, replace canonical histones to contribute to regulation of numerous nuclear processes including transcription, DNA repair, and chromosome segregation. Here we focus on H2A.Bbd, a rapidly evolving variant found in mammals but not in invertebrates. We report that in human cells, nucleosomes bearing H2A.Bbd form unconventional chromatin structures enriched within actively transcribed genes and characterized by shorter DNA protection and nucleosome spacing. Analysis of transcriptional profiles from cells depleted for H2A.Bbd demonstrated widespread changes in gene expression with a net downregulation of transcription and disruption of normal mRNA splicing patterns. In particular, we observed changes in exon inclusion rates and increased presence of intronic sequences in mRNA products upon H2A.Bbd depletion. Taken together, our results indicate that H2A.Bbd is involved in formation of a specific chromatin structure that facilitates both transcription and initial mRNA processing. C1 [Goldman, Joseph A.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Tolstorukov, Michael Y.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Gilbert, Cristele; Ogryzko, Vasily] Univ Paris 11, CNRS, UMR 8126, Inst Cancerol Gustave Roussy, F-94805 Villejuif, France. [Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Tolstorukov, Michael Y.; Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu; peter_park@harvard.edu RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 FU NIH grants [R01GM082798, U01HG00425, R37GM048405] FX We are grateful to Drs. Douglas Black, Erica Larschan, Artyom Alekseyenko, and Andrey Gortchakov for critical reading of the manuscript and many insightful comments. This work was supported by NIH grants R01GM082798 and U01HG00425 to P.J.P. and R37GM048405 to R.E.K. NR 41 TC 36 Z9 40 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 EI 1097-4164 J9 MOL CELL JI Mol. Cell PD AUG 24 PY 2012 VL 47 IS 4 BP 596 EP 607 DI 10.1016/j.molcel.2012.06.011 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100011 PM 22795134 ER PT J AU Bock, C Beerman, I Lien, WH Smith, ZD Gu, HC Boyle, P Gnirke, A Fuchs, E Rossi, DJ Meissner, A AF Bock, Christoph Beerman, Isabel Lien, Wen-Hui Smith, Zachary D. Gu, Hongcang Boyle, Patrick Gnirke, Andreas Fuchs, Elaine Rossi, Derrick J. Meissner, Alexander TI DNA Methylation Dynamics during In Vivo Differentiation of Blood and Skin Stem Cells SO MOLECULAR CELL LA English DT Article ID HEMATOPOIETIC STEM; LINEAGE COMMITMENT; GENE-THERAPY; EXPRESSION; PLURIPOTENT; METHYLOME; STATES; MAPS; HYPERMETHYLATION; MULTIPOTENCY AB DNA methylation is a mechanism of epigenetic regulation that is common to all vertebrates. Functional studies underscore its relevance for tissue homeostasis, but the global dynamics of DNA methylation during in vivo differentiation remain underexplored. Here we report high-resolution DNA methylation maps of adult stem cell differentiation in mouse, focusing on 19 purified cell populations of the blood and skin lineages. DNA methylation changes were locus specific and relatively modest in magnitude. They frequently overlapped with lineage-associated transcription factors and their binding sites, suggesting that DNA methylation may protect cells from aberrant transcription factor activation. DNA methylation and gene expression provided complementary information, and combining the two enabled us to infer the cellular differentiation hierarchy of the blood lineage directly from genome-scale data. In summary, these results demonstrate that in vivo differentiation of adult stem cells is associated with small but informative changes in the genomic distribution of DNA methylation. C1 [Lien, Wen-Hui; Fuchs, Elaine] Rockefeller Univ, Lab Mammalian Cell Biol & Dev, Howard Hughes Med Inst, New York, NY 10065 USA. [Bock, Christoph; Smith, Zachary D.; Gu, Hongcang; Boyle, Patrick; Gnirke, Andreas; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Bock, Christoph; Beerman, Isabel; Smith, Zachary D.; Rossi, Derrick J.; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Bock, Christoph; Beerman, Isabel; Smith, Zachary D.; Rossi, Derrick J.; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02318 USA. [Beerman, Isabel; Rossi, Derrick J.] Boston Childrens Hosp, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02116 USA. RP Fuchs, E (reprint author), Rockefeller Univ, Lab Mammalian Cell Biol & Dev, Howard Hughes Med Inst, New York, NY 10065 USA. EM fuchslb@rockefeller.edu; rossi@idi.harvard.edu; alexander_meissner@harvard.edu RI Bock, Christoph/B-6723-2008; OI Bock, Christoph/0000-0001-6091-3088; Lien, Wen-Hui/0000-0002-2282-3169 FU Feodor Lynen Fellowship (Alexander von Humboldt Foundation); Charles A. King Trust Postdoctoral Fellowship (Charles A. King Trust, N.A., Bank of America, Co-Trustee); Harvey L. Karp Postdoctoral Fellowship; Jane Coffin Child Postdoctoral Fellowship; Massachusetts Life Science Center; Pew Charitable Trusts; New York Stem Cell Foundation; Harvard Stem Cell Institute; NIH/NIAMS [R01AR31737] FX We would like to thank other members of the Meissner, Rossi, and Fuchs labs for their support. From Rockefeller University, we also thank S. Maizel at the flow cytometry facility, as well as Nicole Stokes and the Comparative Biology Center animal facility. Furthermore, we thank Tarjei S. Mikkelsen for his contributions to the early parts of the project and Fontina Kelley for supporting the sequencing efforts. C.B. was supported by a Feodor Lynen Fellowship (Alexander von Humboldt Foundation) and a Charles A. King Trust Postdoctoral Fellowship (Charles A. King Trust, N.A., Bank of America, Co-Trustee). W.-H.L. was supported by a Harvey L. Karp Postdoctoral Fellowship and a Jane Coffin Child Postdoctoral Fellowship. E.F. is a Howard Hughes Medical Institute Investigator. A.M. was supported by the Massachusetts Life Science Center and the Pew Charitable Trusts. D.R. was supported by the New York Stem Cell Foundation. This work was funded by the Harvard Stem Cell Institute (to D.R. and A.M.) and partially supported by a grant (to E.F.) from the NIH/NIAMS (R01AR31737). NR 35 TC 139 Z9 139 U1 2 U2 24 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 AUG 24 PY 2012 VL 47 IS 4 BP 633 EP 647 DI 10.1016/j.molcel.2012.06.019 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 996CH UT WOS:000308061100014 PM 22841485 ER PT J AU Yuan, MS Pino, E Wu, LF Kacergis, M Soukas, AA AF Yuan, Minsheng Pino, Elizabeth Wu, Lianfeng Kacergis, Michael Soukas, Alexander A. TI Identification of Akt-independent Regulation of Hepatic Lipogenesis by Mammalian Target of Rapamycin (mTOR) Complex 2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED INSULIN-RESISTANCE; MOTIF PHOSPHORYLATION; TRANSCRIPTION FACTORS; DIABETES-MELLITUS; LIPID-METABOLISM; KINASE-B; RICTOR; MICE; AKT/PKB; LIVER AB Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (Lrictor(KO)) are unable to respond normally to insulin. In response to insulin, Lrictor(KO) mice failed to inhibit hepatic glucose output. Lrictor(KO) mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. Lrictor(KO) mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3 beta, PRAS40, AS160, and Tsc2. Lrictor(KO) mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of Lrictor(KO) mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet & Diabet Unit,Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Soukas, AA (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN6224, Boston, MA 02114 USA. EM asoukas@chgr.mgh.harvard.edu FU National Institutes of Health Career Development Award through NIDDK [K08DK087941]; Charles H. Hood Foundation FX This research was supported, in whole or in part, by National Institutes of Health Career Development Award K08DK087941 through the NIDDK ( to A. A. S.). This work was also supported by a Child Health Research Award from the Charles H. Hood Foundation ( to A. A. S). NR 41 TC 59 Z9 60 U1 2 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29579 EP 29588 DI 10.1074/jbc.M112.386854 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900033 PM 22773877 ER PT J AU Penniston, JT Caride, AJ Strehler, EE AF Penniston, John T. Caride, Ariel J. Strehler, Emanuel E. TI Alternative Pathways for Association and Dissociation of the Calmodulin-binding Domain of Plasma Membrane Ca2+-ATPase Isoform 4b (PMCA4b) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TARGETED MOLECULAR-DYNAMICS; LIGHT-CHAIN KINASE; CA2+ PUMP; CALCIUM-PUMP; ACTIVATION; MECHANISM; ENZYME; RECOGNITION; SIMULATIONS; COMPLEXES AB The calmodulin (CaM)-binding domain of isoform 4b of the plasma membrane Ca2+-ATPase (PMCA) pump is represented by peptide C28. CaM binds to either PMCA or C28 by a mechanism in which the primary anchor residue Trp-1093 binds to the C-terminal lobe of the extended CaM molecule, followed by collapse of CaM with the N-terminal lobe binding to the secondary anchor Phe-1110 (Juranic, N., Atanasova, E., Filoteo, A. G., Macura, S., Prendergast, F. G., Penniston, J. T., and Strehler, E. E. (2010) J. Biol. Chem. 285, 4015-4024). This is a relatively rapid reaction, with an apparent half-time of similar to 1 s. The dissociation of CaM from PMCA4b or C28 is much slower, with an overall half-time of similar to 10 min. Using targeted molecular dynamics, we now show that dissociation of Ca2+-CaM from C28 may occur by a pathway in which Trp-1093, although deeply embedded in a pocket in the C-terminal lobe of CaM, leaves first. The dissociation begins by relatively rapid release of Trp-1093, followed by very slow release of Phe-1110, removal of C28, and return of CaM to its conformation in the free state. Fluorescence measurements and molecular dynamics calculations concur in showing that this alternative path of release of the PMCA4b CaM-binding domain is quite different from that of binding. The intermediate of dissociation with exposed Trp-1093 has a long lifetime (minutes) and may keep the PMCA primed for activation. C1 [Caride, Ariel J.; Strehler, Emanuel E.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Penniston, John T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Strehler, EE (reprint author), Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 1st St SW, Rochester, MN 55905 USA. EM strehler.emanuel@mayo.edu FU National Institutes of Health [NS51769]; Mayo Foundation for Medical Research and Education FX This work was supported, in whole or in part, by National Institutes of Health Grant NS51769 ( to E. E. S.). This work was also supported by the Mayo Foundation for Medical Research and Education. NR 30 TC 3 Z9 3 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29664 EP 29671 DI 10.1074/jbc.M112.377556 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900042 PM 22767601 ER PT J AU Steffan, JJ Koul, S Meacham, RB Koul, HK AF Steffan, Joshua J. Koul, Sweaty Meacham, Randall B. Koul, Hari K. TI The Transcription Factor SPDEF Suppresses Prostate Tumor Metastasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GELATINASE B EXPRESSION; ETS FACTOR; CANCER-CELLS; BREAST-CANCER; MATRIX METALLOPROTEINASES; AGGRESSIVE PHENOTYPE; PROGNOSTIC MARKER; GENE-EXPRESSION; CARCINOMA CELLS; FACTOR PDEF AB Emerging evidence suggests that the SAM pointed domain containing ETS transcription factor (SPDEF) plays a significant role in tumorigenesis in prostate, breast, colon, and ovarian cancer. However, there are no in vivo studies with respect to the role of SPDEF in tumor metastasis. The present study examined the effects of SPDEF on tumor cell metastasis using prostate tumor cells as a model. Utilizing two experimental metastasis models, we demonstrate that SPDEF inhibits cell migration and invasion in vitro and acts a tumor metastasis suppressor in vivo. Using stable expression of SPDEF in PC3-Luc cells and shRNA-mediated knockdown of SPDEF in LNCaP-Luc cells, we demonstrate for the first time that SPDEF diminished the ability of disseminated tumors cells to survive at secondary sites and establish micrometastases. These effects on tumor metastasis were not a result of the effect of SPDEF on cell growth as SPDEF expression had no effect on cell growth in vitro or subcutaneous tumor xenograft-growth in vivo. Transcriptional analysis of several genes associated with tumor metastasis, invasion, and the epithelial-mesenchymal transition demonstrated that SPDEF expression selectively down-regulated MMP9 and MMP13 in prostate cancer cells. Further analysis indicated that forced MMP9 or MMP13 expression rescued the invasive phenotype in SPDEF expressing PC3 cells in vitro, suggesting that the effects of SPDEF on tumor invasion are mediated, in part, through the suppression of MMP9 and MMP13 expression. These results demonstrate for the first time, in any system, that SPDEF functions as a tumor metastasis suppressor in vivo. C1 [Steffan, Joshua J.; Koul, Sweaty; Meacham, Randall B.; Koul, Hari K.] Univ Colorado, Sch Med, Dept Surg, Program Urosci,Div Urol, Aurora, CO 80045 USA. [Steffan, Joshua J.; Koul, Sweaty; Koul, Hari K.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. [Koul, Hari K.] Univ Colorado, Ctr Comprehens Canc, Aurora, CO 80045 USA. RP Koul, HK (reprint author), 12700 E 19th Ave,RC2-6001,MS-C317, Aurora, CO 80045 USA. EM hari.koul@ucdenver.edu FU Department of Surgery (School of Medicine Academic Enrichment Funds); Veterans Affairs Merit Award [01BX001258]; National Institutes of Health [DK54084]; National Institutes of Health/NCI [R01CA161880] FX This work was supported in part by chair commitment (to H. K. K.) and Department of Surgery (School of Medicine Academic Enrichment Funds) (to H. K. K.).; Supported in part by Veterans Affairs Merit Award 01BX001258, National Institutes of Health Grant DK54084, and National Institutes of Health/NCI Grant R01CA161880. To whom correspondence should be addressed: 12700 E. 19th Ave, RC2-6001; MS-C317, Aurora, CO 80045. Tel.: 303-724-6300; Fax: 303-724-6330; E-mail: hari.koul@ucdenver.edu. NR 44 TC 20 Z9 20 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 24 PY 2012 VL 287 IS 35 BP 29968 EP 29978 DI 10.1074/jbc.M112.379396 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 999CO UT WOS:000308286900070 PM 22761428 ER PT J AU Mattaini, KR Vander Heiden, MG AF Mattaini, Katherine R. Vander Heiden, Matthew G. TI Glycosylation to Adapt to Stress SO SCIENCE LA English DT Editorial Material ID RABBIT MUSCLE PHOSPHOFRUCTOKINASE; CANCER-CELLS; METABOLISM; PHOSPHORYLATION; REGULATOR C1 [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Mattaini, Katherine R.; Vander Heiden, Matthew G.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mattaini, KR (reprint author), MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mvh@mit.edu NR 14 TC 5 Z9 5 U1 0 U2 22 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 AUG 24 PY 2012 VL 337 IS 6097 BP 925 EP 926 DI 10.1126/science.1227513 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600034 PM 22923571 ER PT J AU Lee, E Iskow, R Yang, LX Gokcumen, O Haseley, P Luquette, LJ Lohr, JG Harris, CC Ding, L Wilson, RK Wheeler, DA Gibbs, RA Kucherlapati, R Lee, C Kharchenko, PV Park, PJ AF Lee, Eunjung Iskow, Rebecca Yang, Lixing Gokcumen, Omer Haseley, Psalm Luquette, Lovelace J., III Lohr, Jens G. Harris, Christopher C. Ding, Li Wilson, Richard K. Wheeler, David A. Gibbs, Richard A. Kucherlapati, Raju Lee, Charles Kharchenko, Peter V. Park, Peter J. CA Canc Genome Atlas Res Network TI Landscape of Somatic Retrotransposition in Human Cancers SO SCIENCE LA English DT Article ID HUMAN GENOMES; ELEMENTS; CELLS; DISRUPTION; MECHANISMS; GENE AB Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis. C1 [Lee, Eunjung; Yang, Lixing; Haseley, Psalm; Luquette, Lovelace J., III; Kharchenko, Peter V.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Lee, Eunjung; Haseley, Psalm; Kucherlapati, Raju; Park, Peter J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Iskow, Rebecca; Gokcumen, Omer; Lee, Charles] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lohr, Jens G.] Eli & Edythe Broad Inst, Cambridge, MA 02412 USA. [Lohr, Jens G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Harris, Christopher C.; Ding, Li; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Wheeler, David A.; Gibbs, Richard A.] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA. [Kucherlapati, Raju] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Kharchenko, Peter V.; Park, Peter J.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. RP Kharchenko, PV (reprint author), Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. EM peter.kharchenko@post.harvard.edu; peter_park@harvard.edu RI Yang, Lixing/A-7073-2013; OI Gokcumen, Omer/0000-0003-4371-679X FU NIH [R01GM082798, RC1HG005482, K25AG037596, U01HG005209, U01HG005725, F32AG039979, U24CA144025] FX We thank A. Langdon and U. Samarakoon for technical assistance and T. Golub and the Broad Institute for a myeloma sample obtained under a materials transfer agreement (MTA) from the Multiple Myeloma Research Consortium. This work was supported by NIH grants R01GM082798 and RC1HG005482 (P.J.P.), K25AG037596 (P. V. K.), U01HG005209 and U01HG005725 (C. L.), F32AG039979 (R. I.), and U24CA144025 (R. K.). P.J.P. is a Sloan Research Fellow. R. K. is on the board of directors of AVEO, Metamark, Enlight, and KEW Group. The sequencing data are available at dbGaP (www.ncbi.nlm.nih.gov/gap) with the following accessions: TCGA ovarian cancer, glioblastoma multiforme, and colorectal cancer (phs000178.v5.p5); multiple myeloma (phs000348.v1.p1); and prostate cancer (phs000330.v1.p1). The Tea software is available at http://compbio.med.harvard.edu/Tea. NR 23 TC 222 Z9 225 U1 6 U2 34 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 AUG 24 PY 2012 VL 337 IS 6097 BP 967 EP 971 DI 10.1126/science.1222077 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600046 PM 22745252 ER PT J AU Hu, ZT Hom, S Kudze, T Tong, XJ Choi, S Aramuni, G Zhang, WQ Kaplan, JM AF Hu, Zhitao Hom, Sabrina Kudze, Tambudzai Tong, Xia-Jing Choi, Seungwon Aramuni, Gayane Zhang, Weiqi Kaplan, Joshua M. TI Neurexin and Neuroligin Mediate Retrograde Synaptic Inhibition in C. elegans SO SCIENCE LA English DT Article ID SPECTRUM DISORDERS; AUTISM; MATURATION; MUTATIONS; CELL AB The synaptic adhesion molecules neurexin and neuroligin alter the development and function of synapses and are linked to autism in humans. Here, we found that Caenorhabditis elegans neurexin (NRX-1) and neuroligin (NLG-1) mediated a retrograde synaptic signal that inhibited neurotransmitter release at neuromuscular junctions. Retrograde signaling was induced in mutants lacking a muscle microRNA (miR-1) and was blocked in mutants lacking NLG-1 or NRX-1. Release was rapid and abbreviated when the retrograde signal was on, whereas release was slow and prolonged when retrograde signaling was blocked. The retrograde signal adjusted release kinetics by inhibiting exocytosis of synaptic vesicles (SVs) that are distal to the site of calcium entry. Inhibition of release was mediated by increased presynaptic levels of tomosyn, an inhibitor of SV fusion. C1 [Hu, Zhitao; Hom, Sabrina; Kudze, Tambudzai; Tong, Xia-Jing; Choi, Seungwon; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Hu, Zhitao; Hom, Sabrina; Tong, Xia-Jing; Choi, Seungwon; Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Hom, Sabrina; Choi, Seungwon; Kaplan, Joshua M.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Aramuni, Gayane] Max Planck Inst Neurobiol, D-82152 Martinsried, Germany. [Zhang, Weiqi] Univ Munster, Dept Psychiat, D-48149 Munster, Germany. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu FU NSF; NIH [NS32196]; Simons Foundation for Autism Research [SF177948] FX We thank the following for strains, advice, reagents, and comments on the manuscript: C. elegans stock center, S. Mitani, S. Sassi, B. Seed, and members of the Kaplan and Ruvkun labs. This work was supported by an NSF predoctoral fellowship (S. H.) and by research grants to J.M.K. from the NIH (NS32196) and from the Simons Foundation for Autism Research (SF177948). Additional data described in the manuscript are presented in the supplementary materials. NR 24 TC 34 Z9 38 U1 1 U2 20 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 AUG 24 PY 2012 VL 337 IS 6097 BP 980 EP 984 DI 10.1126/science.1224896 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VI UT WOS:000307807600049 PM 22859820 ER PT J AU Zhang, Y Roccaro, AM Rombaoa, C Flores, L Obad, S Fernandes, SM Sacco, A Liu, Y Ngo, H Quang, P Azab, AK Azab, F Maiso, P Reagan, M Brown, JR Thai, TH Kauppinen, S Ghobrial, IM AF Zhang, Yong Roccaro, Aldo M. Rombaoa, Christopher Flores, Ludmilla Obad, Susanna Fernandes, Stacey M. Sacco, Antonio Liu, Yang Ngo, Hai Quang, Phong Azab, Abdel Kareem Azab, Feda Maiso, Patricia Reagan, Michaela Brown, Jennifer R. Thai, To-Ha Kauppinen, Sakari Ghobrial, Irene M. TI LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; INDUCED CYTIDINE DEAMINASE; MULTIPLE-MYELOMA; WALDENSTROMS MACROGLOBULINEMIA; IN-VIVO; BREAST-CANCER; C-MAF; MICRORNA-155; EXPRESSION; MICROENVIRONMENT AB miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155-based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti-miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti-miR-155 delivered systemically showed uptake in the BM CD19(+) cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155-knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti-miR-155-mediated inhibition of miR-155 in the treatment of WM. (Blood. 2012;120(8):1678-1686) C1 [Zhang, Yong; Roccaro, Aldo M.; Rombaoa, Christopher; Flores, Ludmilla; Fernandes, Stacey M.; Sacco, Antonio; Liu, Yang; Ngo, Hai; Quang, Phong; Azab, Abdel Kareem; Azab, Feda; Maiso, Patricia; Reagan, Michaela; Brown, Jennifer R.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Obad, Susanna; Kauppinen, Sakari] Santaris Pharma, Horsholm, Denmark. [Thai, To-Ha] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Kauppinen, Sakari] Aalborg Univ, Copenhagen, Denmark. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; Reagan, Michaela/E-3549-2017; OI Sacco, Antonio/0000-0003-2945-9416; Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; Reagan, Michaela/0000-0003-2884-6481 FU Leukemia & Lymphoma Society; Kirsch Laboratory for Waldenstrom; Heje Fellowship FX This work was supported in part by research grants from the Leukemia & Lymphoma Society, The Kirsch Laboratory for Waldenstrom, and the Heje Fellowship. mCherry-Luc+-BCWM1 cells were a kind gift from Dr Andrew Kung (Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA). NR 48 TC 64 Z9 67 U1 2 U2 12 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 AUG 23 PY 2012 VL 120 IS 8 BP 1678 EP 1686 DI 10.1182/blood-2012-02-410647 PG 9 WC Hematology SC Hematology GA 009DK UT WOS:000309005600023 PM 22797699 ER PT J AU Chiyomaru, T Yamamura, S Zaman, MS Majid, S Deng, GR Shahryari, V Saini, S Hirata, H Ueno, K Chang, I Tanaka, Y Tabatabai, ZL Enokida, H Nakagawa, M Dahiya, R AF Chiyomaru, Takeshi Yamamura, Soichiro Zaman, Mohd Saif Majid, Shahana Deng, Guoren Shahryari, Varahram Saini, Sharanjot Hirata, Hiroshi Ueno, Koji Chang, Inik Tanaka, Yuichiro Tabatabai, Z. Laura Enokida, Hideki Nakagawa, Masayuki Dahiya, Rajvir TI Genistein Suppresses Prostate Cancer Growth through Inhibition of Oncogenic MicroRNA-151 SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; JAPANESE MEN; CHROMOSOMAL-ABERRATIONS; RISK; ISOFLAVONES; CARCINOMA; FAMILY; CELLS; CONSUMPTION; INVASION AB Genistein has been shown to suppress the growth of several cancers through modulation of various pathways. However, the effects of genistein on the regulation of oncogenic microRNA-151 (miR-151) have not been reported. In this study, we investigated whether genistein could alter the expression of oncogenic miR-151 and its target genes that are involved in the progression and metastasis of prostate cancer (PCa). Real-time RT-PCR showed that the expression of miR-151 was higher in PC3 and DU145 cells compared with RWPE-1 cells. Treatment of PC3 and DU145 cells with 25 mu M genistein down-regulated the expression of miR-151 compared with vehicle control. Inhibition of miR-151 in PCa cells by genistein significantly inhibited cell migration and invasion. In-silico analysis showed that several genes (CASZ1, IL1RAPL1, SOX17, N4BP1 and ARHGDIA) suggested to have tumor suppressive functions were target genes of miR-151. Luciferase reporter assays indicated that miR-151 directly binds to specific sites on the 3'UTR of target genes. Quantitative real-time PCR analysis showed that the mRNA expression levels of the five target genes in PC3 and DU145 were markedly changed with miR-151 mimics and inhibitor. Kaplan-Meier curves and log-rank tests revealed that high expression levels of miR-151 had an adverse effect on survival rate. This study suggests that genistein mediated suppression of oncogenic miRNAs can be an important dietary therapeutic strategy for the treatment of PCa. C1 [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Pathol, San Francisco, CA USA. [Chiyomaru, Takeshi; Yamamura, Soichiro; Zaman, Mohd Saif; Majid, Shahana; Deng, Guoren; Shahryari, Varahram; Saini, Sharanjot; Hirata, Hiroshi; Ueno, Koji; Chang, Inik; Tanaka, Yuichiro; Tabatabai, Z. Laura; Dahiya, Rajvir] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Enokida, Hideki; Nakagawa, Masayuki] Kagoshima Univ, Grad Sch Med & Dent Sci, Dept Urol, Kagoshima 890, Japan. RP Chiyomaru, T (reprint author), San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. EM rdahiya@urology.ucsf.edu RI Jackson, Benjamin/C-4297-2012 FU National Center for Research Resources of the National Institutes of Health [R01CA160079, R01CA138642, T32DK007790]; VA Merit Review and VA Program Project FX This research was supported by the National Center for Research Resources of the National Institutes of Health through Grant Numbers R01CA160079, R01CA138642, T32DK007790 and VA Merit Review and VA Program Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 39 Z9 42 U1 0 U2 9 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 AUG 23 PY 2012 VL 7 IS 8 AR e43812 DI 10.1371/journal.pone.0043812 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 998GE UT WOS:000308224700028 PM 22928040 ER PT J AU Drapkin, MS Kamath, RS Kim, JY AF Drapkin, Mark S. Kamath, Ravi S. Kim, Ji Yeon TI Case 26-2012: A 70-Year-Old Woman with Fever and Back Pain SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LUMBAR SPINE MIMICKING; EPIDURAL ABSCESS; CAMEL BRUCELLOSIS; TOPHACEOUS GOUT; OSTEOMYELITIS; SPONDYLODISCITIS; SPONDYLITIS; INFECTION; REGIMENS C1 [Drapkin, Mark S.] Newton Wellesley Hosp, Infect Dis Serv, Newton, MA USA. [Kamath, Ravi S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kim, Ji Yeon] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Drapkin, Mark S.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Kamath, Ravi S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kim, Ji Yeon] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Drapkin, MS (reprint author), Newton Wellesley Hosp, Infect Dis Serv, Newton, MA USA. NR 27 TC 3 Z9 3 U1 3 U2 11 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 AUG 23 PY 2012 VL 367 IS 8 BP 754 EP 762 DI 10.1056/NEJMcpc1200087 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200012 PM 22913686 ER PT J AU Goldfine, AB AF Goldfine, Allison B. TI Reassessing Benefits and Risks of Statins REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. NR 4 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 AUG 23 PY 2012 VL 367 IS 8 BP 776 EP 776 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200026 ER PT J AU Schroyens, W O'Connell, C Sykes, DB AF Schroyens, Wilfried O'Connell, Casey Sykes, David B. TI Complete and Partial Responses of the TEMPI Syndrome to Bortezomib SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Schroyens, Wilfried] Univ Antwerp Hosp, Antwerp, Belgium. [O'Connell, Casey] Univ So Calif, Los Angeles, CA USA. [Sykes, David B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schroyens, W (reprint author), Univ Antwerp Hosp, Antwerp, Belgium. EM dbsykes@partners.org NR 2 TC 9 Z9 9 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 AUG 23 PY 2012 VL 367 IS 8 BP 778 EP 780 DI 10.1056/NEJMc1205806 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 992CX UT WOS:000307754200030 PM 22913703 ER PT J AU Bourgier, C Acevedo-Henao, C Dunant, A Rossier, C Levy, A El Nemr, M Dumas, I Delaloge, S Mathieu, MC Garbay, JR Taghian, A Marsiglia, H AF Bourgier, Celine Acevedo-Henao, Catalina Dunant, Ariane Rossier, Christine Levy, Antonin El Nemr, Mohamed Dumas, Isabelle Delaloge, Suzette Mathieu, Marie-Christine Garbay, Jean-Remi Taghian, Alphonse Marsiglia, Hugo TI Higher toxicity with 42 Gy in 10 fractions as a total dose for 3D-conformal accelerated partial breast irradiation: results from a dose escalation phase II trial SO RADIATION ONCOLOGY LA English DT Article DE 3D-conformal accelerated partial breast irradiation; Dose escalation ID CONFORMAL EXTERNAL-BEAM; LUMPECTOMY CAVITY; RADIATION-THERAPY AB Objective: Recent recommendations regarding indications of accelerated partial breast irradiation (APBI) have been put forward for selected breast cancer (BC) patients. However, some treatment planning parameters, such as total dose, are not yet well defined. The Institut Gustave Roussy has initiated a dose escalation trial at the 40 Gy/10 fractions/5 days and at a further step of total dose (TD) of 42 Gy/10 fractions/5 days. Here, we report early results of the latest step compared with the 40 Gy dose level. Methods and materials: From October 2007 to March 2010, a total of 48 pT1N0 BC patients were enrolled within this clinical trial: 17 patients at a TD of 42 Gy/10f/5d and 31 at a TD of 40 Gy/10f/5d. Median follow-up was 19 months (min-max, 12-26). All the patients were treated by APBI using a technique with 2 minitangents and an "enface" electrons delivering 20% of the total dose. Toxicities were systematically assessed at 1; 2; 6 months and then every 6 months. Results: Patients' recruitment of 42 Gy step was ended owing to persistent grade 3 toxicity 6 months after APBI completion (n = 1). Early toxicities were statistically higher after a total dose of 42 Gy regarding grade >= 2 dry (p = 0.01) and moist (p = 0.05) skin desquamation. Breast pain was also statistically higher in the 42 Gy step compared to 40 Gy step (p = 0.02). Other late toxicities (grade >= 2 fibrosis and telangectasia) were not statistically different between 42 Gy and 40 Gy. Conclusions: Early toxicities were more severe and higher rates of late toxicities were observed after 42 Gy/10 fractions/5 days when compared to 40 Gy/10 fractions/5 days. This data suggest that 40 Gy/10 fractions/5 days could potentially be the maximum tolerance for PBI although longer follow-up is warranted to better assess late toxicities. C1 [Bourgier, Celine; Dumas, Isabelle] Inst Gustave Roussy, Dept Radiat Oncol, Phys Unit, F-94805 Villejuif, France. [Dunant, Ariane] Inst Gustave Roussy, Biostat & Epidemiol Unit, F-94805 Villejuif, France. [El Nemr, Mohamed] Univ Alexandria, Alexandria, Egypt. [Delaloge, Suzette] Inst Gustave Roussy, Dept Breast Oncol, F-94805 Villejuif, France. [Mathieu, Marie-Christine] Inst Gustave Roussy, Dept Pathol, F-94805 Villejuif, France. [Garbay, Jean-Remi] Inst Gustave Roussy, Dept Breast Surg, F-94805 Villejuif, France. [Taghian, Alphonse] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Marsiglia, Hugo] Grp Imo, Madrid, Spain. RP Bourgier, C (reprint author), Inst Gustave Roussy, Dept Radiat Oncol, Phys Unit, 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM bourgier@igr.fr OI , Antonin/0000-0003-4798-8899 NR 19 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD AUG 22 PY 2012 VL 7 AR 141 DI 10.1186/1748-717X-7-141 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 041QO UT WOS:000311416500001 PM 22913640 ER PT J AU Powner, MW Zheng, SL Szostak, JW AF Powner, Matthew W. Zheng, Shao-Liang Szostak, Jack W. TI Multicomponent Assembly of Proposed DNA Precursors in Water SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEIC-ACID STRUCTURE; AMINO-ACIDS; PRIMITIVE EARTH; CHEMICAL ETIOLOGY; AMMONIUM CYANIDE; RNA; GLYCOLALDEHYDE; SYSTEM; CARBON; SUGARS AB We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and beta-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from beta-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a, stable, crystalline form. C1 [Powner, Matthew W.] UCL, Dept Chem, Christopher Ingold Labs, London WC1H 0AJ, England. [Zheng, Shao-Liang] Harvard Xray Crystallog Ctr, Cambridge, MA 02138 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Powner, Matthew W.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Powner, MW (reprint author), UCL, Dept Chem, Christopher Ingold Labs, 20 Gordon St, London WC1H 0AJ, England. EM matthew.powner@ucl.ac.uk OI Powner, Matthew/0000-0002-6368-3190 FU Harvard Origins Initiative; Howard Hughes Medical Institute; University College London; NSF [CHE-0809413] FX M.W.P. was supported by a fellowship from the Harvard Origins Initiative, the Howard Hughes Medical Institute and University College London. This research was funded in part by Grant CHE-0809413 from the NSF. J.W.S. is an Investigator of the Howard Hughes Medical Institute. The authors thank J.C. Blain, Dr. R.B. Moreno, Dr. A. Ricardo, and Prof. J.D. Sutherland for helpful discussions and The Mass Spectrometry Facility at the FAS Center for Systems Biology for mass spectrometry support. NR 51 TC 27 Z9 28 U1 2 U2 63 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 22 PY 2012 VL 134 IS 33 BP 13889 EP 13895 DI 10.1021/ja306176n PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 991KD UT WOS:000307699000050 PM 22839703 ER PT J AU Kastman, EK Willette, AA Coe, CL Bendlin, BB Kosmatka, KJ McLaren, DG Xu, GF Canu, E Field, AS Alexander, AL Voytko, ML Beasley, TM Colman, RJ Weindruch, RH Johnson, SC AF Kastman, Erik K. Willette, Auriel A. Coe, Christopher L. Bendlin, Barbara B. Kosmatka, Kris J. McLaren, Donald G. Xu, Guofan Canu, Elisa Field, Aaron S. Alexander, Andrew L. Voytko, Mary Lou Beasley, T. Mark Colman, Ricki J. Weindruch, Richard H. Johnson, Sterling C. TI A Calorie-Restricted Diet Decreases Brain Iron Accumulation and Preserves Motor Performance in Old Rhesus Monkeys (vol 30, pg 7940, 2010) SO JOURNAL OF NEUROSCIENCE LA English DT Correction ID TRANSVERSE RELAXATION RATES; VOXEL-BASED MORPHOMETRY; ALZHEIMERS-DISEASE; SUBSTANTIA-NIGRA; PARKINSONS-DISEASE; CEREBROSPINAL-FLUID; NONHUMAN-PRIMATES; OXIDATIVE DAMAGE; HEME OXYGENASE-1; SKELETAL-MUSCLE AB Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan inmanyspecies, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n = 24, 13 males, 11 females) and standard (n = 17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. ADiet x Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species. C1 [Kastman, Erik K.; Bendlin, Barbara B.; Kosmatka, Kris J.; McLaren, Donald G.; Xu, Guofan; Canu, Elisa; Weindruch, Richard H.; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI 53705 USA. [Kastman, Erik K.; Willette, Auriel A.; Bendlin, Barbara B.; Kosmatka, Kris J.; McLaren, Donald G.; Xu, Guofan; Canu, Elisa; Weindruch, Richard H.; Johnson, Sterling C.] Univ Wisconsin, Sch Med & Publ Hlth, Wisconsin Alzheimers Dis Res Ctr, Madison, WI 53705 USA. [Willette, Auriel A.; Coe, Christopher L.] Univ Wisconsin, Dept Psychol, Harlow Primate Lab, Madison, WI 53715 USA. [Willette, Auriel A.; Coe, Christopher L.; Alexander, Andrew L.; Johnson, Sterling C.] Univ Wisconsin, Waisman Imaging Ctr, Madison, WI 53705 USA. [McLaren, Donald G.] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Field, Aaron S.] Univ Wisconsin, Dept Radiol, Madison, WI 53792 USA. [Voytko, Mary Lou] Wake Forest Univ, Bowman Gray Sch Med, Dept Neurobiol & Anat, Winston Salem, NC 27157 USA. [Voytko, Mary Lou] Wake Forest Univ, Bowman Gray Sch Med, Interdisciplinary Neurosci Program, Winston Salem, NC 27157 USA. [Beasley, T. Mark; Colman, Ricki J.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Weindruch, Richard H.; Johnson, Sterling C.] Wisconsin Natl Primate Res Ctr, Madison, WI 53792 USA. RP Johnson, SC (reprint author), D4225 Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM scj@medicine.wisc.edu RI Kastman, Erik/N-6645-2016 OI Kastman, Erik/0000-0001-7221-9042 FU NCRR NIH HHS [P51 RR000167, RR020141-01, RR15459-01]; NIA NIH HHS [R01 AG040178, P01 AG011915, AG000213, P01 AG11915, R01 AG043125]; NIH HHS [P51 OD011106] NR 82 TC 14 Z9 14 U1 1 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 22 PY 2012 VL 32 IS 34 BP 11897 EP 11904 DI 10.1523/JNEUROSCI.2553-12.2012 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 997BZ UT WOS:000308140500034 PM 23082321 ER PT J AU Takada, K Zhu, D Bird, GH Sukhdeo, K Zhao, JJ Mani, M Lemieux, M Carrasco, DE Ryan, J Horst, D Fulciniti, M Munshi, NC Xu, WQ Kung, AL Shivdasani, RA Walensky, LD Carrasco, DR AF Takada, Kohichi Zhu, Di Bird, Gregory H. Sukhdeo, Kumar Zhao, Jian-Jun Mani, Mala Lemieux, Madeleine Carrasco, Daniel E. Ryan, Jeremy Horst, David Fulciniti, Mariateresa Munshi, Nikhil C. Xu, Wenqing Kung, Andrew L. Shivdasani, Ramesh A. Walensky, Loren D. Carrasco, Daniel Ruben TI Targeted Disruption of the BCL9/beta-Catenin Complex Inhibits Oncogenic Wnt Signaling SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CATENIN-BINDING PROTEIN; BETA-CATENIN; MULTIPLE-MYELOMA; ARMADILLO/BETA-CATENIN; UP-REGULATION; IN-VIVO; CANCER; PATHWAY; ACTIVATION AB Deregulated Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of beta-catenin with B cell lymphoma 9 (BCL9), a coactivator for beta-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives beta-catenin signaling through direct binding mediated by its alpha-helical homology domain 2. We developed a stabilized a helix of BCL9 (SAH-BCL9), which we show targets beta-catenin, dissociates native beta-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-beta-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling. C1 [Bird, Gregory H.; Lemieux, Madeleine; Kung, Andrew L.; Walensky, Loren D.] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Takada, Kohichi; Zhu, Di; Sukhdeo, Kumar; Zhao, Jian-Jun; Mani, Mala; Carrasco, Daniel E.; Ryan, Jeremy; Horst, David; Fulciniti, Mariateresa; Munshi, Nikhil C.; Shivdasani, Ramesh A.; Carrasco, Daniel Ruben] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. [Xu, Wenqing] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Carrasco, Daniel Ruben] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Walensky, LD (reprint author), Childrens Hosp Boston, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu; Ruben_Carrasco@dfci.harvard.edu OI Xu, Wenqing/0000-0002-2884-3101; Lemieux, Madeleine/0000-0001-6355-8691 FU Claudia Adams Barr Award; Multiple Myeloma Research Foundation; Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in gastrointestinal cancer [P50CA127003]; Burroughs Welcome Career Award in the Biomedical Sciences; Todd J. Schwartz Pediatric Oncology grant; [1R01CA151391-01] FX Funding: D. R. C. is supported by a Claudia Adams Barr Award, the Multiple Myeloma Research Foundation, a P50CA127003 Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in gastrointestinal cancer, and 1R01CA151391-01. This work was also supported by a Burroughs Welcome Career Award in the Biomedical Sciences and a Todd J. Schwartz Pediatric Oncology grant to L.D.W. NR 57 TC 60 Z9 63 U1 2 U2 27 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 AUG 22 PY 2012 VL 4 IS 148 AR 148ra117 DI 10.1126/scitranslmed.3003808 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 997GB UT WOS:000308151500008 PM 22914623 ER PT J AU Gaziano, JM Wilson, PWF AF Gaziano, J. Michael Wilson, Peter W. F. TI Cardiovascular Risk Assessment in the 21st Century SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY-HEART-DISEASE; PREDICTION C1 [Gaziano, J. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston VA Healthcare Syst, Boston, MA 02120 USA. [Wilson, Peter W. F.] Atlanta VA Med Ctr, Atlanta, GA USA. [Wilson, Peter W. F.] Emory Clin Cardiovasc Res Inst, Atlanta, GA USA. RP Gaziano, JM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston VA Healthcare Syst, 1620 Tremont St, Boston, MA 02120 USA. EM jmgaziano@partners.org NR 10 TC 12 Z9 12 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 22 PY 2012 VL 308 IS 8 BP 816 EP 817 DI 10.1001/2012.jama.10456 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 991ML UT WOS:000307705300027 PM 22910761 ER PT J AU Uccellini, L De Giorgi, V Zhao, YD Tumaini, B Erdenebileg, N Dudley, ME Tomei, S Bedognetti, D Ascierto, ML Liu, QZ Simon, R Kottyan, L Kaufman, KM Harley, JB Wang, E Rosenberg, SA Marincola, FM AF Uccellini, Lorenzo De Giorgi, Valeria Zhao, Yingdong Tumaini, Barbara Erdenebileg, Narnygerel Dudley, Mark E. Tomei, Sara Bedognetti, Davide Ascierto, Maria Libera Liu, Qiuzhen Simon, Richard Kottyan, Leah Kaufman, Kenneth M. Harley, John B. Wang, Ena Rosenberg, Steven A. Marincola, Francesco M. TI IRF5 gene polymorphisms in melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INTERFERON REGULATORY FACTOR; METASTATIC MELANOMA; IMMUNOLOGICAL CONSTANT; MULTIPLE-SCLEROSIS; CELL-LINES; RISK; INTERFERON-REGULATORY-FACTOR-5; VARIANTS; THERAPY AB Background: Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). Methods: 140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. Results: Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. Conclusions: This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness. C1 [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Uccellini, Lorenzo; De Giorgi, Valeria; Erdenebileg, Narnygerel; Tomei, Sara; Bedognetti, Davide; Ascierto, Maria Libera; Liu, Qiuzhen; Wang, Ena; Rosenberg, Steven A.] NIH, Trans NIH Ctr Human Immunol, Bethesda, MD 20892 USA. [Uccellini, Lorenzo] Univ Milan, Inst Infect Dis, L Sacco Hosp, Milan, Italy. [Uccellini, Lorenzo] Univ Milan, Inst Trop Dis, L Sacco Hosp, Milan, Italy. [Zhao, Yingdong] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Tumaini, Barbara] NIH, Cell Proc Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Bedognetti, Davide; Ascierto, Maria Libera] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Dudley, Mark E.; Kottyan, Leah; Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA. [Kaufman, Kenneth M.; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH 45229 USA. [Marincola, Francesco M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Uccellini, L (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM uccellinilorenzo@gmail.com; fmarincola@mail.cc.nih.gov RI De Giorgi, Valeria/D-4582-2017; OI Bedognetti, Davide/0000-0002-5857-773X; Kottyan, Leah/0000-0003-3979-2220 FU Conquer Cancer Foundation of the American Society of Clinical Oncology FX DB's fellowship was supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology. NR 33 TC 17 Z9 17 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD AUG 21 PY 2012 VL 10 AR 170 DI 10.1186/1479-5876-10-170 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 033LJ UT WOS:000310797500001 PM 22909381 ER PT J AU Liu, Q Collin, RWJ Cremers, FPM den Hollander, AI van den Born, LI Pierce, EA AF Liu, Qin Collin, Rob W. J. Cremers, Frans P. M. den Hollander, Anneke I. van den Born, L. Ingeborgh Pierce, Eric A. TI Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype SO PLOS ONE LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; LEBERS CONGENITAL AMAUROSIS; GENE-THERAPY; PHOTORECEPTOR DEGENERATION; RNA SURVEILLANCE; MUTANT RHODOPSIN; TRANSGENIC MICE; MOUSE MODEL; MUTATIONS; FAMILIES AB Mutations in the retinitis pigmentosa 1 (RP1) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3rd exon of RP1 (c.686delC; p.P229QfsX35) found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled. C1 [Liu, Qin; Pierce, Eric A.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Genom Inst, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. [Collin, Rob W. J.; Cremers, Frans P. M.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Collin, Rob W. J.; den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands. [Collin, Rob W. J.; Cremers, Frans P. M.; den Hollander, Anneke I.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, NL-6525 ED Nijmegen, Netherlands. [van den Born, L. Ingeborgh] Rotterdam Eye Hosp, Rotterdam, Netherlands. RP Liu, Q (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ocular Genom Inst, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. EM eric_pierce@meei.harvard.edu RI Cremers, Frans/A-5625-2014; Collin, Rob/N-3575-2014; Hollander, Anneke/N-4911-2014; OI Pierce, Eric/0000-0002-2354-4102 FU NIH [EY12910]; Foundation Fighting Blindness USA; F.M. Kirby Foundation; Research to Prevent Blindness; Rosanne Silbermann Foundation; Mackall Foundation Trust; Stichting Wetenschappelijk; Onderzoek Oogziekenhuis Rotterdam Prof. dr. H.J. Flieringa Foundation, Rotterdam, the Netherlands [2005-13]; Netherlands Organisation for Scientific Research [91209047] FX This work is supported by grants from the NIH (EY12910 to EAP), the Foundation Fighting Blindness USA (EAP, QL), the F.M. Kirby Foundation, Research to Prevent Blindness, Rosanne Silbermann Foundation (EAP), the Mackall Foundation Trust, Stichting Wetenschappelijk, Onderzoek Oogziekenhuis Rotterdam Prof. dr. H.J. Flieringa Foundation (grant 2005-13 to LIvdB, AIdH and FPMC), Rotterdam, the Netherlands, and the Netherlands Organisation for Scientific Research (ZonMw Topsubsidy grant 91209047 to FPMC and AIdH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 3 Z9 3 U1 1 U2 2 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 AUG 21 PY 2012 VL 7 IS 8 AR e43251 DI 10.1371/journal.pone.0043251 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992PA UT WOS:000307789700029 PM 22927954 ER PT J AU Cannon, CP Kohli, P AF Cannon, Christopher P. Kohli, Payal TI Danger Ahead: Watch Out for Indirect Comparisons! SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE anticoagulation; atrial fibrillation; bleeding; stroke ID ACUTE MYOCARDIAL-INFARCTION; TISSUE PLASMINOGEN-ACTIVATOR; ATRIAL-FIBRILLATION; WARFARIN; ANISTREPLASE; THROMBOLYSIS C1 [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Kohli, Payal] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org NR 10 TC 12 Z9 12 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 AUG 21 PY 2012 VL 60 IS 8 BP 747 EP 748 DI 10.1016/j.jacc.2012.05.012 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 988BS UT WOS:000307463800007 PM 22898071 ER PT J AU Ching, SN Brown, EN Kramer, MA AF Ching, ShiNung Brown, Emery N. Kramer, Mark A. TI Distributed control in a mean-field cortical network model: Implications for seizure suppression SO PHYSICAL REVIEW E LA English DT Article ID DESYNCHRONIZING BRAIN-STIMULATION; EPILEPTIFORM ACTIVITY; ELECTRIC-FIELDS; DYNAMICS; EPILEPSY; CONNECTIVITY; OSCILLATORS; POPULATIONS; MODULATION; PARAMETERS AB Brain electrical stimulation (BES) has long been suggested as a means of controlling pathological brain activity. In epilepsy, control of a spatially localized source, the seizure focus, may normalize neuronal dynamics. Consequently, most BES research has been directed at controlling small, local, neuronal populations. At a higher level, pathological seizure activity can be viewed as a network event that may begin without a clear spatial focus or in multiple sites and spread rapidly through a distributed cortical network. In this paper, we begin to address the implications of local control in a network scenario. To do so, we explore the efficacy of local BES when deployed over a larger-scale neuronal network, for instance, using a grid of stimulating electrodes on the cortex. By introducing a mean-field model of neuronal interactions we are able to identify limitations in network controllability based on physiological constraints that suggest the need for more nuanced network control strategies. C1 [Ching, ShiNung; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ching, ShiNung; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kramer, Mark A.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Ching, SN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM shinung@mit.edu RI Kramer, Mark/A-1291-2014 FU Burroughs Wellcome Fund; NIH [DP1-OD003646] FX M.A.K. and S.C. acknowledge support through Career Awards at the Scientific Interface from the Burroughs Wellcome Fund. S.C. and E.N.B. are supported in part by NIH DP1-OD003646. NR 35 TC 15 Z9 15 U1 0 U2 3 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD AUG 21 PY 2012 VL 86 IS 2 AR 021920 DI 10.1103/PhysRevE.86.021920 PN 1 PG 8 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 992BQ UT WOS:000307750700003 PM 23005798 ER PT J AU Roseman, M Turner, EH Lexchin, J Coyne, JC Bero, LA Thombs, BD AF Roseman, Michelle Turner, Erick H. Lexchin, Joel Coyne, James C. Bero, Lisa A. Thombs, Brett D. TI Reporting of conflicts of interest from drug trials in Cochrane reviews: cross sectional study SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID SYSTEMATIC REVIEWS; PHARMACEUTICAL-INDUSTRY; RANDOMIZED-TRIALS; PRISMA STATEMENT; FINANCIAL TIES; METAANALYSES; QUALITY; IMPACT; CONCLUSIONS; PUBLICATION AB Objectives To investigate the degree to which Cochrane reviews of drug interventions published in 2010 reported conflicts of interest from included trials and, among reviews that reported this information, where it was located in the review documents. Design Cross sectional study. Data sources Cochrane Database of Systematic Reviews. Selection criteria Systematic reviews of drug interventions published in 2010 in the Cochrane Database of Systematic Reviews, with review content classified as up to date in 2008 or later and with results from one or more randomised controlled trials. Results Of 151 included Cochrane reviews, 46 (30%, 95% confidence interval 24% to 38%) reported information on the funding sources of included trials, including 30 (20%, 14% to 27%) that reported information on trial funding for all included trials and 16 (11%, 7% to 17%) that reported for some, but not all, trials. Only 16 of the 151 Cochrane reviews (11%, 7% to 17%) provided any information on trial author-industry financial ties or trial author-industry employment. Information on trial funding and trial author-industry ties was reported in one to seven locations within each review, with no consistent reporting location observed. Conclusions Most Cochrane reviews of drug trials published in 2010 did not provide information on trial funding sources or trial author-industry financial ties or employment. When this information was reported, location of reporting was inconsistent across reviews. C1 [Roseman, Michelle; Thombs, Brett D.] Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E4, Canada. [Roseman, Michelle; Thombs, Brett D.] McGill Univ, Montreal, PQ H3T 1E4, Canada. [Turner, Erick H.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turner, Erick H.] Portland VA Med Ctr, Portland, OR USA. [Lexchin, Joel] York Univ, Sch Hlth Policy & Management, Toronto, ON M3J 2R7, Canada. [Coyne, James C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci, Hlth Psychol Sect, NL-9700 AB Groningen, Netherlands. [Bero, Lisa A.] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA. [Bero, Lisa A.] Univ Calif San Francisco, Sch Med, Inst Hlth Policy Studies, San Francisco, CA 94143 USA. RP Thombs, BD (reprint author), Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E4, Canada. EM brett.thombs@mcgill.ca OI Turner, Erick/0000-0002-3522-3357; Thombs, Brett/0000-0002-5644-8432 FU Canadian Institutes of Health Research; Fonds de la Recherche en Sante Quebec; McGill University provost's graduate fellowship; McGill University principal's graduate fellowship; Etablissement de Jeunes Chercheurs award from the Fonds de la Recherche en Sante Quebec; Cochrane Collaboration Methodological Fund FX MR was supported by a Frederick Banting and Charles Best Canadian graduate scholarship-master's award from the Canadian Institutes of Health Research, a master's training award from the Fonds de la Recherche en Sante Quebec, a McGill University provost's graduate fellowship, and a McGill University principal's graduate fellowship. BDT was supported by a new investigator award from the Canadian Institutes of Health Research and an Etablissement de Jeunes Chercheurs award from the Fonds de la Recherche en Sante Quebec. This study received no funding, and no funding body had any input into any aspect of the study.; All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: no authors had any financial support for the submitted work; JL was a consultant to a law firm representing Apotex in 2007, a consultant to the Canadian federal government in a lawsuit challenging the Canadian ban on direct to consumer advertising of prescription drugs in 2007-08, and a consultant to a law firm representing a plaintiff in a case against Allergan in 2010; LAB has received a grant from the Cochrane Collaboration Methodological Fund to examine how systematic reviewers identify unpublished drug trial data, and is an active member of the Cochrane Collaboration. NR 44 TC 18 Z9 18 U1 1 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD AUG 21 PY 2012 VL 345 AR e5155 DI 10.1136/bmj.e5155 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 996GP UT WOS:000308073200004 PM 22906823 ER PT J AU Wesemann, DR Portuguese, AJ Magee, JM Gallagher, MP Zhou, XL Panchakshari, RA Alt, FW AF Wesemann, Duane R. Portuguese, Andrew J. Magee, Jennifer M. Gallagher, Michael P. Zhou, Xiaolong Panchakshari, Rohit A. Alt, Frederick W. TI Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MU REGION; S-MU; RECOMBINATION; GENERATION; DNA; FIBROBLASTS; LYMPHOCYTES; MICE; TRANSCRIPTION; MUTATIONS AB Induced pluripotent stem cells (iPSCs) can be formed from somatic cells by a defined set of genetic factors; however, aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster often hinders their developmental potency and ability to contribute to high-grade chimerism in mice. Here, we describe an approach that allows splenic B cells activated to undergo Ig heavy-chain (IgH) class-switch recombination (CSR) to be reprogrammed into iPSCs that contribute to high-grade chimerism in mice. Treatment of naive splenic B cells in culture with anti-CD40 plus IL-4 induces IgH CSR from IgM to IgG1 and IgE. CSR leads to irreversible IgH locus deletions wherein the IgM-producing C mu exons are permanently excised from the B-cell genome. We find that anti-CD40 plus IL-4-activated B cells produce iPSCs that are uniformly hypermethylated in the imprinted Dlk1-Dio3 gene cluster and fail to produce chimerism in mice. However, treatment of activated B cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine before and at early stages of reprogramming attenuates hypermethylation of the Dlk1-Dio3 locus in resultant iPSCs and enables them to form high-grade chimerism in mice. These conditions allowed us to produce chimeric mice in which all mature B cells were derived entirely from IgG1-expressing B-cell-derived iPSCs. We conclude that culture conditions of activated B cells before and at early stages of reprogramming influence the developmental potency of resultant iPSCs. C1 [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Boston Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wesemann, Duane R.; Portuguese, Andrew J.; Magee, Jennifer M.; Gallagher, Michael P.; Zhou, Xiaolong; Panchakshari, Rohit A.; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. RP Wesemann, DR (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM wesemann@idi.harvard.edu; alt@enders.tch.harvard.edu OI Zhou, Alan/0000-0002-6177-2472 FU National Institutes of Health [AI077595, AI020047, K08AI89972]; American Academy of Allergy, Asthma Immunology; Burroughs Wellcome Fund FX We thank Drs. Hidde Ploegh, Juan Lafaille, and David Schatz for critical review of the manuscript. We thank K. Hochedlinger and M. Stadtfeld for the doxycycline-inducible reprogrammable OKSM transgenic mice and for technical advice in the reprogramming procedure. This work was supported by National Institutes of Health Grants AI077595 and AI020047 (to F.W.A.) and K08AI89972 (to D.R.W.). D.R.W. was also supported by an award from the American Academy of Allergy, Asthma & Immunology and CSL Behring and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. F.W.A. is an Investigator of the Howard Hughes Medical Institute. NR 44 TC 8 Z9 8 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 21 PY 2012 VL 109 IS 34 BP 13745 EP 13750 DI 10.1073/pnas.1210286109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996KJ UT WOS:000308085200061 PM 22869756 ER PT J AU Thon, JN Peters, CG Machlus, KR Aslam, R Rowley, J Macleod, H Devine, MT Fuchs, TA Weyrich, AS Semple, JW Flaumenhaft, R Italiano, JE AF Thon, Jonathan N. Peters, Christopher G. Machlus, Kellie R. Aslam, Rukhsana Rowley, Jesse Macleod, Hannah Devine, Matthew T. Fuchs, Tobias A. Weyrich, Andrew S. Semple, John W. Flaumenhaft, Robert Italiano, Joseph E., Jr. TI T granules in human platelets function in TLR9 organization and signaling SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PROTEIN-DISULFIDE-ISOMERASE; BACTERIAL-DNA; ACTIVATED PLATELETS; BLOOD-PLATELETS; PLASMA-MEMBRANE; IN-VIVO; RECOGNITION; SURFACE; MEGAKARYOCYTES; LOCALIZATION AB Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tubular system-related compartment we have named the T granule. TLR9 colocalizes with protein disulfide isomerase and is associated with either VAMP 7 or VAMP 8, which regulates its distribution in PLTs on contact activation (spreading). Preincubation of PLTs with type IV collagen specifically increased TLR9 and CD62P surface expression and augmented oligodeoxy-nucleotide (ODN) sequestration and PLT clumping upon addition of bacterial/viral ODNs. Collectively, this paper (a) tracks TLR9 to a new intracellular compartment in PLTs and (b) describes a novel mechanism of TLR9 organization and signaling in human PLTs. C1 [Thon, Jonathan N.; Machlus, Kellie R.; Macleod, Hannah; Devine, Matthew T.; Italiano, Joseph E., Jr.] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Thon, Jonathan N.; Peters, Christopher G.; Machlus, Kellie R.; Flaumenhaft, Robert; Italiano, Joseph E., Jr.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Fuchs, Tobias A.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Aslam, Rukhsana; Semple, John W.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto Platelet Immunobiol Grp, Toronto, ON M5B 1W8, Canada. [Rowley, Jesse; Weyrich, Andrew S.] Univ Utah, Program Mol Med, Salt Lake City, UT 84112 USA. [Peters, Christopher G.; Fuchs, Tobias A.] Immune Dis Inst, Boston, MA 02115 USA. [Fuchs, Tobias A.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Flaumenhaft, Robert] Beth Israel Deaconess Med Ctr, Dept Med, Div Hemostasis & Thrombosis, Boston, MA 02115 USA. [Italiano, Joseph E., Jr.] Childrens Hosp, Dept Surg, Vasc Biol Program, Boston, MA 02115 USA. RP Italiano, JE (reprint author), Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. EM jitaliano@rics.bwh.harvard.edu RI Fuchs, Tobias/F-1189-2013; OI Machlus, Kellie/0000-0002-2155-1050 FU National Institutes of Health [Hl68130]; National Institutes of Health NHLBI [HL102101] FX This work was supported in part by the National Institutes of Health grant Hl68130 (to J.E. Italiano Jr.). J.E. Italiano Jr. is an American Society of Hematology Junior Faculty Scholar. J.N. Thon is an American Society of Hematology Scholar. T. A. Fuchs is supported by the National Institutes of Health NHLBI R01 grant HL102101 (to D.D. Wagner). NR 41 TC 50 Z9 50 U1 1 U2 11 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 AUG 20 PY 2012 VL 198 IS 4 BP 561 EP 574 DI 10.1083/jcb.201111136 PG 14 WC Cell Biology SC Cell Biology GA 994LL UT WOS:000307932200010 PM 22908309 ER PT J AU Garraway, LA AF Garraway, Levi A. TI Concordance and Discordance in Tumor Genomic Profiling SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID MUTATIONS; CANCER; SAMPLES C1 [Garraway, Levi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Garraway, Levi A.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Garraway, Levi A.] MIT, Cambridge, MA 02139 USA. RP Garraway, LA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 7 TC 9 Z9 9 U1 0 U2 0 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 AUG 20 PY 2012 VL 30 IS 24 BP 2937 EP 2939 DI 10.1200/JCO.2011.41.3138 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300005 PM 22826272 ER PT J AU Ligibel, JA Winer, EP AF Ligibel, Jennifer A. Winer, Eric P. TI Aromatase Inhibition in Obese Women: How Much Is Enough? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADVANCED BREAST-CANCER; PLASMA ESTROGEN-LEVELS; BODY-MASS INDEX; ADJUVANT ENDOCRINE THERAPY; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; MEGESTROL-ACETATE; DOUBLE-BLIND; FASTING INSULIN; PHASE-III C1 [Ligibel, Jennifer A.] Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ligibel, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 32 TC 9 Z9 9 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 AUG 20 PY 2012 VL 30 IS 24 BP 2940 EP 2942 DI 10.1200/JCO.2012.43.7244 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300006 PM 22802318 ER PT J AU McElligott, S Field, RI Bristol-Demeter, M Domchek, SM Asch, DA AF McElligott, Sean Field, Robert I. Bristol-Demeter, Mirar Domchek, Susan M. Asch, David A. TI How Genetic Variant Libraries Effectively Extend Gene Testing Patents: Implications for Intellectual Property and Good Clinical Care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID UNCERTAIN SIGNIFICANCE; SEQUENCE VARIATION; BRCA2 VARIANTS; RISK C1 [McElligott, Sean; Bristol-Demeter, Mirar; Asch, David A.] Univ Penn, Philadelphia, PA 19104 USA. [Field, Robert I.] Drexel Univ, Philadelphia, PA 19104 USA. [Domchek, Susan M.] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP McElligott, S (reprint author), Univ Penn, Philadelphia, PA 19104 USA. OI Asch, David/0000-0002-7970-286X FU NCI NIH HHS [UC2 CA148310] NR 10 TC 1 Z9 2 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 AUG 20 PY 2012 VL 30 IS 24 BP 2943 EP 2945 DI 10.1200/JCO.2012.42.7757 PG 3 WC Oncology SC Oncology GA 996JR UT WOS:000308082300007 PM 22802312 ER PT J AU Chan, JA Stuart, K Earle, CC Clark, JW Bhargava, P Miksad, R Blaszkowsky, L Enzinger, PC Meyerhardt, JA Zheng, H Fuchs, CS Kulke, MH AF Chan, Jennifer A. Stuart, Keith Earle, Craig C. Clark, Jeffrey W. Bhargava, Pankaj Miksad, Rebecca Blaszkowsky, Lawrence Enzinger, Peter C. Meyerhardt, Jeffrey A. Zheng, Hui Fuchs, Charles S. Kulke, Matthew H. TI Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PANCREATIC ENDOCRINE CARCINOMAS; ISLET-CELL-CARCINOMA; PHASE-II TRIAL; STREPTOZOCIN; FLUOROURACIL; DOXORUBICIN; ONCOLOGY; THERAPY; DACARBAZINE AB Purpose Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. Patients and Methods Thirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m(2) orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival. Results The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). Conclusion Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted. C1 [Chan, Jennifer A.; Earle, Craig C.; Bhargava, Pankaj; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA USA. [Chan, Jennifer A.; Earle, Craig C.; Bhargava, Pankaj; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Kulke, Matthew H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Stuart, Keith; Miksad, Rebecca] Deaconess Med Ctr, Boston, MA USA. [Clark, Jeffrey W.; Blaszkowsky, Lawrence] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Chan, Jennifer A.; Stuart, Keith; Earle, Craig C.; Clark, Jeffrey W.; Bhargava, Pankaj; Miksad, Rebecca; Blaszkowsky, Lawrence; Enzinger, Peter C.; Meyerhardt, Jeffrey A.; Zheng, Hui; Fuchs, Charles S.; Kulke, Matthew H.] Harvard Univ, Sch Med, Boston, MA USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM jang@partners.org OI Miksad, Rebecca/0000-0003-3194-5122 FU Schering-Plough/Merck; Genentech; Merck; Novartis; Onyx Pharmaceuticals; Bayer FX Supported by Genentech and Schering-Plough/Merck.; Research Funding: Jennifer A. Chan, Bayer, Merck, Novartis, Onyx Pharmaceuticals NR 18 TC 92 Z9 94 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2012 VL 30 IS 24 BP 2963 EP 2968 DI 10.1200/JCO.2011.40.3147 PG 6 WC Oncology SC Oncology GA 996JR UT WOS:000308082300010 PM 22778320 ER PT J AU Basch, E Oliver, TK Vickers, A Thompson, I Kantoff, P Parnes, H Loblaw, DA Roth, B Williams, J Nam, RK AF Basch, Ethan Oliver, Thomas K. Vickers, Andrew Thompson, Ian Kantoff, Philip Parnes, Howard Loblaw, D. Andrew Roth, Bruce Williams, James Nam, Robert K. TI Screening for Prostate Cancer With Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SERVICES-TASK-FORCE; FOLLOW-UP; CONSERVATIVE MANAGEMENT; MORTALITY; COMPLICATIONS; STATISTICS; OUTCOMES; BIOPSY; RISK AB Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer. Clinical Context Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection. Recent Data Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic. Results In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern. C1 [Oliver, Thomas K.; Nam, Robert K.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. [Basch, Ethan; Vickers, Andrew] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Thompson, Ian] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Kantoff, Philip] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Parnes, Howard] NCI, Rockville, MD USA. [Loblaw, D. Andrew; Nam, Robert K.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Odette Canc Ctr, Toronto, ON, Canada. [Roth, Bruce] Washington Univ, St Louis, MO USA. [Williams, James] Penn Prostate Canc Coalit, Camp Hill, PA USA. RP Nam, RK (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org OI Vickers, Andrew/0000-0003-1525-6503 NR 46 TC 65 Z9 69 U1 0 U2 15 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 AUG 20 PY 2012 VL 30 IS 24 BP 3020 EP 3025 DI 10.1200/JCO.2012.43.3441 PG 6 WC Oncology SC Oncology GA 996JR UT WOS:000308082300018 PM 22802323 ER PT J AU Hardin, C Tambe, D Zhou, EH Krishnan, R Butler, JP Fredberg, J AF Hardin, Corey Tambe, Dhananjay Zhou, Enhua Krishnan, Ramachandran Butler, James P. Fredberg, Jeffrey TI Jamming and glass transitions in cell mechanics: From single cells to tissues SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc, Amer Chem Soc, Div Chem Educ, Amer Chem Soc, Div Inorgan Chem, Soc Biol Inorgan Chem, Amer Chem Soc, Div Polymer Chem Inc C1 [Tambe, Dhananjay; Zhou, Enhua; Butler, James P.; Fredberg, Jeffrey] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hardin, Corey] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. [Krishnan, Ramachandran] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol, Boston, MA 02115 USA. EM chardin@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 103-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621807266 ER PT J AU Lin, LL Tiemann, K Li, YL Heo, GS Lim, Y Pinkner, J Walker, J Hultgren, S Hunstad, D Wooley, K AF Lin, Lily Tiemann, Kristin Li, Yali Heo, Gyu Seong Lim, Young Pinkner, Jerome Walker, Jennifer Hultgren, Scott Hunstad, David Wooley, Karen TI Bacterial adhesin protein-conjugated polymer nanoparticles as antimicrobial nanodevices that utilize bacterial modes of epithelial cell entry for effective treatment strategies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lin, Lily; Heo, Gyu Seong; Lim, Young; Wooley, Karen] Texas A&M Univ, Dept Chem, College Stn, TX 77842 USA. [Tiemann, Kristin; Pinkner, Jerome; Walker, Jennifer; Hultgren, Scott; Hunstad, David] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Li, Yali] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02129 USA. EM wooley@chem.tamu.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 319-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621808477 ER PT J AU Liong, M Lee, H Weissleder, R AF Liong, Monty Lee, Hakho Weissleder, Ralph TI Multiplexed labeling and signal amplification in diagnostic magnetic resonance SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liong, Monty; Lee, Hakho; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM liong.monty@gmail.com NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 142-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802344 ER PT J AU Liong, M AF Liong, Monty TI Inorganic nanomaterials: Functional scaffold in therapeutics and diagnostics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liong, Monty] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM liong.monty@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 37-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800036 ER PT J AU Liu, R Rallo, R Shaw, S Cohen, Y AF Liu, Rong Rallo, Robert Shaw, Stanley Cohen, Yoram TI Nano-SAR development with application to regulatory decision making SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Liu, Rong; Rallo, Robert; Cohen, Yoram] Univ Calif Los Angeles, Ctr Environm Implicat Nanotechnol, Los Angeles, CA 90095 USA. [Shaw, Stanley] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM rongliu@ucla.edu RI Rallo, Robert/F-4703-2010 OI Rallo, Robert/0000-0003-3812-4458 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 360-ENVR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621804560 ER PT J AU Lusic, H Freedman, JD Snyder, BD Grinstaff, MW AF Lusic, Hrvoje Freedman, Jonathan D. Snyder, Brian D. Grinstaff, Mark W. TI X-ray computed tomography contrast agents for cartilage imaging SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Lusic, Hrvoje; Freedman, Jonathan D.; Grinstaff, Mark W.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Lusic, Hrvoje; Freedman, Jonathan D.; Grinstaff, Mark W.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Snyder, Brian D.] Harvard Univ, Sch Med, Beth Israel Deacones Med Ctr, Boston, MA 02215 USA. EM hlusic@bu.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 534-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621806734 ER PT J AU Perrault, SD Shih, WM AF Perrault, Steven D. Shih, Willam M. TI Directed assembly of lipid bilayers onto 3D DNA nanostructures SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Perrault, Steven D.; Shih, Willam M.] Harvard Univ, Wyss Inst Biol Inspired Engn, Cambridge, MA 02138 USA. [Perrault, Steven D.; Shih, Willam M.] Dana Farber Canc Inst, Boston, MA 02115 USA. EM steven.perrault@wyss.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 463-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621802646 ER PT J AU Sears, RB AF Sears, R. Bryan TI Development of novel therapeutics, combinations, and formulations of photodynamic therapy agents for the treatment of cancers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Sears, R. Bryan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. EM Sears.Bryan@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 43-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800041 ER PT J AU Tamae, D Byrns, MC Balk, SP Nelson, PS Montgomery, B Mostaghel, E Kantoff, P Taplin, ME Blair, IA Penning, TM AF Tamae, Daniel Byrns, Michael C. Balk, Steven P. Nelson, Peter S. Montgomery, Bruce Mostaghel, Elahe Kantoff, Philip Taplin, Mary-Ellen Blair, Ian A. Penning, Trevor M. TI Development of stable isotope dilution liquid chromatography tandem mass spectrometry (LS-MS/MS) methods for the determination of the androgen metabolome in serum following androgen deprivation therapy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 244th National Fall Meeting of the American-Chemical-Society (ACS) CY AUG 19-23, 2012 CL Philadelphia, PA SP Amer Chem Soc, Div Hist Chem, Amer Chem Soc C1 [Tamae, Daniel; Byrns, Michael C.; Blair, Ian A.; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Ctr Excellence Environm Toxicol, Philadelphia, PA 19104 USA. [Tamae, Daniel; Byrns, Michael C.; Blair, Ian A.; Penning, Trevor M.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Ctr Excellence Canc Pharmacol, Philadelphia, PA 19104 USA. [Balk, Steven P.; Nelson, Peter S.; Kantoff, Philip; Taplin, Mary-Ellen] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Boston, MA USA. [Balk, Steven P.; Nelson, Peter S.; Kantoff, Philip; Taplin, Mary-Ellen] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Montgomery, Bruce; Mostaghel, Elahe] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. EM dtamae@mail.med.upenn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2012 VL 244 MA 39-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 220XX UT WOS:000324621800817 ER PT J AU Matzuk, MM McKeown, MR Filippakopoulos, P Li, QL Ma, L Agno, JE Lemieux, ME Picaud, S Yu, RN Qi, J Knapp, S Bradner, JE AF Matzuk, Martin M. McKeown, Michael R. Filippakopoulos, Panagis Li, Qinglei Ma, Lang Agno, Julio E. Lemieux, Madeleine E. Picaud, Sarah Yu, Richard N. Qi, Jun Knapp, Stefan Bradner, James E. TI Small-Molecule Inhibition of BRDT for Male Contraception SO CELL LA English DT Article ID BET BROMODOMAINS; 1ST BROMODOMAIN; BINDING; TESTIS; MYC; DIFFERENTIATION; IDENTIFICATION; INFERTILITY; EXPRESSION; CHROMATIN AB A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood: testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. C1 [Matzuk, Martin M.; Ma, Lang; Agno, Julio E.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA. [Matzuk, Martin M.] Baylor Coll Med, Ctr Reprod Med, Houston, TX 77030 USA. [McKeown, Michael R.; Lemieux, Madeleine E.; Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Filippakopoulos, Panagis; Picaud, Sarah; Knapp, Stefan] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England. [Li, Qinglei] Texas A&M Univ, Dept Vet Integrat Biosci, Coll Vet Med & Biomed Sci, College Stn, TX 77843 USA. [Lemieux, Madeleine E.] Bioinfo, Ottawa, ON K1J 8G4, Canada. [Yu, Richard N.] Childrens Hosp, Dept Urol, Boston, MA 02115 USA. [Knapp, Stefan] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Matzuk, MM (reprint author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. EM mmatzuk@bcm.edu; james_bradner@dfci.harvard.edu OI Lemieux, Madeleine/0000-0001-6355-8691; Filippakopoulos, Panagis/0000-0002-1515-1317; Knapp, Stefan/0000-0001-5995-6494 FU Eunice Kennedy Shriver NICHD/NIH [U01-HD060496]; Alkek Award for Pilot Projects in Experimental Therapeutics; Fidelity Foundation; Burroughs Wellcome Fund; NIH [K08CA128972]; Smith Family Foundation; Damon-Runyon Cancer Research Foundation; CIHR [1097737]; Canada Foundation for Innovation; Genome Canada; GlaxoSmithKline; Pfizer; Eli Lilly; Abbott; Takeda; Novartis Research Foundation; Ontario Ministry of Research and Innovation; Wellcome Trust; Wellcome Trust Career Development Fellowship [095751/Z/11/Z]; NICHD (SCCPRR) [U54-HD28934] FX We are grateful to Drs. J. Brown and J. Plutzky for pharmacodynamic data; Dr. A. Roy for advice on the spermatozoa assays; Y. Vasquez and Dr. Z. Yu for technical help; J. Marineau, K. Shaw, and W. Smith for support of peptide synthesis; Dr. S. Kistler for the generous gift of the anti-TNP2 antibody; and Dr. S. Khochbin for helpful comments. These studies were supported, in part, by the Eunice Kennedy Shriver NICHD/NIH through cooperative agreement U01-HD060496 as part of the Cooperative Program in Male Contraception; an Alkek Award for Pilot Projects in Experimental Therapeutics; and a grant from the Fidelity Foundation (to M. M. M.), the Burroughs Wellcome Fund, the NIH (K08CA128972), the Smith Family Foundation, and Damon-Runyon Cancer Research Foundation (to J. E. B.). The SGC is a registered charity (number 1097737) that receives funds from the CIHR, Canada Foundation for Innovation, Genome Canada, GlaxoSmithKline, Pfizer, Eli Lilly, Abbott, Takeda, Novartis Research Foundation, Ontario Ministry of Research and Innovation, and Wellcome Trust. P. F. is supported by a Wellcome Trust Career Development Fellowship (095751/Z/11/Z). Serum FSH, LH, and testosterone analyses were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core supported by NICHD (SCCPRR) grant U54-HD28934. Baylor College of Medicine and Dana-Farber Cancer Institute have filed patent applications on technologies relating to this work, which have been licensed to Tensha Therapeutics. NR 29 TC 142 Z9 148 U1 5 U2 73 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 17 PY 2012 VL 150 IS 4 BP 673 EP 684 DI 10.1016/j.cell.2012.06.045 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 995IT UT WOS:000308002300004 PM 22901802 ER PT J AU Nijhawan, D Zack, TI Ren, Y Strickland, MR Lamothe, R Schumacher, SE Tsherniak, A Besche, HC Rosenbluh, J Shehata, S Cowley, GS Weir, BA Goldberg, AL Mesirov, JP Root, DE Bhatia, SN Beroukhim, R Hahn, WC AF Nijhawan, Deepak Zack, Travis I. Ren, Yin Strickland, Matthew R. Lamothe, Rebecca Schumacher, Steven E. Tsherniak, Aviad Besche, Henrike C. Rosenbluh, Joseph Shehata, Shyemaa Cowley, Glenn S. Weir, Barbara A. Goldberg, Alfred L. Mesirov, Jill P. Root, David E. Bhatia, Sangeeta N. Beroukhim, Rameen Hahn, William C. TI Cancer Vulnerabilities Unveiled by Genomic Loss SO CELL LA English DT Article ID COPY-NUMBER ALTERATION; OVARIAN-CANCER; PROTEASOMAL ATPASES; ONCOGENE ADDICTION; DRUG-SENSITIVITY; LUNG-CANCER; CELLS; GENE; IDENTIFICATION; THERAPY AB Due to genome instability, most cancers exhibit loss of regions containing tumor suppressor genes and collateral loss of other genes. To identify cancer-specific vulnerabilities that are the result of copy number losses, we performed integrated analyses of genome-wide copy number and RNAi profiles and identified 56 genes for which gene suppression specifically inhibited the proliferation of cells harboring partial copy number loss of that gene. These CYCLOPS (copy number alterations yielding cancer liabilities owing to partial loss) genes are enriched for spliceosome, proteasome, and ribosome components. One CYCLOPS gene, PSMC2, encodes an essential member of the 19S proteasome. Normal cells express excess PSMC2, which resides in a complex with PSMC1, PSMD2, and PSMD5 and acts as a reservoir protecting cells from PSMC2 suppression. Cells harboring partial PSMC2 copy number loss lack this complex and die after PSMC2 suppression. These observations define a distinct class of cancer-specific liabilities resulting from genome instability. C1 [Nijhawan, Deepak; Zack, Travis I.; Strickland, Matthew R.; Lamothe, Rebecca; Schumacher, Steven E.; Rosenbluh, Joseph; Shehata, Shyemaa; Beroukhim, Rameen; Hahn, William C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Nijhawan, Deepak; Zack, Travis I.; Strickland, Matthew R.; Lamothe, Rebecca; Schumacher, Steven E.; Rosenbluh, Joseph; Shehata, Shyemaa; Beroukhim, Rameen; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Nijhawan, Deepak; Zack, Travis I.; Schumacher, Steven E.; Tsherniak, Aviad; Rosenbluh, Joseph; Cowley, Glenn S.; Weir, Barbara A.; Mesirov, Jill P.; Root, David E.; Bhatia, Sangeeta N.; Beroukhim, Rameen; Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Zack, Travis I.] Harvard Univ, Biophys Program, Boston, MA 02115 USA. [Besche, Henrike C.; Goldberg, Alfred L.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ren, Yin; Bhatia, Sangeeta N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Nijhawan, Deepak; Rosenbluh, Joseph; Bhatia, Sangeeta N.; Beroukhim, Rameen; Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bhatia, Sangeeta N.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Beroukhim, R (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM rameen_beroukhim@dfci.harvard.edu; william_hahn@dfci.harvard.edu RI Schumacher, Steven/E-9821-2013 OI Schumacher, Steven/0000-0002-6819-5647 FU NIH/NCI [RC2 CA148268, U54 CA143798, K08 CA122833, T32 GM008313, RO1 GM051923-17, U54 CA112962]; H.L. Snyder Medical Foundation; V Foundation; Conquer Cancer Foundation Young Investigator Award; Sass Foundation Fellowship; Marie D. & Pierre Casimir-Lambert Fund FX We would like to thank Leslie Gaffney and Lauren Solomon for support in generating illustrations and graphics and Jesse Boehm, Scott Carter, George Demartino, and members of the Goldberg and Hahn lab for helpful discussion. This work was supported in part by NIH/NCI grants RC2 CA148268 (W. C. H.), U54 CA143798, K08 CA122833 (R. B.), T32 GM008313 (T.I.Z.), RO1 GM051923-17 (A. L. G and H. C. B.), and U54 CA112962 (A. T., J.P.M., W. C. H.), the H.L. Snyder Medical Foundation (W. C. H.), the V Foundation (R. B.), a Conquer Cancer Foundation Young Investigator Award (D.N.), Sass Foundation Fellowship (D.N.), and the Marie D. & Pierre Casimir-Lambert Fund. S.N.B. is a Howard Hughes Investigator. W. C. H. and R. B. are consultants for Novartis Pharmaceuticals. NR 35 TC 64 Z9 65 U1 1 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 17 PY 2012 VL 150 IS 4 BP 842 EP 854 DI 10.1016/j.cell.2012.07.023 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 995IT UT WOS:000308002300017 PM 22901813 ER PT J AU Hom, JK Wang, BX Chetty, S Giddy, J Mazibuko, M Allen, J Walensky, RP Losina, E Freedberg, KA Bassett, IV AF Hom, Jeffrey K. Wang, Bingxia Chetty, Senica Giddy, Janet Mazibuko, Matilda Allen, Jenny Walensky, Rochelle P. Losina, Elena Freedberg, Kenneth A. Bassett, Ingrid V. TI Drug-Resistant Tuberculosis among HIV-Infected Patients Starting Antiretroviral Therapy in Durban, South Africa SO PLOS ONE LA English DT Article ID MULTIDRUG-RESISTANT; EPIDEMIC AB Objective: To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa. Design: Cross-sectional cohort study. Methods: Consecutive HIV-infected adults (>= 18y/o) initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first-and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed. Results: 1,035 subjects had complete culture results. Median CD4 count was 92/mu l (IQR 42-150/mu l). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5) compared to 5.2% (95% CI 2.1-8.9) among those with no prior TB. 5.1% (95% CI 2.4-9.5) had rifampin or rifampin plus INH resistance. Conclusions: The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence. C1 [Hom, Jeffrey K.; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Bingxia; Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chetty, Senica; Giddy, Janet; Mazibuko, Matilda] McCord Hosp, Durban, South Africa. [Allen, Jenny] Univ KwaZulu Natal, Microbiol Lab, Durban, South Africa. [Allen, Jenny] MRC, Durban, South Africa. [Walensky, Rochelle P.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped, Boston, MA 02115 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.; Bassett, Ingrid V.] Harvard Univ, Harvard Ctr AIDS Res CFAR, Boston, MA 02115 USA. RP Hom, JK (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM ibassett@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU Infectious Disease Society of America Education and Research Foundation; National Institute of Allergy and Infectious Disease [K23 AI 068458, R01 AI058736, K24 AI062476]; National Institute of Mental Health [R01 MH073445, R01MH90326]; Claflin Distinguished Scholar Award; Burke Global Health Fellowship; Doris Duke Charitable Foundation; ORACTA Award FX This work was supported in part by: The Infectious Disease Society of America Education and Research Foundation (JKH) (http://www.idsociety.org/Index.aspx); The National Institute of Allergy and Infectious Disease: K23 AI 068458 (IVB) (http://www.niaid.nih.gov/Pages/default.aspx); A PEPFAR supplement to R01 AI058736 (KAF); K24 AI062476 (KAF) (http://www.pepfar.gov/); The National Institute of Mental Health: R01 MH073445 (RPW); R01MH90326 (IVB) (http://www.nimh.nih.gov/index.shtml); The Claflin Distinguished Scholar Award (IVB) (http://www.massgeneral.org/digestive/news/newsarticle.aspx?id=2850); The Burke Global Health Fellowship (IVB) (http://globalhealth.harvard.edu/icb/icb.do?keyword=k16925&pageid=icb.pa ge240155) and the Doris Duke Charitable Foundation Clinical Scientist Development Award (RPW) and ORACTA Award (KAF) (http://www.ddcf.org/Grants-Awarded/). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 1 Z9 1 U1 0 U2 3 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 AUG 17 PY 2012 VL 7 IS 8 AR e43281 DI 10.1371/journal.pone.0043281 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 996DG UT WOS:000308063700074 PM 22912845 ER PT J AU Zhang, GT Liu, RJ Zhong, YF Plotnikov, AN Zhang, WJ Zeng, L Rusinova, E Gerona-Nevarro, G Moshkina, N Joshua, J Chuang, PY Ohlmeyer, M He, JC Zhou, MM AF Zhang, Guangtao Liu, Ruijie Zhong, Yifei Plotnikov, Alexander N. Zhang, Weijia Zeng, Lei Rusinova, Elena Gerona-Nevarro, Guillermo Moshkina, Natasha Joshua, Jennifer Chuang, Peter Y. Ohlmeyer, Michael He, John Cijiang Zhou, Ming-Ming TI Down-regulation of NF-kappa B Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUBULAR EPITHELIAL-CELLS; PROBE LEVEL DATA; DIABETIC-NEPHROPATHY; TRANSGENIC MICE; APOPTOSIS; ACTIVATION; INFECTION; THERAPY; NMR; GLOMERULOSCLEROSIS AB NF-kappa B-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-kappa B activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappa B transcriptional activity by small molecule blocking NF-kappa B binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription elongation factor b and RNA polymerase II. We showed that our BET (Bromodomain and Extra-Terminal domain)-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-kappa B, effectively attenuates NF-kappa B transcriptional activation of proinflammatory genes in kidney cells treated with TNF alpha or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at the proinflammatory activity of NF-kappa B, represents a new therapeutic approach for treating NF-kappa B-mediated inflammation and kidney injury in HIVAN. C1 [Zhang, Guangtao; Plotnikov, Alexander N.; Zeng, Lei; Rusinova, Elena; Gerona-Nevarro, Guillermo; Moshkina, Natasha; Joshua, Jennifer; Ohlmeyer, Michael; Zhou, Ming-Ming] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. [Liu, Ruijie; Zhang, Weijia; Chuang, Peter Y.; He, John Cijiang] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Liu, Ruijie; He, John Cijiang] James J Peters Vet Affairs Med Ctr, Dept Med, Bronx, NY 10486 USA. [Zhong, Yifei] Shanghai Univ Tradit Chinese Med, Longhua Hosp, Dept Nephrol, Shanghai 201203, Peoples R China. RP He, JC (reprint author), 1425 Madison Ave,Box 1677, New York, NY 10029 USA. EM cijiang.he@mssm.edu; ming-ming.zhou@mssm.edu RI Zhang, Guangtao/C-7341-2011 FU National Institutes of Health [HG004508, DK088541]; Veterans Affairs Merit Award [1I01BX000345] FX This work was supported, in whole or in part, by National Institutes of Health Grants HG004508 (to M.-M. Z.) and DK088541 (to J. C. H.). This work was also supported by Veterans Affairs Merit Award 1I01BX000345 (to J. C. H.). NR 53 TC 82 Z9 89 U1 2 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28840 EP 28851 DI 10.1074/jbc.M112.359505 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600056 PM 22645123 ER PT J AU Jeon, J Leibiger, I Moede, T Walter, B Faul, C Maiguel, D Villarreal, R Guzman, J Berggren, PO Mundel, P Ricordi, C Merscher-Gomez, S Fornoni, A AF Jeon, Jongmin Leibiger, Ingo Moede, Tilo Walter, Britta Faul, Christian Maiguel, Dony Villarreal, Rodrigo Guzman, Johanna Berggren, Per-Olof Mundel, Peter Ricordi, Camillo Merscher-Gomez, Sandra Fornoni, Alessia TI Dynamin-mediated Nephrin Phosphorylation Regulates Glucose-stimulated Insulin Release in Pancreatic Beta Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SLIT DIAPHRAGM; TYROSINE PHOSPHORYLATION; ACTIN REORGANIZATION; GLOMERULAR PODOCYTES; KIDNEY PODOCYTES; PROTEIN; SECRETION; KINASE; COMPLEX; POLYMERIZATION AB We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin-deficient pancreatic beta cells and human islets were transfected with WT-Nephrin or with a mutant Nephrin in which the tyrosine residues responsible for SH2 domain binding were substituted with phenylalanine (3YF-Nephrin). GSIR and live images of Nephrin and vesicle trafficking were studied. Immunoprecipitation experiments and overexpression of WT-Dynamin or dominant negative Dynamin mutant (K44A-Dynamin) in WT-Nephrin, 3YF-Nephrin, or Nephrin siRNA-transfected cells were utilized to study Nephrin-Dynamin interaction. In contrast to WT-Nephrin or to single tyrosine mutants, 3YF-Nephrin did not positively affect GSIR and led to impaired cell-cell contacts and vesicle trafficking. K44A-Dynamin prevented the effect of Nephrin on GSIR in the absence of protein-protein interaction between Nephrin and Dynamin. Nephrin gene silencing abolished the positive effects of WT-Dynamin on GSIR. The effects of protamine sulfate and vanadate on Nephrin phosphorylation and GSIR were studied in MIN6 cells and human islets. WT-Nephrin phosphorylation after glucose occurred at Tyr-1176/1193 and resulted in improved GSIR. On the contrary, protamine sulfate-induced phosphorylation at Tyr-1176/1193/1217 was associated with Nephrin degradation and impaired GSIR. Vanadate, which prevented Nephrin dephosphorylation after glucose stimulation, improved GSIR in human islets and MIN6 cells. In conclusion, Dynamin-dependent Nephrin phosphorylation occurs in response to glucose and is necessary for Nephrin-mediated augmentation of GSIR. Pharmacological modulation of Nephrin phosphorylation may thus facilitate pancreatic beta cell function. C1 [Jeon, Jongmin; Maiguel, Dony; Villarreal, Rodrigo; Guzman, Johanna; Berggren, Per-Olof; Ricordi, Camillo; Fornoni, Alessia] Univ Miami, L Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA. [Jeon, Jongmin; Walter, Britta; Faul, Christian; Maiguel, Dony; Villarreal, Rodrigo; Guzman, Johanna; Merscher-Gomez, Sandra; Fornoni, Alessia] Univ Miami, L Miller Sch Med, Div Nephrol & Hypertens, Dept Med, Miami, FL 33136 USA. [Leibiger, Ingo; Moede, Tilo; Berggren, Per-Olof] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, SE-17177 Stockholm, Sweden. [Mundel, Peter] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Fornoni, A (reprint author), Univ Miami, Miller Sch Med, Diabet Res Inst, 1450 NW 10th Ave, Miami, FL 33136 USA. EM afornoni@med.miami.edu RI Fornoni, Alessia/F-8350-2013; OI Moede, Tilo/0000-0002-2045-9244; Ricordi, Camillo/0000-0001-8092-7153 FU National Institutes of Health [DK82636, DK70460, U42 RR016603]; American Diabetes Association [7-09-JF-23]; Forest County Potawatomi Community Foundation; Max and Yetta Karasik Family Foundation; Diabetes Research Institute Foundation; Swedish Research Council; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Soderberg's Foundation; Swedish Diabetes Association; Family Erling-Persson Foundation; Peggy and Harold Katz Family Foundation; City of Hope, Duarte, CA FX This work was supported, in whole or in part, by National Institutes of Health Grants DK82636, DK70460, and U42 RR016603. This work was also supported by American Diabetes Association Grant 7-09-JF-23, the Forest County Potawatomi Community Foundation, the Max and Yetta Karasik Family Foundation, the Diabetes Research Institute Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Torsten and Ragnar Soderberg's Foundation, the Swedish Diabetes Association, the Family Erling-Persson Foundation, the Peggy and Harold Katz Family Foundation, and the City of Hope, Duarte, CA. NR 52 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2012 VL 287 IS 34 BP 28932 EP 28942 DI 10.1074/jbc.M112.389452 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 996HD UT WOS:000308074600062 PM 22718751 ER PT J AU Wang, JX Bair, AM King, SL Shnayder, R Huang, YF Shieh, CC Soberman, RJ Fuhlbrigge, RC Nigrovic, PA AF Wang, Jun-Xia Bair, Angela M. King, Sandra L. Shnayder, Ruslan Huang, Ya-Fang Shieh, Chi-Chang Soberman, Roy J. Fuhlbrigge, Robert C. Nigrovic, Peter A. TI Ly6G ligation blocks recruitment of neutrophils via a beta 2-integrin-dependent mechanism SO BLOOD LA English DT Article ID AUTOANTIBODY-MEDIATED ARTHRITIS; INFL AMMATORY ARTHRITIS; MAST-CELLS CONTRIBUTE; B-4 RECEPTORS BLT1; MOUSE BONE-MARROW; INFLAMMATORY ARTHRITIS; RHEUMATOID-ARTHRITIS; LEUKOTRIENE B-4; MEMBRANE ORGANIZATION; MONOCLONAL-ANTIBODY AB Ly6G is a glycosylphosphatidylinositol (GPI)-anchored protein of unknown function that is commonly targeted to induce experimental neutrophil depletion in mice. In the present study, we found that doses of anti-Ly6G Abs too low to produce sustained neutropenia remained capable of inhibiting experimental arthritis, leaving joint tissues free of infiltrating neutrophils. Thioglycollate-stimulated peritonitis was also attenuated. No alteration in neutrophil apoptosis was observed, implicating impaired recruitment. Indeed, Ly6G ligation abrogated neutrophil migration toward LTB4 and other chemoattractants in a transwell system. Exploring the basis for this blockade, we identified colocalization of Ly6G and beta 2-integrins by confocal microscopy and confirmed close association by both coimmunoprecipitation and fluorescence lifetime imaging microscopy. Anti-Ly6G Ab impaired surface expression of beta 2-integrins in LTB4-stimulated neutrophils and mimicked CD11a blockade in inhibiting both ICAM-1 binding and firm adhesion to activated endothelium under flow conditions. Correspondingly, migration of beta 2-integrin-deficient neutrophils was no longer inhibited by anti-Ly6G. These results demonstrate that experimental targeting of Ly6G has functional effects on the neutrophil population and identify a previously unappreciated role for Ly6G as a modulator of neutrophil migration to sites of inflammation via a beta 2-integrin-dependent mechanism. (Blood. 2012;120(7):1489-1498) C1 [Wang, Jun-Xia; Shnayder, Ruslan; Nigrovic, Peter A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Bair, Angela M.; Soberman, Roy J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Nephrol, Boston, MA 02115 USA. [King, Sandra L.; Fuhlbrigge, Robert C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Huang, Ya-Fang; Shieh, Chi-Chang] Natl Cheng Kung Univ, Inst Clin Med, Tainan 70101, Taiwan. [Huang, Ya-Fang; Shieh, Chi-Chang] Natl Cheng Kung Univ, Dept Pediat, Tainan 70101, Taiwan. [Fuhlbrigge, Robert C.; Nigrovic, Peter A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Med,Div Immunol, Boston, MA 02115 USA. RP Nigrovic, PA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Rheumatol Immunol & Allergy, Smith Bldg,Rm 516C,1 Jimmy Fund Way, Boston, MA 02115 USA. EM pnigrovic@partners.org FU Arthritis National Research Foundation; Charles H. Hood Foundation; Harvard Skin Disease Research Center; Cogan Family Foundation; National Science Council, Taiwan; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [P30 AR42689]; [5RO1-AI068871]; [3RO1AI068871-04S]; [1S10RR027931]; [1R01HL097796]; [K01 DK089145] FX This work was supported by grants from the Arthritis National Research Foundation, the Charles H. Hood Foundation, the Harvard Skin Disease Research Center, and the Cogan Family Foundation (to P.A.N.); the National Science Council, Taiwan (to C.-C.S.); and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR42689 to R.C.F.; 5RO1-AI068871, 3RO1AI068871-04S, 1S10RR027931, and 1R01HL097796 to R.J.S.; and K01 DK089145 to A.B.). NR 50 TC 24 Z9 24 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 AUG 16 PY 2012 VL 120 IS 7 BP 1489 EP 1498 DI 10.1182/blood-2012-01-404046 PG 10 WC Hematology SC Hematology GA 009CA UT WOS:000309001900023 PM 22661700 ER PT J AU Quintin, J Saeed, S Martens, JHA Giamarellos-Bourboulis, EJ Ifrim, DC Logie, C Jacobs, L Jansen, T Kullberg, BJ Wijmenga, C Joosten, LAB Xavier, RJ van der Meer, JWM Stunnenberg, HG Netea, MG AF Quintin, Jessica Saeed, Sadia Martens, Joost H. A. Giamarellos-Bourboulis, Evangelos J. Ifrim, Daniela C. Logie, Colin Jacobs, Liesbeth Jansen, Trees Kullberg, Bart-Jan Wijmenga, Cisca Joosten, Leo A. B. Xavier, Ramnik J. van der Meer, Jos W. M. Stunnenberg, Hendrik G. Netea, Mihai G. TI Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes SO CELL HOST & MICROBE LA English DT Article ID NATURAL-KILLER-CELLS; EPIGENETIC REGULATION; DENDRITIC CELLS; IMMUNE-RESPONSE; CROHNS-DISEASE; MEMORY; TRANSCRIPTION; ACTIVATION; IMMUNOSUPPRESSION; POLARIZATION AB Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall beta-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the beta-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by beta-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies. C1 [Quintin, Jessica; Ifrim, Daniela C.; Jacobs, Liesbeth; Jansen, Trees; Kullberg, Bart-Jan; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. [Quintin, Jessica; Ifrim, Daniela C.; Jacobs, Liesbeth; Jansen, Trees; Kullberg, Bart-Jan; Joosten, Leo A. B.; van der Meer, Jos W. M.; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun N4i, NL-6525 GA Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Martens, Joost H. A.; Logie, Colin; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Fac Med, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Giamarellos-Bourboulis, Evangelos J.] Univ Athens, Sch Med, Dept Internal Med 4, Athens 12462, Greece. [Giamarellos-Bourboulis, Evangelos J.] Jena Univ Hosp, Ctr Sepsis Control & Care, D-07747 Jena, Germany. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 EX Groningen, Netherlands. [Wijmenga, Cisca] Univ Groningen, NL-9713 EX Groningen, Netherlands. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Cambridge, MA 02142 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. EM m.netea@aig.umcn.nl RI Logie, Colin/A-1528-2010; van der Meer, Jos/C-8521-2013; Kullberg, Bart Jan/C-8520-2013; Wijmenga, Cisca/D-2173-2009; Stunnenberg, Hendrik/D-6875-2012; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; OI Logie, Colin/0000-0002-8534-6582; van der Meer, Jos/0000-0001-5120-3690; Jansen, Tim/0000-0003-3026-3154; Wijmenga, Cisca/0000-0002-5635-1614; Giamarellos-Bourboulis, Evangelos/0000-0003-4713-3911 FU Vici Grant of the Netherlands Organization for Scientific Research; Higher Education Commission of Pakistan; Vidi Grant of the Netherlands Organization for Scientific Research; All-Fun EU-FP7 grant; "DNA-in-action" consortium; Foundation for Fundamental Research on Matter (FOM); Netherlands Organisation for Scientific Research (NWO); US National Institutes of Health [AI 062773, DK 043351, DK 83756]; Helmsley Trust FX J.Q. and M.G.N. were supported by a Vici Grant of the Netherlands Organization for Scientific Research (to M.G.N.). S.S. was supported by the Higher Education Commission of Pakistan and J.H.A.M. by a Vidi Grant of the Netherlands Organization for Scientific Research. D.C.I was supported by the All-Fun EU-FP7 grant. C.L. was supported by the "DNA-in-action" consortium, Foundation for Fundamental Research on Matter (FOM), Netherlands Organisation for Scientific Research (NWO). R.J.X. was supported by grants (AI 062773, DK 043351 DK 83756) from the US National Institutes of Health and the Helmsley Trust. J.Q., S.S., C.W., J.H.A.M., C.L., J.W.M.v.d.M., and M.G.N. designed and analyzed the experiments. J.Q., S.S., M.G.N., E.J.G.-B., L.A.B.J., and T.J. performed the experiments. D.C.I. contributed to some of the experiments. J.Q., S.S., R.J.X., J.W.M.v.d.M., H.G.S., and M.G.N. wrote the manuscript, and all authors contributed to the manuscript preparation. M.G.N. supervised the project. NR 40 TC 149 Z9 151 U1 3 U2 31 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 16 PY 2012 VL 12 IS 2 BP 223 EP 232 DI 10.1016/j.chom.2012.06.006 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 998UM UT WOS:000308265900012 PM 22901542 ER PT J AU Smith, LR Chambers, HG Subramaniam, S Lieber, RL AF Smith, Lucas R. Chambers, Henry G. Subramaniam, Shankar Lieber, Richard L. TI Transcriptional Abnormalities of Hamstring Muscle Contractures in Children with Cerebral Palsy SO PLOS ONE LA English DT Article ID GROSS MOTOR FUNCTION; SKELETAL-MUSCLE; EXTRACELLULAR-MATRIX; MEDIAL GASTROCNEMIUS; SPASTIC DIPLEGIA; GENE ONTOLOGY; STIFFNESS; HYPOEXTENSIBILITY; DIFFERENTIATION; ARCHITECTURE AB Cerebral palsy (CP) is an upper motor neuron disease that results in a spectrum of movement disorders. Secondary to the neurological lesion, muscles from patients with CP are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in CP is a response to aberrant complex neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response in CP using transcriptional profiling correlated with functional measures to broadly investigate muscle adaptations leading to mechanical deficits. Biospsies were obtained from both the gracilis and semitendinosus muscles from a cohort of patients with CP (n = 10) and typically developing patients (n = 10) undergoing surgery. Biopsies were obtained to define the unique expression profile of the contractures and passive mechanical testing was conducted to determine stiffness values in previously published work. Affymetrix HG-U133A 2.0 chips (n = 40) generated expression data, which was validated for selected transcripts using quantitative real-time PCR. Chips were clustered based on their expression and those from patients with CP clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n = 1,398). Significantly altered genes were analyzed for over-representation among gene ontologies and muscle specific networks. The majority of altered transcripts were related to increased extracellular matrix expression in CP and a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and development of novel therapies. C1 [Smith, Lucas R.; Subramaniam, Shankar; Lieber, Richard L.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Chambers, Henry G.] Rady Childrens Hosp, Dept Orthoped Surg, San Diego, CA USA. [Chambers, Henry G.; Lieber, Richard L.] Univ Calif San Diego, Dept Orthoped Surg, La Jolla, CA 92093 USA. [Lieber, Richard L.] US Dept Vet Affairs, Med Ctr, San Diego, CA USA. RP Smith, LR (reprint author), Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. EM rlieber@ucsd.edu FU National Institutes of Health [AR057393] FX This work was supported by the National Institutes of Health [grant number AR057393]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 8 Z9 8 U1 0 U2 5 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 AUG 16 PY 2012 VL 7 IS 8 AR e40686 DI 10.1371/journal.pone.0040686 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 993AN UT WOS:000307824300004 PM 22956992 ER PT J AU Muller, FL Colla, S Aquilanti, E Manzo, VE Genovese, G Lee, J Eisenson, D Narurkar, R Deng, PN Nezi, L Lee, MA Hu, BL Hu, J Sahin, E Ong, D Fletcher-Sananikone, E Ho, D Kwong, L Brennan, C Wang, YA Chin, L DePinho, RA AF Muller, Florian L. Colla, Simona Aquilanti, Elisa Manzo, Veronica E. Genovese, Giannicola Lee, Jaclyn Eisenson, Daniel Narurkar, Rujuta Deng, Pingna Nezi, Luigi Lee, Michelle A. Hu, Baoli Hu, Jian Sahin, Ergun Ong, Derrick Fletcher-Sananikone, Eliot Ho, Dennis Kwong, Lawrence Brennan, Cameron Wang, Y. Alan Chin, Lynda DePinho, Ronald A. TI Passenger deletions generate therapeutic vulnerabilities in cancer SO NATURE LA English DT Article ID ENOLASE DEFICIENCY; GENETIC REDUNDANCY; BREAST-CANCER; GLIOBLASTOMA; INHIBITION; REGIONS; GENOME; TUMORS; CELLS; LUNG AB Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events. C1 [Muller, Florian L.; Colla, Simona; Aquilanti, Elisa; Manzo, Veronica E.; Genovese, Giannicola; Lee, Jaclyn; Eisenson, Daniel; Narurkar, Rujuta; Deng, Pingna; Nezi, Luigi; Lee, Michelle A.; Hu, Baoli; Hu, Jian; Sahin, Ergun; Ong, Derrick; Fletcher-Sananikone, Eliot; Ho, Dennis; Kwong, Lawrence; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Muller, Florian L.; Colla, Simona; Genovese, Giannicola; Deng, Pingna; Nezi, Luigi; Hu, Baoli; Hu, Jian; Ong, Derrick; Fletcher-Sananikone, Eliot; Kwong, Lawrence; Wang, Y. Alan; Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Muller, Florian L.; Colla, Simona; Hu, Jian; Sahin, Ergun; Ong, Derrick; Ho, Dennis; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA 02115 USA. [Lee, Michelle A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hu, Baoli; Wang, Y. Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM rdepinho@mdanderson.org OI Brennan, Cameron/0000-0003-4064-8891; Colla, Simona/0000-0001-6583-8910 FU National Institutes of Health (NIH) [T32-CA009361, P01CA95616]; American Cancer Society [115992-PF-08-261-01-TBE]; Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant; Howard Hughes Medical Institute Medical Research Fellowship [57006984]; Harvard PRISE fellowship; Diversity in Health-Related research award [3 P01 CA095616-08S1]; Ben and Catherine Ivy Foundation FX We thank K. Ligon, C. Maire, D. N. Louis, J. Kimand G. Mohapatra for sharing bioinformatics data from their tumour neurosphere banks. We also thank D. Bigner for sharing the D423-MG and D502-MG cell lines and D. N. Louis and J. Kim for sharing the Gli56 cell line. We thank G. Chu and D. Jakubosky for assistance with necropsy and histopathological analysis. F. L. M. was supported by a training grant from the National Institutes of Health (NIH T32-CA009361) and a fellowship from the American Cancer Society (115992-PF-08-261-01-TBE). S. C. was supported by a Dana-Farber Cancer Institute/Harvard Cancer Center Myeloma SPORE career development grant. E. A. was supported by a Howard Hughes Medical Institute Medical Research Fellowship (57006984). V. M. was supported by a Harvard PRISE fellowship. M. A. L. was supported by a Diversity in Health-Related research award (3 P01 CA095616-08S1). F. L. M. thanks J. Mohr for assistance with figure preparations. We also thank K. Muller for assistance with manuscript editing. We thank all members of the DePinho and Chin laboratories for suggestions and discussions. This work is supported by the NIH (P01CA95616 to C. B., L. C. and R. A. D.) and by the Ben and Catherine Ivy Foundation (to R. A. D. and L.C.). NR 37 TC 79 Z9 82 U1 0 U2 31 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 AUG 16 PY 2012 VL 488 IS 7411 BP 337 EP + DI 10.1038/nature11331 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OS UT WOS:000307501000033 PM 22895339 ER PT J AU Reich, D Patterson, N Campbell, D Tandon, A Mazieres, S Ray, N Parra, MV Rojas, W Duque, C Mesa, N Garcia, LF Triana, O Blair, S Maestre, A Dib, JC Bravi, CM Bailliet, G Corach, D Hunemeier, T Bortolini, MC Salzano, FM Petzl-Erler, ML Acuna-Alonzo, V Aguilar-Salinas, C Canizales-Quinteros, S Tusie-Luna, T Riba, L Rodriguez-Cruz, M Lopez-Alarcon, M Coral-Vazquez, R Canto-Cetina, T Silva-Zolezzi, I Fernandez-Lopez, JC Contreras, AV Jimenez-Sanchez, G Gomez-Vazquez, MJ Molina, J Carracedo, A Salas, A Gallo, C Poletti, G Witonsky, DB Alkorta-Aranburu, G Sukernik, RI Osipova, L Fedorova, SA Vasquez, R Villena, M Moreau, C Barrantes, R Pauls, D Excoffier, L Bedoya, G Rothhammer, F Dugoujon, JM Larrouy, G Klitz, W Labuda, D Kidd, J Kidd, K Di Rienzo, A Freimer, NB Price, AL Ruiz-Linares, A AF Reich, David Patterson, Nick Campbell, Desmond Tandon, Arti Mazieres, Stephane Ray, Nicolas Parra, Maria V. Rojas, Winston Duque, Constanza Mesa, Natalia Garcia, Luis F. Triana, Omar Blair, Silvia Maestre, Amanda Dib, Juan C. Bravi, Claudio M. Bailliet, Graciela Corach, Daniel Huenemeier, Tabita Bortolini, Maria Catira Salzano, Francisco M. Petzl-Erler, Maria Luiza Acuna-Alonzo, Victor Aguilar-Salinas, Carlos Canizales-Quinteros, Samuel Tusie-Luna, Teresa Riba, Laura Rodriguez-Cruz, Maricela Lopez-Alarcon, Mardia Coral-Vazquez, Ramon Canto-Cetina, Thelma Silva-Zolezzi, Irma Fernandez-Lopez, Juan Carlos Contreras, Alejandra V. Jimenez-Sanchez, Gerardo Gomez-Vazquez, Maria Jose Molina, Julio Carracedo, Angel Salas, Antonio Gallo, Carla Poletti, Giovanni Witonsky, David B. Alkorta-Aranburu, Gorka Sukernik, Rem I. Osipova, Ludmila Fedorova, Sardana A. Vasquez, Rene Villena, Mercedes Moreau, Claudia Barrantes, Ramiro Pauls, David Excoffier, Laurent Bedoya, Gabriel Rothhammer, Francisco Dugoujon, Jean-Michel Larrouy, Georges Klitz, William Labuda, Damian Kidd, Judith Kidd, Kenneth Di Rienzo, Anna Freimer, Nelson B. Price, Alkes L. Ruiz-Linares, Andres TI Reconstructing Native American population history SO NATURE LA English DT Article ID COLONIZATION; SETTLEMENT; DISPERSAL; DIVERSITY; PATTERNS; ORIGIN; MODEL; ASIA AB The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved(1-5). One contentious issue is whether the settlement occurred by means of a single(6-8) migration or multiple streams of migration from Siberia(9-15). The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call `First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America. C1 [Reich, David; Tandon, Arti] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Reich, David; Patterson, Nick; Tandon, Arti; Price, Alkes L.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Reich, David; Patterson, Nick; Tandon, Arti] MIT, Cambridge, MA 02142 USA. [Campbell, Desmond; Mazieres, Stephane; Parra, Maria V.; Rojas, Winston; Duque, Constanza; Mesa, Natalia; Bravi, Claudio M.; Huenemeier, Tabita; Ruiz-Linares, Andres] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England. Univ Hong Kong, Dept Psychiat, Pokfulam, Hong Kong, Peoples R China. [Campbell, Desmond] Univ Hong Kong, Ctr Genom Sci, Pokfulam, Hong Kong, Peoples R China. [Mazieres, Stephane] Aix Marseille Univ, CNRS, EFS, ADES,UMR7268, F-13344 Marseille, France. [Ray, Nicolas] Univ Geneva, Inst Environm Sci, CH-1227 Geneva, Switzerland. [Ray, Nicolas] Univ Geneva, Forel Inst, CH-1227 Geneva, Switzerland. [Parra, Maria V.; Rojas, Winston; Duque, Constanza; Mesa, Natalia; Garcia, Luis F.; Triana, Omar; Blair, Silvia; Maestre, Amanda; Bedoya, Gabriel] Univ Antioquia, Medellin, Colombia. [Dib, Juan C.] Fdn Salud Trop, Santa Marta, Colombia. [Bravi, Claudio M.; Bailliet, Graciela] Consejo Nacl Invest Cient & Tecn, CICPCA, CCT La Plata, Inst Multidisciplinario Biol Celular, RA-1900 La Plata, Argentina. [Corach, Daniel] Univ Buenos Aires, Serv Huellas Digitales Genet, RA-1053 Buenos Aires, DF, Argentina. [Corach, Daniel] Univ Buenos Aires, CONICET, RA-1053 Buenos Aires, DF, Argentina. [Huenemeier, Tabita; Bortolini, Maria Catira; Salzano, Francisco M.] Univ Fed Rio Grande do Sul, Inst Biociencias, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil. [Petzl-Erler, Maria Luiza] Univ Fed Parana, Dept Genet, BR-81531980 Curitiba, Parana, Brazil. [Acuna-Alonzo, Victor] Natl Inst Anthropol & Hist, Mexico City 06100, DF, Mexico. [Aguilar-Salinas, Carlos] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Mexico City 14100, DF, Mexico. [Canizales-Quinteros, Samuel; Tusie-Luna, Teresa; Riba, Laura] Univ Nacl Autonoma Mexico, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Unidad Biol Mol & Med Genom, Mexico City 14100, DF, Mexico. [Canizales-Quinteros, Samuel] Univ Nacl Autonoma Mexico, Fac Quim, Dept Biol, Mexico City 04510, DF, Mexico. [Rodriguez-Cruz, Maricela; Lopez-Alarcon, Mardia] Hosp Pediat Mexico City, Inst Mexicano Seguro Social, CMNSXXI, Unidad Invest Med Nutr, Mexico City 06720, DF, Mexico. [Coral-Vazquez, Ramon] Inst Politecn Nacl, Escuela Super Med, Secc Posgrado, Mexico City 11340, DF, Mexico. [Canto-Cetina, Thelma] Ctr Invest Reg, Dept Salud Reprod & Genet, Lab Biol Reproducc, Merida 97000, Mexico. [Silva-Zolezzi, Irma; Fernandez-Lopez, Juan Carlos; Contreras, Alejandra V.; Jimenez-Sanchez, Gerardo] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico. [Gomez-Vazquez, Maria Jose] Univ Autonoma Nuevo Leon, San Nicolas De Los Garza 66451, Nuevo Leon, Mexico. [Molina, Julio] Ctr Invest Biomed Guatemala, Guatemala City, Guatemala. [Carracedo, Angel; Salas, Antonio] Univ Santiago de Compostela, Fdn Med Xenom SERGAS, Inst Ciencias Forenses, Santiago De Compostela, Spain. [Gallo, Carla; Poletti, Giovanni] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Labs Invest & Desarrollo, Lima 15102, Peru. [Witonsky, David B.; Alkorta-Aranburu, Gorka; Di Rienzo, Anna] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Sukernik, Rem I.] Russian Acad Sci, Siberian Branch, Inst Mol & Cellular Biol, Lab Human Mol Genet, Novosibirsk 630090, Russia. [Osipova, Ludmila] Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Fedorova, Sardana A.] Yakut Res Ctr Complex Med Problems, Dept Mol Genet, Sakha 677010, Yakutia, Russia. [Fedorova, Sardana A.] NE Fed Univ, Sakha 677010, Yakutia, Russia. [Vasquez, Rene; Villena, Mercedes] Univ Autonoma Tomas Frias, Inst Boliviano Biol Altura, Potosi, Bolivia. [Moreau, Claudia; Labuda, Damian] Univ Montreal, Dept Pediat, Ctr Rech, CHU St Justine, Montreal, PQ H3T 1C5, Canada. [Barrantes, Ramiro] Univ Costa Rica, Escuela Biol, San Jose, Costa Rica. [Pauls, David] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Excoffier, Laurent] Univ Bern, Inst Ecol & Evolut, Computat & Mol Populat Genet Lab, CH-3012 Bern, Switzerland. [Excoffier, Laurent] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Rothhammer, Francisco] Univ Chile, Fac Med, Programa Genet Humana ICBM, Inst Alta Invest ,Univ Tarapaca, Arica 1001236, Chile. [Rothhammer, Francisco] Ctr Invest Hombre El Desierto, Arica 1001236, Chile. [Dugoujon, Jean-Michel; Larrouy, Georges] Univ Toulouse 3, CNRS, UMR 5288, F-31000 Toulouse, France. [Klitz, William] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Kidd, Judith; Kidd, Kenneth] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Freimer, Nelson B.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Price, Alkes L.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Reich, D (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM reich@genetics.med.harvard.edu; a.ruizlin@ucl.ac.uk RI Contreras, Alejandra Virginia/E-7815-2013; Ray, Nicolas/C-8988-2009; Fernandez, Juan Carlos/C-4976-2013; Excoffier, Laurent/D-3498-2013; Acuna Alonzo, Victor/E-2312-2013; Mazieres, Stephane/G-1702-2010; Osipova, Ludmila/O-6480-2014; Salas, Antonio/E-3977-2012; Salzano, Francisco/L-7916-2015; Sukernik, Rem/N-6990-2015; Petzl-Erler, Maria-Luiza/H-8221-2012 OI Corach, Daniel/0000-0002-0662-7424; Contreras, Alejandra Virginia/0000-0003-3653-5958; Triana, Omar/0000-0001-8031-0225; Ray, Nicolas/0000-0002-4696-5313; Fernandez, Juan Carlos/0000-0003-3680-4193; Gallo, Carla/0000-0001-8348-0473; Campbell, Desmond/0000-0003-1085-714X; Excoffier, Laurent/0000-0002-7507-6494; Acuna Alonzo, Victor/0000-0003-2205-7625; Osipova, Ludmila/0000-0001-7602-1156; Salas, Antonio/0000-0002-2336-702X; Petzl-Erler, Maria-Luiza/0000-0002-0345-5276 FU National Institutes of Health [NS043538, NS037484, MH075007, GM079558, GM079558-S1, GM057672, HG006399]; Biotechnology and Biological Sciences Research Council [BB/1021213/1]; National Science Foundation HOMINID [BCS-1032255]; Canadian Institutes of Health Research grant; Universidad de Antioquia CODI grant; Fondo de Investigacion Sanitaria grant [PS 09/2368]; Ministerio de Ciencia e Innovacion [SAF2011-26983]; Wenner-Gren Foundation [ICRG-65]; Russian Foundation for Basic Research [06-04-048182, 02-06-80524a]; Siberian Branch Russian Academy of Sciences field grant; Centre National de la Recherche Scientifique Programme Interdisciplinaire de Recherche Amazonie grant; Harvard Medical School; Harvard School of Public Health FX We thank the volunteers who provided the samples that made this study possible. We thank E. D. Ruiz for assistance in the collection involving the Mixtec, Zapotec and Mixe; and P. Herrera for assistance in the collection involving the Quechua; A. Carnevale, M. Crawford, M. Metspalu, F. C. Nielsen, X. Soberon, R. Villems and E. Willerslev for facilitating sharing of data from Mexican, Siberian and Arctic populations; C. Stevens and A. Crenshaw for assistance with genotyping; and P. Bellwood, D. Bolnick, K. Bryc, J. Diamond, T. Dillehay, R. Gonzalez-Jose, M. Hammer, J. Hill, B. Kemp, S. LeBlanc, D. Meltzer, P. Moorjani, A. Moreno-Estrada, B. Pakendorf, J. Pickrell, M. Ruhlen, D. G. Smith, M. Stoneking, N. Tuross and A. Williams for critiques and discussions. Support was provided by National Institutes of Health grants NS043538 (A. R.-L.), NS037484 and MH075007 (N. B. F.), GM079558 (A. D.), GM079558-S1 (A. D.), GM057672 (K. K. K. and J. R. K.), and HG006399 (D. R., N. P. & A. L. P); by a Biotechnology and Biological Sciences Research Council grant BB/1021213/1; by a National Science Foundation HOMINID grant BCS-1032255 (D. R. and N. P.); by a Canadian Institutes of Health Research grant (D. L.); by a Universidad de Antioquia CODI grant (G. B.); by a Fondo de Investigacion Sanitaria grant PS 09/2368 (A. C.); by a Ministerio de Ciencia e Innovacion grant SAF2011-26983 (A. S.); by a Wenner-Gren Foundation grant ICRG-65 (A. D. and R. S.); by Russian Foundation for Basic Research grants 06-04-048182 (R. S.) and 02-06-80524a (L.O.); by a Siberian Branch Russian Academy of Sciences field grant (L.O.); by a Centre National de la Recherche Scientifique Programme Interdisciplinaire de Recherche Amazonie grant (J.-M.D.); and by startup funds from Harvard Medical School (D. R.) and the Harvard School of Public Health (A.L.P.). NR 37 TC 204 Z9 212 U1 5 U2 168 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 AUG 16 PY 2012 VL 488 IS 7411 BP 370 EP + DI 10.1038/nature11258 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OS UT WOS:000307501000040 PM 22801491 ER PT J AU Zella, GC Gee, MS Badizadegan, K AF Zella, Garrett C. Gee, Michael S. Badizadegan, Kamran TI Case 25-2012: A 15-Year-Old Boy with Abdominal Pain, Hematochezia, and Anemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; ADULT INTUSSUSCEPTION; CYSTIC-FIBROSIS; COLONIC POLYPS; GASTRIC-MUCOSA; CHILDREN; MANAGEMENT; DIAGNOSIS; RECURRENT; ADENOMAS C1 [Zella, Garrett C.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Gee, Michael S.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zella, Garrett C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Gee, Michael S.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Zella, GC (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 27 TC 1 Z9 1 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 16 PY 2012 VL 367 IS 7 BP 659 EP 667 DI 10.1056/NEJMcpc1111578 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600011 PM 22894579 ER PT J AU Jaff, MR White, CJ AF Jaff, Michael R. White, Christopher J. TI Secondary Prevention after Ischemic Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [White, Christopher J.] Alton Ochsner Med Fdn & Ochsner Clin, New Orleans, LA 70121 USA. RP Jaff, MR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mjaff@partners.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 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 AUG 16 PY 2012 VL 367 IS 7 BP 675 EP 676 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600021 PM 22894587 ER PT J AU Coyle, C Venna, N AF Coyle, Christina Venna, Nagagopal TI THE DISCUSSANTS REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID FOLLOW-UP; NEUROCYSTICERCOSIS; SERUM; DIAGNOSIS; ANTIGEN C1 [Coyle, Christina] Albert Einstein Coll Med, New York, NY USA. [Venna, Nagagopal] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Coyle, C (reprint author), Albert Einstein Coll Med, New York, NY USA. EM christina.coyle@einstein.yu.edu NR 5 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 AUG 16 PY 2012 VL 367 IS 7 BP 679 EP 680 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600028 ER PT J AU D'Amico, AV Smith, MR AF D'Amico, Anthony V. Smith, Matthew R. TI Screening for Prostate Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RADICAL PROSTATECTOMY; FOLLOW-UP; MORTALITY C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 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 AUG 16 PY 2012 VL 367 IS 7 DI 10.1056/NEJMclde1209426 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 988NB UT WOS:000307496600013 ER PT J AU Kaddurah-Daouk, R McEvoy, J Baillie, R Zhu, HJ Yao, JK Nimgaonkar, VL Buckley, PF Keshavan, MS Georgiades, A Nasrallah, HA AF Kaddurah-Daouk, Rima McEvoy, Joseph Baillie, Rebecca Zhu, Hongjie Yao, Jeffrey K. Nimgaonkar, Vishwajit L. Buckley, Peter F. Keshavan, Matcheri S. Georgiades, Anastasia Nasrallah, Henry A. TI Impaired plasmalogens in patients with schizophrenia SO PSYCHIATRY RESEARCH LA English DT Article DE Schizophrenia; Drug-naive; Metabolomics; Lipidomics; Plasmalogen; Phospholipids ID POLYUNSATURATED FATTY-ACIDS; GLOBAL BIOCHEMICAL APPROACH; BLOOD-CELL MEMBRANE; ETHANOLAMINE PLASMALOGEN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; ENDOTHELIAL-CELLS; ARACHIDONIC-ACID; SURROGATE MARKER; ION-TRANSPORT AB Plasmalogens are a subclass of glycerophospholipids and ubiquitous constituents of cellular membranes and serum lipoproteins. Several neurological disorders show decreased level of plasmogens. An earlier study found differences in plasma phospholipids between unmedicated patients with schizophrenia and matched healthy control subjects. We here report a comparison of plasma plasmalogen levels across 20 drug-naive patients experiencing first psychotic episodes, 20 recently unmedicated patients experiencing psychotic relapses after failing to comply with prescribed medications, and 17 matched healthy control subjects. Multiple plasma phosphatidylcholine and phosphatidylethanolamine plasmalogen levels were significantly lower in first episode patients and patients with recurrent disease compared to healthy controls. Reduced plasmalogen levels appear to be a trait evident at the onset of psychotic illness and after multiple psychotic relapses. It is implied that reductions in plasmalogen levels are not related to antipsychotic treatment but due to the illness itself. Reduced plasmalogen levels suggest impairments in membrane structure and function in patients with schizophrenia that might happen early in development This may serve as a clue to the neurobiology of schizophrenia and should be studied as a potential biomarker for individuals at risk for schizophrenia. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Kaddurah-Daouk, Rima; McEvoy, Joseph; Georgiades, Anastasia] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Baillie, Rebecca] Rosa & Co LLC, San Carlos, CA 94070 USA. [Zhu, Hongjie] N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. [Zhu, Hongjie] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Yao, Jeffrey K.; Nimgaonkar, Vishwajit L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Nimgaonkar, Vishwajit L.] Western Psychiat Inst & Clin, Dept Human Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Buckley, Peter F.] Med Coll Georgia, Dept Psychiat, Augusta, GA 30912 USA. [Keshavan, Matcheri S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Nasrallah, Henry A.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45219 USA. RP Kaddurah-Daouk, R (reprint author), Duke Univ, Med Ctr, Dept Psychiat, Box 3950, Durham, NC 27710 USA. EM kaddu001@mc.duke.edu NR 67 TC 23 Z9 23 U1 3 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2012 VL 198 IS 3 BP 347 EP 352 DI 10.1016/j.psychres.2012.02.019 PG 6 WC Psychiatry SC Psychiatry GA 050HQ UT WOS:000312044800002 PM 22513041 ER PT J AU Zhang, Q Liu, Q Austin, C Drummond, I Pierce, EA AF Zhang, Qi Liu, Qin Austin, Chrissy Drummond, Iain Pierce, Eric A. TI Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BARDET-BIEDL SYNDROME; RETINITIS-PIGMENTOSA; PROTEOMIC ANALYSIS; SENSORY ORGANELLE; PRIMARY CILIUM; CAENORHABDITIS-ELEGANS; IN-VITRO; DISEASE; MUTATIONS; GENES AB In our effort to understand genetic disorders of the photoreceptor cells of the retina, we have focused on intraflagellar transport in photoreceptor sensory cilia. From previous mouse proteomic data we identified a cilia protein Ttc26, orthologue of dyf-13 in Caenorhabditis elegans, as a target. We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells. Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy. To study Ttc26 function in sensory cilia in vivo, we utilized a zebrafish vertebrate model system. Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf). In the eyes, the outer segments of photoreceptor cells appeared shortened or absent, whereas cellular lamination appeared normal in retinas at 5 dpf. This suggests that loss of ttc26 function prevents normal ciliogenesis and differentiation in the photoreceptor cells, and that ttc26 is required for normal development and differentiation in retina and pronephros. Our studies support the importance of Ttc26 function in ciliogenesis and suggest that screening for TTC26 mutations in human ciliopathies is justified. C1 [Zhang, Qi; Liu, Qin; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. [Austin, Chrissy; Drummond, Iain] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit CNY 8, Charlestown, MA 02129 USA. [Zhang, Qi; Liu, Qin; Pierce, Eric A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Berman Gund Lab, Boston, MA 02114 USA. RP Pierce, EA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Genom Inst,Dept Ophthalmol, Boston, MA 02114 USA. EM eric_pierce@meei.harvard.edu OI Pierce, Eric/0000-0002-2354-4102 FU National Institutes of Health [R01-EY012910]; Foundation Fighting Blindness USA; F. M. Kirby Foundation; Research to Prevent Blindness; Rosanne Silbermann Foundation FX We thank Gregory Pazour for providing the SSTR-3 mIMCD3 cell line and Michael Pack and Jie He of the Zebrafish Core at Penn Medicine for their assistance. This work was supported by grants from the National Institutes of Health (R01-EY012910 to E.A.P.), the Foundation Fighting Blindness USA, the F. M. Kirby Foundation, Research to Prevent Blindness, and the Rosanne Silbermann Foundation. We also acknowledge the contribution of medical editing by David Titus. NR 51 TC 10 Z9 14 U1 0 U2 5 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG 15 PY 2012 VL 23 IS 16 BP 3069 EP 3078 DI 10.1091/mbc.E12-01-0019 PG 10 WC Cell Biology SC Cell Biology GA 052SX UT WOS:000312219900006 PM 22718903 ER PT J AU Baas, D Caussanel-Boude, S Guiraud, A Calhabeu, F Delaune, E Pilot, F Chopin, E Machuca-Gayet, I Vernay, A Bertrand, S Rual, JF Jurdic, P Hill, DE Vidal, M Schaeffer, L Goillot, E AF Baas, Dominique Caussanel-Boude, Sabine Guiraud, Alexandre Calhabeu, Frederico Delaune, Emilie Pilot, Fanny Chopin, Emilie Machuca-Gayet, Irma Vernay, Aurelia Bertrand, Stephanie Rual, Jean-Francois Jurdic, Pierre Hill, David E. Vidal, Marc Schaeffer, Laurent Goillot, Evelyne TI CKIP-1 regulates mammalian and zebrafish myoblast fusion SO JOURNAL OF CELL SCIENCE LA English DT Article DE CKIP-1; Arp2/3; Actin cytoskeleton; Myoblast fusion; Zebrafish muscle development ID PLECKSTRIN HOMOLOGY DOMAIN; CONTAINING PROTEIN CKIP-1; MUSCLE-CELL MIGRATION; ACTIN-CAPPING PROTEIN; ARP2/3 COMPLEX; PLASMA-MEMBRANE; DANIO-RERIO; KINASE CK2; IN-VIVO; SLOW AB Multinucleated muscle fibres arise by fusion of precursor cells called myoblasts. We previously showed that CKIP-1 ectopic expression in C2C12 myoblasts increased cell fusion. In this work, we report that CKIP-1 depletion drastically impairs C2C12 myoblast fusion in vitro and in vivo during zebrafish muscle development. Within developing fast-twich myotome, Ckip-1 localises at the periphery of fast precursor cells, closed to the plasma membrane. Unlike wild-type myoblasts that form spatially arrayed multinucleated fast myofibres, Ckip-1-deficient myoblasts show a drastic reduction in fusion capacity. A search for CKIP-1 binding partners identified the ARPC1 subunit of Arp2/3 actin nucleation complex essential for myoblast fusion. We demonstrate that CKIP-1, through binding to plasma membrane phosphoinositides via its PH domain, regulates cell morphology and lamellipodia formation by recruiting the Arp2/3 complex at the plasma membrane. These results establish CKIP-1 as a regulator of cortical actin that recruits the Arp2/3 complex at the plasma membrane essential for muscle precursor elongation and fusion. C1 [Baas, Dominique; Caussanel-Boude, Sabine; Guiraud, Alexandre; Calhabeu, Frederico; Delaune, Emilie; Pilot, Fanny; Chopin, Emilie; Vernay, Aurelia; Schaeffer, Laurent; Goillot, Evelyne] Univ Lyon, CNRS UMR 5239, Equipe Differenciat Neuromusculaire,ENS Lyon, Lab Biol Mol Cellule,Biosci Lyon Gerland IFR128, F-69364 Lyon 07, France. [Machuca-Gayet, Irma; Jurdic, Pierre] UCB Lyon 1, Equipe Biol Cellulaire & Physiopathol Osseuse, UMR CNRS 5242, IGFL,ENS Lyon,INRA 1288, F-69364 Lyon 07, France. [Bertrand, Stephanie] Univ Paris 06, CNRS UMR 7628, Observ Oceanog, F-66651 Banyuls Sur Mer, France. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Rual, Jean-Francois; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Goillot, E (reprint author), Univ Lyon, CNRS UMR 5239, Equipe Differenciat Neuromusculaire,ENS Lyon, Lab Biol Mol Cellule,Biosci Lyon Gerland IFR128, 46 Allee Italie, F-69364 Lyon 07, France. EM evelyne.goillot@ens-lyon.fr RI Hill, David/B-6617-2011; Bertrand, Stephanie/D-8482-2014; OI Bertrand, Stephanie/0000-0002-0689-0126; Rual, Jean-Francois/0000-0003-4465-8819 FU NICHD; Association francaise contre les Myopathies [AFM-12130]; Ministere de la Recherche et de l'Enseignement Superieur; Fondation pour la Recherche Medicale [FDT20101221104]; Association pour la Recherche contre le Cancer [ARC-3853]; Ministere de la Recherche et de la Technologie [ANR-11-BSV2-017-01] FX We are grateful to M. D. Welch (Department of Molecular and Cell Biology, University of California) for providing Arp2/3 subunit antibodies. The (MAb 5B12.3) (MAb 3F2.3), (MAb F59) (MAb F310) were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City, IA 52242. We thank the zebrafish (PRECI) and microscopy (Plateau Technique Imagerie/Microscopie) facilities of the IFR128 Biosciences.; This work was supported by the Association francaise contre les Myopathies [grant number AFM-12130 to F. C. and E. G.]; the Ministere de la Recherche et de l'Enseignement Superieur; Fondation pour la Recherche Medicale [grant number FDT20101221104 to A. G.]; the Association pour la Recherche contre le Cancer [grant number ARC-3853 to E. G.]; and the Ministere de la Recherche et de la Technologie [grant number ANR-11-BSV2-017-01 to L.S.]. NR 50 TC 6 Z9 6 U1 0 U2 12 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2012 VL 125 IS 16 BP 3790 EP 3800 DI 10.1242/jcs.101048 PG 11 WC Cell Biology SC Cell Biology GA 016NJ UT WOS:000309525300011 PM 22553210 ER PT J AU Sepucha, KR Feibelmann, S Abdu, WA Clay, CF Cosenza, C Kearing, S Levin, CA Atlas, SJ AF Sepucha, Karen R. Feibelmann, Sandra Abdu, William A. Clay, Catharine F. Cosenza, Carol Kearing, Stephen Levin, Carrie A. Atlas, Steven J. TI Psychometric Evaluation of a Decision Quality Instrument for Treatment of Lumbar Herniated Disc SO SPINE LA English DT Article DE shared decision making; patient-centered care; decision quality; quality measurement; lumbar herniated disc ID INTERACTIVE VIDEO PROGRAM; BACK SURGERY; PATIENT; PREFERENCES; AIDS; CARE; PAIN AB Study Design. Retrospective and prospective patient surveys and a physician survey using a sample from American Medical Association master file. Objective. To evaluate the performance of a new instrument designed to measure the quality of decisions about treatment of herniated disc. Summary of Background Data. There is growing consensus on the importance of engaging and informing patients to improve the quality of significant medical decisions, yet there are no instruments currently available to measure decision quality. Methods. The herniated disc-decision quality instrument (HD-DQI) was developed with input from clinical experts, survey research experts, and patients. The HD-DQI produces 2 scores each scaled to 0% to 100%, with higher scores indicating better quality: (1) a total knowledge score and (2) a concordance score (indicating the percentage of patients who received treatments that matched their goals). We examined hypotheses relating to the acceptability, feasibility, validity, and reliability of the instrument, using data from 3 samples. Results. The HD-DQI survey was feasible to implement and acceptable to patients, with good response rates and low missing data. The knowledge score discriminated between patients who had seen a decision aid or no decision aid (55% vs. 38%, P < 0.001) and between providers and patients (73% vs. 46%, P < 0.001). The knowledge score also had good retest reliability (intraclass correlation coefficient = 0.85). Most patients (78%) received treatments that matched their goals. Patients who received treatments that matched their goals were less likely to regret the decision than those who did not (13% vs. 39%, P = 0.004). Conclusion. The HD-DQI met several criteria for high-quality patient-reported survey instruments. It can be used to determine the quality of decisions for treatment of herniated disc. More work is needed to examine acceptability for use as part of routine patient care. C1 [Sepucha, Karen R.] Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Hlth Decis Sci Ctr,Med Sch, Boston, MA 02114 USA. [Abdu, William A.] Dartmouth Hitchcock Med Ctr, Dept Orthopaed Surg, Lebanon, NH 03766 USA. [Clay, Catharine F.; Kearing, Stephen] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Cosenza, Carol] Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. [Levin, Carrie A.] Informed Med Decis Fdn, Boston, MA USA. RP Sepucha, KR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Hlth Decis Sci Ctr,Med Sch, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ksepucha@partners.org FU Informed Medical Decisions Foundation FX The work was supported by two grants from the Informed Medical Decisions Foundation, one to Massachusetts General Hospital (MGH) and one to Dartmouth. The authors thank the patients and providers whose participation made this research possible. The research involved collaboration between the MGH research team, the Dartmouth research team, and representatives from the funder (CL). The research grant was awarded in compliance with MGH's policies which bar funder interference in scholarly work. NR 24 TC 5 Z9 5 U1 4 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD AUG 15 PY 2012 VL 37 IS 18 BP 1609 EP 1616 DI 10.1097/BRS.0b013e3182532924 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 992OJ UT WOS:000307787300021 PM 22426449 ER PT J AU Vaid, M Prasad, R Singh, T Jones, V Katiyar, SK AF Vaid, Mudit Prasad, Ram Singh, Tripti Jones, Virginia Katiyar, Santosh K. TI Grape seed proanthocyanidins reactivate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Grape seed proanthocyanidins; DNA methylation; Skin cancer cells; Histone acetylation; Tumor suppressor genes and proteins ID SKH-1 HAIRLESS MICE; DNA METHYLATION; HISTONE ACETYLATION; OXIDATIVE STRESS; MECHANISMS; PREVENTION; REPAIR; PHOTOCARCINOGENESIS; HYPERMETHYLATION; INACTIVATION AB Grape seed proanthocyanidins (GSPs) have been shown to have anti-skin carcinogenic effects in in vitro and in vivo models. However, the precise epigenetic molecular mechanisms remain unexplored. This study was designed to investigate whether GSPs reactivate silenced tumor suppressor genes following epigenetic modifications in skin cancer cells. For this purpose, A431 and SCC13 human squamous cell carcinoma cell lines were used as in vitro models. The effects of GSPs on DNA methylation, histone modifications and tumor suppressor gene expressions were studied in these cell lines using enzyme activity assays, western blotting, dot-blot analysis and real-time polymerase chain reaction (RT-PCR). We found that treatment of A431 and SCC13 cells with GSPs decreased the levels of: ( i) global DNA methylation, (ii) 5-methylcytosine, (iii) DNA methyltransferase (DNMT) activity and (iv) messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b in these cells. Similar effects were noted when these cancer cells were treated identically with 5-aza-2'-deoxycytidine, an inhibitor of DNA methylation. GSPs decreased histone deacetylase activity, increased levels of acetylated lysines 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysines 5, 12 and 16 on histone H4, and reduced the levels of methylated H3-Lys 9. Further, GSP treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, RASSF1A, p16(INK4a) and Cip1/p21. Together, this study provides a new insight into the epigenetic mechanisms of GSPs and may have significant implications for epigenetic therapy in the treatment/prevention of skin cancers in humans. (C) 2012 Elsevier Inc. All rights reserved. C1 [Vaid, Mudit; Prasad, Ram; Singh, Tripti; Jones, Virginia; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Katiyar, SK (reprint author), Univ Alabama Birmingham, Dept Dermatol, 1670 Univ Blvd,Volker Hall 557, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration Merit Review Award [ONCA-029-11S]; National Institutes of Health [CA140832] FX This work was supported by funds from the Veterans Administration Merit Review Award (ONCA-029-11S, S.K.K.) and the National Institutes of Health (CA140832, S.K.K.). The human keratinocytes were obtained from the UAB Skin Diseases Research Center (AR050948). Editorial assistance from Dr. Fiona Hunter is gratefully acknowledged. The content of this manuscript does not necessarily reflect the views or policies of the funding sources. NR 33 TC 18 Z9 19 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2012 VL 263 IS 1 BP 122 EP 130 DI 10.1016/j.taap.2012.06.013 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 984RK UT WOS:000307208900015 PM 22749965 ER PT J AU Heist, EK Chalhoub, F Barrett, C Danik, S Ruskin, JN Mansour, M AF Heist, E. Kevin Chalhoub, Fadi Barrett, Conor Danik, Stephan Ruskin, Jeremy N. Mansour, Moussa TI Predictors of Atrial Fibrillation Termination and Clinical Success of Catheter Ablation of Persistent Atrial Fibrillation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LONG-LASTING PERSISTENT; PULMONARY VEIN ISOLATION; PROCEDURAL END-POINT; FOLLOW-UP; FRACTIONATED ELECTROGRAMS; RADIOFREQUENCY ABLATION; SUBSTRATE; REGULARIZATION; MULTICENTER; ARRHYTHMIAS AB The termination of persistent atrial fibrillation (AF) during catheter ablation has been associated in some, but not all, studies with reduced arrhythmia during clinical follow-up. We sought to determine the rate of persistent AF termination achievable with a stepwise ablation strategy, the predictors of AF termination, and the clinical outcomes associated with termination and nontermination. A total of 143 consecutive patients (age 62 +/- 9 years, AF duration 5.7 +/- 5.2 years) with persistent and longstanding persistent AF resistant to antiarrhythmic medication who presented in AF for catheter ablation were studied. Ablation was done with a stepwise approach, including pulmonary vein isolation, followed by complex fractionated atrial electrogram ablation and ablation of resultant atrial tachycardias. Clinical follow-up was then performed after a 2-month blanking period to assess arrhythmia recurrence, defined as AF or atrial tachycardia lasting >= 30 seconds. AF termination by ablation was achieved in 95 (66%) of the 143 patients. Multivariate predictors of AF termination included longer baseline AF cycle length (p < 0.001) and smaller left atrial size (p = 0.002). AF termination by ablation was associated with both a lower incidence of arrhythmia recurrence after a single procedure without antiarrhythmic drugs (p = 0.01) and overall clinical success (single or multiple procedures, with or without antiarrhythmic drugs; p = 0.005). On multivariate analysis, the predictors of overall clinical success included AF termination by ablation (p = 0.001), a shorter ablation duration (p = 0.002), younger age (p = 0.02), male gender (p = 0.03), and the presence of hypertension (p = 0.03). In conclusion, among patients with persistent AF, termination of AF by ablation can be achieved in most patients and is associated with reduced recurrence of arrhythmia. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:545-551) C1 [Mansour, Moussa] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mansour, M (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM mmansour@partners.org FU Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (Massachusetts General Hospital, Boston, Massachusetts) FX This work has been partially supported by the Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (Massachusetts General Hospital, Boston, Massachusetts). NR 28 TC 19 Z9 20 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2012 VL 110 IS 4 BP 545 EP 551 DI 10.1016/j.amjcard.2012.04.028 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 993LK UT WOS:000307861000014 PM 22591670 ER PT J AU Muller, LUW Schlaeger, TM DeVine, AL Williams, DA AF Mueller, Lars U. W. Schlaeger, Thorsten M. DeVine, Alexander L. Williams, David A. TI Induced pluripotent stem cells as a tool for gaining new insights into Fanconi anemia SO CELL CYCLE LA English DT Article DE Fanconi anemia; bone marrow failure; induced pluripotent stem cells; hematopoietic differentiation; drug discovery ID REVERSE MOSAICISM; IFN-GAMMA; TNF-ALPHA; KNOCKDOWN; REVEALS; VIVO AB Induced pluripotent stem cells (iPSC) hold significant promise for advancing biomedical research. In the case of monogenic diseases, patient-iPSC and their derivatives contain the disease-causing mutation, suggesting the possibility of recapitulating salient disease features in vitro. Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The etiology of bone marrow failure in FA remains largely unclear, but limited studies on patient bone marrow cells indicate cell intrinsic defects as causative. We examined the feasibility of modeling FA in a system based on hematopoietic differentiation of patient-specific iPSC. An informative iPSC-based model is predicated on the ability to derive disease-specific (uncorrected) patient iPSC that contain the disease-causing mutation, are pluripotent, maintain a normal karyotype and are capable of hematopoietic differentiation. Careful analysis of hematopoietic differentiation of such iPSC holds the promise of uncovering new insights into bone marrow failure and may enable high-throughput screening with the goal of identifying compounds that ameliorate hematopoietic failure. Ultimately, genetic correction, molecular characterization and successful engraftment of iPSC-derived cells may provide an attractive alternative to current hematopoietic stem cell-targeted gene therapy in some monogenic diseases, including FA. C1 [Mueller, Lars U. W.; Williams, David A.] Harvard Univ, Sch Med, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. [Mueller, Lars U. W.; Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Schlaeger, Thorsten M.; DeVine, Alexander L.] Boston Childrens Hosp, Stem Cell Program, Boston, MA USA. RP Williams, DA (reprint author), Harvard Univ, Sch Med, Div Pediat Hematol Oncol, Boston Childrens Hosp, Boston, MA 02115 USA. EM DAWilliams@childrens.harvard.edu FU St. Baldrick's Foundation; Harvard Stem Cell Institute; Hood Foundation; [NIH1RC4DK090913-01] FX We would like to thank the Dana Farber/Harvard Cancer Center Rodent Histopathology Core for assisting with teratoma histology. We appreciate the assistance with DNA sequence analysis provided by Bai-Lin Wu, Va Lip and Yiping Shen of the Genetics Diagnostic Lab at Boston Children's Hospital. Grant support: Supported by a fellowship grant from the St. Baldrick's Foundation (L. M.), Harvard Stem Cell Institute (L. M.), Hood Foundation (L. M.) and NIH1RC4DK090913-01 (D.A.W.). NR 28 TC 9 Z9 9 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG 15 PY 2012 VL 11 IS 16 BP 2985 EP 2990 DI 10.4161/cc.21109 PG 6 WC Cell Biology SC Cell Biology GA 995JJ UT WOS:000308004000015 PM 22825249 ER PT J AU Stumpfova, M Janne, PA AF Stumpfova, Magda Jaenne, Pasi A. TI Zeroing in on ROS1 Rearrangements in Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID GLIOBLASTOMA; FUSION AB Rimkunas and colleagues report on the development and validation of an immunohistochemical assay evaluating non-small cell lung cancers (NSCLC) for the presence of ROS1 fusions. The diagnostic was validated in a screen of 556 NSCLCs, identifying 9 (1.6%) tumors with oncogenic ROS1 rearrangements. These patients are candidates for ROS1-targeted therapies. Clin Cancer Res; 18(16); 4222-4. (C) 2012 AACR. C1 [Stumpfova, Magda; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Stumpfova, Magda; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, HIM223,450 Brookline Ave, Boston, MA 02215 USA. EM pjanne@partners.org NR 9 TC 12 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4222 EP 4224 DI 10.1158/1078-0432.CCR-12-1812 PG 3 WC Oncology SC Oncology GA 988PY UT WOS:000307504200002 PM 22859716 ER PT J AU Heinrich, MC Griffith, D McKinley, A Patterson, J Presnell, A Ramachandran, A Debiec-Rychter, M AF Heinrich, Michael C. Griffith, Diana McKinley, Arin Patterson, Janice Presnell, Ajia Ramachandran, Abhijit Debiec-Rychter, Maria TI Crenolanib Inhibits the Drug-Resistant PDGFRA D842V Mutation Associated with Imatinib-Resistant Gastrointestinal Stromal Tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; KINASE INHIBITORS; PHASE-II; KIT; MUTANT; CANCER; MECHANISMS; SORAFENIB; ONCOLOGY; MESYLATE AB Purpose: To determine the potential of crenolanib, a potent inhibitor of PDGFRA, to treat malignancies driven by mutant PDGFRA. Experimental Design: The biochemical activity of crenolanib was compared with imatinib using a panel of PDGFRA-mutant kinases expressed in several different cell line models, including primary gastrointestinal stromal tumors (GIST) cells. The antiproliferative activity of crenolanib was also studied in several cell lines with PDGFRA-dependent growth. Results: Crenolanib was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRA kinases (D842I, D842V, D842Y, DI842-843IM, and deletion I843). For example, crenolanib was 135-fold more potent than imatinib against D842V in our isogenic model system, with an IC50 of approximately 10 nmol/L. The relative potency of crenolanib was further confirmed in BaF3 and primary GIST cells expressing PDGFRA D842V. In contrast, imatinib was at least 10-fold more potent than crenolanib in inhibiting the V561D mutation. For all other tested PDGFRA mutations, crenolanib and imatinib had comparable potency. Conclusions: Crenolanib is a potent inhibitor of imatinib-resistant PDGFRA kinases associated with GIST, including the PDGFRA D842V mutation found in approximately 5% of GISTs. The spectrum of activity of crenolanib suggests that this drug is a type I inhibitor (inhibitor of activated conformation of kinase). Based in part on these results, a phase II clinical study of this agent to treat GIST with the PDGFRA D842V mutation has been initiated. Clin Cancer Res; 18(16); 4375-84. (C) 2012 AACR. C1 [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Dept Med, Div Hematol Oncol, Portland, OR 97239 USA. [Heinrich, Michael C.; Griffith, Diana; McKinley, Arin; Patterson, Janice; Presnell, Ajia] Oregon Hlth & Sci Univ, OHSU Knight Canc Inst, Portland, OR 97239 USA. [Ramachandran, Abhijit] AROG Pharmaceut LLC, Dallas, TX USA. [Debiec-Rychter, Maria] Katholieke Univ Leuven, Dept Human Genet, Louvain, Belgium. Univ Hosp, Louvain, Belgium. RP Heinrich, MC (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Dept Med, Div Hematol Oncol, R&D-19 3710 US Vet Hosp Rd, Portland, OR 97239 USA. EM Heinrich@ohsu.edu OI Patterson, Janice/0000-0002-8969-2933 FU AROG; Novartis; Imclone; Ariad; Veterans Affairs Merit Review Grant; AROG Pharmaceuticals LLC; Life Raft Group; GIST Cancer Research Fund FX M.C. Heinrich has received commercial research grants from AROG, Novartis, Imclone, and Ariad, and honoraria from speakers bureau of Novartis. He also has ownership interest (including patents) from MolecularMD and is a consultant and an advisory board member of Novartis, Pfizer, and MolecularMD. No potential conflicts of interest were disclosed by the other authors.; The work was supported in part from funding from a Veterans Affairs Merit Review Grant (M. C. Heinrich), AROG Pharmaceuticals LLC, the Life Raft Group (M. C. Heinrich, M. Debiec-Rychter), and the GIST Cancer Research Fund (M.C. Heinrich). NR 34 TC 56 Z9 57 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4375 EP 4384 DI 10.1158/1078-0432.CCR-12-0625 PG 10 WC Oncology SC Oncology GA 988PY UT WOS:000307504200020 PM 22745105 ER PT J AU Heon, S Yeap, BY Lindeman, NI Joshi, VA Butaney, M Britt, GJ Costa, DB Rabin, MS Jackman, DM Johnson, BE AF Heon, Stephanie Yeap, Beow Y. Lindeman, Neal I. Joshi, Victoria A. Butaney, Mohit Britt, Gregory J. Costa, Daniel B. Rabin, Michael S. Jackman, David M. Johnson, Bruce E. TI The Impact of Initial Gefitinib or Erlotinib versus Chemotherapy on Central Nervous System Progression in Advanced Non-Small Cell Lung Cancer with EGFR Mutations SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; BRAIN METASTASES; RESISTANCE; TRIAL; RISK; ADENOCARCINOMA; CLASSIFICATION; CARBOPLATIN; PACLITAXEL; CRIZOTINIB AB Purpose: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Experimental Design: Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34-0.94]. Conclusions: Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR-TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC. Clin Cancer Res; 18(16); 4406-14. (C) 2012 AACR. C1 [Heon, Stephanie; Butaney, Mohit; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Heon, Stephanie; Yeap, Beow Y.; Britt, Gregory J.; Costa, Daniel B.; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Heon, Stephanie; Lindeman, Neal I.; Joshi, Victoria A.; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lindeman, Neal I.; Joshi, Victoria A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Britt, Gregory J.; Costa, Daniel B.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, 450 Brookline Ave,Dana Bldg 1234, Boston, MA 02215 USA. EM bejohnson@partners.org OI Costa, Daniel/0000-0002-0689-395X FU American Society of Clinical Oncology (ASCO) Cancer Foundation Translational Research Professorship; NIH [5R01-CA114465]; ASCO Conquer Cancer Foundation; Dana-Farber Cancer Institute FX This work was funded in part by the American Society of Clinical Oncology (ASCO) Cancer Foundation Translational Research Professorship (to B. E. Johnson), NIH grant 5R01-CA114465 (to B. E. Johnson and B.Y. Yeap), ASCO Conquer Cancer Foundation Career Development Award (to D. B. Costa), the Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to D. M. Jackman and S. Heon), and the Elaine Promisel Siegel Fund in Thoracic Oncology at Dana-Farber Cancer Institute (to S. Heon). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 37 TC 62 Z9 65 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2012 VL 18 IS 16 BP 4406 EP 4414 DI 10.1158/1078-0432.CCR-12-0357 PG 9 WC Oncology SC Oncology GA 988PY UT WOS:000307504200023 PM 22733536 ER PT J AU Zhu, JH Lee, HP Lim, KM Gordon, BR Wang, DY AF Zhu, Jian Hua Lee, Heow Pueh Lim, Kian Meng Gordon, Bruce R. Wang, De Yun TI Effect of accessory ostia on maxillary sinus ventilation: A computational fluid dynamics (CFD) study SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Accessory ostium; Maxillary sinus ventilation; Maxillary sinus airflow; Ostiomeatal complex; CFD simulation ID HUMAN NASAL CAVITY; AIR-FLOW; NUMERICAL-SIMULATION; HUMAN NOSE; PARANASAL SINUSES; NITRIC-OXIDE; MUCUS; PATTERNS; MODEL; RECIRCULATION AB We evaluated, by CFD simulation, effects of accessory ostium (AO) on maxillary sinus ventilation. A three-dimensional nasal model was constructed from an adult CT scan with two left maxillary AOs (sinus I) and one right AO (sinus II), then compared to an identical control model with all AOs sealed (sinuses III and IV). Transient simulations of quiet inspiration and expiration at 15 L/min, and nasal blow at 48 L/min, were calculated for both models using low-Reynolds-number turbulent analysis. At low flows, ventilation rates in sinuses with AOs (I approximate to 0.46 L/min, II approximate to 0.54 L/min), were both more than a magnitude higher than sinuses without AOs (III approximate to 0.019 L/min, IV approximate to 0.020 L/min). Absence of AO almost completely prevented sinus ventilation. Increased ventilation of sinuses with AOs is complex. Under high flow conditions mimicking nose blowing, in sinuses II. HI, and IV, the sinus flow rate increased. In contrast, the airflow direction through sinus I reversed between inspiration and expiration, while it remained almost constant throughout the respiration cycle in sinus II. CFD simulation demonstrated that AOs markedly increase maxillary sinus airflow rates and alter sinus air circulation patterns. Whether these airflow changes impact maxillary sinus physiology or pathophysiology is unknown. (c) 2012 Elsevier B.V. All rights reserved. C1 [Zhu, Jian Hua] Natl Univ Singapore, Fac Engn, Dept Mech Engn, Singapore 117576, Singapore. [Gordon, Bruce R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Gordon, Bruce R.] Cape Cod Hosp, Div Otolaryngol, Hyannis, MA USA. [Wang, De Yun] Natl Univ Singapore, Dept Otolaryngol, Singapore 117576, Singapore. RP Zhu, JH (reprint author), Natl Univ Singapore, Fac Engn, Dept Mech Engn, 1 Engn Dr 2, Singapore 117576, Singapore. EM jhzhu.me@gmail.com RI Lim, Kian-Meng/B-2556-2010; Lee, Heow Pueh/I-7834-2014 OI Lim, Kian-Meng/0000-0003-4311-9223; Lee, Heow Pueh/0000-0002-4380-3888 FU Academic Research Grant from the Ministry of Education, Singapore [T208A3103] FX The authors would like to acknowledge the support by the Academic Research Grant (T208A3103) from the Ministry of Education, Singapore. This research has been approved by the relevant Institutional Review Board. NR 32 TC 9 Z9 12 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 EI 1878-1519 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD AUG 15 PY 2012 VL 183 IS 2 BP 91 EP 99 DI 10.1016/j.resp.2012.06.026 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 993NU UT WOS:000307867200005 PM 22750570 ER PT J AU Ren, Y Cheung, HW von Maltzhan, G Agrawal, A Cowley, GS Weir, BA Boehm, JS Tamayo, P Karst, AM Liu, JF Hirsch, MS Mesirov, JP Drapkin, R Root, DE Lo, J Fogal, V Ruoslahti, E Hahn, WC Bhatia, SN AF Ren, Yin Cheung, Hiu Wing von Maltzhan, Geoffrey Agrawal, Amit Cowley, Glenn S. Weir, Barbara A. Boehm, Jesse S. Tamayo, Pablo Karst, Alison M. Liu, Joyce F. Hirsch, Michelle S. Mesirov, Jill P. Drapkin, Ronny Root, David E. Lo, Justin Fogal, Valentina Ruoslahti, Erkki Hahn, William C. Bhatia, Sangeeta N. TI Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4 SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID IN-VIVO; CELLS; NANOPARTICLES; EXPRESSION; DELIVERY; PEPTIDE; INTERFERENCE; INHIBITION; PROTEINS; BARRIERS AB The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) that comprised small interfering RNA (siRNA) complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We used TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor-bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets. C1 [Cheung, Hiu Wing; Karst, Alison M.; Liu, Joyce F.; Drapkin, Ronny; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ren, Yin; von Maltzhan, Geoffrey; Agrawal, Amit; Lo, Justin; Bhatia, Sangeeta N.] MIT, Cambridge, MA 02139 USA. [Cheung, Hiu Wing; Cowley, Glenn S.; Weir, Barbara A.; Boehm, Jesse S.; Tamayo, Pablo; Mesirov, Jill P.; Root, David E.; Hahn, William C.; Bhatia, Sangeeta N.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Hirsch, Michelle S.; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hirsch, Michelle S.; Drapkin, Ronny; Hahn, William C.; Bhatia, Sangeeta N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Mesirov, Jill P.; Bhatia, Sangeeta N.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Fogal, Valentina; Ruoslahti, Erkki] Univ Calif Santa Barbara, Ctr Nanomed, Sanford Burnham Med Res Inst, Santa Barbara, CA 93106 USA. [Fogal, Valentina; Ruoslahti, Erkki] Sanford Burnham Med Res Inst, Ctr Canc, La Jolla, CA 92037 USA. [Hahn, William C.; Bhatia, Sangeeta N.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Bhatia, Sangeeta N.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu; sbhatia@mit.edu RI Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Boehm, Jesse/0000-0002-6795-6336 FU Howard Hughes Medical Institute; National Cancer Institute (NCI) [U54 CA119349, U54 CA119335, R01 CA124427, R33 CA128625, RC2 CA148268, U54 CA112962, RO1 CA152327, P50 CA105009]; NIH [U01 CA152990]; Starr Cancer Consortium; Marie D. and Pierre Casimir-Lambert Fund; Mary Kay Foundation; Sandy Rollman Ovarian Cancer Foundation; Canadian Institutes of Health Research Fellowship; Cancer Center Support (Core) from NCI [P30 CA14051] FX Supported by the Howard Hughes Medical Institute (S.N.B.); National Cancer Institute (NCI) grants U54 CA119349 (S.N.B.), U54 CA119335 (S.N.B.), R01 CA124427 (S.N.B.), R33 CA128625 (W.C.H.), RC2 CA148268 (W.C.H.), U54 CA112962 (W.C.H.), RO1 CA152327 (E.R.), and P50 CA105009 (R.D.); NIH grant U01 CA152990 (R.D.); the Starr Cancer Consortium (W.C.H. and S.N.B.); the Marie D. and Pierre Casimir-Lambert Fund (S.N.B.); The Mary Kay Foundation (R.D.); the Sandy Rollman Ovarian Cancer Foundation (R.D.); Canadian Institutes of Health Research Fellowship (A.M.K.); and in part by Cancer Center Support (Core) Grant P30 CA14051 from the NCI. NR 42 TC 63 Z9 63 U1 3 U2 40 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 AUG 15 PY 2012 VL 4 IS 147 AR 147ra112 DI 10.1126/scitranslmed.3003778 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 994UR UT WOS:000307958800006 PM 22896676 ER PT J AU Bouldin, SD Darch, MA Hart, PJ Outten, CE AF Bouldin, Samantha D. Darch, Maxwell A. Hart, P. John Outten, Caryn E. TI Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1 SO BIOCHEMICAL JOURNAL LA English DT Article DE Cu,Zn superoxide dismutase (SOD); disulfide; glutaredoxin; monothiol; redox potential; yeast ID AMYOTROPHIC-LATERAL-SCLEROSIS; COPPER CHAPERONE CCS; MUTANT CU,ZN-SUPEROXIDE DISMUTASE; INTERMEMBRANE SPACE; FAMILIAL ALS; BINDING-SITE; REDUCED FORM; MOUSE MODEL; WILD-TYPE; SOD1 AB The intramolecular disulfide bond in hSOD1 [human SOD1 (Cu,Zn superoxide dismutase 1)] plays a key role in maintaining the protein's stability and quaternary structure. In mutant forms of SOD1 that cause familial ALS (amyotrophic lateral sclerosis), this disulfide bond is more susceptible to chemical reduction, which may lead to destabilization of the dimer and aggregation. During hSOD1 maturation, disulfide formation is catalysed by CCS1 (copper chaperone for SOD1). Previous studies in yeast demonstrate that the yeast GSH/Grx (glutaredoxin) redox system promotes reduction of the hSOD1 disulfide in the absence of CCS1. In the present study, we probe further the interaction between hSOD1, GSH and Grxs to provide mechanistic insight into the redox kinetics and thermodynamics of the hSOD1 disulfide. We demonstrate that hGrx1 (human Grx1) uses a monothiol mechanism to reduce the hSOD1 disulfide, and the GSH/hGrx1 system reduces ALS mutant SOD1 at a faster rate than WT (wild-type) hSOD1. However, redox potential measurements demonstrate that the thermodynamic stability of the disulfide is not consistently lower in ALS mutants compared with WT hSOD1. Furthermore, the presence of metal cofactors does not influence the disulfide redox potential. Overall, these studies suggest that differences in the GSH/hGrx1 reaction rate with WT compared with ALS mutant hSOD1 and not the inherent thermodynamic stability of the hSOD1 disulfide bond may contribute to the greater pathogenicity of ALS mutant hSOD1. C1 [Bouldin, Samantha D.; Darch, Maxwell A.; Outten, Caryn E.] Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, San Antonio, TX 78229 USA. RP Outten, CE (reprint author), Univ S Carolina, Dept Chem & Biochem, Columbia, SC 29208 USA. EM outten@mailbox.sc.edu OI Outten, Caryn/0000-0003-0335-6531 FU National Institutes of Health [K22 ES013780, R01 GM086619, R01 NS039112]; Judith and Jean Pape Adams Charitable Foundation FX This work was supported by the National Institutes of Health [grant numbers K22 ES013780 and R01 GM086619 (to C.E.O.), and R01 NS039112 (to P.J.H.)] and the Judith and Jean Pape Adams Charitable Foundation (to P.J.H.). NR 65 TC 13 Z9 13 U1 0 U2 9 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2012 VL 446 BP 59 EP 67 DI 10.1042/BJ20120075 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 990JH UT WOS:000307626300006 PM 22651090 ER PT J AU Kronenberg, G Balkaya, M Prinz, V Gertz, K Ji, S Kirste, I Heuser, I Kampmann, B Hellmann-Regen, J Gass, P Sohr, R Hellweg, R Waeber, C Juckel, G Hortnagl, H Stumm, R Endres, M AF Kronenberg, Golo Balkaya, Mustafa Prinz, Vincent Gertz, Karen Ji, Shengbo Kirste, Imke Heuser, Isabella Kampmann, Bjoern Hellmann-Regen, Julian Gass, Peter Sohr, Reinhard Hellweg, Rainer Waeber, Christian Juckel, Georg Hoertnagl, Heide Stumm, Ralf Endres, Matthias TI Exofocal Dopaminergic Degeneration as Antidepressant Target in Mouse Model of Poststroke Depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE BDNF; depression; dopamine; mesolimbic reward system; serotonin reuptake inhibition; stroke ID SEROTONIN REUPTAKE INHIBITORS; IPSILATERAL SUBSTANTIA-NIGRA; LESION LOCATION; PARKINSONS-DISEASE; CEREBRAL INFARCTION; RECEPTOR ACTIVATION; TRANSIENT ISCHEMIA; NUCLEUS-ACCUMBENS; CONTROLLED-TRIAL; FOCAL ISCHEMIA AB Background: Although poststroke depression (PSD) is a frequent chronic complication of stroke with high relevance for outcome and survival, underlying pathomechanisms remain inadequately understood. This may be because suitable animal models are largely lacking and existing models are poorly characterized. Methods: Male 129/SV mice were subjected to 30-min middle cerebral artery occlusion (MCAo)/reperfusion and serial magnetic resonance imaging scans. A subset of animals received selective serotonin reuptake inhibitor citalopram starting 7 days after MCAo. Behavioral assessment was performed at 14 weeks. To identify biological correlates of PSD, we quantified corticosterone levels in serum and brain-derived neurotrophic factor levels in brain. The integrity of the mesolimbic dopaminergic system was assessed using tyrosine hydroxylase and dynorphin in situ hybridizations as well as dopamine transporter autoradiography. Results: Left, but not right, MCAo, elicited anhedonia and increased anxiety and despair. This depression-like syndrome was associated with alterations in the mesolimbic reward system. MCAo resulted in delayed degeneration of dopaminergic neurons in ipsilateral midbrain, which was accompanied by reduced dopamine concentrations and decreased levels of dopamine transporter density along with increased brain-derived neurotrophic factor protein levels in ischemic striatum and increased dynorphin messenger RNA expression in nucleus accumbens. Chronic antidepressant treatment initiated as late as 7 days after stroke reversed the behavioral phenotype, prevented degeneration of dopaminergic midbrain neurons, and attenuated striatal atrophy at 4 months. Conclusions: Our results highlight the importance of the dopaminergic system for the development of PSD. Prevention of secondary neurodegeneration by antidepressants may provide a novel target for subacute stroke therapy. C1 [Kronenberg, Golo; Balkaya, Mustafa; Prinz, Vincent; Gertz, Karen; Ji, Shengbo; Endres, Matthias] Charite Univ Med Berlin, Klin & Poliklin Neurol, D-10117 Berlin, Germany. [Kronenberg, Golo; Balkaya, Mustafa; Prinz, Vincent; Gertz, Karen; Ji, Shengbo; Endres, Matthias] Charite Univ Med Berlin, Ctr Stroke Res Berlin, D-10117 Berlin, Germany. [Kampmann, Bjoern; Sohr, Reinhard; Hoertnagl, Heide] Charite Univ Med Berlin, Inst Pharmakol & Toxikol, D-10117 Berlin, Germany. [Hellweg, Rainer] Charite Univ Med Berlin, Klin Psychiat & Psychotherapie, D-10117 Berlin, Germany. [Kronenberg, Golo; Kirste, Imke; Heuser, Isabella; Hellmann-Regen, Julian] Charite Univ Med Berlin, Klin & Hsch Ambulanz Psychiat & Psychotherapie, D-10117 Berlin, Germany. [Kronenberg, Golo] Max Delbruck Ctr, Expt & Clin Res Ctr, Berlin, Germany. [Kronenberg, Golo] Humboldt Univ, Fac Med Charite, Inst Pharmacol & Toxicol, D-10098 Berlin, Germany. [Gass, Peter] Univ Heidelberg, Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Waeber, Christian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. [Juckel, Georg] Ruhr Univ Bochum, Dept Psychiat, Bochum, Germany. [Stumm, Ralf] Otto von Guericke Univ, Res Grp Mol & Syst Neuropharmacol, Ctr Behav Brain Sci, Magdeburg, Germany. RP Endres, M (reprint author), Charite Univ Med Berlin, Klin & Poliklin Neurol, Campus Mitte,Charitepl 1, D-10117 Berlin, Germany. EM matthias.endres@charite.de RI Kronenberg, Golo/F-8772-2010; Waeber, Christian/A-8333-2009; Gertz, Karen/J-1603-2015 OI Waeber, Christian/0000-0001-6078-0027; FU Deutsche Forschungsgemeinschaft; Sonderforschungsbereich [TR 43]; Cluster of Excellence [257]; VolkswagenStiftung (Lichtenberg Program); Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin); European Union [201024, 202213] FX This work was supported by individual grants by the Deutsche Forschungsgemeinschaft (to RH, RSt, ME) as well as through Sonderforschungsbereich TR 43 and Cluster of Excellence 257 (NeuroCure), VolkswagenStiftung (Lichtenberg Program to ME), the Bundesministerium fur Bildung und Forschung (Center for Stroke Research Berlin), and the European Union's Seventh Framework Program (Grant No. FP7/2008-2013) under grant Agreement Nos. 201024 and 202213 (European Stroke Network). NR 78 TC 28 Z9 31 U1 0 U2 7 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 AUG 15 PY 2012 VL 72 IS 4 BP 273 EP 281 DI 10.1016/j.biopsych.2012.02.026 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 980NA UT WOS:000306898800010 PM 22464799 ER PT J AU Dutta, C Day, T Kopp, N van Bodegom, D Davids, MS Ryan, J Bird, L Kommajosyula, N Weigert, O Yoda, A Fung, H Brown, JR Shapiro, GI Letai, A Weinstock, DM AF Dutta, Chaitali Day, Tovah Kopp, Nadja van Bodegom, Diederik Davids, Matthew S. Ryan, Jeremy Bird, Liat Kommajosyula, Naveen Weigert, Oliver Yoda, Akinori Fung, Hua Brown, Jennifer R. Shapiro, Geoffrey I. Letai, Anthony Weinstock, David M. TI BCL2 Suppresses PARP1 Function and Nonapoptotic Cell Death SO CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; HOMOLOGOUS RECOMBINATION; TRANSCRIPTIONAL ACTIVITY; MISMATCH REPAIR; DNA-DAMAGE; APOPTOSIS; ABT-737; MITOCHONDRIAL; INHIBITOR; FAMILY AB BCL2 suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating outer mitochondrial membrane permeabilization. Many tumor types, including B-cell lymphomas and chronic lymphocytic leukemia, are dependent on BCL2 for survival but become resistant to apoptosis after treatment. Here, we identified a direct interaction between the antiapoptotic protein BCL2 and the enzyme PARP1, which suppresses PARP1 enzymatic activity and inhibits PARP1-dependent DNA repair in diffuse large B-cell lymphoma cells. The BH3 mimetic ABT-737 displaced PARP1 from BCL2 in a dose-dependent manner, reestablishing PARP1 activity and DNA repair and promoting nonapoptotic cell death. This form of cell death was unaffected by resistance to single-agent ABT-737 that results from upregulation of antiapoptotic BCL2 family members. On the basis of the ability of BCL2 to suppress PARP1 function, we hypothesized that ectopic BCL2 expression would kill PARP inhibitor-sensitive cells. Strikingly, BCL2 expression reduced the survival of PARP inhibitor-sensitive breast cancer and lung cancer cells by 90% to 100%, and these effects were reversed by ABT-737. Taken together, our findings show that a novel interaction between BCL2 and PARP1 blocks PARP1 enzymatic activity and suppresses PARP1-dependent repair. Targeted disruption of the BCL2-PARP1 interaction therefore may represent a potential therapeutic approach for BCL2-expressing tumors resistant to apoptosis. Cancer Res; 72(16); 4193-203. (C) 2012 AACR. C1 [Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Weinstock, DM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 510B, Boston, MA 02115 USA. EM davidm_weinstock@dfci.harvard.edu FU Burroughs-Wellcome Fund Career Award in the Biomedical Sciences [6150801]; Claudia Adams Barr Program in Cancer Research; John Stellato Fund; American Cancer Society; DF/HCC SPORE in Lung Cancer [P50 CA90578] FX This work was supported by a Burroughs-Wellcome Fund Career Award in the Biomedical Sciences (6150801), the Claudia Adams Barr Program in Cancer Research, and the John Stellato Fund. T. Day is supported by an American Cancer Society Fellowship. N. Kommajosyula and G. I. Shapiro are supported by the DF/HCC SPORE in Lung Cancer P50 CA90578. NR 47 TC 17 Z9 17 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 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2012 VL 72 IS 16 BP 4193 EP 4203 DI 10.1158/0008-5472.CAN-11-4204 PG 11 WC Oncology SC Oncology GA 993SY UT WOS:000307881100030 PM 22689920 ER PT J AU Beker, S Kellner, V Kerti, L Stern, EA AF Beker, Shlomit Kellner, Vered Kerti, Lucia Stern, Edward A. TI Interaction between Amyloid-beta Pathology and Cortical Functional Columnar Organization SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MOUSE BARREL CORTEX; LAYER-IV BARRELS; ALZHEIMERS-DISEASE; TRANSGENIC MICE; IN-VIVO; VISUAL-CORTEX; SPATIOTEMPORAL CONVERGENCE; VIBRISSAL INFORMATION; BRAIN-DEVELOPMENT; RECEPTIVE-FIELDS AB Amyloid-beta plaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of plaques in the vibrissae-receptive primary sensory cortex (barrel cortex), in which the cortical columnar structure is anatomically demarcated by boundaries in Layer IV. We found that the plaques are not distributed randomly with respect to the barrel structures in Layer IV; rather, they are more concentrated in the septal areas than in the barrels. This difference was not preserved in the supragranular extensions of the functional columns. When comparing the degree of clustering of plaques between primary sensory cortices, we found that the degree of plaques clustering is significantly higher in somatosensory cortex than in visual cortex, and these differences are preserved in Layers II/III. The degree of areal discontinuity is therefore correlated with the patterns of neuropathological deposits. The discontinuous anatomical structure of this area allows us to make predictions about the functional effects of plaques on specific patterns of computational disruption in the AD brain. C1 [Beker, Shlomit; Kellner, Vered; Kerti, Lucia; Stern, Edward A.] Bar Ilan Univ, Brain Res Ctr, Fac Life Sci, IL-52900 Ramat Gan, Israel. [Stern, Edward A.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Stern, Edward A.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Kerti, Lucia] Univ Freiburg, Fac Biol, Bernstein Ctr Freiburg, D-79104 Freiburg, Germany. RP Stern, EA (reprint author), Bar Ilan Univ, Brain Res Ctr, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM sterned@mail.biu.ac.il FU National Institute on Aging [AG024238]; Israel Science Foundation [688/10] FX This work was supported by the National Institute on Aging (Grant AG024238) and the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (Grant 688/10). NR 73 TC 4 Z9 4 U1 0 U2 0 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 AUG 15 PY 2012 VL 32 IS 33 BP 11241 EP 11249 DI 10.1523/JNEUROSCI.2426-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 994OJ UT WOS:000307940000008 PM 22895708 ER PT J AU Choi, HG Zhang, JM Weisberg, E Griffin, JD Sim, T Gray, NS AF Choi, Hwan Geun Zhang, Jianming Weisberg, Ellen Griffin, James D. Sim, Taebo Gray, Nathanael S. TI Development of 'DFG-out' inhibitors of gatekeeper mutant kinases SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE T315I Bcr-Abl; Kinase inhibitor; Gatekeeper mutant; Type II inhibitor; Thiazolo[5,4-b]pyridine ID CHRONIC MYELOID-LEUKEMIA; ABL TYROSINE KINASE; BCR-ABL; SELECTIVE INHIBITOR; RESISTANCE; DISCOVERY; IMATINIB; SRC; AMN107; CELLS AB HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I-Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Choi, Hwan Geun; Zhang, Jianming; Sim, Taebo; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Weisberg, Ellen; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sim, Taebo] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 136791, South Korea. [Choi, Hwan Geun; Zhang, Jianming; Sim, Taebo; Gray, Nathanael S.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Sch Med, Boston, MA 02115 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu FU Novartis; NIH [R01 CA130876-02] FX We thank Nam Doo Kim for assistance with molecular modeling and Sara Buhrlage for critical reading of the manuscript. We acknowledge research funding from Novartis and NIH (R01 CA130876-02). NR 19 TC 3 Z9 3 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2012 VL 22 IS 16 BP 5297 EP 5302 DI 10.1016/j.bmcl.2012.06.036 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 981JJ UT WOS:000306962800028 PM 22819762 ER PT J AU O'Horo, JC Thompson, D Safdar, N AF O'Horo, John C. Thompson, Deb Safdar, Nasia TI Is the Gram Stain Useful in the Microbiologic Diagnosis of VAP? A Meta-analysis SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID VENTILATOR-ASSOCIATED PNEUMONIA; BRONCHOALVEOLAR LAVAGE FLUID; APPROPRIATE ANTIBIOTIC-THERAPY; PROTECTED SPECIMEN BRUSH; INTRACELLULAR ORGANISMS; RANDOMIZED-TRIAL; PREDICTIVE-VALUE; MICROSCOPIC EXAMINATION; NOSOCOMIAL PNEUMONIA; INJURED PATIENTS AB In a meta-analysis examining respiratory specimen Gram stain for diagnosis of ventilator-associated pneumonia, absence of bacteria on Gram stain had a high negative predictive value, but a positive Gram stain correlated poorly with organisms recovered in culture. Rapid and accurate diagnosis of ventilator-associated pneumonia (VAP) is a major challenge and no generally accepted gold standard exists for VAP diagnosis. We conducted a meta-analysis to examine the role of respiratory specimen Gram stain to diagnose VAP, and the correlation with final culture results. In 21 studies, pooled sensitivity of Gram stain for VAP was 0.79 (95% confidence interval [CI],.77-0.81; P < .0001) and specificity was 0.75 (95% CI,.73-.78; P < .0001). Negative predictive value of Gram stain for a VAP prevalence of 20%-30% was 91%, suggesting that VAP is unlikely with a negative Gram stain but the positive predictive value of Gram stain was only 40%. Pooled kappa was 0.42 for gram-positive organisms and 0.34 for gram-negative organisms, suggesting fair concordance between organisms on Gram stain and recovery by culture. Therefore, a positive Gram stain should not be used to narrow anti-infective therapy until culture results become available. C1 [O'Horo, John C.] Aurora Healthcare Metro, Dept Grad Med Educ, Milwaukee, WI USA. [Thompson, Deb] Infect Dis Associates, Milwaukee, WI USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, William S Middleton Mem Vet Hosp, Madison, WI 53706 USA. [Safdar, Nasia] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. RP Safdar, N (reprint author), Hlth Sci Learning Ctr, Sect Infect Dis, MFCB 5221,1685 Highland Ave, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu RI O'Horo, John/A-8787-2013; O'Horo, John/N-8681-2013 OI O'Horo, John/0000-0002-0880-4498; O'Horo, John/0000-0002-0880-4498 NR 52 TC 19 Z9 23 U1 1 U2 27 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2012 VL 55 IS 4 BP 551 EP 561 DI 10.1093/cid/cis512 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977RQ UT WOS:000306682500014 PM 22677711 ER PT J AU Coutinho, A Roxo, U Epino, H Muganzi, A Dorward, E Pick, B AF Coutinho, Alex Roxo, Uchechi Epino, Henry Muganzi, Alex Dorward, Emily Pick, Billy TI The Expanding Role of Civil Society in the Global HIV/AIDS Response: What Has The President's Emergency Program For AIDS Relief's Role Been? SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE civil society; PEPFAR ID HEALTH SYSTEMS; SCALE-UP; HIV; SERVICES AB Civil society has been part of the HIV/AIDS response from the very beginning of the epidemic, often becoming engaged before national governments. Traditional roles of civil society-advocacy, activism, serving as government watchdog, and acting as community caretaker-have been critical to the response. In addition, civil society organizations (CSOs) play an integral part in providing world-class HIV prevention and treatment services and helping to ensure continuity of care. The President's Emergency Program for AIDS Relief (PEPFAR) has significantly increased the global scale-up of combination antiretroviral therapy reaching for more than 5 million people in developing countries, as well as implementation of effective evidence-based combination prevention approaches. PEPFAR databases in 5 countries and annual reports from a centrally managed initiative were mined and analyzed to determine the numbers and types of CSOs funded by PEPFAR over a 5-year period (2006-2011). Data are also presented from Uganda showing the overall resource growth in CSO working for HIV. Case studies document the evolution of 3 indigenous CSOs that increased the capacity to implement activities with PEPFAR funding. A legacy of PEPFAR has been the growth of civil society to address social and health issues as well as recognition by governments that partnerships with beneficiaries and civil society result in better outcomes. Scale-up of the global response could not have happened without the involvement of civil society and people living with HIV. This game changing partnership to jointly tackle the problems that countries face may well be the greatest benefit emerging from the HIV epidemic. C1 [Coutinho, Alex; Muganzi, Alex] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Roxo, Uchechi; Dorward, Emily; Pick, Billy] US Agcy Int Dev, Washington, DC 20523 USA. [Epino, Henry] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Epino, Henry] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. RP Coutinho, A (reprint author), Makerere Univ, Infect Dis Inst, POB 22418, Kampala, Uganda. EM acoutinho@idi.co.ug FU PEPRAR FX AC and AM both work for The Infectious Diseases Institute, which receives funding from PEPRAR. NR 26 TC 5 Z9 5 U1 0 U2 7 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 AUG 15 PY 2012 VL 60 SU 3 BP S152 EP S157 DI 10.1097/QAI.0b013e31825d0383 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TR UT WOS:000306994100015 PM 22797737 ER PT J AU Zhi, L Ustyugova, IV Chen, XY Zhang, Q Wu, MX AF Zhi, Liang Ustyugova, Irina V. Chen, Xinyuan Zhang, Qi Wu, Mei X. TI Enhanced Th17 Differentiation and Aggravated Arthritis in IEX-1-Deficient Mice by Mitochondrial Reactive Oxygen Species-Mediated Signaling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HELPER T-CELLS; NF-KAPPA-B; OXIDATIVE STRESS; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; GLUCOSE-OXIDASE; ROR-GAMMA; INTERLEUKIN-17 AB CD4(+) Th1 and Th17 cells both can cause autoimmune diseases, either alone or collaboratively, if left unchecked. However, what determines the dominant Th effector phenotype in a specific autoimmune disease remains poorly understood. Our present investigation shows that null mutation of IEX-1 promotes differentiation of Th17 cells but compromises the survival of Th1 cells. The differential effect gave rise to a greater number of Th17 cells, a higher level of IL-17 production, and more severe arthritis in IEX-1 knockout mice than in wild-type mice after immunizations with collagen. IEX-1 deficiency-facilitated Th17 cell differentiation was mediated by the increased formation of reactive oxygen species (ROS) at mitochondria following T cell activation, as suggested by marked inhibition of Th17 induction with ROS scavenger N-acetylcysteine or mitoquinone, a specific inhibitor for mitochondrial ROS production. Mitochondrial ROS augmented the expression of B cell-activating transcription factor, which may contribute to increased IL-17 production in the absence of IEX-1, in light of its importance in IL-17 transcription. The results demonstrate that mitochondrial ROS contribute significantly to the dominant Th effector phenotype in autoimmunity in addition to the cytokine milieu. The Journal of Immunology, 2012, 189: 1639-1647. C1 [Zhi, Liang; Ustyugova, Irina V.; Chen, Xinyuan; Zhang, Qi; Wu, Mei X.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Boston, MA 02114 USA. [Zhi, Liang; Ustyugova, Irina V.; Chen, Xinyuan; Zhang, Qi; Wu, Mei X.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wu, Mei X.] Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. RP Wu, MX (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Dept Dermatol, Edwards 222,50 Blossom St, Boston, MA 02114 USA. EM mwu2@partners.org FU National Institutes of Health [AI050822, AI070785]; Senior Research Award from the Crohn's and Colitis Foundation of America FX This work was supported in part by National Institutes of Health Grants AI050822 and AI070785 and a Senior Research Award from the Crohn's and Colitis Foundation of America (to M.X.W.). NR 52 TC 19 Z9 21 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 1639 EP 1647 DI 10.4049/jimmunol.1200528 PG 9 WC Immunology SC Immunology GA 984TW UT WOS:000307216000015 PM 22798682 ER PT J AU Lin, T Sammy, F Yang, H Thundivalappil, S Hellman, J Tracey, KJ Warren, HS AF Lin, Tian Sammy, Fatima Yang, Huan Thundivalappil, Sujatha Hellman, Judith Tracey, Kevin J. Warren, H. Shaw TI Identification of Hemopexin as an Anti-Inflammatory Factor That Inhibits Synergy of Hemoglobin with HMGB1 in Sterile and Infectious Inflammation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INNATE IMMUNE-RESPONSE; DENDRITIC CELLS; BIOLOGICAL-ACTIVITY; PRETERM INFANTS; HEME; TRANSFUSION; PROTEIN; LPS; ENDOTOXIN; TOLL-LIKE-RECEPTOR-4 AB Hemoglobin is released from lysed RBCs in numerous clinical settings. High mobility group box 1 (HMGB1) is a nuclear and cytosolic DNA-binding protein released from injured cells that has been shown to play an important role in inducing inflammation. Because both of these endogenous molecules are frequently present in sites of necrosis and inflammation, we studied their interaction on the activation of macrophages. We report in this article that hemoglobin and HMGB1 synergize to activate mouse macrophages to release significantly increased proinflammatory cytokines. Addition of microbial ligands that activate through TLR2 or TLR4 resulted in further significant increases, in a "three-way" synergy between endogenous and microbial ligands. The synergy was strongly suppressed by hemopexin (Hx), an endogenous heme-binding plasma protein. The findings suggest that hemoglobin may play an important role in sterile and infectious inflammation, and that endogenous Hx can modulate this response. Administration of Hx may be beneficial in clinical settings characterized by elevated extracellular hemoglobin and HMGB1. The Journal of Immunology, 2012, 189: 2017-2022. C1 [Lin, Tian; Sammy, Fatima; Thundivalappil, Sujatha; Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02129 USA. [Yang, Huan; Tracey, Kevin J.] Feinstein Inst Med Res, Lab Biomed Sci, Manhasset, NY 11030 USA. [Hellman, Judith] Univ Calif San Francisco, Div Crit Care Med, Dept Anesthesia, San Francisco, CA 94143 USA. RP Lin, T (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, Room 5234,149 13th St, Boston, MA 02129 USA. EM tlin7@partners.org OI Tracey, Kevin J/0000-0003-1884-6314 FU Shriners Hospital for Crippled Children [8720]; National Institutes of Health [AI059010, GM59694, GM62508, GM098446]; Defense Advanced Research Planning Agency [W911NF-10-1-0271] FX This work was supported by the Shriners Hospital for Crippled Children (Grant 8720), the National Institutes of Health (Grants AI059010 and GM59694 to H.S.W., Grant GM62508 to K.J.T., and Grant GM098446 to J.H.), and the Defense Advanced Research Planning Agency (Grant W911NF-10-1-0271 to H.S.W.). NR 40 TC 25 Z9 27 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2012 VL 189 IS 4 BP 2017 EP 2022 DI 10.4049/jimmunol.1103623 PG 6 WC Immunology SC Immunology GA 984TW UT WOS:000307216000055 PM 22772444 ER PT J AU Simoni, JM Huh, D Wilson, IB Shen, J Goggin, K Reynolds, NR Remien, RH Rosen, MI Bangsberg, DR Liu, HH AF Simoni, Jane M. Huh, David Wilson, Ira B. Shen, Jie Goggin, Kathy Reynolds, Nancy R. Remien, Robert H. Rosen, Marc I. Bangsberg, David R. Liu, Honghu TI Racial/Ethnic Disparities in ART Adherence in the United States: Findings From the MACH14 Study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV/AIDS; race/ethnicity; antiretroviral treatment; medication adherence ID ACTIVE ANTIRETROVIRAL THERAPY; MULTICENTER AIDS COHORT; HIV-INFECTED PATIENTS; HEALTH LITERACY; DRUG-USERS; DEPRESSION; SAMPLE; CARE; MEN; DISCRIMINATION AB Background: Minority race/ethnicity is generally associated with antiretroviral therapy nonadherence in US-based studies. Limitations of the existing literature include small samples, subjective adherence measures, and inadequate control for potential confounders such as mental health and substance use, which have been consistently associated with poorer adherence. Methods: Individual-level data were pooled from 13 US-based studies employing electronic drug monitoring to assess adherence. Adherence was operationalized as percent of prescribed doses taken from the first 12 (monthly) waves of data in each study. Depression symptoms were aggregated from several widely used assessments, and substance use was operationalized as any use of cocaine/stimulants, heroin/opiates, ecstasy, hallucinogens, or sedatives in the 30-365 days preceding baseline. Results: The final analytic sample of 1809 participants ranged in age from 18 to 72 years and was 67% male. Participants were 53% African American, 14% Latino, and 34% White. In a logistic regression adjusting for age, gender, income, education, and site, race/ethnicity was significantly associated with adherence (P, 0.001) and persisted in a model that also controlled for depression and substance use (P < 0.001), with African Americans having significantly lower adherence than Latinos [odds ratio (OR) = 0.72, P = 0.04] and whites (OR = 0.60, P < 0.001). Adherence did not differ between whites and Latinos (OR = 0.84, P = 0.27). Conclusions: Racial/ethnic differences in demographics, depression, and substance abuse do not explain the lower level of antiretroviral therapy adherence in African Americans observed in our sample. Further research is needed to explain the persistent disparity and might examine factors such as mistrust of providers, health literacy, and inequities in the health care system. C1 [Simoni, Jane M.; Huh, David; Bangsberg, David R.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Wilson, Ira B.] Brown Univ, Alpert Med Sch, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. [Shen, Jie] Univ Calif Los Angeles, Sch Dent, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Goggin, Kathy] Univ Missouri, Dept Psychol, Kansas City, MO 64110 USA. [Reynolds, Nancy R.] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Remien, Robert H.] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. [Rosen, Marc I.] Yale Univ, Sch Med, West Haven, CT 06516 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02138 USA. [Liu, Honghu] Univ Calif Los Angeles, Dept Med, Div Publ Hlth & Community Dent, Los Angeles, CA 90024 USA. [Liu, Honghu] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA USA. RP Simoni, JM (reprint author), Univ Washington, Dept Psychol, Box 351525, Seattle, WA 98195 USA. EM jsimoni@uw.edu RI Wilson, Ira/F-9190-2016; OI Wilson, Ira/0000-0002-0246-738X; Simoni, Jane/0000-0002-8711-1576 FU National Institute of Mental Health (NIMH), Office on AIDS [R01MH078773]; [R01DA11869]; [R01MH54907]; [R01NR04749]; [R01MH68197]; [R01DA13826]; [K23MH01862]; [R01MH01584]; [R01AI41413]; [R01 MH61173]; [NIH/NIAID AI38858]; [AI069419]; [K02DA017277]; [R01DA15215]; [NIMH P01MH49548]; [R01MH58986]; [R01MH61695]; [CC99-SD003]; [CC02-SD-003]; [R01DA015679] FX Supported by the multisite adherence collaboration in HIV (MACH14) grant R01MH078773 from the National Institute of Mental Health (NIMH), Office on AIDS. The original grants of individual participating studies are: R01DA11869, R01MH54907, R01NR04749, R01NR04749, R01MH68197, R01DA13826, K23MH01862, R01MH01584, R01AI41413, R01 MH61173, NIH/NIAID AI38858, AI069419, K02DA017277, R01DA15215, NIMH P01MH49548, R01MH58986, R01MH61695, CC99-SD003, CC02-SD-003, and R01DA015679. NR 43 TC 44 Z9 44 U1 2 U2 19 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 AUG 15 PY 2012 VL 60 IS 5 BP 466 EP 472 DI 10.1097/QAI.0b013e31825db0bd PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 981TV UT WOS:000306994500006 PM 22595873 ER PT J AU Hempel, S Miles, JNV Shekelle, PG AF Hempel, Susanne Miles, Jeremy N. V. Shekelle, Paul G. TI Probiotics for Antibiotic-Associated Diarrhea Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID THERAPY; BLIND C1 [Hempel, Susanne] RAND Hlth, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. [Miles, Jeremy N. V.] RAND Corp, Santa Monica, CA USA. [Shekelle, Paul G.] W Los Angeles VA Med Ctr, Los Angeles, CA USA. RP Hempel, S (reprint author), RAND Hlth, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. EM Susanne_hempel@rand.org NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 15 PY 2012 VL 308 IS 7 BP 665 EP 666 DI 10.1001/jama.2012.8738 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 988NC UT WOS:000307496700013 ER PT J AU Monson, CM Fredman, SJ Macdonald, A Pukay-Martin, ND Resick, PA Schnurr, PP AF Monson, Candice M. Fredman, Steffany J. Macdonald, Alexandra Pukay-Martin, Nicole D. Resick, Patricia A. Schnurr, Paula P. TI Effect of Cognitive-Behavioral Couple Therapy for PTSD A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PSYCHOTHERAPY; METAANALYSIS; CLINICIAN; SYMPTOMS; MARRIAGE; QUALITY; SCALES AB Context Posttraumatic stress disorder (PTSD) is a prevalent condition associated with intimate relationship problems, and intimate relationship factors have been shown to affect individual PTSD treatment outcomes. Objective To compare cognitive-behavioral conjoint therapy for PTSD (a manualized couple therapy delivered to patients with PTSD and their significant others to simultaneously treat PTSD symptoms and enhance relationship satisfaction) with a wait-list condition. Design, Setting, and Participants Randomized controlled trial of heterosexual and same-sex couples (n = 40 couples; n = 80 individuals) in which one partner met criteria for PTSD according to the Clinician-Administered PTSD Scale, conducted from 2008 to 2012 in a Department of Veterans Affairs outpatient hospital setting in Boston, Massachusetts, and a university-based research center in Toronto, Ontario, Canada. Symptoms of PTSD, comorbid conditions, and relationship satisfaction were collected by blinded assessors at baseline, at mid treatment (median, 8.00 weeks [range, 1.71-20.43 weeks] after baseline), and at posttreatment (median, 15.86 weeks [range, 7.14-38.57 weeks] after baseline). An uncontrolled 3-month follow-up (median, 38.21 weeks [range, 28.43-50.57 weeks] after baseline) was also completed. Intervention Couples were randomly assigned to take part in the 15-session cognitive-behavioral conjoint therapy for PTSD protocol immediately (n = 20) or were placed on a wait list for the therapy (n = 20). Main Outcome Measures Clinician-rated PTSD symptom severity was the primary outcome and was assessed with the Clinician-Administered PTSD Scale. Intimate relationship satisfaction, assessed with the Dyadic Adjustment Scale, patient- and partner-rated PTSD symptoms, and comorbid symptoms were secondary outcomes. Results PTSD symptom severity (score range, 0-136) was significantly more improved in the couple therapy condition than in the wait-list condition (mean change difference, -23.21; 95% CI, -37.87 to -8.55). Similarly, patients' intimate relationship satisfaction (score range, 0-151) was significantly more improved in couple therapy than in the wait-list condition (mean change difference, 9.43; 95% CI, 0.04-18.83). The time x condition interaction effect in the multilevel model predicting PTSD symptoms (t(37.5) = -3.09; P = .004) and patient-reported relationship satisfaction (t(68.5) = 2.00; P = .049) revealed superiority of the couple therapy compared with the wait list. Treatment effects were maintained at 3-month follow-up. Conclusion Among couples in which one partner was diagnosed as having PTSD, a disorder-specific couple therapy, compared with a wait list for the therapy, resulted in decreased PTSD symptom severity and patient comorbid symptom severity and increased patient relationship satisfaction. C1 [Monson, Candice M.] Ryerson Univ, Dept Psychol, Toronto, ON M5B 2K3, Canada. [Monson, Candice M.; Fredman, Steffany J.; Macdonald, Alexandra; Resick, Patricia A.; Schnurr, Paula P.] Natl Ctr PTSD, Dept Vet Affairs VA, Washington, DC USA. [Fredman, Steffany J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fredman, Steffany J.] Harvard Univ, Sch Med, Boston, MA USA. [Macdonald, Alexandra] VA Boston Healthcare Syst, Boston, MA USA. [Macdonald, Alexandra] Boston Univ, Sch Med, Boston, MA 02118 USA. [Schnurr, Paula P.] Geisel Sch Med Dartmouth, Hanover, NH USA. RP Monson, CM (reprint author), Ryerson Univ, Dept Psychol, 350 Victoria Ave, Toronto, ON M5B 2K3, Canada. EM candice.monson@psych.ryerson.ca FU Centers for Disease Control and Prevention; Department of Defense; Canadian Institute of Health Research; National Institute of Mental Health [5R34MH076813]; US Department of Veterans Affairs FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Monson reports that she receives research funding from the Centers for Disease Control and Prevention, Department of Defense, Canadian Institute of Health Research, and National Institute of Mental Health. Drs Monson and Fredman report that they receive royalties for a published book describing CBCT for PTSD. Dr Resick reports that she receives research funding from the Department of Defense and US Department of Veterans Affairs. Dr Schnurr reports that she receives research funding from US Department of Veterans Affairs. Drs Resick and Schnurr report that they have published books on PTSD and its treatment for which they receive income. No other disclosures were reported.; This study was supported by National Institute of Mental Health grant 5R34MH076813 to Dr Monson. NR 32 TC 61 Z9 62 U1 4 U2 33 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 15 PY 2012 VL 308 IS 7 BP 700 EP 709 DI 10.1001/jama.2012.9307 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 988NC UT WOS:000307496700025 PM 22893167 ER PT J AU Najavits, LM AF Najavits, Lisa M. TI Expanding the Boundaries of PTSD Treatment SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID POSTTRAUMATIC-STRESS-DISORDER; EXPOSURE THERAPY; METAANALYSIS C1 [Najavits, Lisa M.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Najavits, Lisa M.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Najavits, LM (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM lisa.najavits@va.gov NR 12 TC 5 Z9 5 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 15 PY 2012 VL 308 IS 7 BP 714 EP 716 DI 10.1001/2012.jama.10368 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 988NC UT WOS:000307496700028 PM 22893170 ER PT J AU Wilkin, TJ Lalama, CM McKinnon, J Gandhi, RT Lin, NN Landay, A Ribaudo, H Fox, L Currier, JS Mellors, JW Gulick, R Tenorio, AR AF Wilkin, Timothy J. Lalama, Christina M. McKinnon, John Gandhi, Rajesh T. Lin, Nina Landay, Alan Ribaudo, Heather Fox, Lawrence Currier, Judith S. Mellors, John W. Gulick, Roy Tenorio, Allan R. TI A Pilot Trial of Adding Maraviroc to Suppressive Antiretroviral Therapy for Suboptimal CD4(+) T-Cell Recovery Despite Sustained Virologic Suppression: ACTG A5256 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; LYMPHOCYTE ACTIVATION; CORECEPTOR USAGE; HAART ERA; COUNT; COMBINATION; CCR5; DEATH; AIDS AB Background. Despite viral suppression, antiretroviral therapy (ART) does not restore CD4(+) T-cell counts in many patients infected with human immunodeficiency virus type 1 (HIV-1). Methods. In a single-arm pilot trial involving ART recipients with suppressed plasma levels of HIV-1 RNA for at least 48 weeks and stable suboptimal CD4(+) T-cell recovery, subjects added maraviroc, a CCR5 antagonist, to their existing ART for 24 weeks. After stopping maraviroc, they were followed for an additional 24 weeks. A Wilcoxon signed-rank test was used to evaluate whether maraviroc was associated with an increase of at least 20 cells/mu L in the CD4(+) T-cell count. Results. A total of 34 subjects were enrolled. The median age was 50 years, and the median baseline CD4(+) T-cell count was 153 cells/mu L. The median increase in CD4(+) T-cell count from baseline to week 22/24 was 12 cells/mu L (90% confidence interval, 1-22). A CD4(+) T-cell count increase of at least 20 cells/mu L was not detected (P = .97). Markers of immune activation and apoptosis decreased during maraviroc intensification; this decline partially reversed after discontinuing maraviroc. Conclusions. Adding maraviroc to suppressive ART for 24 weeks was not associated with an increase in CD4(+) T-cell counts of at least 20 cells/mu L. Further studies of CCR5 antagonists in the dampening of immune activation associated with HIV infection are warranted. C1 [Wilkin, Timothy J.; Gulick, Roy] Weill Cornell Med Coll, Div Infect Dis, New York, NY 10011 USA. [Lalama, Christina M.; Ribaudo, Heather] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [McKinnon, John; Mellors, John W.] Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA 15260 USA. [Gandhi, Rajesh T.; Lin, Nina] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Ragon Inst, Boston, MA USA. [Lin, Nina] Harvard Univ, Sch Med, Boston, MA USA. [Landay, Alan] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Fox, Lawrence] NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. [Currier, Judith S.] Univ Calif Los Angeles, Div Infect Dis, Los Angeles, CA USA. [Tenorio, Allan R.] Rush Univ, Med Ctr, Infect Dis Sect, Chicago, IL 60612 USA. [Tenorio, Allan R.] Univ Philippines, Coll Med, Manila, Philippines. RP Wilkin, TJ (reprint author), Weill Cornell Med Coll, Div Infect Dis, 119 W 24th St, New York, NY 10011 USA. EM tiw2001@med.cornell.edu FU National Institute of Allergy and Infectious Diseases [U01 AI68636, AI068634, AI045008, AI050409, AI050410, AI060354, AI082151, K24 AI51966, R01 AI066992-04A1]; National Institute of Allergy and Infectious Diseases (Virology Support Laboratory) [204VC009]; National Institute of Allergy and Infectious Diseases (Statistical and Data Analysis Center) [AI069418, AI069419, AI069423, AI069424, AI069432, AI069439, AI069447, AI069452, AI069465, AI069471, AI069472, AI069474, AI069477, AI069484, AI069494, AI069495, AI69501, AI069502, AI069503, AI069511, AI069532, AI069556]; National Center for Research Resources [RR023561, RR024160, RR 025747, RR024975, RR024996]; National Library of Medicine [G08LM008830-01]; Pfizer; Tibotec; Gilead Sciences; Merck; ViiV FX National Institute of Allergy and Infectious Diseases (grant U01 AI68636 to the AIDS Clinical Trials Group; Virology Support Laboratory subcontract 204VC009 to the University of Pittsburgh; grant AI068634 to the Statistical and Data Analysis Center; grants AI069418, AI069419, AI069423, AI069424, AI069432, AI069439, AI069447, AI069452, AI069465, AI069471, AI069472, AI069474, AI069477, AI069484, AI069494, AI069495, AI69501, AI069502, AI069503, AI069511, AI069532, and AI069556 to participating clinical trial units; grants AI045008, AI050409, AI050410, AI060354, and AI082151 to the Centers for AIDS Research; grant K24 AI51966 to R. M. G.; and grant R01 AI066992-04A1 to R. T. G.); National Center for Research Resources (grants RR023561, RR024160, RR 025747, RR024975, and RR024996 to the Clinical and Translational Science Centers); National Library of Medicine (grant G08LM008830-01 to R. T. G.); and Pfizer Investigator-Initiated Research Grant (funds for assays and supply of maraviroc).; T. J. W. has served as an ad hoc consultant to Pfizer and Quest Diagnostics and as site principal investigator for research grants (to Weill Cornell Medical College) for Tibotec and GlaxoSmithKline. R. T. G. has received grant support from Tibotec and Gilead Sciences. A. L. receives research grants from Merck and Tobira and has served as a consultant to Merck. J. S. C. has served as the principal investigator for research grants (to UCLA) for Merck and Tibotec. J. W. M. is a consultant for Gilead Sciences, Merck, and RFS Pharma and owns share options in RFS Pharma. R. M. G. served as an ad hoc consultant for Bristol-Myers, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, ViiV, and Virostatics and as site principal investigator for research grants (to Weill Cornell Medical College) for Merck, Pfizer, and ViiV. A. R. T. has served as an ad hoc consultant to Johnson & Johnson and as principal investigator for research grants from Abbott and Gilead Sciences. All other authors report no potential conflicts. NR 35 TC 45 Z9 45 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2012 VL 206 IS 4 BP 534 EP 542 DI 10.1093/infdis/jis376 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977MQ UT WOS:000306667000011 PM 22740718 ER PT J AU Andrews, JR Wood, R Bekker, LG Middelkoop, K Walensky, RP AF Andrews, Jason R. Wood, Robin Bekker, Linda-Gail Middelkoop, Keren Walensky, Rochelle P. TI Projecting the Benefits of Antiretroviral Therapy for HIV Prevention: The Impact of Population Mobility and Linkage to Care SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SOUTH-AFRICA; COHORT ANALYSIS; COITAL ACT; TRANSMISSION; INFECTION; UGANDA; DURBAN; RAKAI; STAGE AB Background. Recent mathematical models suggested that frequent human immunodeficiency virus (HIV) testing with immediate initiation of antiretroviral therapy (ART) to individuals with a positive test result could profoundly curb transmission. The debate about ART as prevention has focused largely on parameter values. We aimed to evaluate structural assumptions regarding linkage to care and population mobility, which have received less attention. Methods. We modified the linkage structure of published models of ART as prevention, such that individuals who decline initial testing or treatment do not link to care until late-stage HIV infection. We then added population mobility to the models. We populated the models with demographic, clinical, immigration, emigration, and linkage data from a South African township. Results. In the refined linkage model, elimination of HIV transmission (defined as an incidence of <0.1%) did not occur by 30 years, even with optimistic assumptions about the linkage rate. Across a wide range of estimates, models were more sensitive to structural assumptions about linkage than to parameter values. Incorporating population mobility further attenuated the reduction in incidence conferred by ART as prevention. Conclusions. Linkage to care and population mobility are critical features of ART-as-prevention models. Clinical trials should incorporate relevant data on linkage to care and migration to evaluate the impact of this strategy. C1 [Andrews, Jason R.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Harvard Univ, Ctr AIDS Res, Harvard Inst Global Hlth Cambridge, Cambridge, MA 02138 USA. [Wood, Robin; Bekker, Linda-Gail; Middelkoop, Keren] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa. RP Andrews, JR (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM jandrews6@partners.org RI Barley, Kamal/F-9579-2011; OI Barley, Kamal/0000-0003-1874-9813; Walensky, Rochelle P./0000-0002-8795-379X; Andrews, Jason/0000-0002-5967-251X FU National Institute of General Medical Sciences [U54 GM088558]; National Institute of Allergy and Infectious Diseases [R01 AI058736]; National Institute of Mental Health [R01 MH087328-02]; AIDS Clinical Trials Group [U01 AI068636]; Doris Duke Charitable Foundation FX This work was supported by the National Institute of General Medical Sciences (U54 GM088558), the National Institute of Allergy and Infectious Diseases (R01 AI058736), the National Institute of Mental Health (R01 MH087328-02), the AIDS Clinical Trials Group (U01 AI068636), and the Doris Duke Charitable Foundation (Clinical Scientist Development Award). NR 35 TC 22 Z9 23 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2012 VL 206 IS 4 BP 543 EP 551 DI 10.1093/infdis/jis401 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977MQ UT WOS:000306667000012 PM 22711905 ER PT J AU Zhang, JL Poznansky, M Crumpacker, C AF Zhang, Jielin Poznansky, Mark Crumpacker, Clyde TI Naive and Memory CD4(+) T Cells in HIV Eradication and Immunization SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID ANTIRETROVIRAL THERAPY; ELITE CONTROLLERS; INFECTION C1 [Zhang, Jielin; Poznansky, Mark; Crumpacker, Clyde] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Mass Gen Hosp,Vaccine Immunotherapy Ctr, Boston, MA 02114 USA. RP Zhang, JL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Mass Gen Hosp,Vaccine Immunotherapy Ctr, Boston, MA 02114 USA. EM jlzhang@partners.org NR 10 TC 3 Z9 3 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2012 VL 206 IS 4 BP 617 EP 618 DI 10.1093/infdis/jis387 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 977MQ UT WOS:000306667000020 PM 22696498 ER PT J AU Westreich, D Cole, SR Young, JG Palella, F Tien, PC Kingsley, L Gange, SJ Hernan, MA AF Westreich, Daniel Cole, Stephen R. Young, Jessica G. Palella, Frank Tien, Phyllis C. Kingsley, Lawrence Gange, Stephen J. Hernan, Miguel A. TI The parametric g-formula to estimate the effect of highly active antiretroviral therapy on incident AIDS or death SO STATISTICS IN MEDICINE LA English DT Article DE cohort study; confounding; g-formula; HIV; AIDS; Monte Carlo methods ID MARGINAL STRUCTURAL MODELS; CAUSAL INFERENCE; CONTROLLED-TRIAL; G-COMPUTATION; TIME; DISEASE; EPIDEMIOLOGY; MORTALITY; SURVIVAL; FAILURE AB The parametric g-formula can be used to contrast the distribution of potential outcomes under arbitrary treatment regimes. Like g-estimation of structural nested models and inverse probability weighting of marginal structural models, the parametric g-formula can appropriately adjust for measured time-varying confounders that are affected by prior treatment. However, there have been few implementations of the parametric g-formula to date. Here, we apply the parametric g-formula to assess the impact of highly active antiretroviral therapy on time to acquired immune deficiency syndrome (AIDS) or death in two US-based human immunodeficiency virus cohorts including 1498 participants. These participants contributed approximately 7300 person-years of follow-up (49% exposed to highly active antiretroviral therapy) during which 382 events occurred and 259 participants were censored because of dropout. Using the parametric g-formula, we estimated that antiretroviral therapy substantially reduces the hazard of AIDS or death (hazard ratio?=?0.55; 95% confidence limits [CL]: 0.42, 0.71). This estimate was similar to one previously reported using a marginal structural model, 0.54 (95% CL: 0.38, 0.78). The 6.5-year difference in risk of AIDS or death was 13% (95% CL: 8%, 18%). Results were robust to assumptions about temporal ordering, and extent of history modeled, for time-varying covariates. The parametric g-formula is a viable alternative to inverse probability weighting of marginal structural models and g-estimation of structural nested models for the analysis of complex longitudinal data. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Westreich, Daniel] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Sch Med, Durham, NC 27710 USA. [Westreich, Daniel] Duke Univ, Duke Global Hlth Inst, Durham, NC 27710 USA. [Cole, Stephen R.] Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Young, Jessica G.; Hernan, Miguel A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hernan, Miguel A.] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Palella, Frank] Northwestern Univ, Div Infect Dis, Feinberg Sch Med, Chicago, IL 60611 USA. [Tien, Phyllis C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Tien, Phyllis C.] San Francisco VA Med Ctr, San Francisco, CA USA. [Kingsley, Lawrence] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Gange, Stephen J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Westreich, D (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Sch Med, Box 3084 Med Ctr, Durham, NC 27710 USA. EM daniel.westreich@duke.edu OI Gange, Stephen/0000-0001-7842-512X FU NIH [K99-HD-063961, 5 T32 AI 07001-32, R01-AA-017594, P30-AI-50410, R01-AI-073127-01A2]; National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute [UO1-AI-35042, 5-MO1-RR-00052, UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041]; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources (UCSF-CTSI) [UL1 RR024131] FX Dr. Daniel Westreich was supported by NIH grants K99-HD-063961 and 5 T32 AI 07001-32. Dr. Stephen R. Cole was partially supported by NIH grants R01-AA-017594 and P30-AI-50410. Drs. Jessica Young and Miguel A. Hernan were supported by NIH grant R01-AI-073127-01A2. The authors would like to thank Dr. James Robins for expert advice.; Data in this manuscript were collected by the WIHS Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC, Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI grant number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.; Data in this manuscript were collected by the MACS with centers (principal investigators) at The Johns Hopkins Bloomberg School of Public Health (Joseph B. Margolick, Lisa P. Jacobson); Howard Brown Health Center, Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services (John P. Phair, Steven M. Wolinsky); University of California, Los Angeles (Roger Detels); and University of Pittsburgh (Charles R. Rinaldo). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (UO1-AI-35042, 5-MO1-RR-00052 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041; website located at http://www.statepi.jhsph.edu/macs/macs.html). NR 35 TC 27 Z9 27 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2012 VL 31 IS 18 BP 2000 EP 2009 DI 10.1002/sim.5316 PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 974XO UT WOS:000306471100008 PM 22495733 ER PT J AU Kwong, KK AF Kwong, Kenneth K. TI Record of a single fMRI experiment in May of 1991 SO NEUROIMAGE LA English DT Review DE fMRI; Deoxyhemoglobin; BOLD; Perfusion; ASL; Magnetic resonance imaging; Brain ID INTRAVOXEL INCOHERENT MOTION; CEREBRAL-BLOOD-FLOW; MAGNETIC-SUSCEPTIBILITY; BRAIN; PERFUSION; CONTRAST; OXYGENATION; MRI; STIMULATION; DIFFUSION AB The discovery of BOLD fMRI at MGH in May 1991 was 1) built on the ongoing effort to develop new MR techniques for perfusion measurement with intrinsic blood contrast, 2) supported by the critical MGH expertise and experience on magnetic susceptibility and deoxyhemoglobin research, 3) inspired by the breakthrough in brain fMRI using dynamic susceptibility contrast (DSC) of the external contrast agent Gd-DTPA, 4) facilitated by the flow-BOLD insight of a hypoxia experiment and 5) made possible by the availability of clinical echo planar imaging (EPI). The simultaneous demonstration of flow-weighted fMRI derived its intellectual origin from work on steady state arterial spin labeling (ASL). The free-wheeling and fertile intellectual environment structured by Dr. Thomas Brady and Dr. Bruce Rosen at the MGH-NMR Center provided the indispensable support for highly risky ideas to roam and succeed. The paper offers a first person account of the steps that led to the May experiment and its aftermath. (C) 2011 Elsevier Inc. All rights reserved. C1 [Kwong, Kenneth K.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, MGH MIT HMS, Charlestown, MA USA. [Kwong, Kenneth K.] Harvard Univ, MIT, Sch Med, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Kwong, KK (reprint author), Athinoula A Martinos Ctr Biomed Imaging, 149-13th St Mailcode 2301, Charlestown, MA 02129 USA. EM kwong@nmr.mgh.harvard.edu FU NCCIH NIH HHS [P01 AT006663, P01 AT006663-02] NR 23 TC 4 Z9 4 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 610 EP 612 DI 10.1016/j.neuroimage.2011.07.089 PG 3 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600006 PM 21839841 ER PT J AU Fischl, B AF Fischl, Bruce TI FreeSurfer SO NEUROIMAGE LA English DT Review DE Morphometry; Registration; Segmentation; MRI ID HUMAN CEREBRAL-CORTEX; WHITE-MATTER MICROSTRUCTURE; SURFACE-BASED ANALYSIS; HUMAN VISUAL-CORTEX; CORTICAL THICKNESS; COORDINATE SYSTEM; GEOMETRICALLY ACCURATE; HUNTINGTONS-DISEASE; FUNCTIONAL-ANALYSIS; IMAGE SEGMENTATION AB FreeSurfer is a suite of tools for the analysis of neuroimaging data that provides an array of algorithms to quantify the functional, connectional and structural properties of the human brain. It has evolved from a package primarily aimed at generating surface representations of the cerebral cortex into one that automatically creates models of most macroscopically visible structures in the human brain given any reasonable T1-weighted input image. It is freely available, runs on a wide variety of hardware and software platforms, and is open source. (C) 2012 Elsevier Inc. All rights reserved. C1 [Fischl, Bruce] Harvard Univ, Massachusetts Gen Hosp, Athinoula Martinos Ctr, Sch Med, Charlestown, MA 02129 USA. RP Fischl, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Athinoula Martinos Ctr, Sch Med, Bldg 149,13th St, Charlestown, MA 02129 USA. EM fischl@nmr.mgh.harvard.edu FU National Center for Research Resources [P41-RR14075]; NCRR BIRN Morphometric Project [BIRN002, U24 RR021382]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute on Aging [AG022381]; National Center for Alternative Medicine [RC1 AT005728-01]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01, 1R21NS072652-01, 1R01NS070963]; Ellison Medical Foundation; [1S10RR023401]; [1S10RR019307]; [1S10RR023043] FX Support for this research was provided in part by the National Center for Research Resources (P41-RR14075, and the NCRR BIRN Morphometric Project BIRN002, U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01EB006758), the National Institute on Aging (AG022381), the National Center for Alternative Medicine (RC1 AT005728-01), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01, 1R21NS072652-01, 1R01NS070963), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation. NR 102 TC 593 Z9 594 U1 18 U2 86 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 774 EP 781 DI 10.1016/j.neuroimage.2012.01.021 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600031 PM 22248573 ER PT J AU Mandeville, JB AF Mandeville, Joseph B. TI IRON fMRI measurements of CBV and implications for BOLD signal SO NEUROIMAGE LA English DT Review DE fMRI; CBV; IRON; Contrast agent; BOLD; Undershoot ID CEREBRAL BLOOD-VOLUME; RAT FOREPAW STIMULATION; EXOGENOUS CONTRAST AGENT; BRAIN ACTIVATION; FUNCTIONAL MRI; OXIDATIVE-METABOLISM; SOMATOSENSORY STIMULATION; POSTSTIMULUS UNDERSHOOT; NEURONAL ACTIVATION; SENSORY STIMULATION AB Changes in cerebral blood volume (CBV) and blood magnetization each induce changes in the transverse relaxation rate of MRI signal that are associated with changes in cerebral activity. BOLD signal, the preeminent method for non-invasive localization of task-induced brain function in human subjects, reflects a combination of changes in CBV and blood magnetization. Intravenous injection of paramagnetic contrast media, usually iron oxide particles surrounded by larger macromolecules, can overwhelm the BOLD response and sensitize signal to blood plasma volume, a method we have deemed "IRON" fMRI. The practical advantage of this technique is the ability to optimize blood magnetization at any echo time, enabling high detection power and the use of short echo times; for these reasons, IRON fMRI has become a valuable imaging tool in animal models. The temporal response of blood plasma volume is quite different from blood flow and BOLD signal; thus. CBV has been identified as a prominent source of transient features of the BOLD response. This article reviews the methodological advantages of the IRON method and how CBV measurements have informed our understanding of the BOLD response. (C) 2012 Elsevier Inc. All rights reserved. C1 [Mandeville, Joseph B.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. RP Mandeville, JB (reprint author), Massachusetts Gen Hosp, Dept Radiol, Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM jbm@nmr.mgh.harvard.edu FU National Institutes of Health; National Institute for Biomedical Imaging and Bioengineering (NIBIB); National Institute on Drug Abuse (NIDA) FX These studies were funded primarily by the National Institutes of Health, and particularly by the National Institute for Biomedical Imaging and Bioengineering (NIBIB) and the National Institute on Drug Abuse (NIDA). Many co-investigators contributed to this work. In particular, John Marota was a key collaborator in the studies that first characterized this methodology, and Wim Vanduffel and colleagues developed the awake non-human primate model for functional MRI that is used in our laboratory and many others. NR 80 TC 19 Z9 19 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1000 EP 1008 DI 10.1016/j.neuroimage.2012.01.070 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600058 PM 22281669 ER PT J AU Jenkins, BG AF Jenkins, Bruce G. TI Pharmacologic magnetic resonance imaging (phMRI): Imaging drug action in the brain SO NEUROIMAGE LA English DT Review DE Drugs; fMRI; Hemodynamics; Neurotransmitters; phMRI; Receptor ID CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; SATURATION-TRANSFER AGENTS; CENTRAL-NERVOUS-SYSTEM; AWAKE RHESUS-MONKEYS; FUNCTIONAL MRI; RAT-BRAIN; NEURONAL-ACTIVITY; BASAL GANGLIA; NITRIC-OXIDE AB The technique of functional magnetic resonance (fMRI), using various cognitive, motor and sensory stimuli has led to a revolution in the ability to map brain function. Drugs can also be used as stimuli to elicit an hemodynamic change. Stimulation with a pharmaceutical has a number of very different consequences compared to user controllable stimuli, most importantly in the time course of stimulus and response that is not, in general, controllable by the experimenter. Therefore, this type of experiment has been termed pharmacologic MRI (phMRI). The-use of a drug stimulus leads to a number of interesting possibilities compared to conventional fMRI. Using receptor specific ligands one can characterize brain circuitry specific to neurotransmitter systems. The possibility exists to measure parameters reflecting neurotransmitter release and binding associated with the pharmacokinetics and/or the pharmacodynamics of drugs. There is also the ability to measure up- and down-regulation of receptors in specific disease states. phMRI can be characterized as a molecular imaging technique using the natural hemodynamic transduction related to neuro-receptor stimulus. This provides a coupling mechanism with very high sensitivity that can rival positron emission tomography (PET) in some circumstances. The large numbers of molecules available, that do not require a radio-label, means that phMRI becomes a very useful tool for performing drug discovery. Data and arguments will be presented to show that phMRI can provide information on neuro-receptor signaling and function that complements the static picture generated by PET studies of receptor numbers and occupancies. (C) 2012 Elsevier Inc. All rights reserved. C1 [Jenkins, Bruce G.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Jenkins, Bruce G.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Jenkins, BG (reprint author), Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Bldg 149,13th St, Charlestown, MA 02129 USA. EM bgj@nmr.mgh.harvard.edu FU NIH [2RO1DA016187-09] FX This work was supported by NIH 2RO1DA016187-09. NR 137 TC 34 Z9 34 U1 4 U2 25 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1072 EP 1085 DI 10.1016/j.neuroimage.2012.03.075 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600069 PM 22495143 ER PT J AU Buckner, RL AF Buckner, Randy L. TI The serendipitous discovery of the brain's default network SO NEUROIMAGE LA English DT Review DE Functional MRI; Default mode network; Resting-state; Prospection ID INTRINSIC FUNCTIONAL CONNECTIVITY; POSITRON-EMISSION-TOMOGRAPHY; STIMULUS-INDEPENDENT THOUGHT; CONSCIOUS RESTING STATE; BLOOD-FLOW CHANGES; ALZHEIMERS-DISEASE; CEREBRAL-CORTEX; MEMORY RETRIEVAL; BETA DEPOSITION; VISUAL TASKS AB One of the most unexpected findings by functional neuroimaging has been the discovery of the brain's default network - a set of brain regions that is spontaneously active during passive moments. The default network's discovery was a fortunate accident that occurred due to the inclusion of rest control conditions in early PET and functional MRI studies. At first, the network was ignored. Later, its presence was shunned as evidence of an experimental confound. Finally, it emerged as a mainstream target of focused study. Here. I describe a personal perspective of the default network's serendipitous discovery. (C) 2011 Elsevier Inc. All rights reserved. C1 [Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Dept Psychol, Cambridge, MA 02138 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Randy L.] Howard Hughes Med Inst, Cambridge, MA USA. RP Buckner, RL (reprint author), Harvard Univ, Ctr Brain Sci, Dept Psychol, 52 Oxford St,NW Bldg 280-06, Cambridge, MA 02138 USA. EM randy_buckner@harvard.edu NR 59 TC 62 Z9 68 U1 6 U2 40 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1137 EP 1145 DI 10.1016/j.neuroimage.2011.10.035 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600077 PM 22037421 ER PT J AU Savoy, RL AF Savoy, Robert L. TI Evolution and current challenges in the teaching of functional MRI and functional brain imaging SO NEUROIMAGE LA English DT Review DE Functional MRI; Teaching; Functional brain imaging education; History of functional MRI AB The report of any new and successful method for studying the world triggers the need to train people in the use of that method. In the case of functional magnetic resonance imaging and its use for examining human brain function in vivo, expertise is required in a greater collection of domains than usual. Development of fMRI training programs started shortly after the announcement of BOLD-based fMRI in humans. These programs had a variety of durations and primary content areas. All programs had to deal with the challenge of bringing interested researchers from a wide variety of areas-many of whom had little or no understanding of MR physics, and/or experimental psychology, and/or the nuances of data analysis and modeling-to a sufficiently detailed level of knowledge that both the funding agencies, and the existing proprietors of the technology (often radiologists or MR physicists at hospitals) would take the research proposals of new investigators seriously. Now that fMRI-based research is well established, there are new educational challenges. Some have to do with the growing list of technologies used to study human brain function in vivo. But perhaps more daunting is the challenge of training consumers of the reports and claims based on fMRI and other brain imaging modalities. As fMRI becomes influential in contexts beyond the research environment-from the clinic to the courtroom to the legislature-training consumers of fMRI-based claims will take on increasing importance, and represents its own unique challenges for education. (C) 2012 Elsevier Inc. All rights reserved. C1 [Savoy, Robert L.] HyperVis Inc, Lexington, MA USA. [Savoy, Robert L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Savoy, Robert L.] Harvard Univ, Sch Med, Boston, MA USA. RP Savoy, RL (reprint author), HyperVis Inc, Lexington, MA USA. EM Robert.L.Savoy@alum.mit.edu NR 32 TC 4 Z9 4 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1201 EP 1207 DI 10.1016/j.neuroimage.2012.02.029 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600087 PM 22374479 ER PT J AU Wald, LL AF Wald, Lawrence L. TI The future of acquisition speed, coverage, sensitivity, and resolution SO NEUROIMAGE LA English DT Review ID STATIC MAGNETIC-FIELDS; 7 T; PHYSIOLOGICAL NOISE; HUMAN BRAIN; SPIN-ECHO; GRADIENT-ECHO; PHASED-ARRAY; HEAD COIL; BOLD FMRI; TESLA AB Two decades of technology development has continually improved the image quality, spatial-temporal resolution, and sensitivity of the fMRI acquisition. In this article, I assess our current acquisition needs, briefly examine the technological breakthroughs that have benefited fMRI in the past, and look at some promising technologies that are currently under development to try to envision what the fMRI acquisition protocol of the future might look like. (C) 2012 Elsevier Inc. All rights reserved. C1 [Wald, Lawrence L.] Harvard Univ, Sch Med, Boston, MA USA. [Wald, Lawrence L.] MIT, Harvard MIT Div Hlth Sci & Technol, Charlestown, MA USA. [Wald, Lawrence L.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA 02129 USA. RP Wald, LL (reprint author), MGH, AA Martinos Imaging Ctr, Bldg 149,13th St,Rm 2301, Charlestown, MA 02129 USA. EM wald@nmr.mgh.harvard.edu RI Wald, Lawrence/D-4151-2009 FU National Institutes of Health [P41RR14075, R01EB006847, U01MH093765] FX Many thanks to Jon Polimeni, Christina Triantafyllou, Boris Keil and Thomas Witzel for supplying results. Preparation of this manuscript was supported by the National Institutes of Health grants P41RR14075, R01EB006847, and U01MH093765. NR 63 TC 15 Z9 15 U1 0 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1221 EP 1229 DI 10.1016/j.neuroimage.2012.02.077 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600090 PM 22421052 ER PT J AU Rosen, BR Savoy, RL AF Rosen, Bruce R. Savoy, Robert L. TI fMRI at 20: Has it changed the world? SO NEUROIMAGE LA English DT Review DE Functional MRI; Clinical impact; Cognitive neuroscience; Mental illness; Neuroethics; Mental health parity ID HUMAN VISUAL-CORTEX; BRAIN ACTIVITY; BLIND; STIMULATION; ACTIVATION; EVOLUTION; ADULTS AB The prevalence of fMRI in cognitive neuroscience research is clear, but the overall impact of the associated research in the broader scope of our scientific community, and of society, is less obvious. The first reports of fMRI garnered huge interest in many areas, giving rise to a wide range of applications and technical developments over the past 20 years. Using five primary areas, i.e. scientific impact, clinical practice, cognitive neuroscience, mental illness, and society-this essay examines the question: Has fMRI changed the world? (C) 2012 Elsevier Inc. All rights reserved. C1 [Rosen, Bruce R.; Savoy, Robert L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Rosen, BR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM bruce@nmr.mgh.harvard.edu NR 41 TC 17 Z9 17 U1 4 U2 26 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2012 VL 62 IS 2 SI SI BP 1316 EP 1324 DI 10.1016/j.neuroimage.2012.03.004 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 973WK UT WOS:000306390600103 PM 22433659 ER PT J AU Schaefer, C Butterfield, LH Lee, S Kim, GG Visus, C Albers, A Kirkwood, JM Whiteside, TL AF Schaefer, Carsten Butterfield, Lisa H. Lee, Sandra Kim, Grace G. Visus, Carmen Albers, Andreas Kirkwood, John M. Whiteside, Theresa L. TI Function but not phenotype of melanoma peptide-specific CD8+ T cells correlate with survival in a multiepitope peptide vaccine trial (ECOG 1696) SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE CD8+T cells; immune monitoring; melanoma; peptide-based vaccine; tetramer ID COLONY-STIMULATING FACTOR; HIGH-DOSE INTERFERON-ALPHA-2B; COOPERATIVE-ONCOLOGY-GROUP; PHASE-II TRIAL; METASTATIC MELANOMA; ADJUVANT IMMUNOTHERAPY; MULTIPEPTIDE VACCINE; RANDOMIZED TRIAL; TUMOR-ANTIGEN; CD8(+) AB ECOG 1696 was a Phase II multi-center trial testing vaccination with melanoma peptides, gp100, MART-1 and tyrosinase delivered alone, with GM-CSF, IFN-a2b or both cytokines to HLA-A2+ patients with metastatic melanoma. Here, the frequency of circulating CD8+tetramer+ (tet+) T cells and maturation stages of responding T cells were serially monitored and compared with baseline values in a subset of patients (n = 37) from this trial. Multiparameter flow cytometry was used to measure the frequency of CD8+ T cells specific for gp100, MART-1, tyrosinase and influenza (FLU) peptides. Expression of CD45RA/CCR7 on CD8+tet+ T cells and CD25, CD27, CD28 on all circulating T cells was determined. Vaccine-induced changes in the CD8+tet+ T cell frequency and phenotype were compared with results of IFN-? ELISPOT assays and with clinical responses. The frequency of CD8+tet+ T cells in the circulation was increased for the melanoma peptides (p < 0.030.0001) but not for FLU (p < 0.9). Only gp100- and MART-1-specific T cells differentiated to CD45RA+CCR7- effector/memory T cells. In contrast to the IFN-? ELISPOT frequency, previously correlated with overall survival (Kirkwood et al., Clin Cancer Res 2009;15:1443-51), neither the frequency nor differentiation stage of CD8+tet+ T cells correlated with clinical responses. Delivery of GM-CSF and/or IFN-a2b had no effects on the frequency or differentiation of CD8+tet+, CD8+ or CD4+ T cells. Phenotypic analyses of CD8+tet+ T cells did not correlate with clinical responses to the vaccine, indicating that functional assessments of peptide-specific T cells are preferable for monitoring of anti-tumor vaccines. C1 [Whiteside, Theresa L.] Univ Pittsburgh, Inst Canc, Dept Pathol, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. [Schaefer, Carsten; Butterfield, Lisa H.; Kim, Grace G.; Visus, Carmen; Albers, Andreas; Kirkwood, John M.; Whiteside, Theresa L.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Butterfield, Lisa H.; Kirkwood, John M.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Butterfield, Lisa H.] Univ Pittsburgh, Dept Surg, Pittsburgh, PA USA. [Butterfield, Lisa H.; Whiteside, Theresa L.] Univ Pittsburgh, Dept Immunol, Pittsburgh, PA USA. [Lee, Sandra] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Whiteside, TL (reprint author), Univ Pittsburgh, Inst Canc, Dept Pathol, Hillman Canc Ctr, 5117 Ctr Ave,Suite 1-27, Pittsburgh, PA 15213 USA. EM whitesidetl@upmc.edu FU ECOG [U10 CA 21115, NIH RO1 CA87904]; NIH [RO1 DE13918, PO1 CA109688]; UPCI CCSG [P30 CA047904] FX Grant sponsor: ECOG; Grant numbers: U10 CA 21115, NIH RO1 CA87904; Grant sponsor: NIH; Grant numbers: RO1 DE13918, PO1 CA109688; Grant sponsor: UPCI CCSG; Grant number: P30 CA047904 NR 36 TC 12 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2012 VL 131 IS 4 BP 874 EP 884 DI 10.1002/ijc.26481 PG 11 WC Oncology SC Oncology GA 961GD UT WOS:000305451300038 PM 22021080 ER PT J AU Bodugoz-Senturk, H Oral, E Choi, J Macias, C Muratoglu, OK AF Bodugoz-Senturk, Hatice Oral, Ebru Choi, Jeeyoung Macias, Celia Muratoglu, Orhun K. TI Molecular weight effect on theta-gel formation in poly(vinyl alcohol)-poly(ethylene glycol) mixtures SO JOURNAL OF APPLIED POLYMER SCIENCE LA English DT Article DE hydrogels; implant; polymer blends ID IN-SITU; CROSS-LINKING; BIOMEDICAL APPLICATIONS; INJECTABLE HYDROGELS; DELIVERY; RELEASE; REPAIR AB Injectable hydrogel formulations that undergo in situ gelation at body temperature are promising for minimally invasive tissue repair. This work focuses on the investigation of injectable poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG) mixtures. The injectable PVAPEG aqueous solutions form a hydrogel as temperature is reduced to near body temperature, while filling a defect in the injection site. Gamma sterilization of these solutions compromises injectability presumably due to crosslinking of PVA. We hypothesized that by modifying the PEG molecular weight and its concentration, injectability of radiation sterilized PVAPEG hydrogels can be optimized without compromising the mechanical properties of the resulting gel. The use of a bimodal mixture of higher and lower molecular weight PEG (600 and 200 g/mol) resulted in lower PVA/PEG solution viscosity, better injectability, and higher gel mechanical strength. The PVA/bimodal-PEG had a lower viscosity at 2733 +/- 149 cP versus a viscosity of 5560 +/- 278 cP for PVA/unimodal-PEG (400 g/mol). The gel formed with the bimodal PEG mixture had higher creep resistance (61% total creep strain under 0.5 MPa) than that formed with unimodal PEG (84%). These hydrogel formulations are promising candidates for minimally invasive tissue repair. (C) 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012 C1 [Bodugoz-Senturk, Hatice; Oral, Ebru; Choi, Jeeyoung; Macias, Celia; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Bodugoz-Senturk, Hatice; Oral, Ebru; Choi, Jeeyoung; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Cambridge, MA 02113 USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM omuratoglu@partners.org FU Zimmer, Inc. FX Contract grant sponsors: Departmental Research and Zimmer, Inc. NR 26 TC 2 Z9 2 U1 2 U2 26 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-8995 J9 J APPL POLYM SCI JI J. Appl. Polym. Sci. PD AUG 15 PY 2012 VL 125 IS 4 BP 2890 EP 2895 DI 10.1002/app.36223 PG 6 WC Polymer Science SC Polymer Science GA 936ND UT WOS:000303596200048 ER PT J AU Zheng, SQ Ghitani, N Blackburn, JS Liu, JP Zeitlin, SO AF Zheng, Shuqiu Ghitani, Nima Blackburn, Jessica S. Liu, Jeh-Ping Zeitlin, Scott O. TI A series of N-terminal epitope tagged Hdh knock-in alleles expressing normal and mutant huntingtin: their application to understanding the effect of increasing the length of normal huntingtin's polyglutamine stretch on CAG140 mouse model pathogenesis SO MOLECULAR BRAIN LA English DT Article DE Huntingtin; Epitope tag; Knock-in; Polyglutamine; Proline-rich region; Sequestration; Huntington's disease ID NEURONAL INTRANUCLEAR INCLUSIONS; TRANSGENIC MOUSE; BODY FORMATION; EARLY MOTOR; DISEASE; PROTEINS; BRAIN; AGGREGATION; TOXICITY; FRAGMENT AB Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that is caused by the expansion of a polyglutamine (polyQ) stretch within Huntingtin (htt), the protein product of the HD gene. Although studies in vitro have suggested that the mutant htt can act in a potentially dominant negative fashion by sequestering wild-type htt into insoluble protein aggregates, the role of the length of the normal htt polyQ stretch, and the adjacent proline-rich region (PRR) in modulating HD mouse model pathogenesis is currently unknown. Results: We describe the generation and characterization of a series of knock-in HD mouse models that express versions of the mouse HD gene (Hdh) encoding N-terminal hemaglutinin (HA) or 3xFlag epitope tagged full-length htt with different polyQ lengths (HA7Q-, 3xFlag7Q-, 3xFlag20Q-, and 3xFlag140Q-htt) and substitution of the adjacent mouse PRR with the human PRR (3xFlag20Q- and 3xFlag140Q-htt). Using co-immunoprecipitation and immunohistochemistry analyses, we detect no significant interaction between soluble full-length normal 7Q-htt and mutant (140Q) htt, but we do observe N-terminal fragments of epitope-tagged normal htt in mutant htt aggregates. When the sequences encoding normal mouse htt's polyQ stretch and PRR are replaced with non-pathogenic human sequence in mice also expressing 140Q-htt, aggregation foci within the striatum, and the mean size of htt inclusions are increased, along with an increase in striatal lipofuscin and gliosis. Conclusion: In mice, soluble full-length normal and mutant htt are predominantly monomeric. In heterozygous knock-in HD mouse models, substituting the normal mouse polyQ and PRR with normal human sequence can exacerbate some neuropathological phenotypes. C1 [Zheng, Shuqiu; Ghitani, Nima; Blackburn, Jessica S.; Liu, Jeh-Ping; Zeitlin, Scott O.] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. [Ghitani, Nima] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Blackburn, Jessica S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. RP Zeitlin, SO (reprint author), Univ Virginia, Sch Med, Dept Neurosci, Box 801392, Charlottesville, VA 22908 USA. EM soz4n@virginia.edu FU NIH [NS043466] FX This work was supported by NIH NS043466. NR 54 TC 6 Z9 6 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-6606 J9 MOL BRAIN JI Mol. Brain PD AUG 14 PY 2012 VL 5 AR 28 DI 10.1186/1756-6606-5-28 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 041AT UT WOS:000311369300001 PM 22892315 ER PT J AU Murphy, TP Cerezo, J Cutlip, DE Reynolds, MR Regensteiner, JG Mohler, ER Cohen, DJ Massaro, JM Lewis, BA Oldenburg, NC Steffes, MW Hirsch, AT Thum, CC Goldberg, S Jaff, MR Comerota, AJ Ehrman, J Treat-Jacobson, D Bronas, U Walsh, ME Badenhop, DT Collins, T AF Murphy, Timothy P. Cerezo, Joselyn Cutlip, Donald E. Reynolds, Matthew R. Regensteiner, Judith G. Mohler, Emile R. Cohen, David J. Massaro, Joseph M. Lewis, Beth A. Oldenburg, Niki C. Steffes, Michael W. Hirsch, Alan T. Thum, Claudia C. Goldberg, Suzanne Jaff, Michael R. Comerota, Anthony J. Ehrman, Jonathan Treat-Jacobson, Diane Bronas, Ulf Walsh, M. Eileen Badenhop, Dalynn T. Collins, Tracie TI Response to Letters Regarding Article, "Supervised Exercise Versus Primary Stenting for Claudication Resulting From Aortoiliac Peripheral Artery Disease: Six-Month Outcomes From the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) Study" SO CIRCULATION LA English DT Letter C1 [Murphy, Timothy P.; Cerezo, Joselyn] Rhode Isl Hosp, Providence, RI 02903 USA. [Cutlip, Donald E.; Reynolds, Matthew R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Regensteiner, Judith G.] Univ Colorado, Sch Med, Aurora, CO USA. [Mohler, Emile R.] Univ Penn, Philadelphia, PA 19104 USA. [Cohen, David J.] Univ Missouri, Kansas City, MO 64110 USA. [Massaro, Joseph M.] Boston Univ, Boston, MA 02215 USA. [Lewis, Beth A.] Univ Minnesota, Sch Kinesiol, Minneapolis, MN USA. [Oldenburg, Niki C.; Steffes, Michael W.; Hirsch, Alan T.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Thum, Claudia C.] Harvard Clin Res Inst, Boston, MA USA. [Goldberg, Suzanne] NHLBI, Bethesda, MD 20892 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Comerota, Anthony J.] Jobst Vasc Ctr, Toledo, OH USA. [Ehrman, Jonathan] Henry Ford Hosp, Detroit, MI 48202 USA. [Treat-Jacobson, Diane; Bronas, Ulf] Univ Minnesota, Sch Nursing, Minneapolis, MN 55455 USA. [Walsh, M. Eileen] Univ Toledo, Coll Nursing, Toledo, OH 43606 USA. [Collins, Tracie] Univ Kansas, Sch Med, Witchita Dept Prevent Med & Publ Hlth, Wichita, KS USA. RP Murphy, TP (reprint author), Rhode Isl Hosp, Providence, RI 02903 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 14 PY 2012 VL 126 IS 7 BP E102 EP E103 DI 10.1161/CIRCULATIONAHA.112.113704 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 993TQ UT WOS:000307882900006 ER PT J AU Sander, S Calado, DP Srinivasan, L Kochert, K Zhang, BC Rosolowski, M Rodig, SJ Holzmann, K Stilgenbauer, S Siebert, R Bullinger, L Rajewsky, K AF Sander, Sandrine Calado, Dinis P. Srinivasan, Lakshmi Koechert, Karl Zhang, Baochun Rosolowski, Maciej Rodig, Scott J. Holzmann, Karlheinz Stilgenbauer, Stephan Siebert, Reiner Bullinger, Lars Rajewsky, Klaus TI Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis SO CANCER CELL LA English DT Article ID B-CELL LYMPHOMAS; CYCLIN D3; GENE-EXPRESSION; C-MYC; ACTIVATION; MICE; RECEPTOR; PATHOGENESIS; DEGRADATION; SIGNATURES AB In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis. C1 [Sander, Sandrine; Calado, Dinis P.; Srinivasan, Lakshmi; Zhang, Baochun; Rajewsky, Klaus] Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp, Boston, MA 02115 USA. [Sander, Sandrine; Calado, Dinis P.; Srinivasan, Lakshmi; Zhang, Baochun; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Sander, Sandrine; Calado, Dinis P.; Koechert, Karl; Rajewsky, Klaus] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Rosolowski, Maciej] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany. [Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Holzmann, Karlheinz] Univ Ulm, Microarray Core Facil, D-89081 Ulm, Germany. [Stilgenbauer, Stephan; Bullinger, Lars] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Siebert, Reiner] Univ Kiel, Inst Human Genet, Univ Hosp Schleswig Holstein Campus Kiel, D-24105 Kiel, Germany. RP Rajewsky, K (reprint author), Harvard Univ, Sch Med, Program Cellular & Mol Med, Childrens Hosp, Boston, MA 02115 USA. EM klaus.rajewsky@mdc-berlin.de RI Siebert, Reiner/A-8049-2010; OI Zhang, Baochun/0000-0003-1759-1161 FU National Institutes of Health [P01 CA92625, R37 AI054636]; Leukemia & Lymphoma Society (Leukemia & Lymphoma Society SCOR); European Research Council (ERC) [ERC-AG-LS6]; Leukemia & Lymphoma Society; Deutsche Forschungsgemeinschaft FX We thank J. Xia, C. Grosse, J. Grundy, X. Chen, D. Ghitza, C. Unitt, and M. Bamberg for technical assistance; M. Ottaviano for administrative assistance; T. Yasuda for contribution of reagents; E. Derudder and J. Seagal for assistance with irradiation; S. Koralov for help with SHM analyses; D. Bolgehn and T. Sommermann for technical support; and present and former Rajewsky lab members for critical comments and suggestions. We are grateful to L. Staudt and R. Schmitz for sharing unpublished results and primer sequences. This work was supported by grants from the National Institutes of Health to K.R. (P01 CA92625; R37 AI054636), the Leukemia & Lymphoma Society (Leukemia & Lymphoma Society SCOR) and the European Research Council (ERC advanced Grant ERC-AG-LS6) to K.R.; Leukemia & Lymphoma Society fellowships to S. Sander, B.Z., and D.P.C., and a Heisenberg scholarship by the Deutsche Forschungsgemeinschaft to L.B. NR 40 TC 89 Z9 91 U1 2 U2 11 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 AUG 14 PY 2012 VL 22 IS 2 BP 167 EP 179 DI 10.1016/j.ccr.2012.06.012 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000006 PM 22897848 ER PT J AU Abdel-Wahab, O Adli, M LaFave, LM Gao, J Hricik, T Shih, AH Pandey, S Patel, JP Chung, YR Koche, R Perna, F Zhao, XY Taylor, JE Park, CY Carroll, M Melnick, A Nimer, SD Jaffe, JD Aifantis, I Bernstein, BE Levine, RL AF Abdel-Wahab, Omar Adli, Mazhar LaFave, Lindsay M. Gao, Jie Hricik, Todd Shih, Alan H. Pandey, Suveg Patel, Jay P. Chung, Young Rock Koche, Richard Perna, Fabiana Zhao, Xinyang Taylor, Jordan E. Park, Christopher Y. Carroll, Martin Melnick, Ari Nimer, Stephen D. Jaffe, Jacob D. Aifantis, Iannis Bernstein, Bradley E. Levine, Ross L. TI ASXL1 Mutations Promote Myeloid Transformation through Loss of PRC2-Mediated Gene Repression SO CANCER CELL LA English DT Article ID CHRONIC MYELOMONOCYTIC LEUKEMIA; EMBRYONIC STEM-CELLS; MYELODYSPLASTIC SYNDROMES; SOMATIC MUTATIONS; HEMATOPOIETIC-CELLS; SELF-RENEWAL; COMPLEX 2; EZH2; CHROMATIN; DIFFERENTIATION AB Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. C1 [Adli, Mazhar; Koche, Richard; Bernstein, Bradley E.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Broad Inst Harvard & MIT, Dept Pathol, Boston, MA 02114 USA. [Adli, Mazhar; Koche, Richard; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Abdel-Wahab, Omar; LaFave, Lindsay M.; Hricik, Todd; Shih, Alan H.; Pandey, Suveg; Patel, Jay P.; Chung, Young Rock; Park, Christopher Y.; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Abdel-Wahab, Omar; LaFave, Lindsay M.; Hricik, Todd; Shih, Alan H.; Pandey, Suveg; Patel, Jay P.; Chung, Young Rock; Park, Christopher Y.; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA. [LaFave, Lindsay M.] Mem Sloan Kettering Canc Ctr, Gerstner Sloan Kettering Sch Biomed Sci, New York, NY 10065 USA. [Perna, Fabiana; Aifantis, Iannis] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA. [Gao, Jie] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [Gao, Jie] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Zhao, Xinyang] Univ Alabama Birmingham, Dept Biochem & Mol Genet, Birmingham, AL 35233 USA. [Taylor, Jordan E.; Jaffe, Jacob D.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Carroll, Martin] Univ Penn, Div Hematol & Oncol, Philadelphia, PA 19104 USA. [Melnick, Ari] Weill Cornell Med Coll, Div Hematol Oncol, New York, NY 10065 USA. [Levine, Ross L.] Weill Cornell Med Coll, Biochem & Mol Biol Program, New York, NY 10065 USA. [Nimer, Stephen D.] Univ Miami, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA. RP Bernstein, BE (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Broad Inst Harvard & MIT, Dept Pathol, MGH Simches Res Bldg,CPZN 8400,185 Cambridge St, Boston, MA 02114 USA. EM bernstein.bradley@mgh.harvard.edu; leviner@mskcc.org OI Perna, Fabiana/0000-0002-3744-8672; Abdel-Wahab, Omar/0000-0002-3907-6171; Zhao, Xinyang/0000-0001-6677-7072 FU Starr Cancer Consortium; Gabrielle's Angel Fund; Anna Fuller Fund; NHLBI [5U01HL100395]; Leukemia and Lymphoma Society SCOR award; American Italian Cancer Foundation award; NIH K08 Clinical Investigator Award [1K08CA160647-01]; American Society of Hematology Trainee Research Award FX This work was supported by a grant from the Starr Cancer Consortium to R.L.L. and B.E.B., by grants from the Gabrielle's Angel Fund to R.L.L. and O.A.-W., by a grant from the Anna Fuller Fund to R.L.L., and by an NHLBI grant to B.E.B. (5U01HL100395). I.A. and B.E.B. are Howard Hughes Medical Institute Early Career Scientists. A.M. is a Burroughs Wellcome Clinical Translational Scholar and Scholar of the Leukemia and Lymphoma Society. X.Z. and S.D.N. are supported by a Leukemia and Lymphoma Society SCOR award, and F.P. is supported by an American Italian Cancer Foundation award. O.A.-W. is an American Society of Hematology Basic Research Fellow and is supported by a grant from the NIH K08 Clinical Investigator Award (1K08CA160647-01). J.P.P. is supported by an American Society of Hematology Trainee Research Award. NR 52 TC 171 Z9 176 U1 4 U2 23 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 AUG 14 PY 2012 VL 22 IS 2 BP 180 EP 193 DI 10.1016/j.ccr.2012.06.032 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000007 PM 22897849 ER PT J AU Kawahara, M Pandolfi, A Bartholdy, B Barreyro, L Will, B Roth, M Okoye-Okafor, UC Todorova, TI Figueroa, ME Melnick, A Mitsiades, CS Steidl, U AF Kawahara, Masahiro Pandolfi, Ashley Bartholdy, Boris Barreyro, Laura Will, Britta Roth, Michael Okoye-Okafor, Ujunwa C. Todorova, Tihomira I. Figueroa, Maria E. Melnick, Ari Mitsiades, Constantine S. Steidl, Ulrich TI H2.0-like Homeobox Regulates Early Hematopoiesis and Promotes Acute Myeloid Leukemia SO CANCER CELL LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; GENE-EXPRESSION SIGNATURE; STEM-CELLS; BONE-MARROW; VERTEBRATE DEVELOPMENT; TRANSCRIPTION FACTORS; MURINE MODEL; AML SHOWS; HOX GENES; IN-VITRO AB Homeobox domain-containing transcription factors are important regulators of hematopoiesis. Here, we report that increased levels of nonclustered H2.0-like homeobox (HLX) lead to loss of functional hematopoietic stem cells and formation of aberrant progenitors with unlimited serial clonogenicity and blocked differentiation. Inhibition of HLX reduces proliferation and clonogenicity of leukemia cells, overcomes the differentiation block, and leads to prolonged survival. HLX regulates a transcriptional program, including PAK1 and BTG1, that controls cellular differentiation and proliferation. HLX is overexpressed in 87% of patients with acute myeloid leukemia (AML) and independently correlates with inferior overall survival (n = 601, p = 2.3 x 10(-6)). Our study identifies HLX as a key regulator in immature hematopoietic and leukemia cells and as a prognostic marker and therapeutic target in AML. C1 [Kawahara, Masahiro; Pandolfi, Ashley; Bartholdy, Boris; Barreyro, Laura; Will, Britta; Roth, Michael; Okoye-Okafor, Ujunwa C.; Todorova, Tihomira I.; Steidl, Ulrich] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Kawahara, Masahiro; Pandolfi, Ashley; Bartholdy, Boris; Barreyro, Laura; Will, Britta; Roth, Michael; Okoye-Okafor, Ujunwa C.; Todorova, Tihomira I.; Steidl, Ulrich] Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10461 USA. [Steidl, Ulrich] Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10461 USA. [Figueroa, Maria E.; Melnick, Ari] Weill Cornell Med Coll, Hematol & Oncol Div, Dept Pharmacol, New York, NY 10065 USA. [Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Steidl, U (reprint author), Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. EM ulrich.steidl@einstein.yu.edu FU NYSTEM [C024172, CO24350]; Leukemia Research Foundation; National Cancer Institute [R00CA131503]; Gabrielle's Angel Foundation for Cancer Research FX We thank the Einstein Human Stem Cell FAGS and Xenotransplantation Facility for expert technical assistance (supported by NYSTEM Grant no. C024172). This work was supported by a new investigator award of the Leukemia Research Foundation, an investigator-initiated research project of NYSTEM (Grant no. CO24350), a Howard Temin Award of the National Cancer Institute (Grant no. R00CA131503), and a Medical Research Award of the Gabrielle's Angel Foundation for Cancer Research (to U.S.). U.S. is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine. NR 56 TC 22 Z9 22 U1 2 U2 5 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 AUG 14 PY 2012 VL 22 IS 2 BP 194 EP 208 DI 10.1016/j.ccr.2012.06.027 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000008 PM 22897850 ER PT J AU Sanda, T Lawton, LN Barrasa, MI Fan, ZP Kohlhammer, H Gutierrez, A Ma, WX Tatarek, J Ahn, Y Kelliher, MA Jamieson, CHM Staudt, LM Young, RA Look, AT AF Sanda, Takaomi Lawton, Lee N. Barrasa, M. Inmaculada Fan, Zi Peng Kohlhammer, Holger Gutierrez, Alejandro Ma, Wenxue Tatarek, Jessica Ahn, Yebin Kelliher, Michelle A. Jamieson, Catriona H. M. Staudt, Louis M. Young, Richard A. Look, A. Thomas TI Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia SO CANCER CELL LA English DT Article ID GENOME-WIDE ANALYSIS; GENE-EXPRESSION; TARGET GENE; PROTEINS; BINDING; DIFFERENTIATION; ALPHA; E2A; SCL; ONCOGENE AB The oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells. C1 [Sanda, Takaomi; Gutierrez, Alejandro; Ahn, Yebin; Look, A. Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Lawton, Lee N.; Barrasa, M. Inmaculada; Fan, Zi Peng; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Fan, Zi Peng] MIT, Computat & Syst Biol Program, Cambridge, MA 02142 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Kohlhammer, Holger; Staudt, Louis M.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Gutierrez, Alejandro; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Ma, Wenxue; Kelliher, Michelle A.; Jamieson, Catriona H. M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Ma, Wenxue; Kelliher, Michelle A.; Jamieson, Catriona H. M.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Tatarek, Jessica] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. RP Look, AT (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. EM thomas_look@dfci.harvard.edu RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Gutierrez, Alejandro/0000-0002-0249-9007 FU National Cancer Institute [5P01CA109901, 5P01CA68484, 1K99CA157951]; National Institutes of Health, National Cancer Institute, Center for Cancer Research; William Lawrence and Blanche Hughes Foundation; Children's Leukemia Research Association; Japan Society for the Promotion of Science; California Institute for Regenerative Medicine Leukemia Team FX We thank the members of the Look and Young laboratories for discussions and critical review and Jennifer O'Neil for initial experimentation and TAL1 plasmids. We are grateful to Garrett Frampton and Dave Orlando for the development of ChIP-seq analysis tools and continued support with the analysis. We are also grateful to the Whitehead Genome Technology Core (V. Dhanapal, J.-A. Kwon, J. Love, S. Gupta, and T. Volkert) for assistance with ChIP-Seq and expression array hybridization and to Bingbing Yuan from BaRC for developing the phenotype ontology analysis. We acknowledge the RNAi Consortium for providing lentivirus shRNA constructs, and we thank John R. Gilbert for editing and critical review of the manuscript. This research was supported by grants (5P01CA109901, 5P01CA68484, and 1K99CA157951) from the National Cancer Institute and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. T.S. is supported by grants from the William Lawrence and Blanche Hughes Foundation, the Children's Leukemia Research Association, and the Japan Society for the Promotion of Science. W.M. and C.J. are supported by the California Institute for Regenerative Medicine Leukemia Team grant. NR 61 TC 66 Z9 67 U1 1 U2 5 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 AUG 14 PY 2012 VL 22 IS 2 BP 209 EP 221 DI 10.1016/j.ccr.2012.06.007 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 991FD UT WOS:000307686000009 PM 22897851 ER PT J AU Zheng, XJ Xu, C Smith, AO Stratman, AN Zou, ZY Kleaveland, B Yuan, LJ Didiku, C Sen, A Liu, X Skuli, N Zaslavsky, A Chen, M Cheng, L Davis, GE Kahn, ML AF Zheng, Xiangjian Xu, Chong Smith, Annie O. Stratman, Amber N. Zou, Zhiying Kleaveland, Benjamin Yuan, Lijun Didiku, Chuka Sen, Aslihan Liu, Xi Skuli, Nicolas Zaslavsky, Alexander Chen, Mei Cheng, Lan Davis, George E. Kahn, Mark L. TI Dynamic Regulation of the Cerebral Cavernous Malformation Pathway Controls Vascular Stability and Growth SO DEVELOPMENTAL CELL LA English DT Article ID CONCENTRIC GROWTH; RHO KINASE; IN-VIVO; ANGIOGENESIS; HEART; ZEBRAFISH; INTEGRITY; PROTEIN; PATHOGENESIS; MECHANISMS AB Cardiovascular growth must balance stabilizing signals required to maintain endothelial connections and network integrity with destabilizing signals that enable individual endothelial cells to migrate and proliferate. The cerebral cavernous malformation (CCM) signaling pathway utilizes the adaptor protein CCM2 to strengthen endothelial cell junctions and stabilize vessels. Here we identify a CCM2 paralog, CCM2L, that is expressed selectively in endothelial cells during periods of active cardiovascular growth. CCM2L competitively blocks CCM2-mediated stabilizing signals biochemically, in cultured endothelial cells, and in developing mice. Loss of CCM2L reduces endocardial growth factor expression and impairs tumor growth and wound healing. Our studies identify CCM2L as a molecular mechanism by which endothelial cells coordinately regulate vessel stability and growth during cardiovascular development, as well as postnatal vessel growth. C1 [Zheng, Xiangjian; Xu, Chong; Zou, Zhiying; Yuan, Lijun; Didiku, Chuka; Sen, Aslihan; Liu, Xi; Chen, Mei; Cheng, Lan; Kahn, Mark L.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Zheng, Xiangjian; Xu, Chong; Zou, Zhiying; Yuan, Lijun; Didiku, Chuka; Sen, Aslihan; Liu, Xi; Chen, Mei; Cheng, Lan; Kahn, Mark L.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Skuli, Nicolas] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Skuli, Nicolas; Zaslavsky, Alexander] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Smith, Annie O.; Stratman, Amber N.; Davis, George E.] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65212 USA. [Kleaveland, Benjamin] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yuan, Lijun; Liu, Xi] Fourth Mil Med Univ, Xian 710032, Peoples R China. RP Kahn, ML (reprint author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM markkahn@mail.med.upenn.edu FU National Institute of Health [R01HL094326, R01HL102138, R01HL059373, T32HL07971]; American Heart Association [11SDG7430025] FX We thank the members of the Kahn laboratory for their thoughtful comments during the course of this work and Katherine Speichinger and Matthew Davis for their technical assistance. We would also like to thank M. Ginsberg and J.J. Liu for generously providing us with HEG-IC and alpha IIb-IC beads. These studies were supported by grants from the National Institute of Health (grants R01HL094326 and R01HL102138 to M.L.K., R01HL059373 to G.E.D., and T32HL07971 to X.Z.) and the American Heart Association (grant 11SDG7430025 to X.Z.). NR 32 TC 20 Z9 20 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 14 PY 2012 VL 23 IS 2 BP 342 EP 355 DI 10.1016/j.devcel.2012.06.004 PG 14 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 991IU UT WOS:000307695500013 PM 22898778 ER PT J AU Feng, P Zhao, H Chai, JH Huang, LQ Wang, H AF Feng, Pu Zhao, Hang Chai, Jinghua Huang, Liquan Wang, Hong TI Expression and Secretion of TNF-alpha in Mouse Taste Buds: A Novel Function of a Specific Subset of Type II Taste Cells SO PLOS ONE LA English DT Article ID NECROSIS-FACTOR-ALPHA; SIGNALING PATHWAYS; MAMMALIAN SWEET; INNATE IMMUNITY; RECEPTORS; LIPOPOLYSACCHARIDE; INFLAMMATION; GUSTDUCIN; APOPTOSIS; PROTEINS AB Taste buds are chemosensory structures widely distributed on the surface of the oral cavity and larynx. Taste cells, exposed to the oral environment, face great challenges in defense against potential pathogens. While immune cells, such as T-cells and macrophages, are rarely found in taste buds, high levels of expression of some immune-response-associated molecules are observed in taste buds. Yet, the cellular origins of these immune molecules such as cytokines in taste buds remain to be determined. Here, we show that a specific subset of taste cells selectively expresses high levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Based on immuno-colocalization experiments using taste-cell-type markers, the TNF-alpha-producing cells are predominantly type II taste cells expressing the taste receptor T1R3. These cells can rapidly increase TNF-alpha production and secretion upon inflammatory challenges, both in vivo and in vitro. The lipopolysaccharide (LPS)-induced TNF-alpha expression in taste cells was completely eliminated in TLR2(-/-)/TLR4(-/-) double-gene-knockout mice, which confirms that the induction of TNF-alpha in taste buds by LPS is mediated through TLR signaling pathways. The taste-cell-produced TNF-alpha may contribute to local immune surveillance, as well as regulate taste sensation under normal and pathological conditions. C1 [Feng, Pu; Chai, Jinghua; Huang, Liquan; Wang, Hong] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Zhao, Hang] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Zhao, Hang] Harvard Univ, Sch Med, Boston, MA USA. RP Feng, P (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM pfeng@monell.org; hwang@monell.org FU National Institutes of Health/National Institute of Deafness and Other Communication Disorders grants [DC010012, DC007487, P30 DC011735]; National Science Foundation [DBJ-0216310] FX The study was supported by National Institutes of Health/National Institute of Deafness and Other Communication Disorders grants DC010012 (H.W.), DC007487 (L.H.), and P30 DC011735 and by a grant from the National Science Foundation DBJ-0216310. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 6 Z9 6 U1 3 U2 10 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 AUG 14 PY 2012 VL 7 IS 8 AR e43140 DI 10.1371/journal.pone.0043140 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OQ UT WOS:000307500800051 PM 22905218 ER PT J AU Yao, JK Condray, R Dougherty, GG Keshavan, MS Montrose, DM Matson, WR McEvoy, J Kaddurah-Daouk, R Reddy, RD AF Yao, Jeffrey K. Condray, Ruth Dougherty, George G., Jr. Keshavan, Matcheri S. Montrose, Debra M. Matson, Wayne R. McEvoy, Joseph Kaddurah-Daouk, Rima Reddy, Ravinder D. TI Associations between Purine Metabolites and Clinical Symptoms in Schizophrenia SO PLOS ONE LA English DT Article ID SERUM URIC-ACID; NEUROLOGIC EXAMINATION ABNORMALITIES; NEUROLEPTIC-NAIVE; NEUROPSYCHOLOGICAL PERFORMANCE; ACHIEVEMENT BEHAVIOR; PARKINSONS-DISEASE; SOFT SIGNS; ARRAY; CHOLESTEROL; CATABOLISM AB Background: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia. Methodology/Principal Findings: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naive patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions. Conclusions/Significance: Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology. C1 [Yao, Jeffrey K.; Condray, Ruth; Dougherty, George G., Jr.; Reddy, Ravinder D.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. [Yao, Jeffrey K.; Condray, Ruth; Dougherty, George G., Jr.; Keshavan, Matcheri S.; Montrose, Debra M.; Reddy, Ravinder D.] Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Med Ctr, Pittsburgh, PA 15213 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Keshavan, Matcheri S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Keshavan, Matcheri S.] Harvard Univ, Boston, MA 02115 USA. [Matson, Wayne R.] Bedford Vet Affairs Med Ctr, Bedford, MA USA. [McEvoy, Joseph; Kaddurah-Daouk, Rima] Duke Univ, Med Ctr, Durham, NC USA. RP Yao, JK (reprint author), Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. EM jkyao@pitt.edu FU Department of Veterans Affairs (VA); Veterans Health Administration; Office of Research and Development; Biomedical Laboratory Research Development; Senior Research Career Scientist Award; VA Pittsburgh Healthcare System; National Institutes of Health [MH58141, MH64118, MH45203, MH84941, R24 GM078233, c UL1 RR024153, M01 RR00056]; Metabolomics Research Network; Stanley Medical Research Institute; National Alliance for Research on Schizophrenia and Affective Disorders; Merck; Psychogenics; Roche; Sunovion FX This material is based on work supported in part by the grants from the Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research & Development [Merit Reviews (JKY) and Senior Research Career Scientist Award (JKY)], VA Pittsburgh Healthcare System (JKY, GGD), National Institutes of Health [MH58141 (JKY), MH64118 (RDR), MH45203 (MSK), MH84941 (RKD), R24 GM078233 (RKD), c UL1 RR024153 and NIH/NCRR/GCRC Grant M01 RR00056], Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD), and National Alliance for Research on Schizophrenia and Affective Disorders (RKD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.; Dr. McEvoy received honoraria from Lilly, Merck, and Sunovion, and grant supports from Merck, Psychogenics, Roche, and Sunovion. Dr. Kaddurah-Daouk is a co-inventor on a series of patents in the metabolomics field. (1. One patent Issued (3/20/12) "Lipidomic approaches to determine drug response - Phenotypes in cardiovascular disease" Patent # 8137977, expires 12/10/27. 2. One patent pending: "Lipidomic approaches for central nervous system disorders" Application # 12/091,213 filed 12/10/08, Publication # US 2009/0305323 12/10/09.) All other authors declare no conflict of interest. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. NR 44 TC 10 Z9 10 U1 0 U2 9 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 AUG 14 PY 2012 VL 7 IS 8 AR e42165 DI 10.1371/journal.pone.0042165 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OQ UT WOS:000307500800009 PM 22916123 ER PT J AU Biris, N Yang, Y Taylor, AB Tomashevski, A Guo, M Hart, PJ Diaz-Griffero, F Ivanov, DN AF Biris, Nikolaos Yang, Yang Taylor, Alexander B. Tomashevski, Andrei Guo, Miao Hart, P. John Diaz-Griffero, Felipe Ivanov, Dmitri N. TI Structure of the rhesus monkey TRIM5 alpha PRYSPRY domain, the HIV capsid recognition module SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MURINE LEUKEMIA-VIRUS; RETROVIRAL RESTRICTION; B30.2(SPRY) DOMAIN; B30.2/SPRY DOMAIN; COMBINING SITE; SPRY DOMAIN; PROTEIN; DETERMINANTS; SPECIFICITY; INFECTION AB Tripartite motif protein TRIM5 alpha blocks retroviral replication after cell entry, and species-specific differences in its activity are determined by sequence variations within the C-terminal B30.2/PRYSPRY domain. Here we report a high-resolution structure of a TRIM5 alpha PRYSPRY domain, the PRYSPRY of the rhesus monkey TRIM5 alpha that potently restricts HIV infection, and identify features involved in its interaction with the HIV capsid. The extensive capsid-binding interface maps on the structurally divergent face of the protein formed by hypervariable loop segments, confirming that TRIM5 alpha evolution is largely determined by its binding specificity. Interactions with the capsid are mediated by flexible variable loops via a mechanism that parallels antigen recognition by IgM antibodies, a similarity that may help explain some of the unusual functional properties of TRIM5 alpha. Distinctive features of this pathogen-recognition interface, such as structural plasticity conferred by the mobile v1 segment and interaction with multiple epitopes, may allow restriction of divergent retroviruses and increase resistance to capsid mutations. C1 [Biris, Nikolaos; Taylor, Alexander B.; Tomashevski, Andrei; Guo, Miao; Hart, P. John; Ivanov, Dmitri N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Ivanov, Dmitri N.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Yang, Yang; Diaz-Griffero, Felipe] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Ivanov, DN (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM ivanov@uthscsa.edu OI Biris, Nikolaos/0000-0003-4055-5521 FU University of Texas Health Science Center Executive Research Committee; Cancer Therapy Research Center (P30 Cancer Center Support Grant from the National Cancer Institute) [CA054174]; National Institutes of Health (NIH) [R21 AI068548, R21 AI084612, R01 AI087390]; Robert A. Welch Foundation [AQ-1399]; Cancer Prevention and Research Institute of Texas (CPRIT); NIH [K99/R00] FX We thank Dr. Oleg Tsodikov and the staff of Life Sciences Collaborative Access Team (LS-CAT) sector at the Advanced Photon Source at the Argonne National Laboratory for assistance with collection of the X-ray diffraction data. Support for the NMR Core Facility and the X-ray Crystallography Core Laboratory is provided by University of Texas Health Science Center Executive Research Committee and the Cancer Therapy Research Center (P30 Cancer Center Support Grant from the National Cancer Institute CA054174). This research was supported in part by National Institutes of Health (NIH) Grants R21 AI068548 (to D. I.), R21 AI084612 (to D. I.), R01 AI087390 (to F. D.-G.), and the Robert A. Welch Foundation grant AQ-1399 (to P.J.H.). The Scholar Award from the Cancer Prevention and Research Institute of Texas (CPRIT) (D. I.) and the NIH K99/R00 Pathway to Independence Award (F. D.-G.) are gratefully acknowledged. NR 48 TC 38 Z9 39 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 AUG 14 PY 2012 VL 109 IS 33 BP 13278 EP 13283 DI 10.1073/pnas.1203536109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VC UT WOS:000307807000036 PM 22847415 ER PT J AU Wang, Y Lomakin, A Hideshima, T Laubach, JP Ogun, O Richardson, PG Munshi, NC Anderson, KC Benedek, GB AF Wang, Ying Lomakin, Aleksey Hideshima, Teru Laubach, Jacob P. Ogun, Olutayo Richardson, Paul G. Munshi, Nikhil C. Anderson, Kenneth C. Benedek, George B. TI Pathological crystallization of human immunoglobulins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LIQUID PHASE-SEPARATION; MONOCLONAL-ANTIBODIES; PERIPHERAL NEUROPATHY; MULTIPLE-MYELOMA; CRYOGLOBULINS; SOLUBILITY AB Condensation of Igs has been observed in pharmaceutical formulations and in vivo in cases of cryoglobulinemia. We report a study of monoclonal IgG cryoglobulins overexpressed by two patients with multiple myeloma. These cryoglobulins form crystals, and we measured their solubility lines. Depending on the supersaturation, we observed a variety of condensate morphologies consistent with those reported in clinical investigations. Remarkably, the crystallization can occur at quite low concentrations. This suggests that, even within the regular immune response to infections, cryoprecipitation of Ig can be possible. C1 [Wang, Ying; Lomakin, Aleksey; Ogun, Olutayo; Benedek, George B.] MIT, Ctr Mat Proc, Cambridge, MA 02139 USA. [Hideshima, Teru; Laubach, Jacob P.; Richardson, Paul G.; Munshi, Nikhil C.; Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Div Hematol Malignancy, Dept Med Oncol, Boston, MA 02215 USA. [Benedek, George B.] MIT, Dept Phys, Cambridge, MA 02139 USA. [Benedek, George B.] MIT, Ctr Mat Sci & Engn, Cambridge, MA 02139 USA. RP Wang, Y (reprint author), MIT, Ctr Mat Proc, Cambridge, MA 02139 USA. EM ywang09@mit.edu; benedek@mit.edu FU Alfred H. Caspary Professorship FX This study was supported by funds from the Alfred H. Caspary Professorship (to Y.W, A. L., O.O., and G.B.B.). NR 23 TC 16 Z9 16 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 AUG 14 PY 2012 VL 109 IS 33 BP 13359 EP 13361 DI 10.1073/pnas.1211723109 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 992VC UT WOS:000307807000050 PM 22847421 ER PT J AU Carignan, CS Yagi, Y AF Carignan, Charles S. Yagi, Yukako TI Optical endomicroscopy and the road to real-time, in vivo pathology: present and future SO DIAGNOSTIC PATHOLOGY LA English DT Review DE Barrett's esophagus; Cancer; Confocal microscopy; Dysplasia; Endoscopy; In vivo imaging; Neoplasia; Optical coherence tomography; Optical imaging ID CONFOCAL LASER ENDOMICROSCOPY; SYNTHETIC-APERTURE MICROSCOPY; COHERENCE TOMOGRAPHY; BARRETTS-ESOPHAGUS; GASTROINTESTINAL-TRACT; UNITED-STATES; INTESTINAL METAPLASIA; INDUCED FLUORESCENCE; GASTRIC CARDIA; GI TRACT AB Epithelial cancers account for substantial mortality and are an important public health concern. With the need for earlier detection and treatment of these malignancies, the ability to accurately detect precancerous lesions has an increasingly important role in controlling cancer incidence and mortality. New optical technologies are capable of identifying early pathology in tissues or organs in which cancer is known to develop through stages of dysplasia, including the esophagus, colon, pancreas, liver, bladder, and cervix. These diagnostic imaging advances, together as a field known as optical endomicroscopy, are based on confocal microscopy, spectroscopy-based imaging, and optical coherence tomography (OCT), and function as "optical biopsies," enabling tissue pathology to be imaged in situ and in real time without the need to excise and process specimens as in conventional biopsy and histopathology. Optical biopsy techniques can acquire high-resolution, cross-sectional images of tissue structure on the micron scale through the use of endoscopes, catheters, laparoscopes, and needles. Since the inception of these technologies, dramatic technological advances in accuracy, speed, and functionality have been realized. The current paradigm of optical biopsy, or single-area, point-based images, is slowly shifting to more comprehensive microscopy of larger tracts of mucosa. With the development of Fourier-domain OCT, also known as optical frequency domain imaging or, more recently, volumetric laser endomicroscopy, comprehensive surveillance of the entire distal esophagus is now achievable at speeds that were not possible with conventional OCT technologies. Optical diagnostic technologies are emerging as clinically useful tools with the potential to set a new standard for real-time diagnosis. New imaging techniques enable visualization of high-resolution, cross-sectional images and offer the opportunity to guide biopsy, allowing maximal diagnostic yields and appropriate staging without the limitations and risks inherent with current random biopsy protocols. However, the ability of these techniques to achieve widespread adoption in clinical practice depends on future research designed to improve accuracy and allow real-time data transmission and storage, thereby linking pathology to the treating physician. These imaging advances are expected to eventually offer a see-and-treat paradigm, leading to improved patient care and potential cost reduction. C1 [Carignan, Charles S.] NinePoint Med, Cambridge, MA 02139 USA. [Yagi, Yukako] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yagi, Yukako] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Carignan, CS (reprint author), NinePoint Med, 1 Kendall Sq B7501, Cambridge, MA 02139 USA. EM CCarignan@ninepointmedical.com NR 88 TC 10 Z9 11 U1 1 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD AUG 13 PY 2012 VL 7 AR 98 DI 10.1186/1746-1596-7-98 PG 12 WC Pathology SC Pathology GA 039IW UT WOS:000311239800001 PM 22889003 ER PT J AU Graham, SM Holte, SE Dragavon, JA Ramko, KM Mandaliya, KN McClelland, RS Peshu, NM Sanders, EJ Krieger, JN Coombs, RW AF Graham, Susan M. Holte, Sarah E. Dragavon, Joan A. Ramko, Kelly M. Mandaliya, Kishor N. McClelland, R. Scott Peshu, Norbert M. Sanders, Eduard J. Krieger, John N. Coombs, Robert W. TI HIV-1 RNA May Decline More Slowly in Semen than in Blood following Initiation of Efavirenz-Based Antiretroviral Therapy SO PLOS ONE LA English DT Article ID HIV-1-INFECTED MEN; DRUG CONCENTRATIONS; GENITAL-TRACT; COMPARTMENTS; PLASMA; TRANSMISSION; METAANALYSIS; PENETRATION; LAMIVUDINE; INFECTION AB Objectives: Antiretroviral therapy (ART) decreases HIV-1 RNA levels in semen and reduces sexual transmission from HIV-1-infected men. Our objective was to study the time course and magnitude of seminal HIV-1 RNA decay after initiation of efavirenz-based ART among 13 antiretroviral-naive Kenyan men. Methods: HIV-1 RNA was quantified (lower limit of detection, 120 copies/mL) in blood and semen at baseline and over the first month of ART. Median log(10) HIV-1 RNA was compared at each time-point using Wilcoxon Signed Rank tests. Perelson's two-phase viral decay model and nonlinear random effects were used to compare decay rates in blood and semen. Results: Median baseline HIV-1 RNA was 4.40 log(10) copies/mL in blood (range, 3.20-5.08 log(10) copies/mL) and 3.69 log(10) copies/mL in semen (range, <2.08-4.90 log(10) copies/mL). The median reduction in HIV-1 RNA by day 28 was 1.90 log(10) copies/mL in blood (range, 0.56-2.68 log(10) copies/mL) and 1.36 log(10) copies/mL in semen (range, 0-2.66 log(10) copies/mL). ART led to a decrease from baseline by day 7 in blood and day 14 in semen (p = 0.005 and p = 0.006, respectively). The initial modeled decay rate was slower in semen than in blood (p = 0.06). There was no difference in second-phase decay rates between blood and semen. Conclusions: Efavirenz-based ART reduced HIV-1 RNA levels more slowly in semen than in blood. Although this difference was of borderline significance in this small study, our observations suggest that there is suboptimal suppression of seminal HIV-1 RNA for some men in the early weeks of treatment. C1 [Graham, Susan M.; McClelland, R. Scott; Coombs, Robert W.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Graham, Susan M.; McClelland, R. Scott; Krieger, John N.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Graham, Susan M.; McClelland, R. Scott] Univ Nairobi, Dept Med Microbiol, Nairobi, Kenya. [Graham, Susan M.; Ramko, Kelly M.; Peshu, Norbert M.; Sanders, Eduard J.] Kenya Govt Med Res Ctr, Ctr Geog Med & Res Coast, Kilifi, Kenya. [Holte, Sarah E.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Holte, Sarah E.] Fred Hutchinson Canc Res Ctr, Dept Biostat & Biomath, Seattle, WA 98104 USA. [Dragavon, Joan A.; Coombs, Robert W.] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Mandaliya, Kishor N.] PathCare Kenya, Mombasa, Kenya. [McClelland, R. Scott] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Sanders, Eduard J.] Univ Oxford, Nuffield Dept Clin Med, Headington, England. [Krieger, John N.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Krieger, John N.] VA Puget Sound Hlth Care Syst, Dept Urol, Seattle, WA USA. RP Graham, SM (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. EM grahamsm@u.washington.edu OI Graham, Susan/0000-0001-7847-8686 FU National Institutes of Health (NIH) [R21 HD-055864, K23 AI-069990, R01 AI-055343, P30 AI027757]; University of Washington Center for AIDS Research (CFAR); NIH (NIAID); NIH (NCI); NIH (NIMH); NIH (NIDA); NIH (NICHD); NIH (NHLBI); NIH (NCCAM); Kenya Medical Research Institute (KEMRI); International AIDS Vaccine Initiative (IAVI) FX This study was supported by National Institutes of Health (NIH) grant R21 HD-055864. Dr. Graham was supported by NIH grant K23 AI-069990, and Dr. Holte was supported by NIH grant R01 AI-055343. Additional funding was provided by the University of Washington Center for AIDS Research (CFAR), an NIH funded program (P30 AI027757), which is supported by the following NIH Institutes and Centers (NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NCCAM). The funders had no role in study design, data collection and analysis, decision to publish, or prepartion of the manuscript.; We would like to thank the research staff who helped make this project a success, the Kenya Medical Research Institute (KEMRI) and the International AIDS Vaccine Initiative (IAVI) for support of E. Sanders and use of clinical space, the Coast Provincial General Hospital for provision of laboratory space, and the KEMRI Director for permission to publish. Special thanks go to the men who participated in this study. NR 30 TC 8 Z9 9 U1 0 U2 2 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 AUG 13 PY 2012 VL 7 IS 8 AR e43086 DI 10.1371/journal.pone.0043086 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OJ UT WOS:000307500100060 PM 22912795 ER PT J AU Yan, G Zhang, YC Yu, JL Yu, Y Zhang, F Zhang, ZZ Wu, AM Yan, XH Zhou, Y Wang, FD AF Yan, Guang Zhang, Yuchao Yu, Junlei Yu, Yu Zhang, Fan Zhang, Zhuzhen Wu, Aimin Yan, Xianghua Zhou, Yi Wang, Fudi TI Slc39a7/zip7 Plays a Critical Role in Development and Zinc Homeostasis in Zebrafish SO PLOS ONE LA English DT Article ID X-RAY-FLUORESCENCE; ACRODERMATITIS-ENTEROPATHICA; SIGNALING PATHWAYS; LIV-1 SUBFAMILY; TRANSPORTER; CELLS; GENE; EXPRESSION; MOUSE; PROTEINS AB Background: Slc39a7/Zip7, also known as Ke4, is a member of solute carrier family 39 (Slc39a) and plays a critical role in regulating cell growth and death. Because the function of Zip7 in vivo was unclear, the present study investigated the function of zip7 in vertebrate development and zinc metabolism using zebrafish as a model organism. Principal Finding: Using real-time PCR to determine the gene expression pattern of zip7 during zebrafish development, we found that zip7 mRNA is expressed throughout embryonic development and into maturity. Interestingly, whole mount in situ hybridization revealed that while zip7 mRNA is ubiquitously expressed until 12 hours post-fertilization (hpf); at 24 hpf and beyond, zip7 mRNA was specifically detected only in eyes. Morpholino-antisense (MO) gene knockdown assay revealed that downregulation of zip7 expression resulted in several morphological defects in zebrafish including decreased head size, smaller eyes, shorter palates, and shorter and curved spinal cords. Analysis by synchrotron radiation X-ray fluorescence (SR-XRF) showed reduced concentrations of zinc in brain, eyes, and gills of zip7-MO-injected embryos. Furthermore, incubation of the zip7 knockdown embryos in a zinc-supplemented solution was able to rescue the MO-induced morphological defects. Significance: Our data suggest that zip7 is required for eye, brain, and skeleton formation during early embryonic development in zebrafish. Moreover, zinc supplementation can partially rescue defects resulting from zip7 gene knockdown. Taken together, our data provide critical insight into a novel function of zip7 in development and zinc homeostasis in vivo in zebrafish. C1 [Yan, Guang; Zhang, Yuchao; Yu, Junlei; Yu, Yu; Zhang, Fan; Zhang, Zhuzhen; Wu, Aimin; Wang, Fudi] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Grp Biomet Metab,Key Lab Nutr & Metab,Grad Sch, Shanghai, Peoples R China. [Zhang, Yuchao; Yan, Xianghua] Huazhong Agr Univ, Minist Agr, Key Lab Swine Genet & Breeding, Coll Anim Sci & Technol, Wuhan, Peoples R China. [Yu, Junlei] Nanchang Univ, Sch Life Engn, Nanchang, Peoples R China. [Yu, Junlei] Nanchang Univ, Sch Food Engn, Nanchang, Peoples R China. [Zhou, Yi] Harvard Univ, Sch Med, Childrens Hosp Boston, Stem Cell Program, Boston, MA USA. [Zhou, Yi] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. [Zhou, Yi] Harvard Univ, Sch Med, Dana Farber Canc Inst, Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Yan, G (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Grp Biomet Metab,Key Lab Nutr & Metab,Grad Sch, Shanghai, Peoples R China. EM wangfd@sibs.ac.cn OI Zhang, Zhuzhen/0000-0001-6787-3920 FU Ministry of Science and Technology of China (973 Program) [2009CB941400, 2011CB966200]; National Natural Science Foundation of China [10979071, 30970665, 31030039, 30901193]; Science & Technology Commission of Shanghai Municipality grant [10JC1416800]; Chinese Academy of Sciences Hundred Talents Program [KSCX2-YW-R-141] FX This work was supported by research grants from the Ministry of Science and Technology of China (973 Program) (grant numbers 2009CB941400, 2011CB966200 to FW); the National Natural Science Foundation of China (grant numbers 10979071, 30970665, 31030039 to FW, 30901193 to YY); Science & Technology Commission of Shanghai Municipality grant (grant number 10JC1416800 to FW) and Chinese Academy of Sciences Hundred Talents Program (grant number KSCX2-YW-R-141 to FW). FW is a scholar of the Hundred Talents Program of the Chinese Academy of Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 11 Z9 12 U1 1 U2 15 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 AUG 13 PY 2012 VL 7 IS 8 AR e42939 DI 10.1371/journal.pone.0042939 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 988OJ UT WOS:000307500100043 PM 22912764 ER PT J AU Zhang, BH Nilsson, ME Prigerson, HG AF Zhang, Baohui Nilsson, Matthew E. Prigerson, Holly G. TI Factors Important to Patients' Quality of Life at the End of Life SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ADVANCED CANCER-PATIENTS; CARE NEAR-DEATH; MENTAL-HEALTH; TREATMENT PREFERENCES; BEREAVED CAREGIVERS; INITIAL VALIDATION; CONTROLLED-TRIAL; MEDICAL-CARE; ILL PATIENTS; ASSOCIATIONS AB Background: When curative treatments are no longer options for patients dying of cancer, the focus of care often turns from prolonging life to promoting quality of life (QOL). Few data exist on what predicts better QOL at the end of life (EOL) for advanced cancer patients. The purpose of this study was to determine the factors that most influence QOL at the EOL, thereby identifying promising targets for interventions to promote QOL at the EOL. Methods: Coping With Cancer is a US multisite, prospective, longitudinal cohort study of 396 advanced cancer patients and their informal caregivers who were enrolled from September 1, 2002, through February 28, 2008. Patients were followed up from enrollment to death a median of 4.1 months later. Patient QOL in the last week of life was a primary outcome of Coping With Cancer and the present report. Results: The following set of 9 factors, preceded by a sign indicating the direction of the effect and presented in rank order of importance, explained the most variance in patients' QOL at the EOL: 1 = (-) intensive care unit stays in the final week (explained 4.4% of the variance in QOL at the EOL), 2 = (-) hospital deaths (2.7%), 3 = (-) patient worry at baseline (2.7%), 4 = ( +) religious prayer or meditation at baseline (2.5%), 5 = site of cancer care (1.8%), 6 = (-) feeding-tube use in the final week (1.1%), 7 = (+) pastoral care within the hospital or clinic (1.0%), 8 = (-) chemotherapy in the final week (0.8%), and 9 = (+) patient-physician therapeutic alliance at baseline (0.7%). The vast majority of the variance in QOL at the EOL, however, remained unexplained. Conclusion: Advanced cancer patients who avoid hospitalizations and the intensive care unit, who are less worried, who pray or meditate, who are visited by a pastor in the hospital/clinic, and who feel a therapeutic alliance with their physicians have the highest QOL at the EOL. C1 [Prigerson, Holly G.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Psychosocial Epidemiol & Outcomes Res, Boston, MA 02115 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA USA. [Prigerson, Holly G.] Harvard Univ, Sch Med, Dept Psychiat, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Psychosocial Epidemiol & Outcomes Res, Dana 1134,450 Brookline Ave, Boston, MA 02115 USA. EM holly_prigerson@dfci.harvard.edu FU National Institute of Mental Health [MH63892]; National Cancer Institute [CA 106370, CA 156732]; Center for Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute FX This research was supported in part by grant MH63892 from the National Institute of Mental Health (Dr Prigerson), grants CA 106370 and CA 156732 from the National Cancer Institute (Dr Prigerson), and the Center for Psychosocial Epidemiology and Outcomes Research, Dana-Farber Cancer Institute. NR 44 TC 61 Z9 63 U1 5 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1133 EP 1142 DI 10.1001/archinternmed.2012.2364 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200007 PM 22777380 ER PT J AU Amin, AP Spertus, JA Cohen, DJ Chhatriwalla, A Kennedy, KF Vilain, K Salisbury, AC Venkitachalam, L Lai, SM Mauri, L Normand, SLT Rumsfeld, JS Messenger, JC Yeh, RW AF Amin, Amit P. Spertus, John A. Cohen, David J. Chhatriwalla, Adnan Kennedy, Kevin F. Vilain, Katherine Salisbury, Adam C. Venkitachalam, Lahshmi Lai, Sue Min Mauri, Laura Normand, Sharon-Lise T. Rumsfeld, John S. Messenger, John C. Yeh, Robert W. TI Use of Drug-Eluting Stents as a Function of Predicted Benefit Clinical and Economic Implications of Current Practice SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; BARE-METAL STENTS; POISSON REGRESSION APPROACH; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; COST-EFFECTIVENESS; AMERICAN-COLLEGE; OUTCOMES; REGISTRY; MULTICENTER AB Background: Benefits of drug-eluting sterns (DES) in percutaneous coronary intervention (PCI) are greatest in those at the highest risk of target-vessel revascularization (TVR). Drug-eluting stents cost more than bare-metal stents (BMS) and necessitate prolonged dual antiplatelet therapy (DAPT), which increases costs, bleeding risk, and risk of complications if DAPT is prematurely discontinued. Our objective was to assess whether DES are preferentially used in patients with higher predicted TVR risk and to estimate if lower use of DES in low-TVR-risk patients would be more cost-effective than the existing DES use pattern. Methods: We analyzed more than 1.5 million PCI procedures in the National Cardiovascular Data Registry (NCDR) CathPCI registry from 2004 through 2010 and estimated 1-year TVR risk with BMS using a validated model. We examined the association between TVR risk and DES use and the cost-effectiveness of lower DES use in low-TVR-risk patients (50% less DES use among patients with <10% TVR risk) compared with existing DES use. Results: There was marked variation in physicians' use of DES (range 2%-100%). Use of DES was high across all predicted TVR risk categories (73.9% in TVR risk <10%; 78.0% in TVR risk 10%-20%; and 83.2% in TVR risk >20%), with a modest relationship between TVR risk and DES use (relative risk, 1.005 per 1% increase in TVR risk [95% CI, 1.005-1.006]). Reducing DES use by 50% in low-TVR-risk patients was projected to lower US health care costs by $205 million per year while increasing the overall TVR event rate by 0.5% (95% Cl, 0.49%-0.51%) in absolute terms. Conclusions: Use of DES in the United States varies widely among physicians, with only a modest correlation to patients' risk of restenosis. Less DES use among patients with low risk of restenosis has the potential for significant cost savings for the US health care system while minimally increasing restenosis events. C1 [Amin, Amit P.] Washington Univ, Sch Med, Dept Med, Cardiovasc Div,Barnes Jewish Hosp, St Louis, MO 63110 USA. [Spertus, John A.; Cohen, David J.; Chhatriwalla, Adnan; Kennedy, Kevin F.; Vilain, Katherine; Salisbury, Adam C.] St Lukes Mid Amer Heart & Vasc Inst, Kansas City, MO USA. [Spertus, John A.; Cohen, David J.; Chhatriwalla, Adnan; Kennedy, Kevin F.; Vilain, Katherine; Salisbury, Adam C.] Univ Missouri, Kansas City, MO USA. [Lai, Sue Min] Univ Kansas, Med Ctr, Dept Prevent Med, Kansas City, MO USA. [Mauri, Laura] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA 02115 USA. [Yeh, Robert W.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Normand, Sharon-Lise T.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Rumsfeld, John S.; Messenger, John C.] Univ Colorado, Div Cardiol, Sch Med, Aurora, CO USA. [Rumsfeld, John S.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Yeh, RW (reprint author), Massachusetts Gen Hosp, Div Cardiol, GRB8 843, Boston, MA 02144 USA. EM ryeh@partners.org FU Boston Scientific; Medtronic; Abbott Vascular; Eli Lilly; Daichi Sankyo; Accumetrix; BMS/Sanofi; Schering-Plough; Edwards Life-sciences; Cordis; Abbott; Daiichi Sankyo; Bristol Myers Squibb; sanofi-aventis; American College of Cardiology Foundation; ACC; American College of Cardiology Foundation National Cardiovascular Data Registry (NCDR); American Heart Association Pharmaceutical Round Table; David and Stevie Spina FX Dr Spertus is the primary investigator of a contract from the American College of Cardiology Foundation to serve as an Analytic Center for the NCDR. He also has an equity position in Health Outcomes Sciences. Dr David J. Cohen has received research grant support from Boston Scientific, Medtronic, Abbott Vascular, Eli Lilly, Daichi Sankyo, Accumetrix, BMS/Sanofi, Schering-Plough, and Edwards Life-sciences. He has also received consulting fees from Cordis and Medtronic and speaking honoraria from Eli Lilly and the Medicines Company. Dr Mauri receives institutional research support from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, and sanofi-aventis and has consulted for Cordis and Medtronic. Dr Rumsfeld is Chief Science Officer for the NCDR. Dr Yeh is an investigator for the Harvard Clinical Research Institute and a consultant for the Kaiser Permanente Division of Research.; Funding for the ACC NCDR CathPCI registry was provided by grants from the American College of Cardiology Foundation. This analysis was funded by the ACC. This research was supported by the American College of Cardiology Foundation National Cardiovascular Data Registry (NCDR). Dr Amin is funded, in part, by an award from the American Heart Association Pharmaceutical Round Table and David and Stevie Spina. NR 34 TC 32 Z9 34 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1145 EP 1152 DI 10.1001/archinternmed.2012.3093 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200010 PM 22777536 ER PT J AU Groeneveld, PW AF Groeneveld, Peter W. TI How Drug-Eluting Stents Illustrate Our Health System's Flawed Relationship With Technology Value Lost SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Groeneveld, Peter W.] Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.] Philadelphia Vet Affairs Med Ctr, Dept Vet Affairs, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Groeneveld, Peter W.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Groeneveld, PW (reprint author), Univ Penn, Sch Med, Dept Med, Div Gen Internal Med, 1229 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM petergro@upenn.edu NR 8 TC 2 Z9 2 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1152 EP 1153 DI 10.1001/archinternmed.2012.2724 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200011 PM 22777509 ER PT J AU Odden, MC Peralta, CA Haan, MN Covinsky, KE AF Odden, Michelle C. Peralta, Carmen A. Haan, Mary N. Covinsky, Kenneth E. TI Rethinking the Association of High Blood Pressure With Mortality in Elderly Adults The Impact of Frailty SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID OLDER-ADULTS; GAIT SPEED; TASK-FORCE; HYPERTENSION; AGE; PREVENTION; SURVIVAL; PROGRAM; DISEASE AB Background: The association of hypertension and mortality is attenuated in elderly adults. Walking speed, as a measure of frailty, may identify which elderly adults are most at risk for the adverse effects of hypertension. We hypothesized that elevated blood pressure (BP) would be associated with a greater risk of mortality in faster-, but not slower-, walking older adults. Methods: Participants included 2340 persons 65 years and older in the National Health and Nutrition Examination Survey, 1999-2000 and 2001-2002. Mortality data were linked to death certificates in the National Death Index. Walking speed was measured over a 20-ft (6 m) walk and classified as faster (>= 0.8 m/s [n=1307]), slower (n = 790), or incomplete (n = 243). Potential confounders included age, sex, race, survey year, lifestyle and physiologic variables, health conditions, and antihypertensive medication use. Results: Among the participants, there were 589 deaths through December 31, 2006. The association between BP and mortality varied by walking speed. Among faster walkers, those with elevated systolic BP (>= 140 mm Hg) had a greater adjusted risk of mortality compared with those without (hazard ratio [HR], 1.35; 95% CI, 1.03-1.77). Among slower walkers, neither elevated systolic nor diastolic BP (>= 90 mm Hg) was associated with mortality. In participants who did not complete the walk test, elevated BP was strongly and independently associated with a lower risk of death: HR, 0.38; 95% CI, 0.23-0.62 (systolic); and HR, 0.10; 95% CI, 0.01-0.81 (diastolic). Conclusions: Walking speed could be a simple measure to identify elderly adults who are most at risk for adverse outcomes related to high BP. C1 [Odden, Michelle C.] Oregon State Univ, Coll Publ Hlth & Human Sci, Corvallis, OR 97331 USA. [Peralta, Carmen A.; Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Haan, Mary N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Peralta, Carmen A.; Covinsky, Kenneth E.] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. RP Odden, MC (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, 401 Waldo Hall, Corvallis, OR 97331 USA. EM Michelle.Odden@oregonstate.edu FU American Heart Association Western States Affiliate Clinical Research Program; National Institute on Aging [K01AG039387] FX Dr Odden is supported by the American Heart Association Western States Affiliate Clinical Research Program and the National Institute on Aging (grant K01AG039387). NR 23 TC 96 Z9 98 U1 3 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1162 EP 1168 DI 10.1001/archinternmed.2012.2555 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200014 PM 22801930 ER PT J AU Quinn, MA Kats, AM Kleinman, K Bates, DW Simon, SR AF Quinn, Mariah A. Kats, Allyson M. Kleinman, Ken Bates, David W. Simon, Steven R. TI The Relationship Between Electronic Health Records and Malpractice Claims SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID PHYSICIANS; ERRORS C1 [Simon, Steven R.] VA Boston Healthcare Syst, Gen Internal Med Sect, Boston, MA 02130 USA. [Quinn, Mariah A.] Harvard Vanguard Med Associates, Dept Internal Med, Boston, MA USA. [Kleinman, Ken] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA USA. [Kats, Allyson M.; Kleinman, Ken] Harvard Univ, Sch Publ Hlth, Harvard Pilgrim Healthcare Inst, Boston, MA 02115 USA. [Bates, David W.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Quinn, Mariah A.; Bates, David W.; Simon, Steven R.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Kats, Allyson M.] Minneapolis Med Res Fdn Inc, Chron Dis Res Grp, Minneapolis, MN USA. RP Simon, SR (reprint author), VA Boston Healthcare Syst, Gen Internal Med Sect, 150 S Huntington Ave,Bldg 9,152G, Boston, MA 02130 USA. EM steven.simon2@va.gov FU AHRQ HHS [1UC1HS015397]; PHS HHS [5 T32 HP11001-19] NR 8 TC 5 Z9 5 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1187 EP 1189 DI 10.1001/archinternmed.2012.2371 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200025 PM 22733224 ER PT J AU Nakamura, K Dudzinski, DM AF Nakamura, Kenta Dudzinski, David M. TI ST-Segment Elevation in Lead aVR on the Presenting Electrocardiogram Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Nakamura, Kenta] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Dudzinski, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cardiol, Boston, MA 02114 USA. RP Nakamura, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, 55 Fruit St,GRB 740, Boston, MA 02114 USA. EM knakamura@partners.org 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 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD AUG 13 PY 2012 VL 172 IS 15 BP 1191 EP 1191 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 986TT UT WOS:000307369200029 ER PT J AU Voight, BF Peloso, GM Orho-Melander, M Frikke-Schmidt, R Barbalic, M Jensen, MK Hindy, G Holm, H Ding, EL Johnson, T Schunkert, H Samani, NJ Clarke, R Hopewell, JC Thompson, JF Li, MY Thorleifsson, G Newton-Cheh, C Musunuru, K Pirruccello, JP Saleheen, D Chen, L Stewart, AFR Schillert, A Thorsteinsdottir, U Thorgeirsson, G Anand, S Engert, JC Morgan, T Spertus, J Stoll, M Berger, K Martinelli, N Girelli, D McKeown, PP Patterson, CC Epstein, SE Devaney, J Burnett, MS Mooser, V Ripatti, S Surakka, I Nieminen, MS Sinisalo, J Lokki, ML Perola, M Havulinna, A de Faire, U Gigante, B Ingelsson, E Zeller, T Wild, P de Bakker, PIW Klungel, OH Maitland-van der Zee, AH Peters, BJM de Boer, A Grobbee, DE Kamphuisen, PW Deneer, VHM Elbers, CC Onland-Moret, NC Hofker, MH Wijmenga, C Verschuren, WMM Boer, JMA van der Schouw, YT Rasheed, A Frossard, P Demissie, S Willer, C Do, R Ordovas, JM Abecasis, GR Boehnke, M Mohlke, KL Daly, MJ Guiducci, C Burtt, NP Surti, A Gonzalez, E Purcell, S Gabriel, S Marrugat, J Peden, J Erdmann, J Diemert, P Willenborg, C Konig, IR Fischer, M Hengstenberg, C Ziegler, A Buysschaert, I Lambrechts, D Van de Werf, F Fox, KA El Mokhtari, NE Rubin, D Schrezenmeir, J Schreiber, S Schafer, A Danesh, J Blankenberg, S Roberts, R McPherson, R Watkins, H Hall, AS Overvad, K Rimm, E Boerwinkle, E Tybjaerg-Hansen, A Cupples, LA Reilly, MP Melander, O Mannucci, PM Ardissino, D Siscovick, D Elosua, R Stefansson, K O'Donnell, CJ Salomaa, V Rader, DJ Peltonen, L Schwartz, SM Altshuler, D Kathiresan, S AF Voight, Benjamin F. Peloso, Gina M. Orho-Melander, Marju Frikke-Schmidt, Ruth Barbalic, Maja Jensen, Majken K. Hindy, George Holm, Hilma Ding, Eric L. Johnson, Toby Schunkert, Heribert Samani, Nilesh J. Clarke, Robert Hopewell, Jemma C. Thompson, John F. Li, Mingyao Thorleifsson, Gudmar Newton-Cheh, Christopher Musunuru, Kiran Pirruccello, James P. Saleheen, Danish Chen, Li Stewart, Alexandre F. R. Schillert, Arne Thorsteinsdottir, Unnur Thorgeirsson, Gudmundur Anand, Sonia Engert, James C. Morgan, Thomas Spertus, John Stoll, Monika Berger, Klaus Martinelli, Nicola Girelli, Domenico McKeown, Pascal P. Patterson, Christopher C. Epstein, Stephen E. Devaney, Joseph Burnett, Mary-Susan Mooser, Vincent Ripatti, Samuli Surakka, Ida Nieminen, Markku S. Sinisalo, Juha Lokki, Marja-Liisa Perola, Markus Havulinna, Aki de Faire, Ulf Gigante, Bruna Ingelsson, Erik Zeller, Tanja Wild, Philipp de Bakker, Paul I. W. Klungel, Olaf H. Maitland-van der Zee, Anke-Hilse Peters, Bas J. M. de Boer, Anthonius Grobbee, Diederick E. Kamphuisen, Pieter W. Deneer, Vera H. M. Elbers, Clara C. Onland-Moret, N. Charlotte Hofker, Marten H. Wijmenga, Cisca Verschuren, W. M. Monique Boer, Jolanda M. A. van der Schouw, Yvonne T. Rasheed, Asif Frossard, Philippe Demissie, Serkalem Willer, Cristen Do, Ron Ordovas, Jose M. Abecasis, Goncalo R. Boehnke, Michael Mohlke, Karen L. Daly, Mark J. Guiducci, Candace Burtt, Noel P. Surti, Aarti Gonzalez, Elena Purcell, Shaun Gabriel, Stacey Marrugat, Jaume Peden, John Erdmann, Jeanette Diemert, Patrick Willenborg, Christina Koenig, Inke R. Fischer, Marcus Hengstenberg, Christian Ziegler, Andreas Buysschaert, Ian Lambrechts, Diether Van de Werf, Frans Fox, Keith A. El Mokhtari, Nour Eddine Rubin, Diana Schrezenmeir, Juergen Schreiber, Stefan Schaefer, Arne Danesh, John Blankenberg, Stefan Roberts, Robert McPherson, Ruth Watkins, Hugh Hall, Alistair S. Overvad, Kim Rimm, Eric Boerwinkle, Eric Tybjaerg-Hansen, Anne Cupples, L. Adrienne Reilly, Muredach P. Melander, Olle Mannucci, Pier M. Ardissino, Diego Siscovick, David Elosua, Roberto Stefansson, Kari O'Donnell, Christopher J. Salomaa, Veikko Rader, Daniel J. Peltonen, Leena Schwartz, Stephen M. Altshuler, David Kathiresan, Sekar TI Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study SO LANCET LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; ISCHEMIC CARDIOVASCULAR-DISEASE; ENDOTHELIAL LIPASE; BLOOD CHOLESTEROL; GENETIC-VARIANTS; ARTERY-DISEASE; LOCI; ATHEROSCLEROSIS; METAANALYSIS AB Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2.6% frequency) had higher HDL cholesterol (0.14 mmol/L higher, p=8x10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0.87, 95% CI 0.84-0.91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0.99, 95% CI 0.88-1.11, p=0.85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0.62, 95% CI 0.58-0.66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0.93, 95% CI 0.68-1.26, p=0.63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1.54, 95% CI 1.45-1.63) was concordant with that from genetic score (OR 2.13, 95% CI 1.69-2.69, p=2x10(-10)). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. C1 [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Voight, Benjamin F.] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Newton-Cheh, Christopher; O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Voight, Benjamin F.; Newton-Cheh, Christopher; Musunuru, Kiran; Pirruccello, James P.; de Bakker, Paul I. W.; Daly, Mark J.; Guiducci, Candace; Burtt, Noel P.; Surti, Aarti; Gonzalez, Elena; Purcell, Shaun; Gabriel, Stacey; Altshuler, David; Kathiresan, Sekar] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Peloso, Gina M.; Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Peloso, Gina M.; Demissie, Serkalem; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Melander, Olle] Lund Univ, Skania Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden. [Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Mol Genet Sect, Copenhagen, Denmark. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Jensen, Majken K.; Rimm, Eric] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA. [Ding, Eric L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ding, Eric L.; Rimm, Eric] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Holm, Hilma; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Johnson, Toby] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Genome Ctr, London, England. [Schunkert, Heribert; Erdmann, Jeanette; Diemert, Patrick] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Schillert, Arne; Willenborg, Christina; Koenig, Inke R.; Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Thompson, John F.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE3 9QP, Leics, England. [Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Saleheen, Danish; Danesh, John] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Chen, Li; Stewart, Alexandre F. R.; Roberts, Robert; McPherson, Ruth] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Clarke, Robert; Hopewell, Jemma C.] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Clarke, Robert; Hopewell, Jemma C.] Univ Oxford, Epidemiol Studies Unit, Oxford, England. [Peden, John; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Thorgeirsson, Gudmundur] Landspitali Univ Hosp, Div Cardiol, Dept Internal Med, Reykjavik, Iceland. [Anand, Sonia] McMaster Univ, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada. [Anand, Sonia] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Anand, Sonia] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Engert, James C.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Engert, James C.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Morgan, Thomas] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Spertus, John] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Spertus, John] Univ Missouri, Kansas City, MO 64110 USA. [Stoll, Monika] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany. [Martinelli, Nicola; Girelli, Domenico] Univ Verona, Dept Med, I-37100 Verona, Italy. [McKeown, Pascal P.; Patterson, Christopher C.] Queens Univ Belfast, Inst Clin Sci, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Epstein, Stephen E.; Devaney, Joseph; Burnett, Mary-Susan] Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. [Mooser, Vincent] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA. [Mooser, Vincent] GlaxoSmithKline, Drug Discovery, King Of Prussia, PA USA. [Ripatti, Samuli; Surakka, Ida; Nieminen, Markku S.; Peltonen, Leena] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Nieminen, Markku S.; Sinisalo, Juha] Univ Helsinki, Cent Hosp, Dept Med, Div Cardiol, Helsinki, Finland. [Lokki, Marja-Liisa] Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland. [Perola, Markus; Havulinna, Aki; Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Zeller, Tanja] Univ Main 2, Med Klin & Poliklin, Mainz, Germany. [de Faire, Ulf; Gigante, Bruna; Wild, Philipp; Blankenberg, Stefan] Karolinska Inst, Div Cardiovasc Epidemiol, Stockholm, Sweden. [de Faire, Ulf; Gigante, Bruna] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [de Bakker, Paul I. W.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Klungel, Olaf H.; Maitland-van der Zee, Anke-Hilse; Peters, Bas J. M.; de Boer, Anthonius] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, NL-3508 TC Utrecht, Netherlands. [de Bakker, Paul I. W.; Grobbee, Diederick E.; Elbers, Clara C.; Onland-Moret, N. Charlotte; van der Schouw, Yvonne T.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.; Elbers, Clara C.; Onland-Moret, N. Charlotte] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Kamphuisen, Pieter W.] Univ Groningen, Univ Med Ctr Groningen, Dept Vasc Med, NL-9713 AV Groningen, Netherlands. [Hofker, Marten H.] Univ Med Ctr Groningen, Dept Pathol & Med Biol, NL-9713 AV Groningen, Netherlands. [Wijmenga, Cisca] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands. [Deneer, Vera H. M.] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands. [Verschuren, W. M. Monique] Natl Inst Publ Hlth & Environm, Ctr Prevent & Hlth Serv Res, NL-3720 BA Bilthoven, Netherlands. [Boer, Jolanda M. A.] Natl Inst Publ Hlth & Environm, Ctr Nutr & Hlth, NL-3720 BA Bilthoven, Netherlands. [Willer, Cristen; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Rasheed, Asif; Frossard, Philippe] Ctr Noncommunicable Dis, Karachi, Pakistan. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer United States Dept Agr Human Nutr, Res Ctr Aging, Boston, MA 02111 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc, Dept Cardiovasc Epidemiol & Populat Genet, Madrid, Spain. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Marrugat, Jaume; Elosua, Roberto] IMIM, Barcelona, Spain. [Elosua, Roberto] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Fischer, Marcus; Hengstenberg, Christian] Univ Klinikum Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Buysschaert, Ian; Lambrechts, Diether] Univ Hosp Gasthuisberg, Vesalius Res Ctr, VIB KU Leuven, B-3000 Louvain, Belgium. [Buysschaert, Ian; Lambrechts, Diether; Van de Werf, Frans] Univ Hosp Gasthuisberg, Dept Cardiol, B-3000 Louvain, Belgium. [Fox, Keith A.] Univ Edinburgh, Div Med & Radiol Sci, Edinburgh, Midlothian, Scotland. [El Mokhtari, Nour Eddine; Schreiber, Stefan; Schaefer, Arne] Univ Kiel, Inst Klin & Mol Biol, Kiel, Germany. [Rubin, Diana] Univ Klinikum Schleswig Holstein, Med Klin 1, Kiel, Germany. [Schrezenmeir, Juergen] Max Rubner Inst, Inst Physiol & Biochem Ernahrung, Kiel, Germany. [Hall, Alistair S.] Univ Leeds, LIGHT Inst, Fac Med & Hlth, Leeds, W Yorkshire, England. [Hall, Alistair S.] Univ Leeds, LIMM Res Inst, Fac Med & Hlth, Leeds, W Yorkshire, England. [Overvad, Kim] Aarhus Univ, Sch Publ Hlth, Dept Epidemiol, Aarhus, Denmark. [Tybjaerg-Hansen, Anne] Bispebjerg Hosp, Copenhagen City Heart Study, Copenhagen, Denmark. [Mannucci, Pier M.] IRCCS Fdn Ca Granda Osped Maggiore Policlin, Dept Internal Med & Med Special, Milan, Italy. [Ardissino, Diego] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Siscovick, David; Schwartz, Stephen M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Siscovick, David; Schwartz, Stephen M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Peltonen, Leena] Wellcome Trust Sanger Inst Cambridge, Cambridge, England. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Kathiresan, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org RI Erdmann, Jeanette/P-7513-2014; Ripatti, Samuli/H-9446-2014; Martinelli, Nicola/J-5622-2016; Klungel, Olaf/I-9563-2016; Konig, Inke/A-4544-2009; Hindy, George/H-1864-2016; Wijmenga, Cisca/D-2173-2009; Verdrengh, Evelien/H-4571-2012; van der Schouw, Yvonne/F-8327-2014; Willenborg, Christina/D-2668-2012; Onland-Moret, N. Charlotte/G-9185-2011; Gigante, Bruna/I-9252-2012; Morgan, Tom/C-3478-2012; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Mannucci, Pier/C-3102-2014; Schreiber, Stefan/B-6748-2008; Grobbee, Diederick/C-7651-2014 OI Abecasis, Goncalo/0000-0003-1509-1825; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; Wijmenga, Cisca/0000-0002-5635-1614; Ziegler, Andreas/0000-0002-8386-5397; Schwartz, Stephen/0000-0001-7499-8502; Marrugat, Jaume/0000-0003-3320-554X; Watkins, Hugh/0000-0002-5287-9016; Sinisalo, Juha/0000-0002-0169-5137; Ripatti, Samuli/0000-0002-0504-1202; Martinelli, Nicola/0000-0001-6465-5119; Cupples, L. Adrienne/0000-0003-0273-7965; Van de Werf, Frans/0000-0001-9479-7767; Willer, Cristen/0000-0001-5645-4966; ELOSUA, ROBERTO/0000-0001-8235-0095; Ding, Eric/0000-0002-5881-8097; Johnson, Toby/0000-0002-5998-3270; Hindy, George/0000-0002-7257-9299; van der Schouw, Yvonne/0000-0002-4605-435X; Willenborg, Christina/0000-0001-5217-6882; Altshuler, David/0000-0002-7250-4107; de Bakker, Paul/0000-0001-7735-7858; Schreiber, Stefan/0000-0003-2254-7771; Grobbee, Diederick/0000-0003-4472-4468 FU US National Institutes of Health; Wellcome Trust; European Union; British Heart Foundation; German Federal Ministry of Education and Research; Pfizer; Shire Therapeutics; Alnylam Pharmaceuticals; Novartis; Boehringer Ingelheim; German Migraine & Headache Society (DMKG); Berlin Chemie; Boots Healthcare; GlaxoSmithKline; McNeil Pharma; MSD Sharp Dohme FX US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.; own stock options in deCODE Genetics, or both. SK serves on a scientific advisory board for Merck and has received research grants from Pfizer, Shire Therapeutics, and Alnylam Pharmaceuticals. HS serves on scientific advisory boards for Merck, Servier, and AstraZeneca and received lecture fees from Pfizer, Novartis, and Boehringer Ingelheim. The collection of clinical and sociodemographic data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from AstraZeneca, Berlin Chemie, Boots Healthcare, GlaxoSmithKline, McNeil Pharma (formerly Woelm Pharma), MSD Sharp & Dohme, and Pfizer to the University of Muenster. VM, DW, CK, and MW are full-time employees of GlaxoSmithKline. All other authors declare that they have no conflicts of interest. NR 36 TC 720 Z9 729 U1 9 U2 96 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 AUG 11 PY 2012 VL 380 IS 9841 BP 572 EP 580 DI 10.1016/S0140-6736(12)60312-2 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 988SQ UT WOS:000307511400030 PM 22607825 ER PT J AU Cudaback, E Li, XW Yang, Y Yoo, T Montine, KS Craft, S Montine, TJ Keene, CD AF Cudaback, Eiron Li, Xianwu Yang, Yue Yoo, Thomas Montine, Kathleen S. Craft, Suzanne Montine, Thomas J. Keene, Christopher Dirk TI Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation SO JOURNAL OF NEUROINFLAMMATION LA English DT Article DE ApoE; ApoC-I; Alzheimer's disease; Cerebrospinal fluid; Targeted replacement mice ID INNATE IMMUNE-RESPONSE; ONSET ALZHEIMERS-DISEASE; CENTRAL-NERVOUS-SYSTEM; TOLL-LIKE RECEPTORS; TARGETED REPLACEMENT; AMYLOID-BETA; GENE-CLUSTER; MEMORY FUNCTIONS; KNOCKOUT MICE; A-BETA AB Background: Inheritance of the human epsilon 4 allele of the apolipoprotein (apo) E gene (APOE) significantly increases the risk of developing Alzheimer's disease (AD), in addition to adversely influencing clinical outcomes of other neurologic diseases. While apoE isoforms differentially interact with amyloid beta (A beta), a pleiotropic neurotoxin key to AD etiology, more recent work has focused on immune regulation in AD pathogenesis and on the mechanisms of innate immunomodulatory effects associated with inheritance of different APOE alleles. APOE genotype modulates expression of proximal genes including APOC1, which encodes a small apolipoprotein that is associated with A beta plaques. Here we tested the hypothesis that APOE-genotype dependent innate immunomodulation may be mediated in part by apoC-I. Methods: ApoC-I concentration in cerebrospinal fluid from control subjects of differing APOE genotypes was quantified by ELISA. Real-time PCR and ELISA were used to analyze apoC-I mRNA and protein expression, respectively, in liver, serum, cerebral cortex, and cultured primary astrocytes derived from mice with targeted replacement of murine APOE for human APOE epsilon 3 or epsilon 4. ApoC-I direct modulation of innate immune activity was investigated in cultured murine primary microglia and astrocytes, as well as human differentiated macrophages, using specific toll-like receptor agonists LPS and PIC as well as A beta. Results: ApoC-I levels varied with APOE genotype in humans and in APOE targeted replacement mice, with epsilon 4 carriers showing significantly less apoC-I in both species. ApoC-I potently reduced pro-inflammatory cytokine secretion from primary murine microglia and astrocytes, and human macrophages, stimulated with LPS, PIC, or A beta. Conclusions: ApoC-I is immunosuppressive. Our results illuminate a novel potential mechanism for APOE genotype risk for AD; one in which patients with an epsilon 4 allele have decreased expression of apoC-I resulting in increased innate immune activity. C1 [Cudaback, Eiron; Li, Xianwu; Yang, Yue; Yoo, Thomas; Montine, Kathleen S.; Montine, Thomas J.; Keene, Christopher Dirk] Univ Washington, Dept Pathol, Seattle, WA 98104 USA. [Craft, Suzanne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Craft, Suzanne] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. RP Keene, CD (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98104 USA. EM cdkeene@uw.edu RI Keene, Christopher/N-1806-2015 FU NIH [AG05136, ES16754, AG10880, T32AG00258] FX The authors wish to thank Meilany Wijaya and Amy Look for technical assistance, and Carol Arnold for managerial support. We also thank Dr. Nobuyo Maeda for the generous gift of apoE2-, apoE3-, and apoE4-targeted replacement mice, and Dr. Cecilia Giachelli for providing the human THP-1 cell line. This work was supported by NIH grants AG05136, ES16754, AG10880, and T32AG00258 (EC). NR 60 TC 10 Z9 10 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD AUG 10 PY 2012 VL 9 AR 192 DI 10.1186/1742-2094-9-192 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 033NA UT WOS:000310802900001 PM 22883744 ER PT J AU Singh, N Singh, MP Wylie, BJ Hussain, M Kojo, YA Shekhar, C Sabin, L Desai, M Udhayakumar, V Hamer, DH AF Singh, Neeru Singh, Mrigendra P. Wylie, Blair J. Hussain, Mobassir Kojo, Yeboah A. Shekhar, Chander Sabin, Lora Desai, Meghna Udhayakumar, V. Hamer, Davidson H. TI Malaria prevalence among pregnant women in two districts with differing endemicity in Chhattisgarh, India SO MALARIA JOURNAL LA English DT Article DE Pregnancy; Malaria; India; Plasmodium falciparum; Plasmodium vivax; Anaemia; Low birth weight ID VERBAL AUTOPSIES; TRANSMISSION; EPIDEMIOLOGY; DEATHS; BURDEN AB Background: In India, malaria is not uniformly distributed. Chhattisgarh is a highly malarious state where both Plasmodium falciparum and Plasmodium vivax are prevalent with a preponderance of P. falciparum. Malaria in pregnancy (MIP), especially when caused by P. falciparum, poses substantial risk to the mother and foetus by increasing the risk of foetal death, prematurity, low birth weight (LBW), and maternal anaemia. These risks vary between areas with stable and unstable transmission. The specific objectives of this study were to determine the prevalence of malaria, its association with maternal and birth outcomes, and use of anti-malarial preventive measures for development of evidence based interventions to reduce the burden of MIP. Methods: A cross-sectional study of pregnant women presenting to antenatal clinics (ANC) or delivery units (DU), or hospitalized for non-obstetric illness was conducted over 12 months in high (Bastar) and low (Rajnandgaon) transmission districts in Chhattisgarh state. Intensity of transmission was defined on the basis of slide positivity rates with a high proportion due to P. falciparum. In each district, a rural and an urban health facility was selected. Results: Prevalence of peripheral parasitaemia was low: 1.3% (35/2696) among women at ANCs and 1.9% at DUs (19/1025). Peripheral parasitaemia was significantly more common in Bastar (2.8%) than in Rajnandgaon (0.1%) (p < 0.0001). On multivariate analysis of ANC participants, residence in Bastar district (stable malaria transmission) was strongly associated with peripheral parasitaemia (adjusted OR [aOR] 43.4; 95% CI, 5.6-335.2). Additional covariates associated with parasitaemia were moderate anaemia (aOR 3.7; 95% CI 1.8-7.7), fever within the past week (aOR 3.2; 95% CI 1.2-8.6), and lack of formal education (aOR 4.6; 95% CI 2.0-10.7). Similarly, analysis of DU participants revealed that moderate anaemia (aOR 2.5; 95% CI 1.1-5.4) and fever within the past week (aOR 5.8; 95% CI 2.4-13.9) were strongly associated with peripheral and/or placental parasitaemia. Malaria-related admissions were more frequent among pregnant women in Bastar, the district with greater malaria prevalence (51% vs. 11%, p < 0.0001). Conclusions: Given the overall low prevalence of malaria, a strategy of enhanced anti-vector measures coupled with intermittent screening and targeted treatment during pregnancy should be considered for preventing malaria-associated morbidity in central India. C1 [Singh, Neeru] Reg Med Res Ctr Tribals, Jabalpur, Madhya Pradesh, India. [Singh, Neeru; Singh, Mrigendra P.; Hussain, Mobassir] Natl Inst Malaria Res Field Stn, Jabalpur, Madhya Pradesh, India. [Wylie, Blair J.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. [Kojo, Yeboah A.; Sabin, Lora; Hamer, Davidson H.] Boston Univ, Ctr Global Hlth & Dev, Boston, MA 02215 USA. [Kojo, Yeboah A.; Sabin, Lora; Hamer, Davidson H.] Boston Univ, Sch Publ Hlth, Dept Int Hlth, Boston, MA USA. [Shekhar, Chander] Indian Council Med Res, Dept Reprod Hlth & Nutr, New Delhi, India. [Desai, Meghna; Udhayakumar, V.] Ctr Dis Control & Prevent, Malaria Branch, Div Parasit Dis & Malaria, Ctr Global Hlth, Atlanta, GA USA. [Hamer, Davidson H.] Boston Univ, Sch Med, Dept Med, Infect Dis Sect, Boston, MA 02118 USA. [Hamer, Davidson H.] Zambia Ctr Appl Hlth Res & Dev, Lusaka, Zambia. RP Singh, N (reprint author), Reg Med Res Ctr Tribals, Jabalpur, Madhya Pradesh, India. EM neeru.singh@gmail.com OI Hamer, Davidson/0000-0002-4700-1495 FU Indo-U.S. Collaborative Network; Indian Council for Medical Research (ICMR); National Institute of Child Health and Development [1 R03 HD52167-01] FX This work was supported by the Indo-U.S. Collaborative Network with funding from the Indian Council for Medical Research (ICMR) and the National Institute of Child Health and Development (1 R03 HD52167-01). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the ICMR or the National Institute of Health. NR 28 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 10 PY 2012 VL 11 AR 274 DI 10.1186/1475-2875-11-274 PG 14 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 033HZ UT WOS:000310786300001 PM 22882903 ER PT J AU Saboo, SS Krajewski, KM Shinagare, AB Jagannathan, JP Hornick, JL Ramaiya, N AF Saboo, Sachin Shyamsunder Krajewski, Katherine M. Shinagare, Atul B. Jagannathan, Jyothi P. Hornick, Jason L. Ramaiya, Nikhil TI Imaging features of primary extranodal histiocytic sarcoma: report of two cases and a review of the literature SO CANCER IMAGING LA English DT Review DE Histiocytic sarcoma; MRI; CT; [F-18]FDG-PET/CT ID LYMPHOMA AB Histiocytic sarcoma is an extremely rare and aggressive malignancy of bone marrow origin that occurs in lymph nodes, skin, and the gastrointestinal tract. We report on the imaging features of two cases of primary histiocytic sarcoma, one in the retroperitoneum causing a tumor-bowel fistula and another with primary bone involvement. C1 [Saboo, Sachin Shyamsunder] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02145 USA. RP Saboo, SS (reprint author), Dana Farber Canc Inst, Dept Radiol, 44 Binney St, Boston, MA 02145 USA. EM ssaboo@partners.org NR 13 TC 4 Z9 4 U1 0 U2 1 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD AUG 10 PY 2012 VL 12 IS 1 BP 253 EP 258 DI 10.1102/1470-7330.2012.0029 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 994PT UT WOS:000307944000003 PM 22935131 ER PT J AU Liu, WJ Liu, YT Challa, P Herndon, LW Wiggs, JL Girkin, CA Allingham, RR Hauser, MA AF Liu, Wenjing Liu, Yutao Challa, Pratap Herndon, Leon W. Wiggs, Janey L. Girkin, Christopher A. Allingham, R. Rand Hauser, Michael A. TI Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma SO MOLECULAR VISION LA English DT Article ID NORMAL-TENSION GLAUCOMA; BALTIMORE EYE SURVEY; VISUAL IMPAIRMENT; GENE; IDENTIFICATION; TIGR/MYOCILIN; PROTEIN; ADULT; POAG; OPTINEURIN AB Purpose: Mutations in the myocilin gene (MYOC) are associated with primary open-angle glaucoma (POAG) in many different populations. This study represents the first large survey of MYOC mutations in an African American population. Methods: We recruited 529 African American subjects with POAG and 270 African American control subjects in this study. A complete eye examination and blood collection was performed in all study subjects. Genomic DNA was extracted. The entire coding sequence of MYOC was amplified and sequenced using the Sanger method. Identified MYOC variants were compared with previously reported MYOC mutations. Results: We identified a total of 29 MYOC variants including six potential MYOC mutations. Two mutations (Thr209Asn and Leu215Gln) are novel and are found only in cases and no controls. We also identified four previously reported MYOC mutations in cases and no controls (Tyr453MetfsX11, Gln368X, Thr377Met, and Ser393Arg). The overall frequency of glaucoma-causing MYOC mutations in our African American population with POAG was 1.4%. Conclusions: We identified two novel probable glaucoma-causing MYOC mutations (Thr209Asn and Leu215Gln). This study indicates that, despite the high prevalence of POAG, MYOC mutations are rare in the African American population. C1 [Liu, Wenjing; Liu, Yutao; Hauser, Michael A.] Duke Univ, Ctr Human Genet, Med Ctr, Durham, NC 27710 USA. [Liu, Yutao; Challa, Pratap; Herndon, Leon W.; Allingham, R. Rand; Hauser, Michael A.] Duke Univ, Ctr Eye, Dept Ophthalmol, Durham, NC 27710 USA. [Wiggs, Janey L.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Wiggs, Janey L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Girkin, Christopher A.] Univ Alabama Birmingham, Dept Ophthalmol, Birmingham, AL 35294 USA. RP Hauser, MA (reprint author), Duke Univ, Ctr Human Genet, Med Ctr, DUMC Box 3445, Durham, NC 27710 USA. EM mike.hauser@duke.edu FU National Institutes of Health (NIH) [R01EY013315, R01EY019126, R03EY014939, R01EY015543, R01EY015872, P30EY014104]; Glaucoma Research Foundation; National Glaucoma Research of American Health Assistance Foundation; Glaucoma Foundation; Research to Prevent Blindness; EyeSight Foundation of Alabama; Duke University's CTSA grant from NCRR/NIH [TL1RR024126] FX The authors would like to thank all of the study participants and study staff at the Duke Center for Human Genetics and the Department of Ophthalmology at Duke University Eye Center for their assistance. We would also like to thank Mr. Benjamin Whigham for his assistance in the sequence analysis process. This work is supported by National Institutes of Health (NIH) grants R01EY013315 (MAH), R01EY019126 (M.A.H.), R03EY014939 (R.R.A.), and R01EY015543 (R.R.A.), R01EY015872 (J.L.W.), and P30EY014104 (Core support at the Massachusetts Eye and Ear Infirmary), Glaucoma Research Foundation (Y.L.), National Glaucoma Research of American Health Assistance Foundation (Y.L.), The Glaucoma Foundation (Y.L.), Research to Prevent Blindness (C.A.G.), and EyeSight Foundation of Alabama (C.A.G.). This research was also supported by Duke University's CTSA grant TL1RR024126 from NCRR/NIH. NR 45 TC 8 Z9 8 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD AUG 10 PY 2012 VL 18 IS 237-39 BP 2241 EP 2246 PG 6 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 994SY UT WOS:000307953400001 PM 22933836 ER PT J AU Duda, DM Olszewski, JL Tron, AE Hammel, M Lambert, LJ Waddell, MB Mittag, T DeCaprio, JA Schulman, BA AF Duda, David M. Olszewski, Jennifer L. Tron, Adriana E. Hammel, Michal Lambert, Lester J. Waddell, M. Brett Mittag, Tanja DeCaprio, James A. Schulman, Brenda A. TI Structure of a Glomulin-RBX1-CUL1 Complex: Inhibition of a RING E3 Ligase through Masking of Its E2-Binding Surface SO MOLECULAR CELL LA English DT Article ID MITOTIC CHECKPOINT COMPLEX; SCFCDC4 UBIQUITIN LIGASE; GLOMUVENOUS MALFORMATIONS; SUBSTRATE RECOGNITION; CONFORMATIONAL-CHANGE; ALLOSTERIC INHIBITOR; SCF; ACTIVATION; GLOMULIN; BINDING AB The approximately 300 human cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1's RING domain, regulates the RBX1-CUL1-containing SCFFBW7 complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains the basis for GLMN's selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation, whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition. C1 [Duda, David M.; Olszewski, Jennifer L.; Lambert, Lester J.; Mittag, Tanja; Schulman, Brenda A.] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA. [Duda, David M.; Schulman, Brenda A.] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA. [Waddell, M. Brett] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Tron, Adriana E.; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Tron, Adriana E.; DeCaprio, James A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Tron, Adriana E.; DeCaprio, James A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hammel, Michal] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA. RP Schulman, BA (reprint author), St Jude Childrens Res Hosp, Dept Biol Struct, 332 N Lauderdale St, Memphis, TN 38105 USA. EM brenda.schulman@stjude.org FU ALSAC; PHS [5P30CA021765, R01GM069530, RO1CA93804, R01CA63113, P01CA050661]; Pew Charitable Trust; International Human Frontier Science Program; NIH NCRR [RR-15301]; US DOE [DE-AC02-05CH11231, W-31-109-ENG-38] FX This work was supported by ALSAC, PHS grants 5P30CA021765, R01GM069530 (B.A.S.), RO1CA93804, R01CA63113, and P01CA050661 (J.A.D.), and fellowships from the Pew Charitable Trust and the International Human Frontier Science Program (A.E.T.). B.A.S. is an Investigator of the Howard Hughes Medical Institute. We are grateful to D.C. Scott, D.W. Miller, D.J. Miller Poison, N. Brown, P. Soule, C.O. Rock, J.W. Harper, and E.J. Enemark for advice and/or reagents; I. Kurinov and C. Ralston for synchrotron assistance; P. Rodrigues and R. Cassell for peptide synthesis and purification; S. Bozeman and J. Bollinger for administrative/computational support; and R. Clubb for providing the sortase clone. NECAT is supported by NIH NCRR RR-15301, APS by US DOE W-31-109-ENG-38, ALS by US DOE DE-AC02-05CH11231. SAXS at the SIBYLS beamline BL12.3.1 of ALS is supported in part by the US DOE Integrated Diffraction Analysis Technologies (IDAT). NR 63 TC 21 Z9 21 U1 2 U2 14 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 AUG 10 PY 2012 VL 47 IS 3 BP 371 EP 382 DI 10.1016/j.molcel.2012.05.044 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 988IT UT WOS:000307484600007 PM 22748924 ER PT J AU Ciccia, A Nimonkar, AV Hu, YD Hajdu, I Achar, YJ Izhar, L Petit, SA Adamson, B Yoon, JC Kowalczykowski, SC Livingston, DM Haracska, L Elledge, SJ AF Ciccia, Alberto Nimonkar, Amitabh V. Hu, Yiduo Hajdu, Ildiko Achar, Yathish Jagadheesh Izhar, Lior Petit, Sarah A. Adamson, Britt Yoon, John C. Kowalczykowski, Stephen C. Livingston, David M. Haracska, Lajos Elledge, Stephen J. TI Polyubiquitinated PCNA Recruits the ZRANB3 Translocase to Maintain Genomic Integrity after Replication Stress SO MOLECULAR CELL LA English DT Article ID BLOOMS-SYNDROME HELICASE; HOMOLOGOUS RECOMBINATION; DNA-REPLICATION; FORK REVERSAL; POSTREPLICATION REPAIR; ANNEALING HELICASE; UBIQUITIN; BINDING; PROTEIN; WRNIP1 AB Completion of DNA replication after replication stress depends on PCNA, which undergoes monoubiquitination to stimulate direct bypass of DNA lesions by specialized DNA polymerases or is polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Here we report that the ZRANB3 translocase, a SNF2 family member related to the SIOD disorder SMARCAL1 protein, is recruited by polyubiquitinated PCNA to promote fork restart following replication arrest. ZRANB3 depletion in mammalian cells results in an increased frequency of sister chromatid exchange and DNA damage sensitivity after treatment with agents that cause replication stress. Using in vitro biochemical assays, we show that recombinant ZRANB3 remodels DNA structures mimicking stalled replication forks and disassembles recombination intermediates. We therefore propose that ZRANB3 maintains genomic stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. C1 [Ciccia, Alberto; Hu, Yiduo; Hajdu, Ildiko; Izhar, Lior; Petit, Sarah A.; Adamson, Britt; Yoon, John C.; Livingston, David M.; Elledge, Stephen J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ciccia, Alberto; Hajdu, Ildiko; Izhar, Lior; Adamson, Britt; Yoon, John C.; Elledge, Stephen J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Howard Hughes Med Inst,Div Genet, Boston, MA 02115 USA. [Nimonkar, Amitabh V.; Kowalczykowski, Stephen C.] Univ Calif Davis, Dept Microbiol, Davis, CA 95616 USA. [Nimonkar, Amitabh V.; Kowalczykowski, Stephen C.] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA 95616 USA. [Hu, Yiduo; Petit, Sarah A.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Achar, Yathish Jagadheesh; Haracska, Lajos] Hungarian Acad Sci, Biol Res Ctr, Inst Genet, H-6726 Szeged, Hungary. RP Elledge, SJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu FU EMBO; U.S. Department of Defense [W81XWH-09-1-0632]; National Institute of Health; National Cancer Institute [GM62653]; Howard Hughes Medical Institute [55005612]; Hungarian Science Foundation [OTKA 77495, TAMOP-4.2.2/08/1] FX We thank Andrea Bredemeyer, Artyom Alekseyenko, Satya Prakash, and Jung-Hoon Yoon for help and advice and Alan Lehmann for reagents. A.C. and I.H. are recipients of EMBO long-term fellowships. Y.H. was supported by a U.S. Department of Defense postdoctoral fellowship award (W81XWH-09-1-0632). This work was supported by grants from the National Institute of Health and the National Cancer Institute to S.J.E., D.M.L., J.C.Y., and S.C.K. (grant GM62653) and by Howard Hughes Medical Institute Grant 55005612 and Hungarian Science Foundation Grants OTKA 77495 and TAMOP-4.2.2/08/1 to L.H. S.J.E. is a Howard Hughes Medical Institute investigator. NR 52 TC 70 Z9 72 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 AUG 10 PY 2012 VL 47 IS 3 BP 396 EP 409 DI 10.1016/j.molcel.2012.05.024 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 988IT UT WOS:000307484600009 PM 22704558 ER PT J AU Dufresne, SF Datta, K Li, XM Dadachova, E Staab, JF Patterson, TF Feldmesser, M Marr, KA AF Dufresne, Simon F. Datta, Kausik Li, Xinming Dadachova, Ekaterina Staab, Janet F. Patterson, Thomas F. Feldmesser, Marta Marr, Kieren A. TI Detection of Urinary Excreted Fungal Galactomannan-like Antigens for Diagnosis of Invasive Aspergillosis SO PLOS ONE LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; LATEX AGGLUTINATION-TEST; ENZYME-IMMUNOASSAY; PULMONARY ASPERGILLOSIS; NEUTROPENIC PATIENTS; INFECTED-RABBITS; FUMIGATUS; SERUM; PCR; SAMPLES AB Mortality associated with invasive aspergillosis (IA) remains high, partly because of delayed diagnosis. Detection of microbial exoantigens, released in serum and other body fluids during infection, may help timely diagnosis. In course of IA, Aspergillus galactomannan (GM), a well established polysaccharide biomarker, is released in body fluids including urine. Urine is an abundant, safely collected specimen, well-suited for point-of-care (POC) testing, which could play an increasing role in screening for early disease. Our main objective was to demonstrate GM antigenuria as a clinically relevant biological phenomenon in IA and establish proof-of-concept that it could be translated to POC diagnosis. Utilizing a novel IgM monoclonal antibody (MAb476) that recognizes GM-like antigens from Aspergillus and other molds, we demonstrated antigenuria in an experimental animal IA model (guinea pig), as well as in human patients. In addition, we investigated the chemical nature of the urinary excreted antigen in human samples, characterized antigen detection in urine by immunoassays, described a putative assay inhibitor in urine, and indicated means of alleviation of the inhibition. We also designed and used a lateral flow immunochromatographic assay to detect urinary excreted antigen in a limited number of IA patient urine samples. In this study, we establish that POC diagnosis of IA based on urinary GM detection is feasible. Prospective studies will be necessary to establish the performance characteristics of an optimized device and define its optimal clinical use. C1 [Dufresne, Simon F.; Datta, Kausik; Staab, Janet F.; Marr, Kieren A.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Marr, Kieren A.] Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Li, Xinming; Dadachova, Ekaterina; Feldmesser, Marta] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Patterson, Thomas F.] S Texas Vet Healthcare Syst, San Antonio, TX USA. [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Dufresne, Simon F.] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada. [Li, Xinming] China Med Univ, Shenyang, Peoples R China. RP Dufresne, SF (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. EM kmarr4@jhmi.edu RI Dadachova, Ekaterina/I-7838-2013; Datta, Kausik/A-2879-2016 OI Datta, Kausik/0000-0001-8666-143X FU Johns Hopkins Accelerated Translational Incubator Pilot (ATIP) program; National Institutes of Health [AI065745, AI060507]; National Institute of Allergy and Infectious Disease [AI30041]; Hopital Maisonneuve-Rosemont and Universite de Montreal FX This work was supported by the Johns Hopkins Accelerated Translational Incubator Pilot (ATIP) program grant to JFS; National Institutes of Health [R21 grant AI065745 to MF, grant AI060507 to ED and National Institute of Allergy and Infectious Disease N01 Contract AI30041 to TFP]; and Hopital Maisonneuve-Rosemont and Universite de Montreal [fellowship grant to SFD]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 12 Z9 14 U1 0 U2 10 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 AUG 10 PY 2012 VL 7 IS 8 AR e42736 DI 10.1371/journal.pone.0042736 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 986XO UT WOS:000307380900063 PM 22900046 ER PT J AU Korin, N Kanapathipillai, M Matthews, BD Crescente, M Brill, A Mammoto, T Ghosh, K Jurek, S Bencherif, SA Bhatta, D Coskun, AU Feldman, CL Wagner, DD Ingber, DE AF Korin, Netanel Kanapathipillai, Mathumai Matthews, Benjamin D. Crescente, Marilena Brill, Alexander Mammoto, Tadanori Ghosh, Kaustabh Jurek, Samuel Bencherif, Sidi A. Bhatta, Deen Coskun, Ahmet U. Feldman, Charles L. Wagner, Denisa D. Ingber, Donald E. TI Shear-Activated Nanotherapeutics for Drug Targeting to Obstructed Blood Vessels SO SCIENCE LA English DT Article ID VON-WILLEBRAND-FACTOR; ACUTE ISCHEMIC-STROKE; PLASMINOGEN-ACTIVATOR; PLATELET-AGGREGATION; THROMBUS FORMATION; WALL SHEAR; NANOPARTICLES; FIBRINOLYSIS; STABILITY; STENOSIS AB Obstruction of critical blood vessels due to thrombosis or embolism is a leading cause of death worldwide. Here, we describe a biomimetic strategy that uses high shear stress caused by vascular narrowing as a targeting mechanism-in the same way platelets do-to deliver drugs to obstructed blood vessels. Microscale aggregates of nanoparticles were fabricated to break up into nanoscale components when exposed to abnormally high fluid shear stress. When coated with tissue plasminogen activator and administered intravenously in mice, these shear-activated nanotherapeutics induce rapid clot dissolution in a mesenteric injury model, restore normal flow dynamics, and increase survival in an otherwise fatal mouse pulmonary embolism model. This biophysical strategy for drug targeting, which lowers required doses and minimizes side effects while maximizing drug efficacy, offers a potential new approach for treatment of life-threatening diseases that result from acute vascular occlusion. C1 [Korin, Netanel; Kanapathipillai, Mathumai; Bencherif, Sidi A.; Ingber, Donald E.] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Matthews, Benjamin D.; Mammoto, Tadanori; Ghosh, Kaustabh; Jurek, Samuel; Ingber, Donald E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Vasc Biol Program,Dept Pathol, Boston, MA 02115 USA. [Matthews, Benjamin D.; Mammoto, Tadanori; Ghosh, Kaustabh; Jurek, Samuel; Ingber, Donald E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Surg, Boston, MA 02115 USA. [Matthews, Benjamin D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Med, Boston, MA 02115 USA. [Crescente, Marilena; Brill, Alexander; Wagner, Denisa D.] Childrens Hosp Boston, Program Cellular & Mol Med, Immune Dis Inst, Boston, MA 02115 USA. [Crescente, Marilena; Brill, Alexander; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Bencherif, Sidi A.; Bhatta, Deen; Ingber, Donald E.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Coskun, Ahmet U.] Northeastern Univ, Boston, MA 02115 USA. [Feldman, Charles L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Ingber, DE (reprint author), Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. EM don.ingber@wyss.harvard.edu OI BENCHERIF, SIDI/0000-0002-7704-5608 FU U.S. Department of Defense [BC074986]; Novartis Pharmaceuticals; Boston Scientific; Wyss Institute for Biologically Inspired Engineering at Harvard University; Wyss Technology Development Fellowship FX We thank D. Huh, K. Roberts, and R. F. Valentini for helpful comments and K. Johnson and D. Stanton for help with the graphics. This work was supported by a U.S. Department of Defense Breast Cancer Innovator award BC074986 (to D. E. I.), grants from Novartis Pharmaceuticals and Boston Scientific (to C. L. F. and A. U. C.), and the Wyss Institute for Biologically Inspired Engineering at Harvard University. N.K. is a recipient of a Wyss Technology Development Fellowship. Harvard University and the authors (D. E. I., N.K., M.K.) have filed two patents related to this work: (i) Shear-Activated Nanotherapeutics for Drug Targeting (patent application pending) and (ii) Shear Controlled Release for Stenotic Lesions and Thrombolytic Therapies (patent application pending WO 2012/074588). NR 25 TC 125 Z9 128 U1 20 U2 180 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 AUG 10 PY 2012 VL 337 IS 6095 BP 738 EP 742 DI 10.1126/science.1217815 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 986PE UT WOS:000307354500056 PM 22767894 ER PT J AU Sheth, SA Mian, MK Patel, SR Asaad, WF Williams, ZM Dougherty, DD Bush, G Eskandar, EN AF Sheth, Sameer A. Mian, Matthew K. Patel, Shaun R. Asaad, Wael F. Williams, Ziv M. Dougherty, Darin D. Bush, George Eskandar, Emad N. TI Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation SO NATURE LA English DT Article ID MULTISOURCE INTERFERENCE TASK; PREFRONTAL CORTEX; COGNITIVE CONTROL; ERROR-LIKELIHOOD; FRONTAL-CORTEX; CONFLICT; PERFORMANCE; INFORMATION; ACTIVATION; ADJUSTMENT AB The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making(1), monitoring for conflict between competing responses(2) and predicting task difficulty(3). Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect(2,4), is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses. C1 [Sheth, Sameer A.; Mian, Matthew K.; Patel, Shaun R.; Williams, Ziv M.; Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Nayef Al Rodhan Labs, Boston, MA 02114 USA. [Patel, Shaun R.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Asaad, Wael F.] Brown Univ, Alpert Med Sch, Dept Neurosurg, Providence, RI 02912 USA. [Asaad, Wael F.] Rhode Isl Hosp, Providence, RI 02912 USA. [Dougherty, Darin D.; Bush, George] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Eskandar, EN (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Nayef Al Rodhan Labs, Boston, MA 02114 USA. EM eeskandar@partners.org RI Asaad, Wael/I-8485-2012 OI Asaad, Wael/0000-0003-4406-9096 FU National Science Foundation [IOB 0645886]; National Institutes of Health [NEI 1R01EY017658-01A1, NIDA 1R01NS063249, MH086400, R25 NS065743]; Klingenstein Foundation; Howard Hughes Medical Institute; Sackler Scholar Programme in Psychobiology; Centers for Disease Control [5 R01 DP000339]; Benson-Henry Institute at Massachusetts General Hospital for Mind-Body Medicine; David Judah Fund; McIngvale Fund; Center for Functional Neuroimaging Technologies [P41RR14075] FX This work was supported by grants from the National Science Foundation (IOB 0645886), the National Institutes of Health (NEI 1R01EY017658-01A1, NIDA 1R01NS063249, NIMH Conte Award MH086400 and R25 NS065743), the Klingenstein Foundation, the Howard Hughes Medical Institute, the Sackler Scholar Programme in Psychobiology, the Centers for Disease Control (5 R01 DP000339), the Benson-Henry Institute at Massachusetts General Hospital for Mind-Body Medicine, the David Judah Fund, the McIngvale Fund, and the Center for Functional Neuroimaging Technologies (P41RR14075). NR 29 TC 126 Z9 127 U1 8 U2 46 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 9 PY 2012 VL 488 IS 7410 BP 218 EP + DI 10.1038/nature11239 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 985LE UT WOS:000307267000035 PM 22722841 ER PT J AU Fuchs, TA Hovinga, JAK Schatzberg, D Wagner, DD Lammle, B AF Fuchs, Tobias A. Hovinga, Johanna A. Kremer Schatzberg, Daphne Wagner, Denisa D. Laemmle, Bernhard TI Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies SO BLOOD LA English DT Article ID HEMOLYTIC-UREMIC SYNDROME; NEUTROPHIL EXTRACELLULAR TRAPS; FACTOR-CLEAVING PROTEASE; THROMBOCYTOPENIC PURPURA; ADAMTS-13 ACTIVITY; ASSAY-METHODS; LIVER-INJURY; CELL-DEATH; HISTONES; PLASMA AB Thrombotic microangiopathies (TMAs) are a group of life-threatening disorders characterized by thrombocytopenia, fragmentation of erythrocytes, and ischemic organ damage. Genetic disorders, autoimmune disease, and cancer are risk factors for TMAs, but an additional, unknown trigger is needed to bring about acute disease. Recent studies suggest that DNA and histones are released during inflammation or infection and stimulate coagulation, thrombosis, thrombocytopenia, and organ damage in mice. We show that extracellular DNA and histones as well as markers of neutrophils are present in acute TMAs. Analysis of plasma from TMA patients of different clinical categories revealed elevated levels of DNA-histone complexes and myeloperoxidase (MPO) from neutrophil granules as well as S100A8/A9, a heterocomplex abundant in neutrophil cytosol. During therapy of thrombotic thrombocytopenic purpura, a subtype of TMAs often associated with severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) deficiency, plasma DNA and MPO were inversely correlated with platelet counts, and their levels indicated amelioration or exacerbation of the disease. ADAMTS13 deficiency together with increased levels of plasma DNA and MPO were characteristic for acute thrombotic thrombocytopenic purpura. A minor infection often precedes acute TMA and extracellular DNA and histones released during the inflammatory response could provide the second hit, which precipitates acute TMA in patients with pre-existing risk factors. (Blood. 2012; 120(6):1157-1164) C1 [Hovinga, Johanna A. Kremer; Laemmle, Bernhard] Univ Hosp Bern, Dept Hematol, Inselspital, CH-3010 Bern, Switzerland. [Hovinga, Johanna A. Kremer; Laemmle, Bernhard] Univ Hosp Bern, Cent Hematol Lab, Inselspital, CH-3010 Bern, Switzerland. [Hovinga, Johanna A. Kremer; Laemmle, Bernhard] Univ Bern, CH-3010 Bern, Switzerland. [Fuchs, Tobias A.; Schatzberg, Daphne; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Fuchs, Tobias A.; Schatzberg, Daphne; Wagner, Denisa D.] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Fuchs, Tobias A.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Lammle, B (reprint author), Univ Hosp Bern, Dept Hematol, Inselspital, CH-3010 Bern, Switzerland. EM wagner@idi.harvard.edu; bernhard.laemmle@insel.ch RI Fuchs, Tobias/F-1189-2013; Kremer Hovinga, Johanna/M-3482-2013 OI Kremer Hovinga, Johanna/0000-0002-1300-7135 FU Swiss National Science Foundation [32003B-124892]; ISTH Presidential Fund; National Institutes of Health National Heart, Lung, and Blood Institute [R01 HL102101]; Deutsche Forschungsgemeinschaft, Germany [FU 742/1-1] FX This work was supported in part by Swiss National Science Foundation grant 32003B-124892 (J.A.K.H., B.L.); the ISTH 2007 Presidential Fund (J.A.K.H.); the National Institutes of Health National Heart, Lung, and Blood Institute grant R01 HL102101 (D.D.W.); and a fellowship from the Deutsche Forschungsgemeinschaft, Germany (FU 742/1-1; T.A.F.). NR 52 TC 73 Z9 73 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 9 PY 2012 VL 120 IS 6 BP 1157 EP 1164 DI 10.1182/blood-2012-02-412197 PG 8 WC Hematology SC Hematology GA 987WT UT WOS:000307449300005 PM 22611154 ER PT J AU Barreyro, L Will, B Bartholdy, B Zhou, L Todorova, TI Stanley, RF Ben-Neriah, S Montagna, C Parekh, S Pellagatti, A Boultwood, J Paietta, E Ketterling, RP Cripe, L Fernandez, HF Greenberg, PL Tallman, MS Steidl, C Mitsiades, CS Verma, A Steidl, U AF Barreyro, Laura Will, Britta Bartholdy, Boris Zhou, Li Todorova, Tihomira I. Stanley, Robert F. Ben-Neriah, Susana Montagna, Cristina Parekh, Samir Pellagatti, Andrea Boultwood, Jacqueline Paietta, Elisabeth Ketterling, Rhett P. Cripe, Larry Fernandez, Hugo F. Greenberg, Peter L. Tallman, Martin S. Steidl, Christian Mitsiades, Constantine S. Verma, Amit Steidl, Ulrich TI Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; WORLD-HEALTH-ORGANIZATION; MAST-CELLS; EXPRESSION; GENE; MARKER; INTERLEUKIN-1-BETA; COMPLEX; KINASE AB Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q-) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 x 10(-7)). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome. (Blood. 2012;120(6):1290-1298) C1 [Barreyro, Laura; Will, Britta; Bartholdy, Boris; Todorova, Tihomira I.; Stanley, Robert F.; Parekh, Samir; Steidl, Ulrich] Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. [Zhou, Li; Verma, Amit] Yeshiva Univ Albert Einstein Coll Med, Dept Dev & Mol Biol, Bronx, NY 10461 USA. [Ben-Neriah, Susana; Steidl, Christian] Univ British Columbia, Ctr Lymphoid Canc, British Columbia Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Ben-Neriah, Susana; Steidl, Christian] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Montagna, Cristina] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA. [Montagna, Cristina] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. [Montagna, Cristina; Parekh, Samir; Paietta, Elisabeth; Verma, Amit; Steidl, Ulrich] Montefiore Med Ctr, Albert Einstein Coll Med, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. [Parekh, Samir; Paietta, Elisabeth; Verma, Amit; Steidl, Ulrich] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med Oncol, Bronx, NY 10467 USA. [Pellagatti, Andrea; Boultwood, Jacqueline] John Radcliffe Hosp, Leukaemia & Lymphoma Res Mol Haematol Unit, Nuffield Dept Clin Lab Sci, Oxford OX3 9DU, England. [Ketterling, Rhett P.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Cripe, Larry] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Fernandez, Hugo F.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Greenberg, Peter L.] Stanford Univ, Ctr Canc, Hematol Div, Stanford, CA 94305 USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Steidl, U (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Chanin Bldg,Rm 606,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM ulrich.steidl@einstein.yu.edu OI Pellagatti, Andrea/0000-0002-6122-0221; Boultwood, Jacqueline/0000-0002-4330-2928 FU National Institutes of Health [U24 CA114737-05S3]; Leukemia & Lymphoma Research United Kingdom; NYSTEM research grant [CO24350]; American Cancer Society-J; National Cancer Institute [R00 CA131503]; Gabrielle's Angel Foundation for Cancer Research; T.Tai & Company Inc postdoctoral fellowship FX This work was supported by the National Institutes of Health grant U24 CA114737-05S3 (E.P.), Leukemia & Lymphoma Research United Kingdom (J.B. and A.P.), a NYSTEM research grant (CO24350, U.S.), and an American Cancer Society-J. T.Tai & Company Inc postdoctoral fellowship (B.W.). U.S. is the recipient of a Howard Temin Award of the National Cancer Institute (R00 CA131503) and a Medical Research Award of the Gabrielle's Angel Foundation for Cancer Research. U.S. is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine. NR 53 TC 51 Z9 56 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 AUG 9 PY 2012 VL 120 IS 6 BP 1290 EP 1298 DI 10.1182/blood-2012-01-404699 PG 9 WC Hematology SC Hematology GA 987WT UT WOS:000307449300020 PM 22723552 ER PT J AU Lowenthal, J Hull, SC Pearson, SD AF Lowenthal, Justin Hull, Sara Chandros Pearson, Steven D. TI The Ethics of Early Evidence - Preparing for a Possible Breakthrough in Alzheimer's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Lowenthal, Justin; Hull, Sara Chandros; Pearson, Steven D.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Hull, Sara Chandros] NHGRI, NIH, Off Clin Director, Bethesda, MD 20892 USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Review, Inst Technol Assessment, Boston, MA 02114 USA. RP Lowenthal, J (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. RI Lowenthal, Justin/H-3728-2013; OI Lowenthal, Justin/0000-0001-5909-0520 FU Intramural NIH HHS [Z99 HG999999] NR 5 TC 12 Z9 12 U1 0 U2 6 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 AUG 9 PY 2012 VL 367 IS 6 BP 488 EP 490 DI 10.1056/NEJMp1203104 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 986AE UT WOS:000307310800002 PM 22873528 ER PT J AU Fathi, AT Chen, YB Carter, BW Ryan, RJH AF Fathi, Amir T. Chen, Yi-Bin Carter, Brett W. Ryan, Russell J. H. TI Case 24-2012: A 38-Year-Old Man with Abdominal Pain and Altered Mental Status SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID T-CELL LEUKEMIA; UMBILICAL-CORD BLOOD; INTERFERON-ALPHA; ARSENIC TRIOXIDE; COMPLETE RESPONSE; BIWEEKLY CHOP; LONG-TERM; PHASE-II; HTLV-I; LEUKEMIA/LYMPHOMA C1 [Fathi, Amir T.; Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol & Med Oncol, Boston, MA 02114 USA. [Fathi, Amir T.; Chen, Yi-Bin] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Carter, Brett W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ryan, Russell J. H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Fathi, Amir T.; Chen, Yi-Bin] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Carter, Brett W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Ryan, Russell J. H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Fathi, AT (reprint author), Massachusetts Gen Hosp, Div Hematol & Med Oncol, Boston, MA 02114 USA. FU Otsuka; Seattle Genetics; Millennium; Bayer FX Dr. Fathi reports serving as a consultant on advisory boards for Genzyme, Seattle Genetics, Teva Pharmaceuticals, and Concert Pharmaceuticals. Dr. Chen reports receiving consulting fees from Otsuka and Seattle Genetics and grant support to his institution from Otsuka, Millennium, Bayer, and Seattle Genetics. No other potential conflict of interest relevant to this article was reported. NR 41 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 AUG 9 PY 2012 VL 367 IS 6 BP 552 EP 563 DI 10.1056/NEJMcpc1110049 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 986AE UT WOS:000307310800011 PM 22873536 ER PT J AU McCarthy, PL Owzar, K Anderson, KC AF McCarthy, Philip L. Owzar, Kouros Anderson, Kenneth C. TI Lenalidomide for Multiple Myeloma REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [McCarthy, Philip L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Owzar, Kouros] Duke Univ, Durham, NC USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP McCarthy, PL (reprint author), Roswell Pk Canc Inst, Buffalo, NY 14263 USA. EM philip.mccarthy@roswellpark.org NR 4 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 AUG 9 PY 2012 VL 367 IS 6 BP 574 EP 575 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 986AE UT WOS:000307310800017 ER PT J AU Prasad, R Vaid, M Katiyar, SK AF Prasad, Ram Vaid, Mudit Katiyar, Santosh K. TI Grape Proanthocyanidin Inhibit Pancreatic Cancer Cell Growth In Vitro and In Vivo through Induction of Apoptosis and by Targeting the PI3K/Akt Pathway SO PLOS ONE LA English DT Article ID SKH-1 HAIRLESS MICE; ACTIVATED AKT; CARCINOMA-CELLS; CYCLE CONTROL; BCL-2 FAMILY; EXPRESSION; PROTEIN; DEATH; PHOSPHORYLATION; KINASES AB Pancreatic cancer is an aggressive malignancy that is frequently diagnosed at an advanced stage with poor prognosis. Here, we report the chemotherapeutic effects of bioactive proanthocyanidins from grape seeds (GSPs) as assessed using In Vitro and In Vivo models. Treatment of human pancreatic cancer cells (Miapaca-2, PANC-1 and AsPC-1) with GSPs In Vitro reduced cell viability and increased G2/M phase arrest of the cell cycle leading to induction of apoptosis in a dose- and time-dependent manner. The GSPs-induced apoptosis of pancreatic cancer cells was associated with a decrease in the levels of Bcl-2 and Bcl-xl and an increase in the levels of Bax and activated caspase-3. Treatment of Miapaca-2 and PANC-1 cells with GSPs also decreased the levels of phosphatidylinositol-3-kinase (PI3K) and phosphorylation of Akt at ser(473). siRNA knockdown of PI3K from pancreatic cancer cells also reduced the phosphorylation of Akt. Further, dietary administration of GSPs (0.5%, w/w) as a supplemented AIN76A control diet significantly inhibited the growth of Miapaca-2 pancreatic tumor xenografts grown subcutaneously in athymic nude mice, which was associated with: (i) inhibition of cell proliferation, (ii) induction of apoptosis of tumor cells, (iii) increased expression of Bax, reduced expression of anti-apoptotic proteins and activation of caspase-3-positive cells, and (iv) decreased expression of PI3K and p-Akt in tumor xenograft tissues. Together, these results suggest that GSPs may have a potential chemotherapeutic effect on pancreatic cancer cell growth. C1 [Prasad, Ram; Vaid, Mudit; Katiyar, Santosh K.] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Katiyar, Santosh K.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Nutr Obes Res Ctr, Birmingham, AL USA. [Katiyar, Santosh K.] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Prasad, R (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. EM skatiyar@uab.edu FU Veterans Administration Merit Review Award FX This work was supported by funds from the Veterans Administration Merit Review Award (SKK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 31 Z9 36 U1 0 U2 11 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 AUG 8 PY 2012 VL 7 IS 8 AR e43064 DI 10.1371/journal.pone.0043064 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 986GX UT WOS:000307331100082 PM 22905202 ER PT J AU Faustman, DL Wang, LM Okubo, Y Burger, D Ban, LQ Man, GT Zheng, H Schoenfeld, D Pompei, R Avruch, J Nathan, DM AF Faustman, Denise L. Wang, Limei Okubo, Yoshiaki Burger, Douglas Ban, Liqin Man, Guotong Zheng, Hui Schoenfeld, David Pompei, Richard Avruch, Joseph Nathan, David M. TI Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes SO PLOS ONE LA English DT Article ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; BETA-CELL FUNCTION; NOD MICE; MULTIPLE-SCLEROSIS; TNF-ALPHA; T-CELLS; AUTOIMMUNE-DISEASES; FREUND ADJUVANT AB Background: No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration. Methodology/Principal Findings: Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95-3.8], 2.57 [95% CI 1.65-3.49]) and the EBV-infected subject (3.16 [95% CI 2.54-3.69]) vs. 1.65 [95% CI 1.55-3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level. Conclusions/Significance: We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes. C1 [Faustman, Denise L.; Wang, Limei; Okubo, Yoshiaki; Burger, Douglas; Ban, Liqin; Man, Guotong] Massachusetts Gen Hosp, Immunobiol Lab, Boston, MA 02114 USA. [Faustman, Denise L.; Wang, Limei; Okubo, Yoshiaki; Burger, Douglas; Ban, Liqin; Man, Guotong] Harvard Univ, Sch Med, Boston, MA USA. [Zheng, Hui; Schoenfeld, David] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Pompei, Richard; Avruch, Joseph; Nathan, David M.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Faustman, DL (reprint author), Massachusetts Gen Hosp, Immunobiol Lab, Boston, MA 02114 USA. EM faustman@helix.mgh.harvard.edu FU Iacocca Foundation; Charlton Fund for Innovative Diabetes Research; NIH [P30DK057521] FX The Iacocca Foundation and philanthropic dollars supported this study. The authors also reserve gratitude to the James B Pendleton Charitable Trust. Finally, the authors extend their appreciation to the Friends United for Juvenile Diabetes Research and Partnership for Cures. DMN was supported in part by the Charlton Fund for Innovative Diabetes Research. NIH support included #P30DK057521 to DLF. No drug company or for-profit resources supported this trial. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was funded by philanthropic grants only. NR 56 TC 32 Z9 34 U1 6 U2 14 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 AUG 8 PY 2012 VL 7 IS 8 AR e41756 DI 10.1371/journal.pone.0041756 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 986GX UT WOS:000307331100016 PM 22905105 ER PT J AU Walcott, BP Nahed, BV Coumans, JV AF Walcott, Brian P. Nahed, Brian V. Coumans, Jean-Valery TI Helicopter vs Ground Transportation for Patients With Trauma SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Walcott, Brian P.; Nahed, Brian V.; Coumans, Jean-Valery] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 8 PY 2012 VL 308 IS 6 BP 564 EP 564 DI 10.1001/jama.2012.7776 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 984YA UT WOS:000307228400013 PM 22871859 ER PT J AU Goroll, AH Schoenbaum, SC AF Goroll, Allan H. Schoenbaum, Stephen C. TI Payment Reform for Primary Care Within the Accountable Care Organization A Critical Issue for Health System Reform SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Goroll, Allan H.] Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. [Goroll, Allan H.] Harvard Univ, Sch Med, Boston, MA USA. [Schoenbaum, Stephen C.] Josiah Macy Jr Fdn, New York, NY USA. RP Goroll, AH (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 15 Parkman St,Ste 645, Boston, MA 02114 USA. EM ahgoroll@partners.org NR 8 TC 12 Z9 12 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 8 PY 2012 VL 308 IS 6 BP 577 EP 578 DI 10.1001/jama.2012.8696 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 984YA UT WOS:000307228400023 PM 22871868 ER PT J AU Demers, M Krause, DS Schatzberg, D Martinod, K Voorhees, JR Fuchs, TA Scadden, DT Wagner, DD AF Demers, Melanie Krause, Daniela S. Schatzberg, Daphne Martinod, Kimberly Voorhees, Jaymie R. Fuchs, Tobias A. Scadden, David T. Wagner, Denisa D. TI Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COLONY-STIMULATING FACTOR; CHRONIC MYELOID-LEUKEMIA; CELL LUNG-CANCER; INNATE IMMUNITY; RISK-FACTORS; MICE; HEALTHY; DONORS; BLOOD; BIOMARKER AB Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients. C1 [Demers, Melanie; Schatzberg, Daphne; Martinod, Kimberly; Voorhees, Jaymie R.; Fuchs, Tobias A.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Demers, Melanie; Schatzberg, Daphne; Martinod, Kimberly; Voorhees, Jaymie R.; Fuchs, Tobias A.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Demers, Melanie; Fuchs, Tobias A.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Krause, Daniela S.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Krause, Daniela S.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Martinod, Kimberly] Harvard Univ, Sch Med, Div Med Sci, Grad Program Immunol, Boston, MA 02115 USA. RP Wagner, DD (reprint author), Immune Dis Inst, Boston, MA 02115 USA. EM wagner@idi.harvard.edu RI Fuchs, Tobias/F-1189-2013; OI Martinod, Kimberly/0000-0002-1026-6107 FU National Heart, Lung, and Blood Institute of the National Institutes of Health Grant [R01 HL102101]; Terry Fox Foundation Grant through the Canadian Cancer Society [TF-018748]; National Cancer Institute Grant [5K08CA138916-02] FX We thank Lesley Cowan for help with manuscript preparation, Myriam Armant for help with G-CSF studies, and Julian I. Borissoff for help with regression analysis and thoughtful discussions. This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health Grant R01 HL102101 (to D.D.W.), Terry Fox Foundation Grant TF-018748 through the Canadian Cancer Society (to M.D.), and National Cancer Institute Grant 5K08CA138916-02 (to D.S.K.). NR 46 TC 146 Z9 149 U1 4 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 7 PY 2012 VL 109 IS 32 BP 13076 EP 13081 DI 10.1073/pnas.1200419109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 989HU UT WOS:000307551700051 PM 22826226 ER PT J AU Buxton, OM Ellenbogen, JM Wang, W Carballeira, A O'Connor, S Cooper, D Gordhandas, AJ McKinney, SM Solet, JM AF Buxton, Orfeu M. Ellenbogen, Jeffrey M. Wang, Wei Carballeira, Andy O'Connor, Shawn Cooper, Dan Gordhandas, Ankit J. McKinney, Scott M. Solet, Jo M. TI Sleep Disruption due to Hospital Noises A Prospective Evaluation SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NEONATAL INTENSIVE-CARE; AIRCRAFT NOISE; AROUSAL; QUALITY; DEPRIVATION; AGE; IDENTIFICATION; ENVIRONMENT; ACTIVATION; DURATION AB Background: Sleep plays a critical role in maintaining health and well-being; however, patients who are hospitalized are frequently exposed to noise that can disrupt sleep. Efforts to attenuate hospital noise have been limited by incomplete information on the interaction between sounds and sleep physiology. Objective: To determine profiles of acoustic disruption of sleep by examining the cortical (encephalographic) arousal responses during sleep to typical hospital noises by sound level and type and sleep stage. Design: 3-day polysomnographic study. Setting: Sound-attenuated sleep laboratory. Participants: Volunteer sample of 12 healthy participants. Intervention: Baseline (sham) night followed by 2 intervention nights with controlled presentation of 14 sounds that are common in hospitals (for example, voice, intravenous alarm, phone, ice machine, outside traffic, and helicopter). The sounds were administered at calibrated, increasing decibel levels (40 to 70 dBA [decibels, adjusted for the range of normal hearing]) during specific sleep stages. Measurements: Encephalographic arousals, by using established criteria, during rapid eye movement (REM) sleep and non-REM (NREM) sleep stages 2 and 3. Results: Sound presentations yielded arousal response curves that varied because of sound level and type and sleep stage. Electronic sounds were more arousing than other sounds, including human voices, and there were large differences in responses by sound type. As expected, sounds in NREM stage 3 were less likely to cause arousals than sounds in NREM stage 2; unexpectedly, the probability of arousal to sounds presented in REM sleep varied less by sound type than when presented in NREM sleep and caused a greater and more sustained elevation of instantaneous heart rate. Limitations: The study included only 12 participants. Results for these healthy persons may underestimate the effects of noise on sleep in patients who are hospitalized. Conclusion: Sounds during sleep influence both cortical brain activity and cardiovascular function. This study systematically quantifies the disruptive capacity of a range of hospital sounds on sleep, providing evidence that is essential to improving the acoustic environments of new and existing health care facilities to enable the highest quality of care. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Berklee Coll Mus, Boston, MA USA. Cambridge Hlth Alliance, Cambridge, England. Cavanaugh Tocci Assoc, Sudbury, MA USA. RP Buxton, OM (reprint author), 221 Longwood Ave,BLI438-K, Boston, MA 02115 USA. EM orfeu_buxton@hms.harvard.edu FU Academy of Architecture for Health; Facilities Guidelines Institute; Center for Health Design FX This study was funded by investigator-initiated grants (Dr. Solet) from the Academy of Architecture for Health, the Facilities Guidelines Institute, and The Center for Health Design. Sleep laboratory work was completed through the generosity of Massachusetts General Hospital and with acoustic consultation by Cavanaugh Tocci Associates. NR 54 TC 34 Z9 34 U1 0 U2 16 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 AUG 7 PY 2012 VL 157 IS 3 BP 170 EP + DI 10.7326/0003-4819-156-12-201208070-00472 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 992PB UT WOS:000307789900004 PM 22868834 ER PT J AU Denberg, TD Humphrey, LL Shekelle, P Qaseem, A AF Denberg, Thomas D. Humphrey, Linda L. Shekelle, Paul Qaseem, Amir TI Screening for Colorectal Cancer RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Denberg, Thomas D.] Harvard Vanguard Med Associates & Atrius Hlth, Auburndale, MA 02466 USA. [Humphrey, Linda L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Shekelle, Paul] W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. RP Denberg, TD (reprint author), Harvard Vanguard Med Associates & Atrius Hlth, Auburndale, MA 02466 USA. NR 1 TC 0 Z9 0 U1 1 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 AUG 7 PY 2012 VL 157 IS 3 BP 218 EP 219 DI 10.7326/0003-4819-157-3-201208070-00020 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 992PB UT WOS:000307789900014 ER PT J AU St John, MA Wang, G Luo, J Dohadwala, M Hu, D Lin, Y Dennis, M Lee, JM Elashoff, D Lawhon, T Zaknoen, SL Burrows, FJ Dubinett, SM AF St John, M. A. Wang, G. Luo, J. Dohadwala, M. Hu, D. Lin, Y. Dennis, M. Lee, J. M. Elashoff, D. Lawhon, T. Zaknoen, S. L. Burrows, F. J. Dubinett, S. M. TI Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies SO BRITISH JOURNAL OF CANCER LA English DT Article DE EMT; PGT; 15-PGDH; HNSCC; metastasis; COX-2 inhibitor ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; LUNG-CANCER; PHASE-II; HEAD; NECK; CYCLOOXYGENASE-2; DEHYDROGENASE; COMBINATION; INHIBITION AB BACKGROUND: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains similar to 15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. METHODS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. RESULTS: Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. CONCLUSION: In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC. British Journal of Cancer (2012) 107, 707-712. doi:10.1038/bjc.2012.203 www.bjcancer.com Published online 24 July 2012 (C) 2012 Cancer Research UK C1 [St John, M. A.; Hu, D.; Dennis, M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Wang, G.; Luo, J.; Dohadwala, M.; Lee, J. M.; Dubinett, S. M.] Jonsson Comprehens Canc Ctr, Lung Canc Res Program, Los Angeles, CA 90095 USA. [Wang, G.; Luo, J.; Dohadwala, M.; Lin, Y.; Lee, J. M.; Elashoff, D.; Dubinett, S. M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Wang, G.; Luo, J.; Dohadwala, M.; Lin, Y.; Lee, J. M.; Elashoff, D.; Dubinett, S. M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. [Dohadwala, M.; Dubinett, S. M.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Lawhon, T.; Zaknoen, S. L.; Burrows, F. J.] Tragara Pharmaceut, San Diego, CA 92130 USA. RP St John, MA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Head & Neck Surg, 10833 Le Conte Ave,CHS 62-132, Los Angeles, CA 90095 USA. EM MStJohn@mednet.ucla.edu RI lin, yuan/E-6062-2011 FU NCATS NIH HHS [UL1 TR000124] NR 26 TC 2 Z9 2 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 7 PY 2012 VL 107 IS 4 BP 707 EP 712 DI 10.1038/bjc.2012.203 PG 6 WC Oncology SC Oncology GA 992IY UT WOS:000307770300019 PM 22828609 ER PT J AU Capo-Ramos, DE Gao, Y Lubin, JH Check, DP Goldin, LR Pesatori, AC Consonni, D Bertazzi, PA Saxon, AJ Bergen, AW Caporaso, NE Landi, MT AF Capo-Ramos, David E. Gao, Ying Lubin, Jay H. Check, David P. Goldin, Lynn R. Pesatori, Angela C. Consonni, Dario Bertazzi, Pier Alberto Saxon, Andrew J. Bergen, Andrew W. Caporaso, Neil E. Landi, Maria Teresa TI Mood Disorders and Risk of Lung Cancer in the EAGLE Case-Control Study and in the US Veterans Affairs Inpatient Cohort SO PLOS ONE LA English DT Article ID BIPOLAR DISORDER; MAJOR DEPRESSION; RECORD-LINKAGE; SEROTONIN; GENETICS; SMOKING; ANTIDEPRESSANTS; SCHIZOPHRENIA; ENVIRONMENT; POPULATION AB Background: Mood disorders may affect lung cancer risk. We evaluated this hypothesis in two large studies. Methodology/Principal Findings: We examined 1,939 lung cancer cases and 2,102 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study conducted in Italy (2002-2005), and 82,945 inpatients with a lung cancer diagnosis and 3,586,299 person-years without a lung cancer diagnosis in the U. S. Veterans Affairs Inpatient Cohort (VA study), composed of veterans with a VA hospital admission (1969-1996). In EAGLE, we calculated odds ratios (ORs) and 95% confidence intervals (CI), with extensive adjustment for tobacco smoking and multiple lifestyle factors. In the VA study, we estimated lung cancer relative risks (RRs) and 95% CIs with time-dependent Poisson regression, adjusting for attained age, calendar year, hospital visits, time within the study, and related previous medical diagnoses. In EAGLE, we found decreased lung cancer risk in subjects with a personal history of mood disorders (OR: 0.59, 95% CI: 0.44-0.79, based on 121 lung cancer incident cases and 192 controls) and family history of mood disorders (OR: 0.62, 95% CI: 0.50-0.77, based on 223 lung cancer cases and 345 controls). The VA study analyses yielded similar results (RR: 0.74, 95% CI: 0.71-0.77, based on 2,304 incident lung cancer cases and 177,267 non-cancer person-years) in men with discharge diagnoses for mood disorders. History of mood disorders was associated with nicotine dependence, alcohol and substance use and psychometric scales of depressive and anxiety symptoms in controls for these studies. Conclusions/Significance: The consistent finding of a relationship between mood disorders and lung cancer risk across two large studies calls for further research into the complex interplay of risk factors associated with these two widespread and debilitating diseases. Although we adjusted for smoking effects in EAGLE, residual confounding of the results by smoking cannot be ruled out. C1 [Capo-Ramos, David E.; Gao, Ying; Lubin, Jay H.; Check, David P.; Goldin, Lynn R.; Caporaso, Neil E.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, Milan, Italy. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Saxon, Andrew J.] Addict Psychiat Residency Program, Seattle, WA USA. [Saxon, Andrew J.] Univ Washington, Seattle, WA 98195 USA. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Mol Genet Program, Menlo Pk, CA 94025 USA. RP Capo-Ramos, DE (reprint author), Ctr Dis Control & Prevent, Off Anal & Epidemiol, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM landim@mail.nih.gov RI Consonni, Dario/K-7943-2016; bertazzi, pietro alberto/D-5039-2017; OI Consonni, Dario/0000-0002-8935-3843; bertazzi, pietro alberto/0000-0003-3475-2449; pesatori, angela/0000-0002-0261-3252; Bergen, Andrew/0000-0002-1237-7644 FU National Institutes of Health, National Cancer Institute (Division of Cancer Epidemiology and Genetics); Region of Lombardy, Milan, Italy (Environmental Epidemiology Program); Center of Excellence in Substance Abuse Treatment and Education at VA Puget Sound Health Care System; NIH [U01DA020830, RC2DA028793] FX Funding for this study was provided by the Intramural Research Program of the National Institutes of Health, National Cancer Institute (Division of Cancer Epidemiology and Genetics) and by the Region of Lombardy, Milan, Italy (Environmental Epidemiology Program). Dr. Saxon is supported by the Center of Excellence in Substance Abuse Treatment and Education at VA Puget Sound Health Care System. Dr. Bergen is supported by NIH grants U01DA020830 and RC2DA028793. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 1 Z9 1 U1 0 U2 5 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 AUG 7 PY 2012 VL 7 IS 8 AR e42945 DI 10.1371/journal.pone.0042945 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 987SL UT WOS:000307437900063 PM 22880133 ER PT J AU Hein, R Maranian, M Hopper, JL Kapuscinski, MK Southey, MC Park, DJ Schmidt, MK Broeks, A Hogervorst, FBL Bueno-de-Mesquit, HB Muir, KR Lophatananon, A Rattanamongkongul, S Puttawibul, P Fasching, PA Hein, A Ekici, AB Beckmann, MW Fletcher, O Johnson, N Silva, ID Peto, J Sawyer, E Tomlinson, I Kerin, M Miller, N Marmee, F Schneeweiss, A Sohn, C Burwinkel, B Guenel, P Cordina-Duverger, E Menegaux, F Truong, T Bojesen, SE Nordestgaard, BG Flyger, H Milne, RL Perez, JIA Zamora, MP Benitez, J Anton-Culver, H Ziogas, A Bernstein, L Clarke, CA Brenner, H Muller, H Arndt, V Stegmaier, C Rahman, N Seal, S Turnbull, C Renwick, A Meindl, A Schott, S Bartram, CR Schmutzler, RK Brauch, H Hamann, U Ko, YD Wang-Gohrke, S Dork, T Schurmann, P Karstens, JH Hillemanns, P Nevanlinna, H Heikkinen, T Aittomaki, K Blomqvist, C Bogdanova, NV Zalutsky, IV Antonenkova, NN Bermisheva, M Prokovieva, D Farahtdinova, A Khusnutdinova, E Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, J Chen, XQ Beesley, J Lambrechts, D Zhao, H Neven, P Wildiers, H Nickels, S Flesch-Janys, D Radice, P Peterlongo, P Manoukian, S Barile, M Couch, FJ Olson, JE Wang, XS Fredericksen, Z Giles, GG Baglietto, L McLean, CA Severi, G Offit, K Robson, M Gaudet, MM Vijai, J Alnaes, GG Kristensen, V Borresen-Dale, AL John, EM Miron, A Winqvist, R Pylkas, K Jukkola-Vuorinen, A Grip, M Andrulis, IL Knight, JA Glendon, G Mulligan, AM Figueroa, JD Garcia-Closas, M Lissowska, J Sherman, ME Hooning, M Martens, JWM Seynaeve, C Collee, M Hall, P Humpreys, K Czene, K Liu, JJ Cox, A Brock, IW Cross, SS Reed, MWR Ahmed, S Ghoussaini, M Pharoah, PDP Kang, D Yoo, KY Noh, DY Jakubowska, A Jaworska, K Durda, K Zlowocka, E Sangrajrang, S Gaborieau, V Brennan, P McKay, J Shen, CY Yu, JC Hsu, HM Hou, MF Orr, N Schoemaker, M Ashworth, A Swerdlow, A Trentham-Dietz, A Newcomb, PA Titus, L Egan, KM Chenevix-Trench, G Antoniou, AC Humphreys, MK Morrison, J Chang-Claude, J Easton, DF Dunning, AM AF Hein, Rebecca Maranian, Melanie Hopper, John L. Kapuscinski, Miroslaw K. Southey, Melissa C. Park, Daniel J. Schmidt, Marjanka K. Broeks, Annegien Hogervorst, Frans B. L. Bueno-de-Mesquit, H. Bas Muir, Kenneth R. Lophatananon, Artitaya Rattanamongkongul, Suthee Puttawibul, Puttisak Fasching, Peter A. Hein, Alexander Ekici, Arif B. Beckmann, Matthias W. Fletcher, Olivia Johnson, Nichola Silva, Isabel dos Santos Peto, Julian Sawyer, Elinor Tomlinson, Ian Kerin, Michael Miller, Nicola Marmee, Frederick Schneeweiss, Andreas Sohn, Christof Burwinkel, Barbara Guenel, Pascal Cordina-Duverger, Emilie Menegaux, Florence Truong, Therese Bojesen, Stig E. Nordestgaard, Borge G. Flyger, Henrik Milne, Roger L. Arias Perez, Jose Ignacio Pilar Zamora, M. Benitez, Javier Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Clarke, Christina A. Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Rahman, Nazneen Seal, Sheila Turnbull, Clare Renwick, Anthony Meindl, Alfons Schott, Sarah Bartram, Claus R. Schmutzler, Rita K. Brauch, Hiltrud Hamann, Ute Ko, Yon-Dschun Wang-Gohrke, Shan Doerk, Thilo Schuermann, Peter Karstens, Johann H. Hillemanns, Peter Nevanlinna, Heli Heikkinen, Tuomas Aittomaki, Kristiina Blomqvist, Carl Bogdanova, Natalia V. Zalutsky, Iosif V. Antonenkova, Natalia N. Bermisheva, Marina Prokovieva, Darya Farahtdinova, Albina Khusnutdinova, Elza Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana Chen, Xiaoqing Beesley, Jonathan Lambrechts, Diether Zhao, Hui Neven, Patrick Wildiers, Hans Nickels, Stefan Flesch-Janys, Dieter Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Barile, Monica Couch, Fergus J. Olson, Janet E. Wang, Xianshu Fredericksen, Zachary Giles, Graham G. Baglietto, Laura McLean, Catriona A. Severi, Gianluca Offit, Kenneth Robson, Mark Gaudet, Mia M. Vijai, Joseph Alnaes, Grethe Grenaker Kristensen, Vessela Borresen-Dale, Anne-Lise John, Esther M. Miron, Alexander Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi Andrulis, Irene L. Knight, Julia A. Glendon, Gord Mulligan, Anna Marie Figueroa, Jonine D. Garcia-Closas, Montserrat Lissowska, Jolanta Sherman, Mark E. Hooning, Maartje Martens, John W. M. Seynaeve, Caroline Collee, Margriet Hall, Per Humpreys, Keith Czene, Kamila Liu, Jianjun Cox, Angela Brock, Ian W. Cross, Simon S. Reed, Malcolm W. R. Ahmed, Shahana Ghoussaini, Maya Pharoah, Paul D. P. Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Jakubowska, Anna Jaworska, Katarzyna Durda, Katarzyna Zlowocka, Elzbieta Sangrajrang, Suleeporn Gaborieau, Valerie Brennan, Paul McKay, James Shen, Chen-Yang Yu, Jyh-Cherng Hsu, Huan-Ming Hou, Ming-Feng Orr, Nick Schoemaker, Minouk Ashworth, Alan Swerdlow, Anthony Trentham-Dietz, Amy Newcomb, Polly A. Titus, Linda Egan, Kathleen M. Chenevix-Trench, Georgia Antoniou, Antonis C. Humphreys, Manjeet K. Morrison, Jonathan Chang-Claude, Jenny Easton, Douglas F. Dunning, Alison M. CA GENICA Network kConFab Investigators AOCS Grp TI Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) SO PLOS ONE LA English DT Article ID SUSCEPTIBILITY LOCUS; CHINESE; WOMEN AB The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6x10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8x10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2x10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8x10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8x10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3x10(-7), p(heterogeneity) = 5.1x10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours. C1 [Hein, Rebecca; Nickels, Stefan; Chang-Claude, Jenny] German Canc Res Ctr, Unit Genet Epidemiol, Div Canc Epidemiol, Heidelberg, Germany. [Hein, Rebecca] Univ Cologne, PMV Primarmed Versorgung Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Maranian, Melanie; Ahmed, Shahana; Ghoussaini, Maya; Pharoah, Paul D. P.; Dunning, Alison M.] Univ Cambridge, Dept Oncol, Cambridge, England. [Hopper, John L.; Kapuscinski, Miroslaw K.; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. 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[Shen, Chen-Yang] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Shen, Chen-Yang] Taiwan Biobank, Taipei, Taiwan. [Yu, Jyh-Cherng; Hsu, Huan-Ming] Tri Serv Gen Hosp, Dept Surg, Taipei, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Ctr Canc, Kaohsiung, Taiwan. [Hou, Ming-Feng] Kaohsiung Med Univ, Chung Ho Mem Hosp, Dept Surg, Kaohsiung, Taiwan. [Schoemaker, Minouk; Swerdlow, Anthony] Inst Canc Res, Epidemiol Sect, Sutton, Surrey, England. [Trentham-Dietz, Amy; Newcomb, Polly A.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Titus, Linda] Dartmouth Hitchcock Med Ctr, Dept Community & Family Med, Dept Pediat, Dartmouth Med Sch, Lebanon, NH 03766 USA. [Egan, Kathleen M.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Populat Sci, Tampa, FL 33612 USA. RP Hein, R (reprint author), German Canc Res Ctr, Unit Genet Epidemiol, Div Canc Epidemiol, Heidelberg, Germany. EM rebecca.hein@uk-koeln.de; alisond@srl.cam.ac.uk RI Jakubowska, Anna/O-8050-2014; Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Hartikainen, Jaana/E-6256-2015; Bowtell, David/H-1007-2016; Bruning, Thomas/G-8120-2015; Khusnutdinova, Elza/A-4810-2013; Brenner, Hermann/B-4627-2017; manoukian, siranoush/E-7132-2017; Peissel, Bernard/E-8187-2017; Rahman, Nazneen/D-2802-2013; Dork, Thilo/J-8620-2012; Verdrengh, Evelien/H-4571-2012; Noh, Dong-Young/G-5531-2011; Yoo, Keun-Young/J-5548-2012; Bernard, Loris/K-5953-2014; truong, therese/A-2837-2013; Kerin, Michael/D-6748-2013; Ekici, Arif/C-3971-2013; Hein, Alexander/F-6999-2010; Andrulis, Irene/E-7267-2013; Joseph, Vijai/J-9158-2013; Radice, Paolo/O-3119-2013; Knight, Julia/A-6843-2012 OI Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; Park, Daniel/0000-0002-6354-0931; Giles, Graham/0000-0003-4946-9099; Garcia-Closas, Montserrat /0000-0003-1033-2650; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Peissel, Bernard/0000-0001-9233-3571; Rahman, Nazneen/0000-0003-4376-0440; Schoemaker, Minouk/0000-0001-8403-2234; Robson, Mark/0000-0002-3109-1692; Hein, Alexander/0000-0003-2601-3398; Joseph, Vijai/0000-0002-7933-151X; FU European Community [223175, HEALTH-F2-2009-223175]; Cancer Research-UK [C1287/A10118, C1287/A12014, C8197/A10865]; European Union [BM0606]; Joseph Mitchell Trust; United States National Cancer Institute, National Institutes of Health (NIH) [RFA-CA-06-503]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Victorian Breast Cancer Research Consortium; Dutch Cancer Society [NKI 2001-2423; 2007-3839, DDHK 2004-3124, DDHK 2009-4318]; Dutch National Genomics Initiative; Breast Cancer Research Trust; ELAN-Fond of the University Hospital of Erlangen; Cancer Research UK; Breakthrough Breast Cancer; National Health Service (NHS); National Cancer Research Network (NCRN); National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Guy's & St. Thomas' National Health Service Foundation Trust; King's College London; Oxford Biomedical Research Centre; Dietmar-Hopp Foundation; Helmholtz Society; Fondation de France; French National Institute of Cancer [INCa]; French Agency for Environmental and Occupational Health [ANSES (ex-AFSSET)]; French League Against Cancer; National Research Agency (ANR); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Medical Research Council; Herlev Hospital; Genome Spain Foundation; Red Tematica de Investigacion Cooperativa en Cancer; Asociacion Espanola Contra el Cancer; Fondo de Investigacion Sanitario [PI081120, PI081583]; California Breast Cancer Act; National Institutes of Health [R01 CA77398, R01CA122340, R01 CA128978]; Lon V Smith Foundation [LVS39420]; California Breast Cancer Research Fund [97-10500]; California Department of Public Health [103885]; Baden Wurttemberg Ministry of Science, Research and Arts; German Cancer Aid (Deutsche Krebshilfe); Cancer Research UK [C8620/A8372, C8620/A8857, C490/A11021]; US Military Acquisition (ACQ) Activity, Era of Hope Award [W81XWH-05-1-0204]; Institute of Cancer Research (UK) a Medical Research Council (UK); Deutsche Krebshilfe [107054]; Center of Molecular Medicine, Cologne; Dietmar Hopp Foundation; Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart; University of Tubingen, Germany; Department of Internal Medicine, Evangelische Kliniken Bonn GmbH, Johanniter Krankenhaus, Bonn, Germany; Institute of Pathology, University of Bonn, Bonn, Germany; Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany; Deutsche Krebshilfe e.V. [70492, 70-2892-BR I]; Hannover Medical School; German Research Foundation [DFG] [Do761/2-1]; Helsinki University Central Hospital Research Fund, Academy of Finland [132473]; Finnish Cancer Society; Sigrid Juselius Foundation; short-term fellowships from the German Academic Exchange Program; Friends of Hannover Medical School; German Federal Ministry of Research and Education [RUS08/017]; Swedish Cancer Society; Stockholm Cancer Society; Kuopio University Hospital of North Savo; Finnish Cancer Organizations; Academy of Finland; University of Eastern Finland; National Breast Cancer Foundation; National Health and Medical Research Council (NHMRC); Queensland Cancer Fund; Cancer Council of New South Wales, Victoria, Tasmania; Cancer Council of New South Wales, Victoria, South Australia; Cancer Foundation of Western Australia; NHMRC [145684, 288704, 454508, 199600]; United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council of Tasmania and Cancer Foundation of Western Australia; Stichting tegen Kanker [232-2008, 196-2010]; Hamburg Cancer Society; German Cancer Research Center; Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; Ministero della Salute; Ministero dell'Universita e Ricerca [RBLAO3-BETH]; Fondazione Italiana per la Ricerca sul Cancro; Associazione Italiana per la Ricerca sul Cancro [4017]; Fondazione IRCCS Istituto Nazionale Tumori [561000]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; VicHealth; Cancer Council Victoria; Australian National Health and Medical Research Council (NHMRC) [209057, 251553, 504711]; Breast Cancer Research Foundation; Sharon Levine Corzine Fund; Niehaus Cancer Research Initiative; Andrew Sabin Family Fund; Charles Krasne Research Fund; Norman and Carol Stone Research Initiative; Norwegian Research council [155218/V40, 175240/S10, FUGE-NFR 181600/V11]; Swizz Bridge Award; Finnish Cancer Foundation; University of Oulu; Oulu University Hospital; National Cancer Institute, National Institutes of Health [RFA] [CA-06-503]; University of Melbourne [U01 CA69638]; Cancer Care Ontario; National Cancer Institute, Department of Health and Human Services, USA; Marit and Hans Rausing Initiative Against Breast Cancer; Agency for Science, Technology and Research of Singapore (ASTAR); United States National Institutes of Health (NIH); Susan G. Komen Breast Cancer Foundation; Yorkshire Cancer Research; Breast Cancer Campaign; Ministry of Health and Welfare, Republic of Korea [AO30001]; Polish Foundation of Science; National Cancer Institute Thailand; Institute of Biomedical Sciences, Academia Sinica, Taiwan; National Institute of Health [CA58860, CA92044]; Massachusetts center [R01CA47305]; Wisconsin center [R01 CA47147]; New Hampshire center [R01CA69664]; [PBZ_KBN_122/P05/2004] FX This work was partly supported by the European Community's Seventh Framework Programme (COGS; http://cogseu.org/) [grant agreement number 223175, grant number HEALTH-F2-2009-223175]. The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research-UK (http://science.cancerresearchuk.org/) [C1287/A10118 and C1287/A12014]. Meetings of the BCAC have been funded by the European Union COST programme (http://www.srl.cam.ac.uk/consortia/cost/index.html) [BM0606]. D. F. E. is a Principal Research Fellow of Cancer Research-UK. A. C. A. is a Cancer Research-UK Senior Cancer Research Fellow. A. M. D has been funded by Cancer Research-UK [C8197/A10865] and The Joseph Mitchell Trust. The Australian Breast Cancer Family Study (ABCFS) and Northern California Breast Cancer Family Registry (NC-BCFR) work was supported by the United States National Cancer Institute, National Institutes of Health (NIH) [RFA-CA-06-503]; and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR); and Principal Investigators, including Cancer Care Ontario [U01 CA69467]; Northern California Cancer Center [U01 CA69417]; University of Melbourne [U01 CA69638]. Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government or the BCFR. The ABCFS was also supported by the National Health and Medical Research Council of Australia; the New South Wales Cancer Council; the Victorian Health Promotion Foundation (Australia); and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast Cancer Research Consortium Group Leader. M. C. S. is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. The Amsterdam Breast Cancer Study (ABCS) study was supported by the Dutch Cancer Society [NKI 2001-2423; 2007-3839]; and the Dutch National Genomics Initiative. The Asian Cancer Program (ACP) study was supported by the Breast Cancer Research Trust. The Bavarian Breast Cancer Cases and Controls (BBCC) study was partly supported by ELAN-Fond of the University Hospital of Erlangen. The British Breast Cancer Study (BBCS) study is supported by Cancer Research UK; and Breakthrough Breast Cancer; and acknowledges National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre; and the National Cancer Research Network (NCRN). Breast Cancer in Galway Genetic Study (BIGGS) is supported by National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre [to E. S.]; Guy's & St. Thomas' National Health Service Foundation Trust in partnership with King's College London [to E. S.]; and the Oxford Biomedical Research Centre [to I. T.]. The Breast Cancer Study of the University Clinic Heidelberg (BSUCH) study was supported by the Dietmar-Hopp Foundation; and the Helmholtz Society. The CECILE Breast Cancer Study (CECILE) study was supported by Fondation de France (2007), French National Institute of Cancer [INCa grant 2007, 2008, 2009]; French Agency for Environmental and Occupational Health [ANSES (ex-AFSSET) grant 2008 and 2009]; the French League Against Cancer; and National Research Agency (ANR).; The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund; the Danish Medical Research Council; and Herlev Hospital. The Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) was supported by the Genome Spain Foundation; the Red Tematica de Investigacion Cooperativa en Cancer and grants from the Asociacion Espanola Contra el Cancer and the Fondo de Investigacion Sanitario [PI081120 to J.B., PI081583 to R. L. M.]. The California Teachers Study (CTS) was supported by the California Breast Cancer Act of 1993; National Institutes of Health [R01 CA77398]; the Lon V Smith Foundation [LVS39420]; and the California Breast Cancer Research Fund [contract 97-10500]. Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ESTHER Breast Cancer Study (ESTHER) study was supported by a grant from the Baden Wurttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The ICR Familial Breast Cancer Study (FBCS) is supported by funds from Cancer Research UK [C8620/A8372; C8620/A8857]; a US Military Acquisition (ACQ) Activity, Era of Hope Award [W81XWH-05-1-0204]; the Institute of Cancer Research (UK) a Medical Research Council (UK) Clinical Research Fellowship [to C. T.]. The FBCS acknowledges National Health Service (NHS) funding to the Royal Marsden/Institute of Cancer Research, National Institute for Health Research (NIHR) Specialist Cancer. The German Consortium for Hereditary Breast & Ovarian Cancer (GC-HBOC) was supported by Deutsche Krebshilfe [107054]; the Center of Molecular Medicine, Cologne; the Helmholtz society; and the Dietmar Hopp Foundation [to B. B.]. The Gene Environment Interaction and Breast Cancer in Germany (GENICA) network was supported by the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and the University of Tubingen, Germany [to C.J. and H. B.]; the Department of Internal Medicine, Evangelische Kliniken Bonn GmbH, Johanniter Krankenhaus, Bonn, Germany [to Y.D.K. and C.B.]; the Institute of Pathology, University of Bonn, Bonn, Germany [to HP. F.]; Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [to U. H.]; the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany [to T. B., B. P., S. R., A. S. and V. H.]. The Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) was supported by the Deutsche Krebshilfe e.V. [70492]; and genotyping in part by the state of Baden-Wurttemberg through the Medical Faculty of the University of Ulm [P.685]. The Hannover Breast Cancer Study (HABCS) study was supported by an intramural grant from Hannover Medical School; and by a grant from the German Research Foundation [DFG, Do761/2-1]. The Helsinki Breast Cancer Study (HEBCS) study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland [132473]; the Finnish Cancer Society; and the Sigrid Juselius Foundation. The Hannover-Minsk Breast Cancer Study (HMBCS) was supported by short-term fellowships from the German Academic Exchange Program [to N.B.]; and the Friends of Hannover Medical School [to N.B.].; The Hannover-Ufa Breast Cancer Study (HUBCS) was supported by a grant from the German Federal Ministry of Research and Education [RUS08/017]. The Karolinska Breast Cancer Study (KARBAC) was supported by the Swedish Cancer Society and the Stockholm Cancer Society. The Kuopio Breast Cancer Project (KBCP) was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo; the Finnish Cancer Organizations; the Academy of Finland; and by the strategic funding of the University of Eastern Finland. Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer/Australian Ovarian Cancer Study (KConFab/AOCS) is supported by grants from the National Breast Cancer Foundation; the National Health and Medical Research Council (NHMRC); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC [145684; 288704; 454508]. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]; the Cancer Council of Tasmania and Cancer Foundation of Western Australia; and the NHMRC [199600]. G. C. T. and P. W. are supported by the NHMRC. Leuven Multidisciplinary Breast Centre (LMBC) is supported by the 'Stichting tegen Kanker' [232-2008; 196-2010]. The Mammary Carcinoma Risk Factor Investigation (MARIE) study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I]; the Hamburg Cancer Society; the German Cancer Research Center; and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. Milan Breast Cancer Study Group (MBCSG) was supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 "Alleanza contro il Cancro", and "Progetto Tumori Femminili") [to P. R.]; Ministero dell'Universita e Ricerca (RBLAO3-BETH) [to P. R.]; Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors"); Associazione Italiana per la Ricerca sul Cancro (4017) [to P. P.]; and by funds from Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects "561000"). The Mayo Clinic Breast Cancer Study (MCBCS) was supported by National Institutes of Health grants [R01CA122340; R01 CA128978]; and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]. Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth; and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council (NHMRC) grants [209057; 251553; 504711]; and by infrastructure provided by Cancer Council Victoria. The Memorial Sloan-Kettering Cancer Center (MSKCC) was supported by the Breast Cancer Research Foundation; the Sharon Levine Corzine Fund; the Niehaus Cancer Research Initiative; the Andrew Sabin Family Fund; the Charles Krasne Research Fund; and the Norman and Carol Stone Research Initiative. The Norwegian Breast Cancer Study (NBCS) was supported by grants from the Norwegian Research council [155218/V40, 175240/S10 to A. L. B. D.; FUGE-NFR 181600/V11 to V.N.K.]; and a Swizz Bridge Award [to A. L. B. D.].; The Oulu Breast Cancer Study (OBCS) was supported by research grants from the Finnish Cancer Foundation; the Sigrid Juselius Foundation; the Academy of Finland; the University of Oulu; and the Oulu University Hospital. The Ontario Familial Breast Cancer Registry (OFBCR) work was supported by the National Cancer Institute, National Institutes of Health [RFA # CA-06-503]; and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR); and Principal Investigators, including Cancer Care Ontario [U01 CA69467]; Northern California Cancer Center [U01 CA69417]; and University of Melbourne [U01 CA69638]; and by Cancer Care Ontario. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government or the BCFR. The National Cancer Institute Polish Breast Cancer Study (PBCS) was supported by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Rotterdam Breast Cancer Study (RBCS) was funded by the Dutch Cancer Society [DDHK 2004-3124; DDHK 2009-4318]. The Singapore and Sweden Breast Cancer Study (SASBAC) was funded by the Marit and Hans Rausing Initiative Against Breast Cancer; the Agency for Science, Technology and Research of Singapore (ASTAR); the United States National Institutes of Health (NIH); and the Susan G. Komen Breast Cancer Foundation. The Sheffield Breast Cancer Study (SBCS) was funded by Yorkshire Cancer Research; and the Breast Cancer Campaign. The Study of Epidemiology and Risk factors in Cancer Heredity (SEARCH) study is funded by a programme grant from Cancer Research UK [C490/A11021] and laboratory infrastructure by [C8197/A10123]. The Seoul Breast Cancer Study (SEBCS) was supported by the Korea Health 21 R&D Project [AO30001], Ministry of Health and Welfare, Republic of Korea. The IHCC-Szczecin Breast Cancer Study (SZBCS) was supported by Grant PBZ_KBN_122/P05/2004; and the Polish Foundation of Science [to K.J.]. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. The International Agency for Research on Cancer-Thai Breast Cancer Study (TBCS) was funded by The National Cancer Institute Thailand. The Taiwanese Breast Cancer Study (TWBCS) is supported by the Taiwan Biobank project of the Institute of Biomedical Sciences, Academia Sinica, Taiwan. The University of California, Irvine, Breast Cancer Study (UCIBCS) component of this research was supported by the National Institute of Health [CA58860; CA92044]; and the Lon V Smith Foundation [LVS39420]. The UK Breakthrough Generations Study (UKBGS) is funded by Breakthrough Breast Cancer. The US Three State Study (US3SS) study was supported by Massachusetts [R01CA47305 to K. M. E.]; Wisconsin [R01 CA47147 to P.A.N.]; and New Hampshire [R01CA69664 to L. T.-E.] centers; and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 13 TC 28 Z9 28 U1 3 U2 24 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 AUG 7 PY 2012 VL 7 IS 8 AR e42380 DI 10.1371/journal.pone.0042380 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 987SL UT WOS:000307437900035 PM 22879957 ER PT J AU Milanesi, A Lee, JW Li, ZH Da Sacco, S Villani, V Cervantes, V Perin, L Yu, JS AF Milanesi, Anna Lee, Jang-Won Li, Zhenhua Da Sacco, Stefano Villani, Valentina Cervantes, Vanessa Perin, Laura Yu, John S. TI beta-Cell Regeneration Mediated by Human Bone Marrow Mesenchymal Stem Cells SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; INSULIN-PRODUCING CELLS; PROTEIN-KINASE-B; IN-VIVO; STROMAL CELLS; PANCREATIC-ISLETS; DIABETIC MICE; FACTOR-A; DIFFERENTIATION; EXPRESSION AB Bone marrow mesenchymal stem cells (BMSCs) have been shown to ameliorate diabetes in animal models. The mechanism, however, remains largely unknown. An unanswered question is whether BMSCs are able to differentiate into beta-cells in vivo, or whether BMSCs are able to mediate recovery and/or regeneration of endogenous beta-cells. Here we examined these questions by testing the ability of hBMSCs genetically modified to transiently express vascular endothelial growth factor (VEGF) or pancreatic-duodenal homeobox 1 (PDX1) to reverse diabetes and whether these cells were differentiated into beta-cells or mediated recovery through alternative mechanisms. Human BMSCs expressing VEGF and PDX1 reversed hyperglycemia in more than half of the diabetic mice and induced overall improved survival and weight maintenance in all mice. Recovery was sustained only in the mice treated with hBMSCs-VEGF. However, de novo beta-cell differentiation from human cells was observed in mice in both cases, treated with either hBMSCs-VEGF or hBMSCs-PDX1, confirmed by detectable level of serum human insulin. Sustained reversion of diabetes mediated by hBMSCs-VEGF was secondary to endogenous beta-cell regeneration and correlated with activation of the insulin/IGF receptor signaling pathway involved in maintaining beta-cell mass and function. Our study demonstrated the possible benefit of hBMSCs for the treatment of insulin-dependent diabetes and gives new insight into the mechanism of beta-cell recovery after injury mediated by hBMSC therapy. C1 [Milanesi, Anna] Cedars Sinai Med Ctr, Div Endocrinol, Los Angeles, CA 90048 USA. [Milanesi, Anna] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Lee, Jang-Won; Li, Zhenhua; Cervantes, Vanessa; Yu, John S.] Cedars Sinai Med Ctr, Dept Neurosurg, Los Angeles, CA 90048 USA. [Da Sacco, Stefano; Villani, Valentina; Perin, Laura] Univ So Calif, Dept Urol, Childrens Hosp Los Angeles, Los Angeles, CA USA. RP Milanesi, A (reprint author), Cedars Sinai Med Ctr, Div Endocrinol, Los Angeles, CA 90048 USA. EM john.yu@cshs.org RI Da Sacco, Stefano/G-6346-2011 FU Endocrine Fellow Foundation; Cedars-Sinai Clinical Scholar Program FX Funding source: Endocrine Fellow Foundation, and Cedars-Sinai Clinical Scholar Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 21 Z9 22 U1 0 U2 11 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 AUG 7 PY 2012 VL 7 IS 8 AR e42177 DI 10.1371/journal.pone.0042177 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 987SL UT WOS:000307437900023 PM 22879915 ER PT J AU Toriseva, M Laato, M Carpen, O Ruohonen, ST Savontaus, E Inada, M Krane, SM Kahari, VM AF Toriseva, Mervi Laato, Matti Carpen, Olli Ruohonen, Suvi T. Savontaus, Eriika Inada, Masaki Krane, Stephen M. Kahari, Veli-Matti TI MMP-13 Regulates Growth of Wound Granulation Tissue and Modulates Gene Expression Signatures Involved in Inflammation, Proteolysis, and Cell Viability SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; MATRIX-METALLOPROTEINASE; COLLAGENASE-3 MMP-13; HYPERTROPHIC CHONDROCYTES; NEUROPEPTIDE-Y; HUMAN SKIN; 3-DIMENSIONAL COLLAGEN; KERATINOCYTE MIGRATION; ENDOTHELIAL-CELLS; CUTANEOUS WOUNDS AB Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (Mmp13(-/-)) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in Mmp13(-/-) mice. Granulation tissue in Mmp13(-/-) mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in Mmp13(-/-) mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13(-/-) mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13(-/-) granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13(-/-) mice compared to WT mice. Mmp13(-/-) mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis. C1 [Toriseva, Mervi; Kahari, Veli-Matti] Univ Turku, Dept Dermatol, Turku, Finland. [Toriseva, Mervi; Kahari, Veli-Matti] Univ Turku, MediCity Res Lab, Turku, Finland. [Laato, Matti] Turku Univ Hosp, Dept Surg, FIN-20520 Turku, Finland. [Carpen, Olli] Univ Turku, Dept Pathol, Turku, Finland. [Ruohonen, Suvi T.; Savontaus, Eriika] Univ Turku, Dept Pharmacol Drug Dev & Therapeut, Turku, Finland. [Inada, Masaki] Tokyo Univ Agr & Technol, Fac Engn, Dept Life Sci & Biotechnol, Tokyo, Japan. [Krane, Stephen M.] Harvard Univ, Sch Med, Dept Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Krane, Stephen M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Toriseva, M (reprint author), Univ Turku, Dept Dermatol, Turku, Finland. EM veli-matti.kahari@utu.fi RI inada, masaki/D-1581-2013 OI inada, masaki/0000-0002-5066-8506 FU Academy of Finland [137687]; Turku University Hospital [13336]; Sigrid Juselius Foundation; Cancer Research Foundation of Finland; Orion-Farmos Research Foundation; K. Albin Johansson's Foundation; Southwestern Finnish Cancer Foundation; Maud Kuistila's Memory Foundation; Paulo Foundation; Finnish Cultural Foundation; U.S. National Institutes of Health FX The study has been supported by grants from the Academy of Finland (project 137687), Turku University Hospital (project 13336), the Sigrid Juselius Foundation, the Cancer Research Foundation of Finland, and by personal grants (to M. Toriseva) from Orion-Farmos Research Foundation, K. Albin Johansson's Foundation, Southwestern Finnish Cancer Foundation, Maud Kuistila's Memory Foundation, Paulo Foundation and Finnish Cultural Foundation. Generation of the Mmp13-/- mice and backcrossing into WT mice was supported by grants from the U.S. National Institutes of Health to S. M. Krane. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 28 Z9 29 U1 3 U2 15 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 AUG 7 PY 2012 VL 7 IS 8 AR e42596 DI 10.1371/journal.pone.0042596 PG 18 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 987SL UT WOS:000307437900045 PM 22880047 ER PT J AU Reynolds, MR Magnuson, EA Wang, KJ Thourani, VH Williams, M Zajarias, A Rihal, CS Brown, DL Smith, CR Leon, MB Cohen, DJ AF Reynolds, Matthew R. Magnuson, Elizabeth A. Wang, Kaijun Thourani, Vinod H. Williams, Mathew Zajarias, Alan Rihal, Charanjit S. Brown, David L. Smith, Craig R. Leon, Martin B. Cohen, David J. CA PARTNER Trial Investigators TI Health-Related Quality of Life After Transcatheter or Surgical Aortic Valve Replacement in High-Risk Patients With Severe Aortic Stenosis Results From the PARTNER (Placement of AoRTic TraNscathetER Valve) Trial (Cohort A) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE aortic stenosis; AVR; quality of life; TAVR ID ACUTE MYOCARDIAL-INFARCTION; HEART-FAILURE; GREATER-THAN-80 YEARS; IMPLANTATION; SURVIVAL; SURGERY; FEASIBILITY; EFFICACY; OUTCOMES; EPHESUS AB Objectives This study sought to compare health status and quality-of-life outcomes for patients with severe aortic stenosis (AS) and high surgical risk treated with either transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (AVR). Background For high-risk patients with severe AS, TAVR has been shown to result in similar 12-month survival but differing adverse events compared with AVR. Methods We evaluated the health status of 628 patients with severe, symptomatic AS at high risk of surgical complications who were randomized to either TAVR or AVR in the PARTNER Trial. Health status was assessed at baseline and 1, 6, and 12 months using the Kansas City Cardiomyopathy Questionnaire, the Short Form-12, and the EuroQol-5D. Results The primary outcome, the Kansas City Cardiomyopathy Questionnaire summary score, improved more rapidly with TAVR, but was similar for the 2 groups at 6 and 12 months. However, there was a significant interaction between the benefit of TAVR and access site (transapical vs. transfemoral). Patients eligible for transfemoral TAVR demonstrated significant health status benefits with TAVR versus AVR at 1 month (difference, 9.9 points; 95% confidence interval: 4.9 to 14.9; p < 0.001), whereas patients treated via the TA approach demonstrated no benefits with TAVR compared with AVR at any time point. Results for Kansas City Cardiomyopathy Questionnaire subscales and generic measures demonstrated similar patterns. Conclusions In high-risk patients with severe AS, health status improved substantially between baseline and 1 year after either TAVR or AVR. TAVR via the transfemoral, but not the transapical route, was associated with a short-term advantage compared with surgery. (Placement of AoRTic TraNscathetER Valve [PARTNER] trial; NCT00530894) (J Am Coll Cardiol 2012;60:548-58) (C) 2012 by the American College of Cardiology Foundation C1 [Cohen, David J.] Univ Missouri, Sch Med, St Lukes Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Reynolds, Matthew R.] Boston VA Healthcare Syst, Harvard Clin Res Inst, Boston, MA USA. [Thourani, Vinod H.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Williams, Mathew; Smith, Craig R.; Leon, Martin B.] Columbia Univ, Ctr Med, New York Presbyterian Hosp, New York, NY USA. [Zajarias, Alan] Washington Univ, Sch Med, St Louis, MO USA. [Rihal, Charanjit S.] Mayo Clin, Rochester, MN USA. [Brown, David L.] Med City Dallas Hosp, Dallas, TX USA. RP Cohen, DJ (reprint author), Univ Missouri, Sch Med, St Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA. EM dcohen@saint-lukes.org FU Edwards Lifesciences, Inc.; Edwards Lifesciences; Medtronic; Abbott Vascular; Boston Scientific; AstraZeneca; Eli Lilly; Edwards for educational programs FX Supported by Edwards Lifesciences, Inc. Dr. Reynolds receives research grant support from Edwards Lifesciences; and is a consultant for Medtronic and St. Jude Medical. Dr. Cohen receives research grants from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, AstraZeneca, and Eli Lilly; is a consultant for Medtronic and Abbott Vascular; and has received speaking honoraria from Eli Lilly. Dr. Leon has received reimbursement from Edwards Lifesciences for travel expenses related to his unpaid participation as a member of the Executive Committee for the PARTNER Trial; in addition, his institution (Columbia University) has received grant support from Edwards for educational programs. Dr. Thourani is a member of advisory boards for Edwards Lifescience, Sorin Medical, and St. Jude. Dr. Williams is a consultant/proctor for Edwards Lifesciences; and his institution (Columbia University) has received grant support from Edwards for educational programs. Dr. Zajarias is a consultant/proctor for Edwards Lifesciences; and has received travel reimbursement from Edwards as a member of the PARTNER Steering Committee. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 92 Z9 95 U1 0 U2 13 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 AUG 7 PY 2012 VL 60 IS 6 BP 548 EP 558 DI 10.1016/j.jacc.2012.03.075 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 982UR UT WOS:000307071400012 PM 22818074 ER PT J AU Mantha, S Karp, R Raghavan, V Terrin, N Bauer, KA Zwicker, JI AF Mantha, S. Karp, R. Raghavan, V. Terrin, N. Bauer, K. A. Zwicker, J. I. TI Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis SO BRITISH MEDICAL JOURNAL LA English DT Article ID 3RD-GENERATION ORAL-CONTRACEPTIVES; DEPOT-MEDROXYPROGESTERONE ACETATE; FACTOR PATHWAY INHIBITOR; TISSUE FACTOR; INTRAUTERINE-DEVICE; PROTEIN-C; THROMBOSIS; LEVONORGESTREL; DISEASE; EXPRESSION AB Objectives To evaluate the risk of venous thromboembolic events associated with the use of progestin-only contraception and whether that risk differs with the mode of drug delivery (oral, intrauterine, or depot injection). Design Systematic review and meta-analysis of randomised controlled trials and observational studies. Data sources Pubmed, Embase, Cochrane Library, and reference lists of relevant reviews. Study selection Randomised controlled trials and case-control, cohort, and cross sectional studies with venous thromboembolic outcome for progestin-only contraception reported relative to a non-hormone comparator group. Data extraction Data were extracted by two independent investigators, and consensus for inclusion was reached after assessment by additional investigators. Results Among the 2022 unique references identified by all searches, eight observational studies fulfilled inclusion criteria. A total of 147 women across all studies were diagnosed with a venous thromboembolic event while taking progestin-only contraception, and the summary measure for the adjusted relative risk of a venous thromboembolic episode for users versus non-users of a progestin-only contraceptive was, based on the random effects model, 1.03 (95% CI 0.76 to 1.39). Subgroup analysis confirmed there was no association between venous thromboembolic risk and progestin-only pills (relative risk 0.90 (0.57 to 1.45)) or a progestin intrauterine device (0.61 (0.24 to 1.53)). The relative risk of a venous thromboembolic event for users of an injectable progestin versus non-users was 2.67 (1.29 to 5.53). Conclusions Published data assessing the risk of venous thromboembolism in women prescribed progestin-only contraception are limited. In this meta-analysis of eight observational studies, the use of progestin-only contraception was not associated with an increased risk of venous thromboembolism compared with non-users of hormonal contraception. The potential association between injectable progestins and thrombosis requires further study. C1 [Karp, R.; Bauer, K. A.; Zwicker, J. I.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Thrombosis & Hemostasis, Boston, MA 02215 USA. [Karp, R.; Bauer, K. A.; Zwicker, J. I.] Harvard Univ, Div Hematol Oncol, Boston, MA 02215 USA. [Mantha, S.] Lahey Clin Fdn, Div Hematol Oncol, Burlington, MA USA. [Raghavan, V.] Harvard Univ, Sch Med, Mt Auburn Hosp, Cambridge, MA 02138 USA. [Terrin, N.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Bauer, K. A.] Harvard Univ, VA Boston Healthcare Syst, Sch Med, Boston, MA 02215 USA. RP Zwicker, JI (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Thrombosis & Hemostasis, 330 Brookline Ave, Boston, MA 02215 USA. EM jzwicker@bidmc.harvard.edu OI Zwicker, Jeffrey/0000-0001-5810-6893 FU National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 RR025752]; US National Institute of Health FX This study was funded by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (grant No UL1 RR025752). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.; All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from US National Institute of Health for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. NR 37 TC 41 Z9 41 U1 5 U2 16 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD AUG 7 PY 2012 VL 345 AR e4944 DI 10.1136/bmj.e4944 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 988NA UT WOS:000307496500002 PM 22872710 ER PT J AU Li, RJ Lewis, JH Berbeco, RI Xing, L AF Li, Ruijiang Lewis, John H. Berbeco, Ross I. Xing, Lei TI Real-time tumor motion estimation using respiratory surrogate via memory-based learning SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID FIDUCIAL MARKERS; TRACKING SYSTEM; LUNG-TUMORS; RADIOTHERAPY; RADIATION; PREDICTION; ACCURACY; SURFACE; CANCER; RISKS AB Respiratory tumor motion is a major challenge in radiation therapy for thoracic and abdominal cancers. Effective motion management requires an accurate knowledge of the real-time tumor motion. External respiration monitoring devices (optical, etc) provide a noninvasive, non-ionizing, low-cost and practical approach to obtain the respiratory signal. Due to the highly complex and nonlinear relations between tumor and surrogate motion, its ultimate success hinges on the ability to accurately infer the tumor motion from respiratory surrogates. Given their widespread use in the clinic, such a method is critically needed. We propose to use a powerful memory-based learning method to find the complex relations between tumor motion and respiratory surrogates. The method first stores the training data in memory and then finds relevant data to answer a particular query. Nearby data points are assigned high relevance (or weights) and conversely distant data are assigned low relevance. By fitting relatively simple models to local patches instead of fitting one single global model, it is able to capture highly nonlinear and complex relations between the internal tumor motion and external surrogates accurately. Due to the local nature of weighting functions, the method is inherently robust to outliers in the training data. Moreover, both training and adapting to new data are performed almost instantaneously with memory-based learning, making it suitable for dynamically following variable internal/external relations. We evaluated the method using respiratory motion data from 11 patients. The data set consists of simultaneous measurement of 3D tumor motion and 1D abdominal surface (used as the surrogate signal in this study). There are a total of 171 respiratory traces, with an average peak-to-peak amplitude of similar to 15 mm and average duration of similar to 115 s per trace. Given only 5 s (roughly one breath) pretreatment training data, the method achieved an average 3D error of 1.5 mm and 95th percentile error of 3.4 mm on unseen test data. The average 3D error was further reduced to 1.4 mm when the model was tuned to its optimal setting for each respiratory trace. In one trace where a few outliers are present in the training data, the proposed method achieved an error reduction of as much as similar to 50% compared with the best linear model (1.0 mm versus 2.1 mm). The memory-based learning technique is able to accurately capture the highly complex and nonlinear relations between tumor and surrogate motion in an efficient manner (a few milliseconds per estimate). Furthermore, the algorithm is particularly suitable to handle situations where the training data are contaminated by large errors or outliers. These desirable properties make it an ideal candidate for accurate and robust tumor gating/tracking using respiratory surrogates. C1 [Li, Ruijiang; Xing, Lei] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. [Lewis, John H.; Berbeco, Ross I.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lewis, John H.; Berbeco, Ross I.] Harvard Univ, Sch Med, Boston, MA USA. RP Li, RJ (reprint author), Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. EM rli2@stanford.edu FU National Cancer Institute [1R21 CA153587, 1R01 CA133474]; National Science Foundation [0854492] FX The authors would like to thank Dr Seiko Nishioka of the Department of Radiology, NTT Hospital, Sapporo, Japan and Dr Hiroki Shirato of the Department of Radiation Medicine, Hokkaido University School of Medicine, Sapporo, Japan, for sharing the respiratory motion data with them. This work is partially supported by the National Cancer Institute (1R21 CA153587 and 1R01 CA133474) and National Science Foundation (0854492). NR 31 TC 7 Z9 9 U1 4 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 AUG 7 PY 2012 VL 57 IS 15 BP 4771 EP 4786 DI 10.1088/0031-9155/57/15/4771 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 975OY UT WOS:000306521900007 PM 22772042 ER PT J AU Lank, SM Golbach, BA Creager, HM Wiseman, RW Keskin, DB Reinherz, EL Brusic, V O'Connor, DH AF Lank, Simon M. Golbach, Brittney A. Creager, Hannah M. Wiseman, Roger W. Keskin, Derin B. Reinherz, Ellis L. Brusic, Vladimir O'Connor, David H. TI Ultra-high resolution HLA genotyping and allele discovery by highly multiplexed cDNA amplicon pyrosequencing SO BMC GENOMICS LA English DT Article DE HLA; Genotyping; Roche/454; Pyrosequencing; Galaxy; Tissue typing; Cellular immunity; Multiplexing ID HIGH-THROUGHPUT; DOWN-REGULATION; NOMENCLATURE; MOLECULES; EPITOPE; SYSTEM; TIME AB Background: High-resolution HLA genotyping is a critical diagnostic and research assay. Current methods rarely achieve unambiguous high-resolution typing without making population-specific frequency inferences due to a lack of locus coverage and difficulty in exon-phase matching. Achieving high-resolution typing is also becoming more challenging with traditional methods as the database of known HLA alleles increases. Results: We designed a cDNA amplicon-based pyrosequencing method to capture 94% of the HLA class I open-reading-frame with only two amplicons per sample, and an analogous method for class II HLA genes, with a primary focus on sequencing the DRB loci. We present a novel Galaxy server-based analysis workflow for determining genotype. During assay validation, we performed two GS Junior sequencing runs to determine the accuracy of the HLA class I amplicons and DRB amplicon at different levels of multiplexing. When 116 amplicons were multiplexed, we unambiguously resolved 99% of class I alleles to four-or six-digit resolution, as well as 100% unambiguous DRB calls. The second experiment, with 271 multiplexed amplicons, missed some alleles, but generated high-resolution, concordant typing for 93% of class I alleles, and 96% for DRB1 alleles. In a third, preliminary experiment we attempted to sequence novel amplicons for other class II loci with mixed success. Conclusions: The presented assay is higher-throughput and higher-resolution than existing HLA genotyping methods, and suitable for allele discovery or large cohort sampling. The validated class I and DRB primers successfully generated unambiguously high-resolution genotypes, while further work is needed to validate additional class II genotyping amplicons. C1 [Lank, Simon M.; Golbach, Brittney A.; Creager, Hannah M.; Wiseman, Roger W.; O'Connor, David H.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53201 USA. [Keskin, Derin B.; Reinherz, Ellis L.; Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Keskin, Derin B.; Reinherz, Ellis L.; Brusic, Vladimir] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53201 USA. EM dhoconno@wisc.edu OI o'connor, david/0000-0003-2139-470X FU University of Wisconsin Foundation-Wisconsin Partnership-Medical Education and Research Committee [20070709]; NIH; Human Immunology Project Consortium [4 U01 AI08959-02]; [NIH-U01 A190043] FX Work at UW-Madison was supported in part by University of Wisconsin Foundation-Wisconsin Partnership-Medical Education and Research Committee grant number 20070709. Work at Dana Farber was supported by grant NIH-U01 A190043. Additional funding was provided by an award from the NIH, distributed by the Human Immunology Project Consortium, number 4 U01 AI08959-02. NR 34 TC 17 Z9 17 U1 1 U2 6 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 AUG 6 PY 2012 VL 13 AR 378 DI 10.1186/1471-2164-13-378 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 091EB UT WOS:000315031000001 PM 22866951 ER PT J AU Yamaki, T Kawasaki, M Jang, IK Raffel, OC Ishihara, Y Okubo, M Kubota, T Hattori, A Nishigaki, K Takemura, G Fujiwara, H Minatoguchi, S AF Yamaki, Takahiko Kawasaki, Masanori Jang, Ik-Kyung Raffel, Owen Christopher Ishihara, Yoshiyuki Okubo, Munenori Kubota, Tomoki Hattori, Arihiro Nishigaki, Kazuhiko Takemura, Genzou Fujiwara, Hisayoshi Minatoguchi, Shinya TI Comparison between integrated backscatter intravascular ultrasound and 64-slice multi-detector row computed tomography for tissue characterization and volumetric assessment of coronary plaques SO CARDIOVASCULAR ULTRASOUND LA English DT Article DE Computed tomography; Integrated backscatter; Intravascular ultrasound; Coronary plaque ID EX-VIVO MODEL; ATHEROSCLEROTIC PLAQUE; NONINVASIVE ASSESSMENT; ARTERY-DISEASE; ANGIOGRAPHY; CLASSIFICATION; ACCURACY; LESIONS; MORPHOLOGY; CULPRIT AB Background: The purpose of this study was to determine the cut-off values of Hounsfield units (HU) for the discrimination of plaque components and to evaluate the feasibility of measurement of the volume of plaque components using multi-detector row computed tomography (MDCT). Methods: Coronary lesions (125 lesions in 125 patients) were visualized by both integrated backscatter intravascular ultrasound (IB-IVUS) and 64-slice MDCT at the same site. The IB values were used as a gold standard to determine the cut off values of HU for the discrimination of plaque components. Results: Plaques were classified as lipid pool (n = 50), fibrosis (n = 65) or calcification (n = 35) by IB-IVUS. The HU of lipid pool, fibrosis and calcification were 18 +/- 18 HU (-19 to 58 HU), 95 +/- 24 HU (46 to 154 HU) and 378 +/- 99 HU (188 to 605 HU), respectively. Using receiver operating characteristic curve analysis, a threshold of 50 HU was the optimal cutoff values to discriminate lipid pool from fibrosis. Lipid volume measured by MDCT was correlated with that measured by IB-IVUS (r = 0.66, p < 0.001), whereas fibrous volume was not (r = 0.21, p = 0.059). Conclusion: Lipid volume measured by MDCT was moderately correlated with that measured by IB-IVUS. MDCT may be useful for volumetric assessment of the lipid volume of coronary plaques, whereas the assessment of fibrosis volume was unstable. C1 [Yamaki, Takahiko; Kawasaki, Masanori; Ishihara, Yoshiyuki; Okubo, Munenori; Kubota, Tomoki; Hattori, Arihiro; Nishigaki, Kazuhiko; Takemura, Genzou; Fujiwara, Hisayoshi; Minatoguchi, Shinya] Gifu Univ, Dept Cardiol, Grad Sch Med, Gifu 5011194, Japan. [Jang, Ik-Kyung; Raffel, Owen Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Jang, Ik-Kyung; Raffel, Owen Christopher] Harvard Univ, Sch Med, Boston, MA USA. RP Kawasaki, M (reprint author), Gifu Univ, Dept Cardiol, Grad Sch Med, 1-1 Yanagido, Gifu 5011194, Japan. EM masanori@ya2.so-net.ne.jp FU [20590822] FX This study was supported, in part, by a Grant-in-Aid for Scientific Research (C), Ministry of Education, Culture, Sports, Science and Technology of Japan (20590822) (2008-2010). NR 31 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-7120 J9 CARDIOVASC ULTRASOUN JI Cardiovasc. Ultrasound PD AUG 6 PY 2012 VL 10 AR 33 DI 10.1186/1476-7120-10-33 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 040LE UT WOS:000311323300001 PM 22867277 ER PT J AU Arany, Z Patten, I Rana, S Shahul, S Rowe, G Jang, C Liu, L Hacker, M Rhee, J Mitchell, J Mahmood, F Hess, P Farrell, C Koulisis, N Khankin, E Burke, S Tudorache, I Bauersachs, J del Monte, F Hilfiker-Kleiner, D Karumanchi, A AF Arany, Zolt Patten, Ian Rana, Sarosh Shahul, Sajid Rowe, Glenn Jang, Cholsoon Liu, Laura Hacker, Michele Rhee, Julie Mitchell, John Mahmood, Feroze Hess, Phil Farrell, Caitlin Koulisis, Nicole Khankin, Eliyahu Burke, Suzanne Tudorache, Igor Bauersachs, Johann del Monte, Federica Hilfiker-Kleiner, Denise Karumanchi, Ananth TI Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Scientific Session CY JUL 23-26, 2012 CL New Orleans, LA DE Heart failure, pregnancy; Angiogenesis; Gene expression C1 [Arany, Zolt; Patten, Ian; Rana, Sarosh; Shahul, Sajid; Rowe, Glenn; Jang, Cholsoon; Liu, Laura; Hacker, Michele; Rhee, Julie; Mitchell, John; Mahmood, Feroze; Hess, Phil; Farrell, Caitlin; Koulisis, Nicole; Khankin, Eliyahu; Burke, Suzanne; Tudorache, Igor; del Monte, Federica; Karumanchi, Ananth] BIDMC, Boston, MA USA. [Bauersachs, Johann; Hilfiker-Kleiner, Denise] Hannover Med Sch, D-3000 Hannover, Germany. RI Hess, Philip/A-8577-2013; Khankin, Eli/M-7648-2013 OI Hess, Philip/0000-0002-1206-0102; NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 3 PY 2012 VL 111 IS 4 SU S MA 219 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 056QO UT WOS:000312506400208 ER PT J AU Smith, RR Kreke, M Malliaras, K Kanazawa, H Huang, CA Valle, I Blusztajn, A Yee, K Sachs, DH Terrovitis, J Marban, L AF Smith, Rachel R. Kreke, Michelle Malliaras, Konstantinos Kanazawa, Hideaki Huang, Christene A. Valle, Ileana Blusztajn, Agnieszka Yee, Kristine Sachs, David H. Terrovitis, John Marban, Linda TI Allogeneic Cardiosphere-Derived Cells Are Safe and Effective in a Pig Model of Myocardial Infarction SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Scientific Session CY JUL 23-26, 2012 CL New Orleans, LA DE Stem cell therapy; Myocardial infarction; Regenerative medicine stem cells C1 [Smith, Rachel R.; Kreke, Michelle; Valle, Ileana; Blusztajn, Agnieszka; Terrovitis, John; Marban, Linda] Capricor Inc, W Hollywood, CA USA. [Malliaras, Konstantinos; Kanazawa, Hideaki; Yee, Kristine] Cedars Sinai Med Cntr, W Hollywood, CA USA. [Huang, Christene A.; Sachs, David H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Kanazawa, Hideaki/A-2874-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 3 PY 2012 VL 111 IS 4 SU S MA 114 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 056QO UT WOS:000312506400107 ER PT J AU Xu, ZB Wheeler, DG Mahamud, SD Dwyer, KM Robson, SC Cowan, PJ d'Apice, AJ Gumina, RJ AF Xu, Zhaobin Wheeler, Debra G. Mahamud, Shouvik D. Dwyer, Karen M. Robson, Simon C. Cowan, Peter J. d'Apice, Anthony J. Gumina, Richard J. TI Cardiac-Specific Ectonucleoside Triphosphate Diphosphohydrolase 1 Overexpression Affords Protection from Myocardial Infarction and Reperfusion Injury SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Scientific Session CY JUL 23-26, 2012 CL New Orleans, LA DE Adenosine; Myocardial infarction; Cardioprotection C1 [Xu, Zhaobin; Wheeler, Debra G.; Mahamud, Shouvik D.; Gumina, Richard J.] Ohio State Univ, Columbus, OH 43210 USA. [Dwyer, Karen M.; Cowan, Peter J.; d'Apice, Anthony J.] Univ Melbourne, St Vincents Hosp, Immunol Rsch Cntr, Melbourne, Vic 3010, Australia. [Robson, Simon C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Rsch Cntr, 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 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 3 PY 2012 VL 111 IS 4 SU S MA 289 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 056QO UT WOS:000312506400275 ER PT J AU Lee, JH Lee, JM Ramos, EM Gillis, T Mysore, JS Kishikawa, S Hadzi, T Hendricks, AE Hayden, MR Morrison, PJ Nance, M Ross, CA Margolis, RL Squitieri, F Gellera, C Gomez-Tortosa, E Ayuso, C Suchowersky, O Trent, RJ McCusker, E Novelletto, A Frontali, M Jones, R Ashizawa, T Frank, S Saint-Hilaire, MH Hersch, SM Rosas, HD Lucente, D Harrison, MB Zanko, A Abramson, RK Marder, K Sequeiros, J Landwehrmeyer, GB Shoulson, I Richard, RH Marcy, ME James, JF AF Lee, Ji-Hyun Lee, Jong-Min Ramos, Eliana Marisa Gillis, Tammy Mysore, Jayalakshmi S. Kishikawa, Shotaro Hadzi, Tiffany Hendricks, Audrey E. Hayden, Michael R. Morrison, Patrick J. Nance, Martha Ross, Christopher A. Margolis, Russell L. Squitieri, Ferdinando Gellera, Cinzia Gomez-Tortosa, Estrella Ayuso, Carmen Suchowersky, Oksana Trent, Ronald J. McCusker, Elizabeth Novelletto, Andrea Frontali, Marina Jones, Randi Ashizawa, Tetsuo Frank, Samuel Saint-Hilaire, Marie-Helene Hersch, Steven M. Rosas, Herminia D. Lucente, Diane Harrison, Madaline B. Zanko, Andrea Abramson, Ruth K. Marder, Karen Sequeiros, Jorge Landwehrmeyer, G. Bernhard Shoulson, Ira Myers, Richard H. MacDonald, Marcy E. Gusella, James F. CA Registry Study European Huntington Huntington Study Grp COHORt Projec TI TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Huntington's disease (HD); Age at onset; GRIK2; Genetic modifier ID TRINUCLEOTIDE REPEAT; OF-ONSET; VENEZUELAN KINDREDS; AT-ONSET; MODIFIER; POLYMORPHISM; ASSOCIATION; CHROMOSOMES; LENGTH AB Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3' untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the CRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease. (C) 2012 Elsevier Inc. All rights reserved. C1 [Lee, Ji-Hyun] Yonsei Univ, Coll Med, Dept Pharmacol, Pharmacogenom Res Ctr Membrane Transporters, Seoul 120752, South Korea. [Lee, Ji-Hyun; Lee, Jong-Min; Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S.; Kishikawa, Shotaro; Lucente, Diane; MacDonald, Marcy E.; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA. [Ramos, Eliana Marisa; Sequeiros, Jorge] Univ Porto, IBMC Inst Mol & Cell Biol, UnIGENe, P-4150180 Oporto, Portugal. [Hadzi, Tiffany; Frank, Samuel; Saint-Hilaire, Marie-Helene; Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Hendricks, Audrey E.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Hayden, Michael R.] Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada. [Morrison, Patrick J.] Belfast HSC Trust, Reg Med Genet Ctr, Belfast BT9 7AB, Antrim, North Ireland. [Morrison, Patrick J.] Univ Ulster, Coleraine BT52 15A, Londonderry, North Ireland. [Nance, Martha] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Ross, Christopher A.; Margolis, Russell L.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Squitieri, Ferdinando] IRCCS Neuromed, Ctr Neurogenet & Rare Dis, I-86077 Pozzilli, IS, Italy. [Gellera, Cinzia] Ist Nazl Neurol Carlo Besta, I-20133 Milan, Italy. [Gomez-Tortosa, Estrella] Fdn Jimenez Diaz, Dept Neurol, E-28040 Madrid, Spain. [Ayuso, Carmen; Suchowersky, Oksana] Fdn Jimenez Diaz, Dept Genet, E-28040 Madrid, Spain. [Suchowersky, Oksana] Univ Alberta, Div Neurol, Edmonton, AB T6G 2B7, Canada. [Trent, Ronald J.] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia. [McCusker, Elizabeth] Westmead Hosp, Dept Neurol, Westmead, NSW 2145, Australia. [Novelletto, Andrea] Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy. [Frontali, Marina] Inst Neurobiol & Mol Med, I-00133 Rome, Italy. [Jones, Randi] Emory Univ, Sch Medicine, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Ashizawa, Tetsuo] Univ Florida, Dept Neurol, Gainesville, FL 32610 USA. [Hersch, Steven M.; Rosas, Herminia D.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Disorders, Boston, MA 02129 USA. [Harrison, Madaline B.] Univ Virginia, Dept Neurol, Charlottesville, VA 22908 USA. [Zanko, Andrea] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94143 USA. [Abramson, Ruth K.] Univ S Carolina, Sch Med, Dept Neuropsychiat & Behav Sci, Columbia, SC 29209 USA. [Marder, Karen] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA. [Sequeiros, Jorge] Univ Porto, ICBAS, P-4099003 Oporto, Portugal. [Landwehrmeyer, G. Bernhard] Univ Ulm, Dept Neurol, D-89081 Ulm, Germany. [Shoulson, Ira] Georgetown Univ, Med Ctr, Dept Neurol, Washington, DC 20007 USA. [Shoulson, Ira] Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. [Shoulson, Ira] Georgetown Univ, Med Ctr, Dept Human Sci, Washington, DC 20007 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Lee, JH (reprint author), Yonsei Univ, Coll Med, Dept Pharmacol, Pharmacogenom Res Ctr Membrane Transporters, 50 Yonsei Ro, Seoul 120752, South Korea. EM jihyni@yuhs.ac RI Ross, Christopher/H-8395-2013; Hayden, Michael/D-8581-2011; Hendricks, Audrey/I-4127-2016; GELLERA, CINZIA/J-7887-2016; OI Squitieri, Ferdinando /0000-0002-7397-1727; Landwehrmeyer, Georg Bernhard/0000-0003-3375-790X; Hayden, Michael/0000-0001-5159-1419; Ayuso, Carmen/0000-0002-9242-7065; Hendricks, Audrey/0000-0002-7152-0287; Frank, Samuel/0000-0002-1866-162X; Saint-Hilaire, Marie-Helene/0000-0002-2355-5979; Myers, Richard/0000-0002-8365-2674; Sequeiros, Jorge/0000-0002-9846-1037; GELLERA, CINZIA/0000-0002-3582-665X; Novelletto, Andrea/0000-0002-1146-7680 FU National Institutes of Health NINDS Huntington's Disease Center Without Walls [NS16367]; CHDI Foundation Inc.; Huntington's Disease Society of America's Coalition for the Cure; National Research Foundation of Korea; Korean Government [NRF-2009-352-E00010]; FCT [SFRH/BD/44335/2008]; CHDI Foundation, Inc.; High Q Foundation FX The authors thank contributors to the HD-MAPS, COHORT and Registry studies, listed in Appendix 1. This work was supported by grants from the National Institutes of Health NINDS Huntington's Disease Center Without Walls NS16367, the CHDI Foundation Inc., and the Huntington's Disease Society of America's Coalition for the Cure. JHL received support from a National Research Foundation of Korea Grant funded by the Korean Government [NRF-2009-352-E00010]. EMR is the recipient of a scholarship from FCT (SFRH/BD/44335/2008). The Huntington Study Group COHORT project was supported by the CHDI Foundation, Inc. and the REGISTRY study of the European Huntington's Disease Network was supported by the High Q Foundation. NR 25 TC 8 Z9 9 U1 1 U2 12 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 AUG 3 PY 2012 VL 424 IS 3 BP 404 EP 408 DI 10.1016/j.bbrc.2012.06.120 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 990GK UT WOS:000307618800007 PM 22771793 ER PT J AU Sienko, KH Balkwill, MD Wall, C AF Sienko, Kathleen H. Balkwill, M. David Wall, Conrad, III TI Biofeedback improves postural control recovery from multi-axis discrete perturbations SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Vibrotactile; Biofeedback; Balance; Perturbations; Intuitive display; Sensory augmentation; Sensory substitution; Vestibular ID BILATERAL VESTIBULAR LOSS; VIBROTACTILE FEEDBACK; BALANCE PROSTHESIS; TILT; SWAY; DEFICITS; DISPLAY AB Background: Multi-axis vibrotactile feedback has been shown to significantly reduce the root-mean-square (RMS) sway, elliptical fits to sway trajectory area, and the time spent outside of the no feedback zone in individuals with vestibular deficits during continuous multidirectional support surface perturbations. The purpose of this study was to examine the effect of multidirectional vibrotactile biofeedback on postural stability during discrete multidirectional support surface perturbations. Methods: The vibrotactile biofeedback device mapped tilt estimates onto the torso using a 3-row by 16-column tactor array. The number of columns displayed was varied to determine the effect of spatial resolution upon subject response. Torso kinematics and center of pressure data were measured in six subjects with vestibular deficits. Transient and steady state postural responses with and without feedback were characterized in response to eight perturbation directions. Four feedback conditions in addition to the tactors off (no feedback) configuration were evaluated. Postural response data captured by both a force plate and an inertial measurement unit worn on the torso were partitioned into three distinct phases: ballistic, recovery, and steady state. Results: The results suggest that feedback has minimal effects during the ballistic phase (body's outbound trajectory in response to the perturbation), and the greatest effects during the recovery (return toward baseline) and steady state (post-recovery) phases. Specifically, feedback significantly decreases the time required for the body tilt to return to baseline values and significantly increases the velocity of the body's return to baseline values. Furthermore, feedback significantly decreases root mean square roll and pitch sway and significantly increases the amount of time spent in the no feedback zone. All four feedback conditions produced comparable performance improvements. Incidences of delayed and uncontrolled responses were significantly reduced with feedback while erroneous (sham) feedback resulted in poorer performance when compared with the no feedback condition. Conclusions: The results show that among the displays evaluated in this study, no one tactor column configuration was optimal for standing tasks involving discrete surface perturbations. Feedback produced larger effects on body tilt versus center of pressure parameters. Furthermore, the subjects' performance worsened when erroneous feedback was provided, suggesting that vibrotactile stimulation applied to the torso is actively processed and acted upon rather than being responsible for simply triggering a stiffening response. C1 [Sienko, Kathleen H.] MIT, Cambridge, MA 02139 USA. [Sienko, Kathleen H.; Balkwill, M. David; Wall, Conrad, III] Massachusetts Eye & Ear Infirm, Jenks Vestibular Diagnost Lab, Boston, MA 02114 USA. [Wall, Conrad, III] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sienko, Kathleen H.] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Sienko, Kathleen H.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. RP Sienko, KH (reprint author), MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM sienko@umich.edu FU National Institutes of Health (NIH NIDCD) [R01 DC6201]; National Science Foundation's CAREER program [RAPD-0846471]; American Recovery and Reinvestment Act FX We acknowledge Dr. Lars Oddsson for the use of his laboratory; Dr. Steven Rauch and Dr. Richard Lewis for assistance in subject recruitment; Jimmy Robertsson, Heather Kubert, Dr. Ken Statler, and Matthew Christensen for their help in data collection; Dominic Piro for assistance with data analysis; and Seunghun Baek for producing the illustration. This research was supported by the National Institutes of Health (NIH NIDCD R01 DC6201(CW)) and the National Science Foundation's CAREER program (RAPD-0846471(KS), funded under the American Recovery and Reinvestment Act of 2009). NR 23 TC 16 Z9 16 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD AUG 3 PY 2012 VL 9 AR 53 DI 10.1186/1743-0003-9-53 PG 11 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 023KK UT WOS:000310031100001 PM 22863399 ER PT J AU Cocucci, E Aguet, F Boulant, S Kirchhausen, T AF Cocucci, Emanuele Aguet, Francois Boulant, Steeve Kirchhausen, Tom TI The First Five Seconds in the Life of a Clathrin-Coated Pit SO CELL LA English DT Article ID MEDIATED ENDOCYTOSIS; LIVING CELLS; DYNAMICS; ADAPTER; RECRUITMENT; ACTIN; MEMBRANE; PROTEINS; RECEPTOR; CARGO AB Coated pits assemble by growth of a clathrin lattice, which is linked by adaptors to the underlying membrane. How does this process start? We used live-cell TIRF imaging with single-molecule EGFP sensitivity and high temporal resolution to detect arrival of the clathrin triskelions and AP2 adaptors that initiate coat assembly. Unbiased object identification and trajectory tracking, together with a statistical model, yield the arrival times and numbers of individual proteins, as well as experimentally confirmed estimates of the extent of substitution of endogenous by expressed, fluorescently tagged proteins. Pits initiate by coordinated arrival of clathrin and AP2, which is usually detected as two sequential steps, each of one triskelion with two adaptors. PI-4,5-P-2 is essential for initiation. The accessory proteins FCHo1/2 are not; instead, they are required for sustained growth. This objective picture of coated pit initiation also shows that methods outlined here will be broadly useful for studies of dynamic assemblies in living cells. C1 [Cocucci, Emanuele; Aguet, Francois; Boulant, Steeve; Kirchhausen, Tom] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Cocucci, Emanuele; Boulant, Steeve; Kirchhausen, Tom] Boston Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Cocucci, Emanuele; Boulant, Steeve; Kirchhausen, Tom] Boston 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 FU NIH [GM-075252, GM-073165, U54 AI057159]; GlaxoSmithKline; Swiss National Science Foundation; Harvard Digestive Disease Consortium Feasibility Award; New England Regional Center of Excellence in Biodefense and Emerging Infectious Diseases FX This work was supported by NIH grant GM-075252 (T. K.), a GlaxoSmithKline Fellowship (E. C.), a Swiss National Science Foundation fellowship (F. A.) and partial support from NIH grant GM-073165 (to G. Danuser, Harvard Medical School) (F. A.), and a Harvard Digestive Disease Consortium Feasibility Award (S. B.). We thank E. Marino (supported by NIH grant U54 AI057159, New England Regional Center of Excellence in Biodefense and Emerging Infectious Diseases) for maintaining the imaging resources, G. Findlay for qtPCR determinations, Janet Iwasa for the graphical abstract, and S. C. Harrison for editorial assistance. We gratefully acknowledge G. Danuser, K. Jaqaman, S. C. Harrison, and members of the Kirchhausen lab for thought-provoking discussions. E. C. and T. K. designed experiments; E. C. and S. B. performed experiments; E. C. and F. A. designed and implemented the computational methods; and E. C. and F. A. analyzed data. E. C., F. A., and T. K. discussed the results and contributed to the final manuscript. NR 41 TC 118 Z9 118 U1 7 U2 55 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 495 EP 507 DI 10.1016/j.cell.2012.05.047 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400010 PM 22863004 ER PT J AU Chaki, M Airik, R Ghosh, AK Giles, RH Chen, R Slaats, GG Wang, H Hurd, TW Zhou, WB Cluckey, A Gee, HY Ramaswami, G Hong, CJ Hamilton, BA Cervenka, I Ganji, RS Bryja, V Arts, HH van Reeuwijk, J Oud, MM Letteboer, SJF Roepman, R Husson, H Ibraghimov-Beskrovnaya, O Yasunaga, T Walz, G Eley, L Sayer, JA Schermer, B Liebau, MC Benzing, T Le Corre, S Drummond, I Janssen, S Allen, SJ Natarajan, S O'Toole, JF Attanasio, M Saunier, S Antignac, C Koenekoop, RK Ren, HN Lopez, I Nayir, A Stoetzel, C Dollfus, H Massoudi, R Gleeson, JG Andreoli, SP Doherty, DG Lindstrad, A Golzio, C Katsanis, N Pape, L Abboud, EB Al-Rajhi, AA Lewis, RA Omran, H Lee, EYHP Wang, SH Sekiguchi, JM Saunders, R Johnson, CA Garner, E Vanselow, K Andersen, JS Shlomai, J Nurnberg, G Nurnberg, P Levy, S Smogorzewska, A Otto, EA Hildebrandt, F AF Chaki, Moumita Airik, Rannar Ghosh, Amiya K. Giles, Rachel H. Chen, Rui Slaats, Gisela G. Wang, Hui Hurd, Toby W. Zhou, Weibin Cluckey, Andrew Gee, Heon Yung Ramaswami, Gokul Hong, Chen-Jei Hamilton, Bruce A. Cervenka, Igor Ganji, Ranjani Sri Bryja, Vitezslav Arts, Heleen H. van Reeuwijk, Jeroen Oud, Machteld M. Letteboer, Stef J. F. Roepman, Ronald Husson, Herve Ibraghimov-Beskrovnaya, Oxana Yasunaga, Takayuki Walz, Gerd Eley, Lorraine Sayer, John A. Schermer, Bernhard Liebau, Max C. Benzing, Thomas Le Corre, Stephanie Drummond, Iain Janssen, Sabine Allen, Susan J. Natarajan, Sivakumar O'Toole, John F. Attanasio, Massimo Saunier, Sophie Antignac, Corinne Koenekoop, Robert K. Ren, Huanan Lopez, Irma Nayir, Ahmet Stoetzel, Corinne Dollfus, Helene Massoudi, Rustin Gleeson, Joseph G. Andreoli, Sharon P. Doherty, Dan G. Lindstrad, Anna Golzio, Christelle Katsanis, Nicholas Pape, Lars Abboud, Emad B. Al-Rajhi, Ali A. Lewis, Richard A. Omran, Heymut Lee, Eva Y. -H. P. Wang, Shaohui Sekiguchi, Joann M. Saunders, Rudel Johnson, Colin A. Garner, Elizabeth Vanselow, Katja Andersen, Jens S. Shlomai, Joseph Nurnberg, Gudrun Nurnberg, Peter Levy, Shawn Smogorzewska, Agata Otto, Edgar A. Hildebrandt, Friedhelm TI Exome Capture Reveals ZNF423 and CEP164 Mutations, Linking Renal Ciliopathies to DNA Damage Response Signaling SO CELL LA English DT Article ID MULTIPOINT LINKAGE ANALYSIS; POLYCYSTIC KIDNEY-DISEASE; ATAXIA-TELANGIECTASIA; SECKEL-SYNDROME; CENTROSOMAL PROTEIN; GENOMIC STABILITY; JOUBERT-SYNDROME; HUMAN-CELLS; GENE; MOUSE AB Nephronophthisis-related ciliopathies (NPHP-RC) are degenerative recessive diseases that affect kidney, retina, and brain. Genetic defects in NPHP gene products that localize to cilia and centrosomes defined them as "ciliopathies.'' However, disease mechanisms remain poorly understood. Here, we identify by whole-exome resequencing, mutations of MRE11, ZNF423, and CEP164 as causing NPHP-RC. All three genes function within the DNA damage response (DDR) pathway. We demonstrate that, upon induced DNA damage, the NPHP-RC proteins ZNF423, CEP164, and NPHP10 colocalize to nuclear foci positive for TIP60, known to activate ATM at sites of DNA damage. We show that knockdown of CEP164 or ZNF423 causes sensitivity to DNA damaging agents and that cep164 knockdown in zebrafish results in dysregulated DDR and an NPHP-RC phenotype. Our findings link degenerative diseases of the kidney and retina, disorders of increasing prevalence, to mechanisms of DDR. C1 [Chaki, Moumita; Airik, Rannar; Ghosh, Amiya K.; Hurd, Toby W.; Zhou, Weibin; Cluckey, Andrew; Gee, Heon Yung; Ramaswami, Gokul; Janssen, Sabine; Allen, Susan J.; Natarajan, Sivakumar; Otto, Edgar A.; Hildebrandt, Friedhelm] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Sekiguchi, Joann M.; Saunders, Rudel; Hildebrandt, Friedhelm] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Giles, Rachel H.; Slaats, Gisela G.] Univ Med Ctr, Dept Hypertens & Nephrol, Utrecht, Netherlands. [Chen, Rui; Wang, Hui] Baylor Coll Med, HGSC Dept Mol & Human Genet, Houston, TX 77030 USA. [Lewis, Richard A.] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. [Hong, Chen-Jei; Hamilton, Bruce A.] Univ Calif San Diego, Sch Med, Dept Med, Div Med Genet,Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Hong, Chen-Jei; Hamilton, Bruce A.] Univ Calif San Diego, Sch Med, Inst Genom Med, George Palade Labs, La Jolla, CA 92093 USA. [Cervenka, Igor; Ganji, Ranjani Sri; Bryja, Vitezslav] Masaryk Univ, Fac Sci, Inst Expt Biol, CS-61137 Brno, Czech Republic. [Bryja, Vitezslav] Acad Sci Czech Republic, Inst Biophys, Dept Cytokinet, CS-61265 Brno, Czech Republic. [Arts, Heleen H.; van Reeuwijk, Jeroen; Oud, Machteld M.; Letteboer, Stef J. F.; Roepman, Ronald] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands. [Arts, Heleen H.; van Reeuwijk, Jeroen; Oud, Machteld M.; Letteboer, Stef J. F.; Roepman, Ronald] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, NL-6525 GA Nijmegen, Netherlands. [Husson, Herve; Ibraghimov-Beskrovnaya, Oxana] Genzyme Corp, Cell Biol, Framingham, MA 01701 USA. [Yasunaga, Takayuki; Walz, Gerd] Univ Freiburg, Div Renal, Med Ctr, D-79001 Freiburg, Germany. [Eley, Lorraine; Sayer, John A.] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Schermer, Bernhard; Liebau, Max C.; Benzing, Thomas] Univ Cologne, Dept Internal Med 2, D-50937 Cologne, Germany. [Schermer, Bernhard; Liebau, Max C.; Benzing, Thomas] Univ Cologne, Ctr Mol Med, D-50937 Cologne, Germany. [Schermer, Bernhard; Benzing, Thomas; Nurnberg, Gudrun; Nurnberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50937 Cologne, Germany. [Liebau, Max C.] Univ Cologne, Dept Pediat & Adolescent Med, D-50937 Cologne, Germany. [Schermer, Bernhard; Benzing, Thomas] Univ Cologne, Syst Biol Aging, D-50937 Cologne, Germany. [Nurnberg, Gudrun; Nurnberg, Peter] Univ Cologne, Cologne Ctr Genom & Mol Med, D-50937 Cologne, Germany. [Shlomai, Joseph] Hebrew Univ Hadassah Med Sch, Fac Med, Dept Microbiol & Mol Genet, IMRIC, IL-91120 Jerusalem, Israel. [Le Corre, Stephanie; Drummond, Iain] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Nephrol Div, Charlestown, MA 02129 USA. [Le Corre, Stephanie; Drummond, Iain] Harvard Univ, Sch Med, Dept Genet, Charlestown, MA 02129 USA. [O'Toole, John F.] Metrohlth Med Ctr, Dept Internal Med, Div Nephrol, Cleveland, OH 44109 USA. [O'Toole, John F.] Case Western Reserve Univ, Sch Med, Cleveland, OH 44109 USA. [Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Attanasio, Massimo] Univ Texas SW Med Ctr Dallas, Eugene McDermott Ctr Growth & Dev, Dallas, TX 75390 USA. [Saunier, Sophie; Antignac, Corinne] Paris Descartes Univ, Hop Necker Enfants Malades, Inserm U983, AP HP, Paris, France. [Koenekoop, Robert K.; Ren, Huanan; Lopez, Irma] McGill Univ, Montreal Childrens Hosp, McGill Ocular Genet Lab, Ctr Hlth, Montreal, PQ H3H 1P3, Canada. [Nayir, Ahmet] Istanbul Univ, Fac Med, Dept Pediat Nephrol, Istanbul, Turkey. [Stoetzel, Corinne; Dollfus, Helene] Univ Strasbourg, Fac Med, Lab Genet Med EA3949, Equipe AVENIR Inserm, F-67000 Strasbourg, France. [Massoudi, Rustin; Gleeson, Joseph G.] Univ Calif San Diego, Howard Hughes Med Inst, Dept Pediat, La Jolla, CA 92093 USA. [Andreoli, Sharon P.] Indiana Univ, James Whitcomb Riley Hosp Children, Dept Pediat, Med Ctr, Indianapolis, IN 46202 USA. [Doherty, Dan G.] Univ Washington, Seattle Childrens Hosp, Dept Pediat, Div Genet Med,Ctr Integrat Brain Res, Seattle, WA 98101 USA. [Lindstrad, Anna; Golzio, Christelle; Katsanis, Nicholas] Duke Univ, Ctr Human Dis Modeling, Med Ctr, Durham, NC 27710 USA. [Pape, Lars] Hannover Med Sch, Dept Pediat Nephrol, D-30625 Hannover, Germany. [Abboud, Emad B.; Al-Rajhi, Ali A.] King Khalid Eye Specialist Hosp, Riyadh 11462, Saudi Arabia. [Omran, Heymut] Univ Klinikum Munster, Klin & Poliklin Kinder & Jugendmed Allgemeine Pad, D-48149 Munster, Germany. [Lee, Eva Y. -H. P.; Wang, Shaohui] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. [Johnson, Colin A.] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Garner, Elizabeth; Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. [Vanselow, Katja; Andersen, Jens S.] Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. [Levy, Shawn] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hildebrandt, F (reprint author), Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. EM fhilde@umich.edu RI Katsanis, Nicholas/E-1837-2012; Roepman, Ronald/B-1339-2014; Bryja, Vit?zslav/H-1925-2014; Schermer, Bernhard/E-9972-2014; Lindstrand, Anna/J-3566-2012; Andersen, Jens/L-2100-2015; van Reeuwijk, Jeroen/P-8665-2015; Janssen, S./F-2917-2016 OI Sayer, John/0000-0003-1881-3782; Liebau, Max Christoph/0000-0003-0494-9080; Katsanis, Nicholas/0000-0002-2480-0171; Saunders, Rudel/0000-0001-6042-556X; Otto, Edgar/0000-0002-2387-9973; Bryja, Vit?zslav/0000-0002-9136-5085; Sekiguchi, JoAnn/0000-0002-7178-4258; Schermer, Bernhard/0000-0002-5194-9000; Lindstrand, Anna/0000-0003-0806-5602; Andersen, Jens/0000-0002-6091-140X; van Reeuwijk, Jeroen/0000-0002-0658-4399; Janssen, S./0000-0001-8470-3050 FU NIH [DK068306, DK090917, NS054871, NS060109, HD042601, DK075972, DK072301, DK091405, F32EY19430]; March of Dimes Foundation; Center for Organogenesis of the University of Michigan; Netherlands Organization for Scientific Research [NWO Vidi-91786396, NWO Vidi-917.66.354]; Avenir-INSERM program; Agence Nationale pour la Recherche; Union Nationale pour les Aveugles et Deficients Visuels; RETINA France; Programme Hospitalier de Recherche National; Association Bardet-Biedl, France; European Community [241955, SYSCILIA]; Dutch Kidney Foundation [KJPB09.009, IP11.58]; Retina Research Foundation; National Eye Institute [R01EY018571]; DFG [SCHE1562, SFB832, SFB829, SFB592]; FFB-Canada; CIHR; FRSQ; Reseau Vision; Lundbeck Foundation; Ministry of Education, Youth and Sports of the Czech Republic [MSM0021622430]; Czech Science Foundation [204/09/H058, 204/09/0498]; EMBO Installation Grant; Brno PhD Talent of South Moravian Center for International Mobility; Burroughs Wellcome Fund Career Award for Medical Scientists; Doris Duke Charitable Foundation FX We are grateful to the study individuals for their contributions. This research was supported by grants from the NIH to F. H. (DK068306, DK090917), B. A. H (NS054871, NS060109), N.K. (HD042601, DK075972, DK072301), and W.Z. (DK091405); the March of Dimes Foundation and the Center for Organogenesis of the University of Michigan to F. H.; the Netherlands Organization for Scientific Research to R. R. (NWO Vidi-91786396) and R. H. G. (NWO Vidi-917.66.354), the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et Deficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007, and the Association Bardet-Biedl, France to H. D. and C. S.; the European Community's Seventh Framework Programme FP7/2009 under grant agreement no: 241955, SYSCILIA (to R. H. G., G. G. S., N.K., R. R., H.O., C.A.J. and G. W.); the Dutch Kidney Foundation (KJPB09.009 and IP11.58 to H. H. A); the Retina Research Foundation and the National Eye Institute (R01EY018571) to R.C.; the NIH to H. W. (F32EY19430); and the DFG (SCHE1562 and SFB832 to B. S.; SFB829 to T. B.; SFB592 to H.O.). R. K. K. is supported by FFB-Canada, CIHR, FRSQ, and Reseau Vision. J.S.A. is supported by the Lundbeck Foundation. V. B. is supported by MSM0021622430 (Ministry of Education, Youth and Sports of the Czech Republic), 204/09/H058, and 204/09/0498 (Czech Science Foundation) and EMBO Installation Grant; I. C. is supported by the programme, Brno PhD Talent of South Moravian Center for International Mobility. S. S. is a laureate of the "Equipe FRM" (DEQ20071210558) and the Agence National de la Recherche (R09087KS, R11012KK). W.Z. is a Carl. W. Gottschalk research scholar of the American Society of Nephrology. J.A.S. is a GlaxoSmithKline clinician scientist. A. S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists and the Doris Duke Charitable Foundation Clinical Scientist Development Awards and is a Rita Allen Foundation and an Irma T. Hirschl scholar. F. H. is an Investigator of the Howard Hughes Medical Institute, a Frederick G. L. Huetwell Professor, and a Doris Duke Distinguished Clinical Scientist. NR 51 TC 124 Z9 136 U1 1 U2 35 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 533 EP 548 DI 10.1016/j.cell.2012.06.028 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400013 PM 22863007 ER PT J AU Wen, Q Goldenson, B Silver, SJ Schenone, M Dancik, V Huang, Z Wang, LZ Lewis, TA An, WF Li, XY Bray, MA Thiollier, C Diebold, L Gilles, L Vokes, MS Moore, CB Bliss-Moreau, M VerPlank, L Tolliday, NJ Mishra, R Vemula, S Shi, JJ Wei, L Kapur, R Lopez, CK Gerby, B Ballerini, P Pflumio, F Gilliland, DG Goldberg, L Birger, Y Izraeli, S Gamis, AS Smith, FO Woods, WG Taub, J Scherer, CA Bradner, JE Goh, BC Mercher, T Carpenter, AE Gould, RJ Clemons, PA Carr, SA Root, DE Schreiber, SL Stern, AM Crispino, JD AF Wen, Qiang Goldenson, Benjamin Silver, Serena J. Schenone, Monica Dancik, Vlado Huang, Zan Wang, Ling-Zhi Lewis, Timothy A. An, W. Frank Li, Xiaoyu Bray, Mark-Anthony Thiollier, Clarisse Diebold, Lauren Gilles, Laure Vokes, Martha S. Moore, Christopher B. Bliss-Moreau, Meghan VerPlank, Lynn Tolliday, Nicola J. Mishra, Rama Vemula, Sasidhar Shi, Jianjian Wei, Lei Kapur, Reuben Lopez, Cecile K. Gerby, Bastien Ballerini, Paola Pflumio, Francoise Gilliland, D. Gary Goldberg, Liat Birger, Yehudit Izraeli, Shai Gamis, Alan S. Smith, Franklin O. Woods, William G. Taub, Jeffrey Scherer, Christina A. Bradner, James E. Goh, Boon-Cher Mercher, Thomas Carpenter, Anne E. Gould, Robert J. Clemons, Paul A. Carr, Steven A. Root, David E. Schreiber, Stuart L. Stern, Andrew M. Crispino, John D. TI Identification of Regulators of Polyploidization Presents Therapeutic Targets for Treatment of AMKL SO CELL LA English DT Article ID ACUTE MEGAKARYOBLASTIC LEUKEMIA; ACUTE MEGAKARYOCYTIC LEUKEMIA; AURORA-A KINASE; INHIBITOR MLN8237; DOWN-SYNDROME; CELL-CYCLE; B KINASE; PHOSPHORYLATION; MEGAKARYOPOIESIS; VALIDATION AB The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL. C1 [Silver, Serena J.; Schenone, Monica; Dancik, Vlado; Lewis, Timothy A.; An, W. Frank; Li, Xiaoyu; Bray, Mark-Anthony; Vokes, Martha S.; Moore, Christopher B.; Bliss-Moreau, Meghan; VerPlank, Lynn; Tolliday, Nicola J.; Scherer, Christina A.; Bradner, James E.; Carpenter, Anne E.; Gould, Robert J.; Clemons, Paul A.; Carr, Steven A.; Root, David E.; Schreiber, Stuart L.; Stern, Andrew M.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Wen, Qiang; Goldenson, Benjamin; Huang, Zan; Diebold, Lauren; Gilles, Laure; Crispino, John D.] Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. [Wang, Ling-Zhi; Goh, Boon-Cher] Natl Univ Singapore, Canc Sci Inst, Singapore 117599, Singapore. [Thiollier, Clarisse; Lopez, Cecile K.; Mercher, Thomas] Inst Gustave Roussy, INSERM, U985, F-94805 Villejuif, France. [Mishra, Rama] CMIDD, Evanston, IL USA. [Mishra, Rama] Northwestern Univ, Chicago, IL 60208 USA. [Vemula, Sasidhar; Shi, Jianjian; Wei, Lei; Kapur, Reuben] Indiana Univ, Dept Pediat, Indianapolis, IN 46202 USA. [Gerby, Bastien; Pflumio, Francoise] INSERM, CEA, Inst Radiobiol Cellulaire & Mol, EA 92265,UMR967, Fontenay Aux Roses, France. [Ballerini, Paola] Hop Trousseau, AP HP, F-75571 Paris, France. [Gilliland, D. Gary] Merck Sharp & Dohme Ltd, West Point, PA 19446 USA. [Goldberg, Liat; Birger, Yehudit; Izraeli, Shai] Tel Aviv Univ, Sheba Med Ctr, IL-52621 Ramat Gan, Israel. [Gamis, Alan S.] Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA. [Smith, Franklin O.] Univ Cincinnati, Inst Canc, Cincinnati, OH 45229 USA. [Woods, William G.] Childrens Healthcare Atlanta, Aflac Canc Ctr, Atlanta, GA 30322 USA. [Woods, William G.] Emory Univ, Atlanta, GA 30322 USA. [Taub, Jeffrey] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Stern, AM (reprint author), Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. EM astern@broadinstitute.org; j-crispino@northwestern.edu RI Bray, Mark/C-5973-2008; Mercher, Thomas/J-2446-2014; Carpenter, Anne/C-4982-2008; Pflumio, Francoise/E-2074-2017; OI Bray, Mark/0000-0002-9748-3592; Mercher, Thomas/0000-0003-1552-087X; Carpenter, Anne/0000-0003-1555-8261; Crispino, John/0000-0002-8182-8306 FU Samuel Waxman Cancer Research Foundation; US Israel Binational Science Foundation; Leukemia and Lymphoma Society Translational Research Program; Children with Leukaemia UK; Israel Science Foundation; European Hematology Association; Leukemia Research Foundation; NIH [CA101774, HL077177, HL075816, HL081111, GM089652, U54 HG005032, RL1-CA133834, RL1-GM084437, RL1-HG004671, UL1-DE019585]; Foundation Gustave Roussy; Jose Carreras Leukemia Foundation- European Hematology Association; CEA-EA; Ligue Nationale Contre le Cancer; Association Laurette Fugain; Societe Francaise d'Hematologie; Foundation pour la Recherche Medicale; National Cancer Institute (NCI) [U10 CA98543]; NCI's Initiative for Chemical Genetics [N01-CO-12400] FX The authors thank Sandeep Gurbuxani, Alex Minella, and Lou Dore for critical reading of the manuscript and Bang Wong for valuable advice on figures of the manuscript. This research was funded by grants from the Samuel Waxman Cancer Research Foundation (J.D.C. and S. I.), the US Israel Binational Science Foundation (to S. I. and J.D.C.), the Leukemia and Lymphoma Society Translational Research Program (J.D.C.), the Children with Leukaemia UK (S. I.), the Israel Science Foundation (S. I.), European Hematology Association (Y.B.), and the Leukemia Research Foundation (Y.B.) and by NIH grants CA101774 (J.D.C.), HL077177 (R. K.), HL075816 (R. K.), and HL081111 (R. K.). Other support included an NIH grant to A. E. C. supporting CellProfiler (GM089652), an NIH grant supporting screening informatics (U54 HG005032), NIH Genomics Based Drug Discovery U54 grants Discovery Pipeline RL1-CA133834, and Driving Medical Projects RL1-GM084437, administratively linked to NIH grants RL1-HG004671 and UL1-DE019585 (A. E. C., P. A. C., V. D., C. B. M., A. M. S., C. A. S., and M. S.). Y.B. is a European Hematology Association Fellow. In vivo treatment of human AMKL samples was supported by Foundation Gustave Roussy and Jose Carreras Leukemia Foundation- European Hematology Association (T. M.), CEA-EA, Ligue Nationale Contre le Cancer (F. P.), Association Laurette Fugain (F. P.), Societe Francaise d'Hematologie (B. G., F. P.), and Foundation pour la Recherche Medicale (C. T.). The authors would also like to thank Jason Berman, Soheil Meshinchi, Todd Alonzo, and Sommer Castro and the Children's Oncology Group (COG) for their assistance with DS-AMKL specimens. Research with DS-AMKL samples was supported by the Chair's Grant U10 CA98543 (to COG) from the National Cancer Institute (NCI). The project has also been funded in part with Federal funds from the NCI's Initiative for Chemical Genetics under Contract N01-CO-12400. The content of this publication is solely the responsibility of the authors and 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. A part of this work was performed by the Northwestern University ChemCore at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust. D. G. G. is an employee and shareholder of Merck and Co., Inc. R.J.G. is an employee, shareholder, and board member of Epizyme, Inc. and a member of the SAB of the Michael J. Fox Foundation. NR 41 TC 52 Z9 55 U1 3 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 575 EP 589 DI 10.1016/j.cell.2012.06.032 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400016 PM 22863010 ER PT J AU Van Handel, B Montel-Hagen, A Sasidharan, R Nakano, H Ferrari, R Boogerd, CJ Schredelseker, J Wang, YL Hunter, S Org, T Zhou, J Li, XM Pellegrini, M Chen, JN Orkin, SH Kurdistani, SK Evans, SM Nakano, A Mikkola, HKA AF Van Handel, Ben Montel-Hagen, Amelie Sasidharan, Rajkumar Nakano, Haruko Ferrari, Roberto Boogerd, Cornelis J. Schredelseker, Johann Wang, Yanling Hunter, Sean Org, Tonis Zhou, Jian Li, Xinmin Pellegrini, Matteo Chen, Jau-Nian Orkin, Stuart H. Kurdistani, Siavash K. Evans, Sylvia M. Nakano, Atsushi Mikkola, Hanna K. A. TI Scl Represses Cardiomyogenesis in Prospective Hemogenic Endothelium and Endocardium SO CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; AORTIC ENDOTHELIUM; PROGENITOR CELLS; CARDIOVASCULAR PROGENITORS; HAEMOGENIC ENDOTHELIUM; DEFINED FACTORS; SMOOTH-MUSCLE; MOUSE EMBRYO; DIFFERENTIATION; BLOOD AB Endothelium in embryonic hematopoietic tissues generates hematopoietic stem/progenitor cells; however, it is unknown how its unique potential is specified. We show that transcription factor Scl/Tal1 is essential for both establishing the hematopoietic transcriptional program in hemogenic endothelium and preventing its misspecification to a cardiomyogenic fate. Scl(-/-) embryos activated a cardiac transcriptional program in yolk sac endothelium, leading to the emergence of CD31(+)Pdgfr alpha(+) cardiogenic precursors that generated spontaneously beating cardiomyocytes. Ectopic cardiogenesis was also observed in Scl(-/-) hearts, where the disorganized endocardium precociously differentiated into cardiomyocytes. Induction of mosaic deletion of Scl in Scl(fl/fl)Rosa26Cre-ERT2 embryos revealed a cell-intrinsic, temporal requirement for Scl to prevent cardiomyogenesis from endothelium. Scl(-/-) endothelium also upregulated the expression of Wnt antagonists, which promoted rapid cardiomyocyte differentiation of ectopic cardiogenic cells. These results reveal unexpected plasticity in embryonic endothelium such that loss of a single master regulator can induce ectopic cardiomyogenesis from endothelial cells. C1 [Van Handel, Ben; Montel-Hagen, Amelie; Sasidharan, Rajkumar; Nakano, Haruko; Schredelseker, Johann; Wang, Yanling; Hunter, Sean; Org, Tonis; Pellegrini, Matteo; Chen, Jau-Nian; Nakano, Atsushi; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Ferrari, Roberto; Kurdistani, Siavash K.] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA. [Zhou, Jian; Li, Xinmin] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Pellegrini, Matteo; Kurdistani, Siavash K.; Nakano, Atsushi; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Pellegrini, Matteo; Kurdistani, Siavash K.; Nakano, Atsushi; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Pellegrini, Matteo; Kurdistani, Siavash K.; Nakano, Atsushi; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Mikkola, Hanna K. A.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Boogerd, Cornelis J.; Evans, Sylvia M.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA. [Boogerd, Cornelis J.; Evans, Sylvia M.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Mikkola, HKA (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. EM hmikkola@mcdb.ucla.edu RI Evans, Sylvia/G-1980-2015; Boogerd, Cornelis/A-7470-2016; Org, Tonis/E-8596-2010; Boogerd, Cornelis/D-3244-2009; OI Org, Tonis/0000-0003-3071-2183; Boogerd, Cornelis/0000-0002-7119-5381; Chen, Jau-Nian/0000-0001-8807-3607 FU California Institute for Regenerative Medicine (CIRM) New Faculty Award; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Innovation Award; NIH [HL097766-01]; Ruth L. Kirschstein National Research Service Award [GM07185]; NIH/National Heart, Lung, and Blood Institute [T32 HL69766]; European Molecular Biology Organisation; Human Frontier Science Program; CIRM; Netherlands Organization for Scientific Research [825.10.016]; European Union [MJD284]; Center of Excellence in Molecular Hematology award from the National Institute of Diabetes and Digestive and Kidney Diseases FX The authors thank Dr. Joshua Bloomekatz and Dr. Deborah Yelon for critical reading of the manuscript and sharing unpublished data and Guillaume Hagen for preparing the movies. The authors thank the Broad Stem Cell Research Center Flow Cytometry Core for FACS sorting. This work was funded by the California Institute for Regenerative Medicine (CIRM) New Faculty Award, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Innovation Award and NIH/RO1 (HL097766-01) grants to H. K. A. M. B. V. H. was supported by the Ruth L. Kirschstein National Research Service Award GM07185 and NIH/National Heart, Lung, and Blood Institute Grant T32 HL69766. A. M.-H was supported by successive fellowships from the European Molecular Biology Organisation and the Human Frontier Science Program. R. F. was funded in part by a CIRM grant to S. K. K. C.J.B. was funded by Rubicon Grant 825.10.016 from the Netherlands Organization for Scientific Research. T.O. was supported by the European Union through the European Social Fund (Mobilitas Grant No. MJD284). S.H.O., an Investigator of the Howard Hughes Medical Institute, is supported in part by a Center of Excellence in Molecular Hematology award from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 47 TC 71 Z9 71 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 590 EP 605 DI 10.1016/j.cell.2012.06.026 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400017 PM 22863011 ER PT J AU Rathinam, VAK Vanaja, SK Waggoner, L Sokolovska, A Becker, C Stuart, LM Leong, JM Fitzgerald, KA AF Rathinam, Vijay A. K. Vanaja, Sivapriya Kailasan Waggoner, Lisa Sokolovska, Anna Becker, Christine Stuart, Lynda M. Leong, John M. Fitzgerald, Katherine A. TI TRIF Licenses Caspase-11-Dependent NLRP3 Inflammasome Activation by Gram-Negative Bacteria SO CELL LA English DT Article ID NF-KAPPA-B; CASPASE-1 ACTIVATION; GENE-EXPRESSION; DENDRITIC CELLS; INTERFERON-BETA; INNATE IMMUNITY; ASC; APOPTOSIS; RECEPTOR; TRAM AB Systemic infections with Gram-negative bacteria are characterized by high mortality rates due to the "sepsis syndrome," a widespread and uncontrolled inflammatory response. Though it is well recognized that the immune response during Gram-negative bacterial infection is initiated after the recognition of endotoxin by Toll-like receptor 4, the molecular mechanisms underlying the detrimental inflammatory response during Gram-negative bacteremia remain poorly defined. Here, we identify a TRIF pathway that licenses NLRP3 inflammasome activation by all Gram-negative bacteria. By engaging TRIF, Gram-negative bacteria activate caspase-11. TRIF activates caspase-11 via type I IFN signaling, an event that is both necessary and sufficient for caspase-11 induction and autoactivation. Caspase-11 subsequently synergizes with the assembled NLRP3 inflammasome to regulate caspase-1 activation and leads to caspase-1-independent cell death. These events occur specifically during infection with Gram-negative, but not Gram-positive, bacteria. The identification of TRIF as a regulator of caspase-11 underscores the importance of TLRs as master regulators of inflammasomes during Gram-negative bacterial infection. C1 [Rathinam, Vijay A. K.; Vanaja, Sivapriya Kailasan; Waggoner, Lisa; Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [Vanaja, Sivapriya Kailasan; Leong, John M.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Sokolovska, Anna; Becker, Christine; Stuart, Lynda M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Fitzgerald, KA (reprint author), Univ Massachusetts, Sch Med, Dept Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. EM kate.fitzgerald@umassmed.edu FU NIH [AI083713, AI046454, AI079198]; NERCE [NIH/NIAID U54 AI057159] FX The authors thank Anna Cerny for animal husbandry and genotyping; Sanjay Ram, Douglas Golenbock, Rahul Gupta, Victor Boyartchuk, Brian Akerley, Sandy Wong, Beth McCormick, and Stephen Lory for bacterial strains; Christine Biron and Delia Demers for Stat-1-/- femurs; Karen Mossman and Derek Cummings for Irf9-/- femurs; Vishva Dixit and Nobuhiko Kayagaki for caspase-11-/- mice and additional reagents; Bill Kaiser for caspase-8-/-Rip3-/- and caspase-8+/-Rip3-/- femurs; Jakob von Moltke and Russell Vance for immortalized BMDMs; Egil Lien, Douglas Golenbock, and Ann Rothstein for critical reading of the manuscript; and all members of the Fitzgerald lab for helpful discussions. This work is supported by NIH grants AI083713 (to K. A. F.), AI046454 (to J.M.L.), and AI079198 (to L. M. S.) and NERCE Post-Doctoral Fellowship Awards NIH/NIAID U54 AI057159 to V. A. K. R and S.K.V. NR 46 TC 236 Z9 240 U1 4 U2 33 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 606 EP 619 DI 10.1016/j.cell.2012.07.007 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400018 PM 22819539 ER PT J AU Khalil, AS Lu, TK Bashor, CJ Ramirez, CL Pyenson, NC Joung, JK Collins, JJ AF Khalil, Ahmad S. Lu, Timothy K. Bashor, Caleb J. Ramirez, Cherie L. Pyenson, Nora C. Joung, J. Keith Collins, James J. TI A Synthetic Biology Framework for Programming Eukaryotic Transcription Functions SO CELL LA English DT Article ID ZINC-FINGER NUCLEASES; STRUCTURE-BASED DESIGN; CAMP RECEPTOR PROTEIN; POOL ENGINEERING OPEN; GENE NETWORKS; ESCHERICHIA-COLI; SYNERGISTIC ACTIVATION; DNA RECOGNITION; CANCER-CELLS; PDZ DOMAINS AB Eukaryotic transcription factors (TFs) perform complex and combinatorial functions within transcriptional networks. Here, we present a synthetic framework for systematically constructing eukaryotic transcription functions using artificial zinc fingers, modular DNA-binding domains found within many eukaryotic TFs. Utilizing this platform, we construct a library of orthogonal synthetic transcription factors (sTFs) and use these to wire synthetic transcriptional circuits in yeast. We engineer complex functions, such as tunable output strength and transcriptional cooperativity, by rationally adjusting a decomposed set of key component properties, e. g., DNA specificity, affinity, promoter design, protein-protein interactions. We show that subtle perturbations to these properties can transform an individual sTF between distinct roles (activator, cooperative factor, inhibitory factor) within a transcriptional complex, thus drastically altering the signal processing behavior of multi-input systems. This platform provides new genetic components for synthetic biology and enables bottom-up approaches to understanding the design principles of eukaryotic transcriptional complexes and networks. C1 [Lu, Timothy K.] MIT, Dept Elect Engn & Comp Sci, Synthet Biol Grp, Cambridge, MA 02139 USA. [Khalil, Ahmad S.; Bashor, Caleb J.; Pyenson, Nora C.; Collins, James J.] Boston Univ, Dept Biomed Engn, Howard Hughes Med Inst, Boston, MA 02215 USA. [Khalil, Ahmad S.; Bashor, Caleb J.; Pyenson, Nora C.; Collins, James J.] Boston Univ, Ctr BioDynam, Boston, MA 02215 USA. [Ramirez, Cherie L.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Ctr Canc Res, Charlestown, MA 02129 USA. [Ramirez, Cherie L.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Charlestown, MA 02129 USA. [Ramirez, Cherie L.] Harvard Univ, Sch Med, Div Med Sci, Biol & Biomed Sci Program, Boston, MA 02115 USA. [Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Collins, James J.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. RP Lu, TK (reprint author), MIT, Dept Elect Engn & Comp Sci, Synthet Biol Grp, Cambridge, MA 02139 USA. EM timlu@mit.edu RI Lu, Timothy/G-4267-2012; OI Lu, Timothy/0000-0002-3918-8923 FU Howard Hughes Medical Institute; NIH [DP1 OD003644, DP1 OD006862]; Office of Naval Research Multidisciplinary University Research Initiative (MURI); National Science Foundation [CCF-1124247]; Defense Advanced Research Projects Agency [DARPA-BAA-11-23]; National Science Foundation Graduate Research Fellowship FX We thank members of the Collins Lab for helpful discussions, Carl O. Pabo for helpful suggestions on reducing nonspecific affinity of zinc fingers, and Katie M. Flynn for help with artwork. This work was supported by the Howard Hughes Medical Institute (J.J.C.), NIH Director's Pioneer Awards DP1 OD003644 (J.J.C.) and DP1 OD006862 (J.K.J.), an Office of Naval Research Multidisciplinary University Research Initiative (MURI) grant (T. K. L.), the National Science Foundation CCF-1124247 (T. K. L.), a Defense Advanced Research Projects Agency grant (DARPA-BAA-11-23), and a National Science Foundation Graduate Research Fellowship (C.L.R.). NR 60 TC 122 Z9 126 U1 10 U2 93 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 3 PY 2012 VL 150 IS 3 BP 647 EP 658 DI 10.1016/j.cell.2012.05.045 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 985WO UT WOS:000307301400021 PM 22863014 ER PT J AU Dey, N Ghosh-Choudhury, N Kasinath, BS Choudhury, GG AF Dey, Nirmalya Ghosh-Choudhury, Nandini Kasinath, Balakuntalam S. Choudhury, Goutam Ghosh TI TGF beta-Stimulated MicroRNA-21 Utilizes PTEN to Orchestrate AKT/mTORC1 Signaling for Mesangial Cell Hypertrophy and Matrix Expansion SO PLOS ONE LA English DT Article ID MESSENGER-RNA TRANSLATION; GROWTH-FACTOR-BETA; PLASMINOGEN-ACTIVATOR INHIBITOR-1; PROMOTES RENAL FIBROSIS; CHRONIC KIDNEY-DISEASE; SMOOTH-MUSCLE-CELLS; DIABETIC-NEPHROPATHY; MAMMALIAN TARGET; HIGH GLUCOSE; AKT KINASE AB Transforming growth factor-beta (TGF beta) promotes glomerular hypertrophy and matrix expansion, leading to glomerulosclerosis. MicroRNAs are well suited to promote fibrosis because they can repress gene expression, which negatively regulate the fibrotic process. Recent cellular and animal studies have revealed enhanced expression of microRNA, miR-21, in renal cells in response to TGF beta. Specific miR-21 targets downstream of TGF beta receptor activation that control cell hypertrophy and matrix protein expression have not been studied. Using 3'UTR-driven luciferase reporter, we identified the tumor suppressor protein PTEN as a target of TGF beta-stimulated miR-21 in glomerular mesangial cells. Expression of miR-21 Sponge, which quenches endogenous miR-21 levels, reversed TGF beta-induced suppression of PTEN. Additionally, miR-21 Sponge inhibited TGF beta-stimulated phosphorylation of Akt kinase, resulting in attenuation of phosphorylation of its substrate GSK3 beta. Tuberin and PRAS40, two other Akt substrates, and endogenous inhibitors of mTORC1, regulate mesangial cell hypertrophy. Neutralization of endogenous miR-21 abrogated TGF beta-stimulated phosphorylation of tuberin and PRAS40, leading to inhibition of phosphorylation of S6 kinase, mTOR and 4EBP-1. Moreover, downregulation of miR-21 significantly suppressed TGF beta-induced protein synthesis and hypertrophy, which were reversed by siRNA-targeted inhibition of PTEN expression. Similarly, expression of constitutively active Akt kinase reversed the miR-21 Sponge-mediated inhibition of TGF beta-induced protein synthesis and hypertrophy. Furthermore, expression of constitutively active mTORC1 prevented the miR-21 Sponge-induced suppression of mesangial cell protein synthesis and hypertrophy by TGF beta. Finally, we show that miR-21 Sponge inhibited TGF beta-stimulated fibronectin and collagen expression. Suppression of PTEN expression and expression of both constitutively active Akt kinase and mTORC1 independently reversed this miR-21-mediated inhibition of TGF beta-induced fibronectin and collagen expression. Our results uncover an essential role of TGF beta-induced expression of miR-21, which targets PTEN to initiate a non-canonical signaling circuit involving Akt/mTORC1 axis for mesangial cell hypertrophy and matrix protein synthesis. C1 [Dey, Nirmalya; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Ghosh-Choudhury, Nandini; Kasinath, Balakuntalam S.; Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Vet Adm Res, San Antonio, TX USA. RP Dey, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institutes of Health (NIH) [RO1 DK50190, RO1 AR 52425, RO1 DK 077295, RC2A 036613]; VA (Veterans Administration) Research Service Merit Review grant; Juvenile Diabetes Research Foundation [1-2008-185]; VA Senior Research Career Scientist Award; VA Merit Review; Cancer Therapy and Research Center, San Antonio, Texas FX National Institutes of Health (NIH) RO1 DK50190 grant to GGC supported this work. Part of this work was also supported by VA (Veterans Administration) Research Service Merit Review grant to GGC. GGC is also supported by Juvenile Diabetes Research Foundation 1-2008-185 grants and is recipient of VA Senior Research Career Scientist Award. NGC is supported by VA Merit Review, NIH RO1 AR 52425 grants and Ronald P. Williams Orthopedic Oncology Developmental Research Award from Cancer Therapy and Research Center, San Antonio, Texas. BSK is supported by NIH RO1 DK 077295, NIH RC2A 036613 and VA Merit Review Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 102 TC 44 Z9 51 U1 1 U2 23 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 AUG 3 PY 2012 VL 7 IS 8 AR e42316 DI 10.1371/journal.pone.0042316 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 985QT UT WOS:000307284100066 PM 22879939 ER PT J AU Heng, TSP Reiseger, JJ Fletcher, AL Leggatt, GR White, OJ Vlahos, K Frazer, IH Turner, SJ Boyd, RL AF Heng, Tracy S. P. Reiseger, Jessica J. Fletcher, Anne L. Leggatt, Graham R. White, Olivia J. Vlahos, Katerina Frazer, Ian H. Turner, Stephen J. Boyd, Richard L. TI Impact of Sex Steroid Ablation on Viral, Tumour and Vaccine Responses in Aged Mice SO PLOS ONE LA English DT Article ID T-CELLS; INFLUENZA VACCINATION; VIRUS; DIVERSITY; TRANSPLANTATION; REGENERATION; LYMPHOCYTES; GENERATION; INDUCTION; INFECTION AB Recent evidence suggests that the decline in resistance to viral infections with age occurs predominantly as a result of a gradual loss of naive antigen-specific T cells. As such, restoration of the naive T cell repertoire to levels seen in young healthy adults may improve defence against infection in the aged. We have previously shown that sex steroid ablation (SSA) rejuvenates the ageing thymus and increases thymic export of naive T cells, but it remains unclear whether T cell responses are improved. Using mouse models of clinically relevant diseases, we now demonstrate that SSA increases the number of naive T cells able to respond to antigen, thereby enhancing effector responses in aged mice. Specifically, aged mice exhibit a delay in clearing influenza A virus, which correlates with diminished specific cytotoxic activity. This is due to a decreased magnitude of response and not an intrinsic defect in effector T cell function. Upon SSA, aged mice exhibit increased T cell responsiveness that restores efficient viral clearance. We further demonstrate that SSA decreases the incidence of an inducible tumour in aged mice and can potentially increase their responsiveness to a low-dose human papillomavirus vaccine in clearing pre-formed tumours. As thymectomy abrogates the increase in T cell numbers and responsiveness following SSA, we propose that the T cell effects of SSA are dependent on thymic reactivation and subsequent replenishment of the peripheral T cell pool with newly emigrated naive T cells. These findings have important implications for strategies to improve protection from infection and responsiveness to vaccination in the aged. C1 [Heng, Tracy S. P.; Reiseger, Jessica J.; Fletcher, Anne L.; Vlahos, Katerina; Boyd, Richard L.] Monash Univ, Monash Immunol & Stem Cell Labs, Clayton, Vic, Australia. [Fletcher, Anne L.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Leggatt, Graham R.; White, Olivia J.; Frazer, Ian H.] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Woolloongabba, Qld, Australia. [Turner, Stephen J.] Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3052, Australia. RP Heng, TSP (reprint author), Monash Univ, Monash Immunol & Stem Cell Labs, Clayton, Vic, Australia. EM tracy.heng@monash.edu; richard.boyd@monash.edu OI Turner, Stephen/0000-0002-1002-0000; Leggatt, Graham/0000-0002-4078-5653; Frazer, Ian/0000-0002-8002-4680 FU Australian National Health and Medical Research Council; Norwood Immunology Ltd; NHMRC RD Wright Fellowship; Pfizer Senior Research Fellowship; Queensland Government Smart State Fellowship FX This work was supported by program grants from the Australian National Health and Medical Research Council, Norwood Immunology Ltd, an NHMRC RD Wright Fellowship and Pfizer Senior Research Fellowship to ST, and a Queensland Government Smart State Fellowship to IF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 5 Z9 5 U1 0 U2 3 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 AUG 3 PY 2012 VL 7 IS 8 AR e42677 DI 10.1371/journal.pone.0042677 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 985QT UT WOS:000307284100156 PM 22880080 ER PT J AU Maeng, CH Lee, J van Hummelen, P Park, SH Palescandolo, E Jang, J Park, HY Kang, SY MacConaill, L Kim, KM Shim, YM AF Maeng, Chi Hoon Lee, Jeeyun van Hummelen, Paul Park, Se Hoon Palescandolo, Emanuele Jang, Jiryeon Park, Ha Young Kang, So Young MacConaill, Laura Kim, Kyoung-Mee Shim, Young-Mog TI High-Throughput Genotyping in Metastatic Esophageal Squamous Cell Carcinoma Identifies Phosphoinositide-3-Kinase and BRAF Mutations SO PLOS ONE LA English DT Article ID HUMAN CANCER; PIK3CA MUTATIONS; GENE; SURVIVAL AB Background: Given the high incidence of metastatic esophageal squamous cell carcinoma, especially in Asia, we screened for the presence of somatic mutations using OncoMap platform with the aim of defining subsets of patients who may be potential candidate for targeted therapy. Methods and Materials: We analyzed 87 tissue specimens obtained from 80 patients who were pathologically confirmed with esophageal squamous cell carcinoma and received 5-fluoropyrimidine/platinum-based chemotherapy. OncoMap 4.0, a mass-spectrometry based assay, was used to interrogate 471 oncogenic mutations in 41 commonly mutated genes. Tumor specimens were prepared from primary cancer sites in 70 patients and from metastatic sites in 17 patients. In order to test the concordance between primary and metastatic sites from the patient for mutations, we analyzed 7 paired (primary-metastatic) specimens. All specimens were formalin-fixed paraffin embedded tissues and tumor content was >70%. Results: In total, we have detected 20 hotspot mutations out of 80 patients screened. The most frequent mutation was PIK3CA mutation (four E545K, five H1047R and one H1047L) (N = 10, 11.5%) followed by MLH1 V384D (N = 7, 8.0%), TP53 (R306, R175H and R273C) (N = 3, 3.5%), BRAF V600E (N = 1, 1.2%), CTNNB1 D32N (N = 1, 1.2%), and EGFR P733L (N = 1, 1.2%). Distributions of somatic mutations were not different according to anatomic sites of esophageal cancer (cervical/upper, mid, lower). In addition, there was no difference in frequency of mutations between primary-metastasis paired samples. Conclusions: Our study led to the detection of potentially druggable mutations in esophageal SCC which may guide novel therapies in small subsets of esophageal cancer patients. C1 [Maeng, Chi Hoon; Lee, Jeeyun; Park, Se Hoon; Jang, Jiryeon] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Hematol Oncol,Dept Med, Seoul, South Korea. [van Hummelen, Paul; Palescandolo, Emanuele; MacConaill, Laura] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [van Hummelen, Paul; Palescandolo, Emanuele; MacConaill, Laura] Harvard Univ, Sch Med, Boston, MA USA. [Park, Ha Young; Kang, So Young; Kim, Kyoung-Mee] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Shim, Young-Mog] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Thorac Surg, Seoul, South Korea. RP Maeng, CH (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Hematol Oncol,Dept Med, Seoul, South Korea. EM jyunlee@skku.edu RI Lee, Jee Yun/C-9646-2011; Lee, Jeeyun/I-7171-2015 FU Ministry for Health & Welfare Affairs, Republic of Korea [A092255, A101130]; Samsung Biomedical Research Institute [SBRI-CB11031, SBRI-CB02202]; Sungkyunkwan University [S-2009-1181-000] FX This paper was supported by grants from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (A092255 & A101130), a grant from Samsung Biomedical Research Institute (#SBRI-CB11031, SBRI-CB02202), and a grant from Sungkyunkwan University (#S-2009-1181-000). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 24 Z9 25 U1 0 U2 5 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 AUG 3 PY 2012 VL 7 IS 8 AR e41655 DI 10.1371/journal.pone.0041655 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 985QT UT WOS:000307284100028 PM 22870241 ER PT J AU Saini, V Hose, CD Monks, A Nagashima, K Han, BN Newton, DL Millione, A Shah, J Hollingshead, MG Hite, KM Burkett, MW Delosh, RM Silvers, TE Scudiero, DA Shoemaker, RH AF Saini, Vaibhav Hose, Curtis D. Monks, Anne Nagashima, Kunio Han, Bingnan Newton, Dianne L. Millione, Angelena Shah, Jalpa Hollingshead, Melinda G. Hite, Karen M. Burkett, Mark W. Delosh, Rene M. Silvers, Thomas E. Scudiero, Dominic A. Shoemaker, Robert H. TI Identification of CBX3 and ABCA5 as Putative Biomarkers for Tumor Stem Cells in Osteosarcoma SO PLOS ONE LA English DT Article ID PROSTATE-CANCER CELLS; ALDEHYDE DEHYDROGENASE; LUNG-CANCER; OSTEOBLASTIC PROPERTIES; INITIATING CELLS; DRUG-RESISTANCE; LINE SAOS-2; EXPRESSION; MARKER; OCT-4 AB Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma. C1 [Saini, Vaibhav; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. [Hose, Curtis D.; Monks, Anne; Nagashima, Kunio; Han, Bingnan; Newton, Dianne L.; Millione, Angelena; Shah, Jalpa; Hite, Karen M.; Burkett, Mark W.; Delosh, Rene M.; Silvers, Thomas E.; Scudiero, Dominic A.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Hollingshead, Melinda G.] NCI, Biol Testing Branch, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Saini, V (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM Shoemakr@mail.nih.gov FU National Cancer Institute (NCI); National Institutes of Health (NIH); Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute; NCI, NIH [HHSN261200800001E] FX VS was supported by a visiting fellowship, National Cancer Institute (NCI), and National Institutes of Health (NIH). The research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, and in part with federal funds from the NCI, NIH, under contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 31 Z9 34 U1 0 U2 10 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 AUG 3 PY 2012 VL 7 IS 8 AR e41401 DI 10.1371/journal.pone.0041401 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 985QT UT WOS:000307284100017 PM 22870217 ER PT J AU Willems, E Cabral-Teixeira, J Schade, D Cai, WQ Reeves, P Bushway, PJ Lanier, M Walsh, C Kirchhausen, T Belmonte, JCI Cashman, J Mercola, M AF Willems, Erik Cabral-Teixeira, Joaquim Schade, Dennis Cai, Wenqing Reeves, Patrick Bushway, Paul J. Lanier, Marion Walsh, Christopher Kirchhausen, Tomas Izpisua Belmonte, Juan Carlos Cashman, John Mercola, Mark TI Small Molecule-Mediated TGF-beta Type II Receptor Degradation Promotes Cardiomyogenesis in Embryonic Stem Cells SO CELL STEM CELL LA English DT Article ID DIFFERENTIATION; MOUSE; HEMATOPOIESIS; BIOLOGY AB The cellular signals controlling the formation of cardiomyocytes, vascular smooth muscle, and endothelial cells from stem cell-derived mesoderm are poorly understood. To identify these signals, a mouse embryonic stem cell (ESC)-based differentiation assay was screened against a small molecule library resulting in a 1,4-dihydropyridine inducer of type II TGF-beta receptor (TGFBR2) degradation-1 (ITD-1). ITD analogs enhanced proteasomal degradation of TGFBR2, effectively clearing the receptor from the cell surface and selectively inhibiting intracellular signaling (IC50 similar to 0.4-0.8 mu M). ITD-1 was used to evaluate TGF-beta involvement in mesoderm formation and cardiopoietic differentiation, which occur sequentially during early development, revealing an essential role in both processes in ESC cultures. ITD-1 selectively enhanced the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. ITD-1 is a highly selective TGF-beta inhibitor and reveals an unexpected role for TGF-beta signaling in controlling cardiomyocyte differentiation from multipotent cardiovascular precursors. C1 [Willems, Erik; Cabral-Teixeira, Joaquim; Schade, Dennis; Cai, Wenqing; Bushway, Paul J.; Mercola, Mark] Sanford Burnham Med Res Inst, Muscle Dev & Regenerat Program, La Jolla, CA 92037 USA. [Cai, Wenqing] Sanford Burnham Med Res Inst, Grad Sch Biomed Sci, La Jolla, CA 92037 USA. [Willems, Erik; Schade, Dennis; Lanier, Marion; Cashman, John; Mercola, Mark] ChemRegen Inc, San Diego, CA 92130 USA. [Schade, Dennis; Lanier, Marion; Cashman, John] Human Biomol Res Inst, San Diego, CA 92121 USA. [Reeves, Patrick; Kirchhausen, Tomas] Harvard Univ, Sch Med, Immune Dis Inst, Dept Cell Biol, Boston, MA 02115 USA. [Walsh, Christopher; Izpisua Belmonte, Juan Carlos] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. [Izpisua Belmonte, Juan Carlos] Ctr Regenerat Med Barcelona, Barcelona 08003, Spain. RP Willems, E (reprint author), Sanford Burnham Med Res Inst, Muscle Dev & Regenerat Program, La Jolla, CA 92037 USA. EM ewillems@sanfordburnham.org; mmercola@sanfordburnham.org OI Cabral Teixeira, Joaquim/0000-0002-8949-1701 FU CIRM [T2-00004, RS-00169-1, RC1-000132]; AHA; German Research Foundation [SCHA 1663/1-1]; NIH [HL088293, HL059502]; MINECO; T Foundation; NIH STIR [R41-HL108714] FX The authors would like to thank Fabio Cerignoli and Karl Willert for running calcium transient assays and Wnt TOPflash assays, respectively. This work was supported by CIRM T2-00004 and AHA fellowship to E.W., German Research Foundation Grant SCHA 1663/1-1 to D.S., NIH HL088293 and MINECO to J.C.I.B., CIRM Seed RS-00169-1 and T Foundation to J.C., CIRM RC1-000132 and NIH HL059502 to M.M., and NIH STIR R41-HL108714 to ChemRegen Inc. E.W., M.M., and J.C. are cofounders of ChemRegen, Inc. NR 20 TC 48 Z9 51 U1 1 U2 16 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 AUG 3 PY 2012 VL 11 IS 2 BP 242 EP 252 DI 10.1016/j.stem.2012.04.025 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 987QQ UT WOS:000307432600014 PM 22862949 ER PT J AU Padmanabhan, K Robles, MS Westerling, T Weitz, CJ AF Padmanabhan, Kiran Robles, Maria S. Westerling, Thomas Weitz, Charles J. TI Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex SO SCIENCE LA English DT Article ID NEGATIVE FEEDBACK; COMPONENTS; MECHANISM; PROTEINS; LIMB; REPRESSION; OSCILLATOR; NEUROSPORA; ALPHA AB Eukaryotic circadian clocks are built on transcriptional feedback loops. In mammals, the PERIOD (PER) and CRYPTOCHROME (CRY) proteins accumulate, form a large nuclear complex (PER complex), and repress their own transcription. We found that mouse PER complexes included RNA helicases DDX5 and DHX9, active RNA polymerase II large subunit, Per and Cry pre-mRNAs, and SETX, a helicase that promotes transcriptional termination. During circadian negative feedback, RNA polymerase II accumulated near termination sites on Per and Cry genes but not on control genes. Recruitment of PER complexes to the elongating polymerase at Per and Cry termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. Circadian clock negative feedback thus includes direct control of transcriptional termination. C1 [Padmanabhan, Kiran; Robles, Maria S.; Weitz, Charles J.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Westerling, Thomas] Harvard Univ, Sch Med, Ctr Funct Canc Epigenet, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weitz, CJ (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. EM cweitz@hms.harvard.edu RI Robles, Maria /D-6307-2015; OI Robles, Maria /0000-0001-9149-8761; Padmanabhan, Kiran/0000-0001-7020-1682 FU G. Harold and Leila Y. Mathers Charitable Foundation; David Mahoney Fellowship; Edward R. and Anne G. Lefler Center fellowship FX We thank M. Liu for technical assistance and J. Gray and M. Greenberg (Harvard Medical School) for helpful comments. All data are tabulated in the paper and supplementary materials. This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation (C. J. W.), a David Mahoney Fellowship (K. P.), and an Edward R. and Anne G. Lefler Center fellowship (M.S.R.). NR 21 TC 65 Z9 74 U1 0 U2 8 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 AUG 3 PY 2012 VL 337 IS 6094 BP 599 EP 602 DI 10.1126/science.1221592 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 982PU UT WOS:000307058700050 PM 22767893 ER PT J AU Sundstrom, E Imsland, F Mikko, S Wade, C Sigurdsson, S Pielberg, GR Golovko, A Curik, I Seltenhammer, MH Solkner, J Lindblad-Toh, K Andersson, L AF Sundstrom, Elisabeth Imsland, Freyja Mikko, Sofia Wade, Claire Sigurdsson, Snaevar Pielberg, Gerli Rosengren Golovko, Anna Curik, Ino Seltenhammer, Monika H. Soelkner, Johann Lindblad-Toh, Kerstin Andersson, Leif TI Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses SO BMC GENOMICS LA English DT Article DE STX17; Melanoma; Hair greying; Copy number variation; Melanocytes ID DOMINANT WHITE COLOR; COAT COLOR; HUMAN GENOME; GENE; KIT; SUSCEPTIBILITY; POLYMORPHISMS; MUTATION; RECEPTOR; PIGS AB Background: Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation. Results: We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the similar to 350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present. Conclusions: These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research. C1 [Sundstrom, Elisabeth; Andersson, Leif] Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75124 Uppsala, Sweden. [Sundstrom, Elisabeth; Imsland, Freyja; Pielberg, Gerli Rosengren; Golovko, Anna; Lindblad-Toh, Kerstin; Andersson, Leif] Uppsala Univ, Sci Life Lab Uppsala, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden. [Mikko, Sofia] Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden. [Wade, Claire; Sigurdsson, Snaevar; Lindblad-Toh, Kerstin] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Wade, Claire] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wade, Claire] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Curik, Ino] Univ Zagreb, Fac Agr, Dept Anim Sci, HR-10000 Zagreb, Croatia. [Seltenhammer, Monika H.] Univ Vet Med, Clin Dept Small Anim Surg, Vienna, Austria. [Soelkner, Johann] Univ Nat Resources & Appl Life Sci, Dept Sustainable Agr Syst, A-1180 Vienna, Austria. RP Andersson, L (reprint author), Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Box 597, SE-75124 Uppsala, Sweden. EM leif.andersson@imbim.uu.se OI Mikko, Sofia/0000-0002-6375-1376; Wade, Claire/0000-0003-3413-4771 FU Swedish Cancer Society; Foundation for Strategic Research; National Human Genome Research Institute; European Science Foundation FX We are grateful to Michael O. Hottiger, Institute of Veterinary Biochemistry, University of Zurich for kindly providing the equine melanoma cell lines, and to Jenny Hagenblad for information about late greying Connemara horses. The project received support from the Swedish Cancer Society, the Foundation for Strategic Research and the National Human Genome Research Institute. K.L.-T. is the recipient of a European Young Investigator award funded by the European Science Foundation. NR 25 TC 12 Z9 12 U1 2 U2 13 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 AUG 2 PY 2012 VL 13 AR 365 DI 10.1186/1471-2164-13-365 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 008EK UT WOS:000308940000001 PM 22857264 ER PT J AU Lucas, G Lluis-Ganella, C Subirana, I Musameh, MD Gonzalez, JR Nelson, CP Senti, M Schwartz, SM Siscovick, D O'Donnell, CJ Melander, O Salomaa, V Purcell, S Altshuler, D Samani, NJ Kathiresan, S Elosua, R AF Lucas, Gavin Lluis-Ganella, Carla Subirana, Isaac Musameh, Muntaser D. Ramon Gonzalez, Juan Nelson, Christopher P. Senti, Mariano Schwartz, Stephen M. Siscovick, David O'Donnell, Christopher J. Melander, Olle Salomaa, Veikko Purcell, Shaun Altshuler, David Samani, Nilesh J. Kathiresan, Sekar Elosua, Roberto CA Myocardial Infarction Genetics Con Wellcome Trust Case Control Consor TI Hypothesis-Based Analysis of Gene-Gene Interactions and Risk of Myocardial Infarction SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; COMPLEX DISEASES; HEART-DISEASE; EPISTASIS; LOCI; POLYMORPHISMS; HERITABILITY; CHOLESTEROL; STRATEGIES AB The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework. Despite having reasonable power to detect interaction effects of plausible magnitudes, we observed no statistically significant evidence of interaction under these hypotheses, and no clear consistency between the top results in our discovery sample and those in a large validation sample of 1,766 cases of coronary heart disease and 2,938 controls from the Wellcome Trust Case-Control Consortium. Our results do not support the existence of strong interaction effects as a common risk factor for MI. Within the scope of the hypotheses we have explored, this study places a modest upper limit on the magnitude that epistatic risk effects are likely to have at the population level (odds ratio for MI risk 1.3-2.0, depending on allele frequency and interaction model). C1 [Lucas, Gavin; Lluis-Ganella, Carla; Subirana, Isaac; Senti, Mariano; Elosua, Roberto] IMIM, Barcelona, Spain. [Lluis-Ganella, Carla; Ramon Gonzalez, Juan; Elosua, Roberto] Epidemiol & Publ Hlth Network CIBERESP, Barcelona, Spain. [Musameh, Muntaser D.; Nelson, Christopher P.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Musameh, Muntaser D.; Nelson, Christopher P.; Samani, Nilesh J.] Glenfield Gen Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Ramon Gonzalez, Juan] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain. [Ramon Gonzalez, Juan] IMIM Hosp Mar Res Inst, Barcelona, Spain. [Senti, Mariano] Pompeu Fabra Univ, Barcelona, Spain. [Schwartz, Stephen M.; Siscovick, David] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schwartz, Stephen M.; Siscovick, David] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [O'Donnell, Christopher J.] NHLBI, Framingham, MA USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Melander, Olle] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Purcell, Shaun] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Purcell, Shaun] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Altshuler, David; Kathiresan, Sekar] Broad Inst MIT & Harvard, Cambridge, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Lucas, G (reprint author), IMIM, Barcelona, Spain. EM glucas@imim.es RI Lluis-Ganella, Carla/G-5998-2012; Altshuler, David/A-4476-2009; Senti, M/D-4309-2014; Ramos , Rafel/D-9627-2016; OI Hattersley, Andrew/0000-0001-5620-473X; Lluis-Ganella, Carla/0000-0001-7609-5497; Altshuler, David/0000-0002-7250-4107; Ramos , Rafel/0000-0001-8146-5288; Ramos , Rafel/0000-0001-7970-5537; ELOSUA, ROBERTO/0000-0001-8235-0095; Piazza, Alberto/0000-0002-2355-4183; Senti, Mariano/0000-0002-6983-3831; Schwartz, Stephen/0000-0001-7499-8502; Marrugat, Jaume/0000-0003-3320-554X; Ouwehand, Willem/0000-0002-7744-1790 FU National Institutes of Health, USA [R01 HL087676]; Wellcome Trust [085475]; ACC1O [RD08-1-0024]; European Regional Development Fund (ERDF-FEDER); Spanish Ministry of Science and Innovation through Carlos III Health Institute (CIBER Epidemiologia y Salud Publica, Red HERACLES and GENOMet network) [RD06/0009, PI061254, PI09/90506, MTM2010-09526-E]; Catalan Research and Technology Innovation Interdepartmental Commission [SGR 1195]; Fundacio La Marato de TV3 [1081810, 080431]; Academy of Finland [129494, 139635]; Juan de la Cierva Program, Ministerio de Educacion [JCI-2009-04684] FX The Myocardial Infarction Genetics Consortium (MIGen) was funded by grant R01 HL087676 from the National Institutes of Health, USA. The Wellcome Trust Case-Control Consortium 2 was funded by the Wellcome Trust under award 085475. This work was supported by a grant from ACC1O (RD08-1-0024), the European Regional Development Fund (ERDF-FEDER), the Spanish Ministry of Science and Innovation through the Carlos III Health Institute (CIBER Epidemiologia y Salud Publica, Red HERACLES RD06/0009, PI061254, PI09/90506 and the GENOMet network, MTM2010-09526-E), the Catalan Research and Technology Innovation Interdepartmental Commission (SGR 1195) and Fundacio La Marato de TV3 (1081810; 080431). VS was supported by the Academy of Finland (grants # 129494 and 139635). GL was funded by the Juan de la Cierva Program, Ministerio de Educacion (JCI-2009-04684). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 9 Z9 9 U1 0 U2 7 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 AUG 2 PY 2012 VL 7 IS 8 AR e41730 DI 10.1371/journal.pone.0041730 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 984JA UT WOS:000307184700020 PM 22876292 ER PT J AU Moreau, P Richardson, PG Cavo, M Orlowski, RZ San Miguel, JF Palumbo, A Harousseau, JL AF Moreau, Philippe Richardson, Paul G. Cavo, Michele Orlowski, Robert Z. San Miguel, Jesus F. Palumbo, Antonio Harousseau, Jean-Luc TI Proteasome inhibitors in multiple myeloma: 10 years later SO BLOOD LA English DT Review ID STEM-CELL TRANSPLANTATION; BORTEZOMIB PLUS DEXAMETHASONE; HIGH-DOSE MELPHALAN; INDUCTION TREATMENT PRIOR; EXTENDED FOLLOW-UP; PHASE-I TRIAL; PEGYLATED LIPOSOMAL DOXORUBICIN; ELDERLY UNTREATED PATIENTS; HEMATOLOGIC MALIGNANCIES; PERIPHERAL NEUROPATHY AB Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade. (Blood. 2012;120(5):947-959) C1 [Moreau, Philippe] Univ Hosp Hotel Dieu, Dept Hematol, F-44093 Nantes 01, France. [Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cavo, Michele] Univ Bologna, Policlin S Orsola Malpighi, Ist Ematol Seragnoli, Bologna, Italy. [Orlowski, Robert Z.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [San Miguel, Jesus F.] Univ Salamanca, Consejo Super Invest Cient, Hosp Univ Salamanca, Inst Invest Biomed Salamanca,Inst Biol Mol & Celu, E-37008 Salamanca, Spain. [Palumbo, Antonio] Azienda Osped Univ San Giovanni Battista, Osped Molinette, Unita Operat Ematol, Turin, Italy. [Harousseau, Jean-Luc] Inst Cancerol Ouest, Nantes, France. RP Moreau, P (reprint author), Univ Hosp Hotel Dieu, Dept Hematol, F-44093 Nantes 01, France. EM philippe.moreau@chu-nantes.fr RI richard, chrystelle/K-8595-2015; OI SAN MIGUEL, JESUS/0000-0002-9183-4857; CAVO, MICHELE/0000-0003-4514-3227 FU University Hospital Hotel-Dieu, Nantes, France FX This work was supported by the University Hospital Hotel-Dieu, Nantes, France. NR 99 TC 187 Z9 190 U1 5 U2 31 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 AUG 2 PY 2012 VL 120 IS 5 BP 947 EP 959 DI 10.1182/blood-2012-04-403733 PG 13 WC Hematology SC Hematology GA 987VS UT WOS:000307446500006 PM 22645181 ER PT J AU Huang, XG Di Liberto, M Jayabalan, D Liang, J Ely, S Bretz, J Shaffer, AL Louie, T Chen, I Randolph, S Hahn, WC Staudt, LM Niesvizky, R Moore, MAS Chen-Kiang, S AF Huang, Xiangao Di Liberto, Maurizio Jayabalan, David Liang, Jun Ely, Scott Bretz, Jamieson Shaffer, Arthur L., III Louie, Tracey Chen, Isan Randolph, Sophia Hahn, William C. Staudt, Louis M. Niesvizky, Ruben Moore, Malcolm A. S. Chen-Kiang, Selina TI Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4 SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA; CDK INHIBITORS; KINASE-ACTIVITY; BREAST-CANCER; IN-VITRO; P18(INK4C); TUMORIGENESIS; EXPRESSION; DIFFERENTIATION; DYSREGULATION AB Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. (Blood. 2012;120(5):1095-1106) C1 [Huang, Xiangao; Di Liberto, Maurizio; Jayabalan, David; Liang, Jun; Ely, Scott; Louie, Tracey; Chen-Kiang, Selina] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Jayabalan, David; Niesvizky, Ruben] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Bretz, Jamieson; Chen-Kiang, Selina] Weill Cornell Med Coll, Grad Program Immunol & Microbial Pathogenesis, New York, NY 10065 USA. [Shaffer, Arthur L., III; Staudt, Louis M.] NIH, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Isan; Randolph, Sophia] Pfizer Oncol, San Diego, CA USA. [Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02115 USA. [Moore, Malcolm A. S.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Chen-Kiang, S (reprint author), Weill Cornell Med Coll, Dept Pathol & Lab Med, 1300 York Ave,C-338, New York, NY 10065 USA. EM sckiang@med.cornell.edu FU National Institutes of Health, National Cancer Institute, Center for Cancer Research [NCI R01 120531]; Leukemia & Lymphoma Society; Starr Cancer Consortium grant FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (A.L.S. and L.M.S.; NCI R01 120531, S.C.-K.), a Leukemia & Lymphoma Society Translational Research Program grant (S.C.-K.), and a Starr Cancer Consortium grant (W.C.H. and S.C.-K.). NR 47 TC 29 Z9 31 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 AUG 2 PY 2012 VL 120 IS 5 BP 1095 EP 1106 DI 10.1182/blood-2012-03-415984 PG 12 WC Hematology SC Hematology GA 987VS UT WOS:000307446500021 PM 22718837 ER PT J AU Northcott, PA Shih, DJH Peacock, J Garzia, L Morrissy, AS Zichner, T Stutz, AM Korshunov, A Reimand, J Schumacher, SE Beroukhim, R Ellison, DW Marshall, CR Lionel, AC Mack, S Dubuc, A Yao, Y Ramaswamy, V Luu, B Rolider, A Cavalli, FMG Wang, X Remke, M Wu, XC Chiu, RYB Chu, A Chuah, E Corbett, RD Hoad, GR Jackman, SD Li, YS Lo, A Mungall, KL Nip, KM Qian, JQ Raymond, AGJ Thiessen, N Varhol, RJ Birol, I Moore, RA Mungall, AJ Holt, R Kawauchi, D Roussel, MF Kool, M Jones, DTW Witt, H Fernandez-L, A Kenney, AM Wechsler-Reya, RJ Dirks, P Aviv, T Grajkowska, WA Perek-Polnik, M Haberler, CC Delattre, O Reynaud, SS Doz, FF Pernet-Fattet, SS Cho, BK Kim, SK Wang, KC Scheurlen, W Eberhart, CG Fevre-Montange, M Jouvet, A Pollack, IF Fan, X Muraszko, KM Gillespie, GY Di Rocco, C Massimi, L Michiels, EMC Kloosterhof, NK French, PJ Kros, JM Olson, JM Ellenbogen, RG Zitterbart, K Kren, L Thompson, RC Cooper, MK Lach, B McLendon, RE Bigner, DD Fontebasso, A Albrecht, S Jabado, N Lindsey, JC Bailey, S Gupta, N Weiss, WA Bognar, L Klekner, A Van Meter, TE Kumabe, T Tominaga, T Elbabaa, SK Leonard, JR Rubin, JB Liau, LM Van Meir, EG Fouladi, M Nakamura, H Cinalli, G Garami, M Hauser, P Saad, AG Iolascon, A Jung, S Carlotti, CG Vibhakar, R Ra, YS Robinson, S Zollo, M Faria, CC Chan, JA Levy, ML Sorensen, PHB Meyerson, M Pomeroy, SL Cho, YJ Bader, GD Tabori, U Hawkins, CE Bouffet, E Scherer, SW Rutka, JT Malkin, D Clifford, SC Jones, SJM Korbel, JO Pfister, SM Marra, MA Taylor, MD AF Northcott, Paul A. Shih, David J. H. Peacock, John Garzia, Livia Morrissy, A. Sorana Zichner, Thomas Stuetz, Adrian M. Korshunov, Andrey Reimand, Jueri Schumacher, Steven E. Beroukhim, Rameen Ellison, David W. Marshall, Christian R. Lionel, Anath C. Mack, Stephen Dubuc, Adrian Yao, Yuan Ramaswamy, Vijay Luu, Betty Rolider, Adi Cavalli, Florence M. G. Wang, Xin Remke, Marc Wu, Xiaochong Chiu, Readman Y. B. Chu, Andy Chuah, Eric Corbett, Richard D. Hoad, Gemma R. Jackman, Shaun D. Li, Yisu Lo, Allan Mungall, Karen L. Nip, Ka Ming Qian, Jenny Q. Raymond, Anthony G. J. Thiessen, Nina Varhol, Richard J. Birol, Inanc Moore, Richard A. Mungall, Andrew J. Holt, Robert Kawauchi, Daisuke Roussel, Martine F. Kool, Marcel Jones, David T. W. Witt, Hendrick Fernandez-L, Africa Kenney, Anna M. Wechsler-Reya, Robert J. Dirks, Peter Aviv, Tzvi Grajkowska, Wieslawa A. Perek-Polnik, Marta Haberler, Christine C. Delattre, Olivier Reynaud, Stephanie S. Doz, Francois F. Pernet-Fattet, Sarah S. Cho, Byung-Kyu Kim, Seung-Ki Wang, Kyu-Chang Scheurlen, Wolfram Eberhart, Charles G. Fevre-Montange, Michelle Jouvet, Anne Pollack, Ian F. Fan, Xing Muraszko, Karin M. Gillespie, G. Yancey Di Rocco, Concezio Massimi, Luca Michiels, Erna M. C. Kloosterhof, Nanne K. French, Pim J. Kros, Johan M. Olson, James M. Ellenbogen, Richard G. Zitterbart, Karel Kren, Leos Thompson, Reid C. Cooper, Michael K. Lach, Boleslaw McLendon, Roger E. Bigner, Darell D. Fontebasso, Adam Albrecht, Steffen Jabado, Nada Lindsey, Janet C. Bailey, Simon Gupta, Nalin Weiss, William A. Bognar, Laszlo Klekner, Almos Van Meter, Timothy E. Kumabe, Toshihiro Tominaga, Teiji Elbabaa, Samer K. Leonard, Jeffrey R. Rubin, Joshua B. Liau, Linda M. Van Meir, Erwin G. Fouladi, Maryam Nakamura, Hideo Cinalli, Giuseppe Garami, Miklos Hauser, Peter Saad, Ali G. Iolascon, Achille Jung, Shin Carlotti, Carlos G. Vibhakar, Rajeev Ra, Young Shin Robinson, Shenandoah Zollo, Massimo Faria, Claudia C. Chan, Jennifer A. Levy, Michael L. Sorensen, Poul H. B. Meyerson, Matthew Pomeroy, Scott L. Cho, Yoon-Jae Bader, Gary D. Tabori, Uri Hawkins, Cynthia E. Bouffet, Eric Scherer, Stephen W. Rutka, James T. Malkin, David Clifford, Steven C. Jones, Steven J. M. Korbel, Jan O. Pfister, Stefan M. Marra, Marco A. Taylor, Michael D. TI Subgroup-specific structural variation across 1,000 medulloblastoma genomes SO NATURE LA English DT Article ID HEDGEHOG PATHWAY INHIBITOR; COPY-NUMBER ALTERATION; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; HUMAN CANCERS; BETA FAMILY; SYNPHILIN-1; PROTEIN; MYC; CHILDHOOD AB Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy. C1 [Holt, Robert; Marra, Marco A.] Michael Smith Genome Sci Ctr, BC Canc Agcy, Vancouver, BC V5Z 1L3, Canada. [Northcott, Paul A.; Shih, David J. H.; Peacock, John; Garzia, Livia; Morrissy, A. Sorana; Mack, Stephen; Dubuc, Adrian; Yao, Yuan; Ramaswamy, Vijay; Luu, Betty; Rolider, Adi; Cavalli, Florence M. G.; Wang, Xin; Remke, Marc; Wu, Xiaochong; Taylor, Michael D.] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 1L7, Canada. [Northcott, Paul A.; Kool, Marcel; Jones, David T. W.; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Shih, David J. H.; Peacock, John; Mack, Stephen; Dubuc, Adrian; Yao, Yuan; Ramaswamy, Vijay; Wang, Xin; Taylor, Michael D.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada. [Zichner, Thomas; Stuetz, Adrian M.; Korbel, Jan O.] European Mol Biol Lab, D-69117 Heidelberg, Germany. [Korshunov, Andrey] Univ Heidelberg, German Canc Res Ctr DKFZ, Dept Neuropathol, CCU Neuropathol, D-69120 Heidelberg, Germany. [Reimand, Jueri; Bader, Gary D.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Schumacher, Steven E.; Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Beroukhim, Rameen; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Beroukhim, Rameen] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen] Broad Inst, Canc Program, Cambridge, MA 02142 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Ellison, David W.; Kawauchi, Daisuke; Roussel, Martine F.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Marshall, Christian R.; Bader, Gary D.; Scherer, Stephen W.] Univ Toronto, McLaughlin Ctr, Toronto, ON M5G 1L7, Canada. [Marshall, Christian R.; Bader, Gary D.; Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada. [Lionel, Anath C.; Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom & Program Genet & Genome Biol, Toronto, ON M5G 1L7, Canada. [Chiu, Readman Y. B.; Chu, Andy; Chuah, Eric; Corbett, Richard D.; Hoad, Gemma R.; Jackman, Shaun D.; Li, Yisu; Lo, Allan; Mungall, Karen L.; Nip, Ka Ming; Qian, Jenny Q.; Raymond, Anthony G. J.; Thiessen, Nina; Varhol, Richard J.; Birol, Inanc; Moore, Richard A.; Mungall, Andrew J.; Jones, Steven J. M.] Michael Smith Genome Sci Ctr, BC Canc Agcy, Vancouver, BC V5Z 4S6, Canada. [Witt, Hendrick; Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Oncol, D-69120 Heidelberg, Germany. [Witt, Hendrick] Univ Heidelberg Hosp, Dept Hematol, D-69120 Heidelberg, Germany. [Witt, Hendrick] Univ Heidelberg Hosp, Dept Immunol, D-69120 Heidelberg, Germany. [Fernandez-L, Africa] Mem Sloan Kettering Canc Ctr, Pediat Clin Trials Off, New York, NY 10174 USA. [Wechsler-Reya, Robert J.] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA. [Dirks, Peter; Rutka, James T.; Taylor, Michael D.] Hosp Sick Children, Dept Surg, Div Neurosurg, Toronto, ON M5G 1X8, Canada. [Dirks, Peter; Rutka, James T.; Taylor, Michael D.] Hosp Sick Children, Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada. [Grajkowska, Wieslawa A.] Childrens Mem Hlth Inst, Dept Pathol, PL-04730 Warsaw, Poland. [Perek-Polnik, Marta] Childrens Mem Hlth Inst, Dept Oncol, Warsaw, Poland. [Haberler, Christine C.] Med Univ Vienna, Inst Neurol, A-1097 Vienna, Austria. [Delattre, Olivier] Inst Curie, INSERM, U830, F-75238 Paris 5, France. [Reynaud, Stephanie S.] Inst Curie, Unit Somat Genet, F-75238 Paris 5, France. [Doz, Francois F.] Inst Curie, Dept Pediat Oncol, F-75248 Paris 5, France. [Pernet-Fattet, Sarah S.] CHUV Univ Hosp, CH-1011 Lausanne, Switzerland. [Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang] Seoul Natl Univ, Childrens Hosp, Dept Neurosurg, Div Pediat Neurosurg, Seoul 110744, South Korea. [Scheurlen, Wolfram] Cnopfsche Kinderklin, D-90419 Nurnberg, Germany. [Eberhart, Charles G.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Eberhart, Charles G.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol & Oncol, Baltimore, MD 21205 USA. [Fevre-Montange, Michelle] Univ Lyon, Ctr Rech Neurosci, CNRS UMR5292, INSERM U1028, F-69336 Lyon, France. [Jouvet, Anne] Univ Lyon, Grp Hosp EST, Ctr Pathol EST, F-69500 Bron, France. [Pollack, Ian F.] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15224 USA. [Fan, Xing; Muraszko, Karin M.] Univ Michigan, Sch Med, Dept Neurosurg, Ann Arbor, MI 48109 USA. [Fan, Xing] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI 48109 USA. [Gillespie, G. Yancey] Univ Alabama Birmingham, Dept Surg, Div Neurosurg, Birmingham, AL 35294 USA. [Di Rocco, Concezio; Massimi, Luca] Catholic Univ, Sch Med, I-00186 Rome, Italy. [Michiels, Erna M. C.; Kloosterhof, Nanne K.] Erasmus MC, Dept Pediat Oncol & Hematol, NL-3000 Rotterdam, Netherlands. [Kloosterhof, Nanne K.; French, Pim J.] Erasmus MC, Dept Neurol, NL-3000 CA Rotterdam, Netherlands. [Kros, Johan M.] Erasmus MC, Dept Pathol, NL-3015 GE Rotterdam, Netherlands. [Olson, James M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Olson, James M.] Seattle Childrens Hosp, Seattle, WA 98104 USA. [Ellenbogen, Richard G.] Univ Washington, Sch Med, Harborview Med Ctr, Seattle, WA 98104 USA. [Zitterbart, Karel] Masaryk Univ, Sch Med, Dept Pediat Oncol, Brno 61300, Czech Republic. [Zitterbart, Karel] Univ Hosp Brno, Dept Pediat Oncol, Brno 62500, Czech Republic. [Kren, Leos] Univ Hosp Brno, Dept Pathol, Brno 62500, Czech Republic. [Cooper, Michael K.] Vanderbilt Univ Sch Med, Dept Neurol, Nashville, TN 37232 USA. [Lach, Boleslaw] McMaster Univ, Dept Pathol & Mol Med, Div Anat Pathol, Hamilton, ON L8S 4L8, Canada. [Lach, Boleslaw] Hamilton Gen Hosp, Dept Pathol, Hamilton, ON L8L 2X2, Canada. [Lach, Boleslaw] Hamilton Gen Hosp, Lab Med, Hamilton, ON L8L 2X2, Canada. [McLendon, Roger E.; Bigner, Darell D.] Duke Univ, Dept Pathol, DUMC 3712, Durham, NC 27710 USA. [Fontebasso, Adam; Jabado, Nada] McGill Univ, Div Expt Med, Montreal, PQ H3Z 2Z3, Canada. [Albrecht, Steffen] McGill Univ, Dept Pathol, Montreal, PQ H3A 2B4, Canada. [Albrecht, Steffen] Montreal Childrens Hosp, Dept Pathol, Montreal, PQ H3H 1P3, Canada. [Jabado, Nada] McGill Univ, Dept Pediat, Div Hemato Oncol, Montreal, PQ H3H 1P3, Canada. [Lindsey, Janet C.; Bailey, Simon; Clifford, Steven C.] Newcastle Univ, No Inst Canc Res, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Gupta, Nalin] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Gupta, Nalin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Weiss, William A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA. [Weiss, William A.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA. [Weiss, William A.] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94158 USA. [Bognar, Laszlo; Klekner, Almos] Univ Debrecen, Med & Hlth Sci Ctr, Dept Neurosurg, H-4032 Debrecen, Hungary. [Van Meter, Timothy E.] Virginia Commonwealthy Univ, Sch Med, Richmond, VA 23298 USA. [Kumabe, Toshihiro; Tominaga, Teiji] Tohoku Univ, Grad Sch Med, Dept Neurosurg, Aoba Ku, Sendai, Miyagi 9808574, Japan. [Elbabaa, Samer K.] St Louis Univ, Sch Med, Dept Neurosurg, Div Pediat Neurosurg, St Louis, MO 63104 USA. [Leonard, Jeffrey R.] Washington Univ, Sch Med, Dept Neurosurg, Div Pediat Neurosurg, St Louis, MO 63110 USA. [Leonard, Jeffrey R.; Rubin, Joshua B.] St Louis Childrens Hosp, St Louis, MO 63110 USA. [Rubin, Joshua B.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Rubin, Joshua B.] Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Liau, Linda M.] David Geffen Sch Med UCLA, Dept Neurosurg, Los Angeles, CA 90095 USA. [Van Meir, Erwin G.] Emory Univ, Dept Neurosurg, Mol Neurooncol Lab, Atlanta, GA 30322 USA. [Van Meir, Erwin G.] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA 30322 USA. [Van Meir, Erwin G.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Fouladi, Maryam] Univ Cincinnati, Cincinnati Childrens Hosp, Med Ctr, Div Oncol, Cincinnati, OH 45229 USA. [Nakamura, Hideo] Kumamoto Univ, Grad Sch Med Sci, Dept Neurosurg, Honjo, Kumamoto 8608556, Japan. [Cinalli, Giuseppe] Osped Santobono Pausilipon, I-80145 Naples, Italy. [Garami, Miklos; Hauser, Peter] Semmelweis Univ, Dept Pediat 2, H-1085 Budapest, Hungary. [Saad, Ali G.] Univ Arkansas Med Sci, Little Rock, AR 72202 USA. [Iolascon, Achille; Zollo, Massimo] Univ Naples Federico II, Dipartimento Biochim & Biotecnol Med, I-80145 Naples, Italy. [Iolascon, Achille; Zollo, Massimo] CEINGE Biotecnol Avanzate, I-80145 Naples, Italy. [Jung, Shin] Chonnam Natl Univ, Hwasun Hosp, Res Inst Med Sci, Dept Neurosci, Chungnam 519763, South Korea. [Jung, Shin] Sch Med, Chungnam 519763, South Korea. [Carlotti, Carlos G.] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Surg & Anat, BR-14049900 Sao Paulo, Brazil. [Vibhakar, Rajeev] Univ Colorado Denver, Aurora, CO 80045 USA. [Ra, Young Shin] Univ Ulsan, Asan Med Ctr, Dept Neurosurg, Seoul 138736, South Korea. [Robinson, Shenandoah] Div Pediat Neurosurg, Cleveland, OH 44106 USA. [Faria, Claudia C.] Hosp Santa Maria, Ctr Hosp Lisboa Norte EPE, Div Neurosurg, P-1169050 Lisbon, Portugal. [Faria, Claudia C.] Hosp Sick Children, Cell Biol Program, Toronto, ON MSG 1L7, Canada. [Chan, Jennifer A.] Univ Calgary, Dept Pathol, Calgary, AB T2N 4N1, Canada. [Chan, Jennifer A.] Univ Calgary, Lab Med, Calgary, AB T2N 4N1, Canada. [Levy, Michael L.] Rady Childrens Hosp San Diego, UCSD Div Neurosurg, San Diego, CA 92123 USA. [Sorensen, Poul H. B.] British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada. [Pomeroy, Scott L.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Neurol, Boston, MA 02115 USA. [Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Bader, Gary D.] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada. [Bader, Gary D.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON MSG 1X5, Canada. [Tabori, Uri; Bouffet, Eric; Malkin, David] Hosp Sick Children, Dept Haematol & Oncol, Toronto, ON M5G 1X8, Canada. [Hawkins, Cynthia E.] Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada. [Malkin, David] Univ Toronto, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Marra, Marco A.] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1L3, Canada. RP Marra, MA (reprint author), Michael Smith Genome Sci Ctr, BC Canc Agcy, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM mmarra@bcgsc.ca; mdtaylor@sickkids.ca RI Witt, Hendrik/L-7810-2015; Pfister, Stefan/F-6860-2013; Jones, Steven/C-3621-2009; Zollo, Massimo/K-5857-2016; Marra, Marco/B-5987-2008; Birol, Inanc/G-5440-2011; Kim, Seung-Ki/J-2742-2012; Wang, Kyu-Chang/J-5545-2012; Doz, Francois/K-8616-2012; Scherer, Stephen /B-3785-2013; Jones, David/G-9588-2013; Kool, Marcel/H-2541-2013; Iolascon, Achille/A-4461-2014; Carlotti, Carlos/C-1608-2012; Korbel, Jan/G-6470-2012; Meyerson, Matthew/E-7123-2012; Howe, Jennifer/I-9013-2012; Tang, Macy/B-9798-2014; Holt, Robert/C-3303-2009; Shih, David/H-3186-2011 OI Ramaswamy, Vijay/0000-0002-6557-895X; Van Meir, Erwin G./0000-0003-2444-7707; Remke, Marc/0000-0002-9404-9993; Elbabaa, Samer/0000-0003-1733-1941; Roussel, Martine F./0000-0002-1740-8139; Weiss, William/0000-0003-2230-9132; Pfister, Stefan/0000-0002-5447-5322; Zollo, Massimo/0000-0002-0970-7243; Birol, Inanc/0000-0003-0950-7839; Mack, Stephen C./0000-0001-9620-4742; Tabori, Uri/0000-0002-5019-2683; Stuetz, Adrian/0000-0001-7650-3470; Zichner, Thomas/0000-0001-9848-7598; Scherer, Stephen /0000-0002-8326-1999; Jones, David/0000-0002-2036-5141; Carlotti, Carlos/0000-0002-7055-0564; Korbel, Jan/0000-0002-2798-3794; Shih, David/0000-0002-9802-4937 FU CIHR Clinician-Scientist Phase II award; Sontag Foundation; Pediatric Brain Tumour Foundation; National Institutes of Health [CA159859]; The Family of Kathleen Lorette; Clark H. Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre; Chief of Research Fund; Cancer Genetics Program; Garron Family Cancer Centre; B.R.A.I.N. Child; CIHR [ATE-110814]; University of Toronto McLaughlin Centre; CIHR Institute of Cancer Research [AT1-112286]; BC Cancer Foundation; Children's Discovery Institute; Restracomp Fellowship (Hospital for Sick Children); Ontario Institute for Cancer Research; Government of Ontario; NIH [CA86335, CA116804, CA138292]; NCI [28XS100, 29XS193]; Southeastern Brain Tumour Foundation; Brain Tumour Foundation for Children; UK Children's Cancer and Leukaemia Group (CCLG) [BS-2007-04]; German Cancer Aid [109252] FX M. D. T. is the recipient of a CIHR Clinician-Scientist Phase II award, and was formerly a Sontag Distinguished Scholar with funds from the Sontag Foundation. Funding is acknowledged from the Pediatric Brain Tumour Foundation (M. D. T. and J.T.R.), and the National Institutes of Health (CA159859 to M. D. T., R. W. R. and B. W.), The Canadian Cancer Society, Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from 'The Family of Kathleen Lorette' and the Clark H. Smith Brain Tumour Centre, Montreal Children's Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, CIHR (grant no. ATE-110814); the University of Toronto McLaughlin Centre, CIHR Institute of Cancer Research (grant no. AT1-112286) and C17 through the Advancing Technology Innovation through Discovery competition (Project Title: The Canadian Pediatric Cancer Genome Consortium: Translating next-generation sequencing technologies into improved therapies for high-risk childhood cancer). Canada's Michael Smith Genome Sciences Centre is supported by the BC Cancer Foundation. J.R. is supported by The Children's Discovery Institute. P.A.N. was supported by a Restracomp Fellowship (Hospital for Sick Children) and is currently a Roman-Herzog Postdoctoral Fellow (Hertie Foundation). Salary support for L. G. was provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. E. V. G. M. is supported by NIH grants CA86335, CA116804, CA138292, NCI contracts 28XS100 and 29XS193, the Southeastern Brain Tumour Foundation, and the Brain Tumour Foundation for Children. This study includes samples provided by the UK Children's Cancer and Leukaemia Group (CCLG) as part of CCLG-approved biological study BS-2007-04. J.K. and S. P. were supported by a grant from the German Cancer Aid (109252). We thank C. Lu, K. Otaka and The Centre for Applied Genomics for technical assistance. We thank N. S. Devi and Z. Zhang for technical assistance. We thank D. Stoll for project management, S. Archer for technical writing, and P. Paroutis for artwork. The MAGIC project is part of the International Cancer Genome Consortium. NR 40 TC 238 Z9 245 U1 4 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 2 PY 2012 VL 488 IS 7409 BP 49 EP 56 DI 10.1038/nature11327 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ZE UT WOS:000307010700030 PM 22832581 ER PT J AU Jones, DTW Jager, N Kool, M Zichner, T Hutter, B Sultan, M Cho, YJ Pugh, TJ Hovestadt, V Stutz, AM Rausch, T Warnatz, HJ Ryzhova, M Bender, S Sturm, D Pleier, S Cin, H Pfaff, E Sieber, L Wittmann, A Remke, M Witt, H Hutter, S Tzaridis, T Weischenfeldt, J Raeder, B Avci, M Amstislavskiy, V Zapatka, M Weber, UD Wang, Q Lasitschka, B Bartholomae, CC Schmidt, M von Kalle, C Ast, V Lawerenz, C Eils, J Kabbe, R Benes, V van Sluis, P Koster, J Volckmann, R Shih, D Betts, MJ Russell, RB Coco, S Tonini, GP Schuller, U Hans, V Graf, N Kim, YJ Monoranu, C Roggendorf, W Unterberg, A Herold-Mende, C Milde, T Kulozik, AE von Deimling, A Witt, O Maass, E Rossler, J Ebinger, M Schuhmann, MU Fruhwald, MC Hasselblatt, M Jabado, N Rutkowski, S von Bueren, AO Williamson, D Clifford, SC McCabe, MG Collins, VP Wolf, S Wiemann, S Lehrach, H Brors, B Scheurlen, W Felsberg, J Reifenberger, G Northcott, PA Taylor, MD Meyerson, M Pomeroy, SL Yaspo, ML Korbel, JO Korshunov, A Eils, R Pfister, SM Lichter, P AF Jones, David T. W. Jaeger, Natalie Kool, Marcel Zichner, Thomas Hutter, Barbara Sultan, Marc Cho, Yoon-Jae Pugh, Trevor J. Hovestadt, Volker Stuetz, Adrian M. Rausch, Tobias Warnatz, Hans-Joerg Ryzhova, Marina Bender, Sebastian Sturm, Dominik Pleier, Sabrina Cin, Huriye Pfaff, Elke Sieber, Laura Wittmann, Andrea Remke, Marc Witt, Hendrik Hutter, Sonja Tzaridis, Theophilos Weischenfeldt, Joachim Raeder, Benjamin Avci, Meryem Amstislavskiy, Vyacheslav Zapatka, Marc Weber, Ursula D. Wang, Qi Lasitschka, Baerbel Bartholomae, Cynthia C. Schmidt, Manfred von Kalle, Christof Ast, Volker Lawerenz, Chris Eils, Juergen Kabbe, Rolf Benes, Vladimir van Sluis, Peter Koster, Jan Volckmann, Richard Shih, David Betts, Matthew J. Russell, Robert B. Coco, Simona Tonini, Gian Paolo Schueller, Ulrich Hans, Volkmar Graf, Norbert Kim, Yoo-Jin Monoranu, Camelia Roggendorf, Wolfgang Unterberg, Andreas Herold-Mende, Christel Milde, Till Kulozik, Andreas E. von Deimling, Andreas Witt, Olaf Maass, Eberhard Roessler, Jochen Ebinger, Martin Schuhmann, Martin U. Fruehwald, Michael C. Hasselblatt, Martin Jabado, Nada Rutkowski, Stefan von Bueren, Andre O. Williamson, Dan Clifford, Steven C. McCabe, Martin G. Collins, V. Peter Wolf, Stephan Wiemann, Stefan Lehrach, Hans Brors, Benedikt Scheurlen, Wolfram Felsberg, Joerg Reifenberger, Guido Northcott, Paul A. Taylor, Michael D. Meyerson, Matthew Pomeroy, Scott L. Yaspo, Marie-Laure Korbel, Jan O. Korshunov, Andrey Eils, Roland Pfister, Stefan M. Lichter, Peter TI Dissecting the genomic complexity underlying medulloblastoma SO NATURE LA English DT Article ID TETRAPLOID TUMOR-CELLS; MUTATIONS; PATHWAY; CANCER; ACTIVATION; SUBGROUPS; LANDSCAPE; GENES; TBR1 AB Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity(1). Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified(2,3). WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens(4). SHH tumours show hedgehog pathway activation, and have an intermediate prognosis(2). Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges(2,3,5). The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients. C1 [Jaeger, Natalie; Hutter, Barbara; Wang, Qi; Kabbe, Rolf; Brors, Benedikt; Eils, Roland] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany. [Jones, David T. W.; Kool, Marcel; Bender, Sebastian; Sturm, Dominik; Pleier, Sabrina; Cin, Huriye; Pfaff, Elke; Sieber, Laura; Wittmann, Andrea; Remke, Marc; Witt, Hendrik; Hutter, Sonja; Tzaridis, Theophilos; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Zichner, Thomas; Stuetz, Adrian M.; Weischenfeldt, Joachim; Raeder, Benjamin; Korbel, Jan O.] European Mol Biol Lab, D-69117 Heidelberg, Germany. [Sultan, Marc; Warnatz, Hans-Joerg; Avci, Meryem; Amstislavskiy, Vyacheslav; Lehrach, Hans; Yaspo, Marie-Laure] Max Planck Inst Mol Genet, D-14195 Berlin, Germany. [Cho, Yoon-Jae] Stanford Univ, Div Child Neurol, Palo Alto, CA 94304 USA. [Pugh, Trevor J.; Meyerson, Matthew; Pomeroy, Scott L.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Hovestadt, Volker; Zapatka, Marc; Weber, Ursula D.; Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Ryzhova, Marina] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia. [Witt, Hendrik; Milde, Till; Kulozik, Andreas E.; Pfister, Stefan M.] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany. [Bartholomae, Cynthia C.; Schmidt, Manfred; von Kalle, Christof] German Canc Res Ctr, Div Translat Oncol, D-69120 Heidelberg, Germany. [Bartholomae, Cynthia C.; Schmidt, Manfred; von Kalle, Christof] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany. [van Sluis, Peter; Koster, Jan; Volckmann, Richard] Univ Amsterdam, AMC, Dept Oncogenom, NL-1105 AZ Amsterdam, Netherlands. [Shih, David; Northcott, Paul A.] Hosp Sick Children, Arthur & Sonia Labbatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada. [Betts, Matthew J.; Russell, Robert B.] Univ Heidelberg, Cell Networks Cluster Excellence, D-69120 Heidelberg, Germany. [Coco, Simona; Tonini, Gian Paolo] IRCCS Azienda Osped Univ San Martino, IST Ist Nazl Ric Canc, Dept Adv Diagnost Technol, I-16132 Genoa, Italy. [Schueller, Ulrich] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany. [Hans, Volkmar] Evangel Krankenhaus, Inst Neuropathol, D-33617 Bielefeld, Germany. [Graf, Norbert] Saarland Univ Hosp, Dept Paediat Oncol & Haematol, D-66421 Homburg, Germany. [Kim, Yoo-Jin] Saarland Univ Hosp, Inst Pathol, D-66424 Homburg, Germany. [Monoranu, Camelia; Roggendorf, Wolfgang] Inst Pathol, Dept Neuropathol, D-97080 Wurzburg, Germany. [Unterberg, Andreas; Herold-Mende, Christel] Univ Heidelberg Hosp, Dept Neurosurg, D-69120 Heidelberg, Germany. [Milde, Till; Witt, Olaf] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, D-69120 Heidelberg, Germany. [von Deimling, Andreas; Korshunov, Andrey] Univ Heidelberg, Dept Neuropathol, D-69120 Heidelberg, Germany. [von Deimling, Andreas; Korshunov, Andrey] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany. [Maass, Eberhard] Klinikum Stuttgart Olgahosp, Dept Pediat Oncol Hematol & Immunol, D-70176 Stuttgart, Germany. [Roessler, Jochen] Univ Hosp Freiburg, Dept Paediat Haematol & Oncol, D-79106 Freiburg, Germany. [Ebinger, Martin] Childrens Univ Hosp, Dept Hematol & Oncol, D-72076 Tubingen, Germany. [Schuhmann, Martin U.] Univ Hosp, Dept Neurosurg, D-72076 Tubingen, Germany. [Fruehwald, Michael C.] Childrens Hosp Augsburg, D-86156 Augsburg, Germany. [Hasselblatt, Martin] Univ Hosp Munster, Inst Neuropathol, D-48149 Munster, Germany. [Jabado, Nada] McGill Univ, Dept Pediat, Montreal, PQ H3Z 2Z3, Canada. [Jabado, Nada] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada. [Jabado, Nada] McGill Univ Hlth Ctr Res Inst, Montreal, PQ H3Z 2Z3, Canada. [Rutkowski, Stefan; von Bueren, Andre O.] Univ Med Ctr Hamburg Eppendorf, Dept Paediat Haematol & Oncol, D-20246 Hamburg, Germany. [Williamson, Dan; Clifford, Steven C.] Newcastle Univ, Royal Victoria Infirm, No Inst Canc Res, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [McCabe, Martin G.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Canc & Enabling Sci, Manchester M13 9PL, Lancs, England. [Collins, V. Peter] Univ Cambridge, Dept Pathol, Div Mol Histopathol, Cambridge CB2 0QQ, England. [Wiemann, Stefan] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany. [Scheurlen, Wolfram] Nurnberg Childrens Hosp, Cnopfsche Kinderklinik, D-90419 Nurnberg, Germany. [Felsberg, Joerg; Reifenberger, Guido] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany. [Taylor, Michael D.] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada. [Taylor, Michael D.] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada. [Meyerson, Matthew] Dana Farber Canc Inst, Boston, MA 02215 USA. [Pomeroy, Scott L.] Childrens Hosp, Boston, MA 02115 USA. [Eils, Roland] Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. [Eils, Roland] Univ Heidelberg, Bioquant Ctr, D-69120 Heidelberg, Germany. RP Eils, R (reprint author), German Canc Res Ctr, Div Theoret Bioinformat, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM r.eils@dkfz-heidelberg.de; s.pfister@dkfz-heidelberg.de; m.macleod@dkfz-heidelberg.de RI Zapatka, Marc/G-9896-2013; Kool, Marcel/H-2541-2013; Korbel, Jan/G-6470-2012; Wiemann, Stefan/E-4424-2013; Shih, David/H-3186-2011; von Deimling, Andreas/F-7774-2013; Milde, Till/L-7755-2015; Witt, Hendrik/L-7810-2015; Weischenfeldt, Joachim/O-3681-2015; McCabe, Martin/P-5896-2015; Meyerson, Matthew/E-7123-2012; Brors, Benedikt/E-5620-2013; Jones, David/G-9588-2013; Eils, Roland/B-6121-2009; Pfister, Stefan/F-6860-2013; Coco, Simona/J-6051-2016; Ebinger, Martin/O-4936-2016; OI Zapatka, Marc/0000-0001-8287-5967; Korbel, Jan/0000-0002-2798-3794; Wiemann, Stefan/0000-0003-4683-3174; Shih, David/0000-0002-9802-4937; von Deimling, Andreas/0000-0002-5863-540X; Weischenfeldt, Joachim/0000-0002-3917-5524; McCabe, Martin/0000-0002-5138-0707; Brors, Benedikt/0000-0001-5940-3101; Jones, David/0000-0002-2036-5141; Eils, Roland/0000-0002-0034-4036; Pfister, Stefan/0000-0002-5447-5322; Coco, Simona/0000-0002-5296-4325; Ebinger, Martin/0000-0002-4229-8058; Warnatz, Hans-Jorg/0000-0002-0327-9209; Jaeger, Natalie/0000-0002-9589-7580; Stuetz, Adrian/0000-0001-7650-3470; Zichner, Thomas/0000-0001-9848-7598; Benes, Vladimir/0000-0002-0352-2547; Hutter, Barbara/0000-0002-9034-0329; Remke, Marc/0000-0002-9404-9993; Sturm, Dominik/0000-0003-0250-1696; Hovestadt, Volker/0000-0002-3480-6649; Hasselblatt, Martin/0000-0003-2707-8484; Raeder, Benjamin/0000-0002-9494-8884; Rausch, Tobias/0000-0001-5773-5620 FU PedBrain Tumor Project contributing to the International Cancer Genome Consortium (ICGC PedBrain Tumor Project); German Cancer Aid [109252]; German Federal Ministry of Education and Research (BMBF) [01GS0883]; German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO); Max Planck Society; Pediatric Brain Tumor Foundation; Italian Neuroblastoma Foundation; Samantha Dickson Brain Tumour Trust; UK Children's Cancer and Leukaemia Group (CCLG) [BS-2007-04] FX We thank GATC Biotech AG for sequencing services. For technical support and expertise we thank: B. Haase, D. Pavlinic, B. Baying, M. Wahlers, R. Luck, I. Kutschera, K. Schlangen, M. Metsger, K. Schulz, A. Nurnberger, A. Kovacsovics, M. Linser, J. C. Lindsey, S. Bailey, D. M. Pearson, the EMBL Genomics Core Facility, the EMBL High-performance Computing Core Facility and the DKFZ Genomics and Proteomics Core Facility. This work was principally supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium (ICGC PedBrain Tumor Project, http://www.pedbraintumor.org/), funded by German Cancer Aid (109252) and the German Federal Ministry of Education and Research (BMBF, NGFNplus #01GS0883). Additional support came from the German Cancer Research Center-Heidelberg Center for Personalized Oncology (DKFZ-HIPO), the Max Planck Society, the Pediatric Brain Tumor Foundation, the Italian Neuroblastoma Foundation and the Samantha Dickson Brain Tumour Trust. This study included samples provided by the UK Children's Cancer and Leukaemia Group (CCLG) as part of CCLG-approved biological study BS-2007-04. NR 25 TC 309 Z9 314 U1 5 U2 87 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 2 PY 2012 VL 488 IS 7409 BP 100 EP 105 DI 10.1038/nature11284 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ZE UT WOS:000307010700041 PM 22832583 ER PT J AU Pugh, TJ Weeraratne, SD Archer, TC Krummel, DAP Auclair, D Bochicchio, J Carneiro, MO Carter, SL Cibulskis, K Erlich, RL Greulich, H Lawrence, MS Lennon, NJ McKenna, A Meldrim, J Ramos, AH Ross, MG Russ, C Shefler, E Sivachenko, A Sogoloff, B Stojanov, P Tamayo, P Mesirov, JP Amani, V Teider, N Sengupta, S Francois, JP Northcott, PA Taylor, MD Yu, FR Crabtree, GR Kautzman, AG Gabriel, SB Getz, G Jager, N Jones, DTW Lichter, P Pfister, SM Roberts, TM Meyerson, M Pomeroy, SL Cho, YJ AF Pugh, Trevor J. Weeraratne, Shyamal Dilhan Archer, Tenley C. Krummel, Daniel A. Pomeranz Auclair, Daniel Bochicchio, James Carneiro, Mauricio O. Carter, Scott L. Cibulskis, Kristian Erlich, Rachel L. Greulich, Heidi Lawrence, Michael S. Lennon, Niall J. McKenna, Aaron Meldrim, James Ramos, Alex H. Ross, Michael G. Russ, Carsten Shefler, Erica Sivachenko, Andrey Sogoloff, Brian Stojanov, Petar Tamayo, Pablo Mesirov, Jill P. Amani, Vladimir Teider, Natalia Sengupta, Soma Francois, Jessica Pierre Northcott, Paul A. Taylor, Michael D. Yu, Furong Crabtree, Gerald R. Kautzman, Amanda G. Gabriel, Stacey B. Getz, Gad Jaeger, Natalie Jones, David T. W. Lichter, Peter Pfister, Stefan M. Roberts, Thomas M. Meyerson, Matthew Pomeroy, Scott L. Cho, Yoon-Jae TI Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations SO NATURE LA English DT Article ID STRUCTURAL BASIS; CANCER GENES; PATHWAY; CHILDHOOD; LANDSCAPE; LEUKEMIA; COMPLEX AB Medulloblastomas are themost commonmalignant brain tumours in children(1). Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes ofmedulloblastoma on the basis of transcriptional and copy number profiles(2-5). Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 andTP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, beta-catenin. Together, our study reveals the alteration ofWNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates theRNA helicase DDX3X as a component of pathogenic b-catenin signalling in medulloblastoma. C1 [Pugh, Trevor J.; Auclair, Daniel; Bochicchio, James; Carneiro, Mauricio O.; Carter, Scott L.; Cibulskis, Kristian; Erlich, Rachel L.; Greulich, Heidi; Lawrence, Michael S.; Lennon, Niall J.; McKenna, Aaron; Meldrim, James; Ramos, Alex H.; Ross, Michael G.; Russ, Carsten; Shefler, Erica; Sivachenko, Andrey; Sogoloff, Brian; Stojanov, Petar; Tamayo, Pablo; Mesirov, Jill P.; Gabriel, Stacey B.; Getz, Gad; Meyerson, Matthew; Pomeroy, Scott L.; Cho, Yoon-Jae] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Pugh, Trevor J.; Greulich, Heidi; Ramos, Alex H.; Roberts, Thomas M.; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Pugh, Trevor J.; Greulich, Heidi; Ramos, Alex H.; Roberts, Thomas M.; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Med Oncol, Boston, MA 02115 USA. [Pugh, Trevor J.; Weeraratne, Shyamal Dilhan; Archer, Tenley C.; Greulich, Heidi; Ramos, Alex H.; Amani, Vladimir; Teider, Natalia; Sengupta, Soma; Francois, Jessica Pierre; Roberts, Thomas M.; Meyerson, Matthew; Pomeroy, Scott L.; Cho, Yoon-Jae] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Weeraratne, Shyamal Dilhan; Archer, Tenley C.; Amani, Vladimir; Teider, Natalia; Sengupta, Soma; Francois, Jessica Pierre; Pomeroy, Scott L.; Cho, Yoon-Jae] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Krummel, Daniel A. Pomeranz] Brandeis Univ, Waltham, MA 02453 USA. [Northcott, Paul A.; Taylor, Michael D.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Yu, Furong; Crabtree, Gerald R.; Kautzman, Amanda G.; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurol, Stanford, CA 94305 USA. [Yu, Furong; Crabtree, Gerald R.; Kautzman, Amanda G.; Cho, Yoon-Jae] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA. [Crabtree, Gerald R.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Jaeger, Natalie; Jones, David T. W.; Lichter, Peter; Pfister, Stefan M.] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Meyerson, Matthew] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Cho, YJ (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM matthew_meyerson@dfci.harvard.edu; scott.pomeroy@childrens.harvard.edu; yjcho1@stanford.edu RI Meyerson, Matthew/E-7123-2012; Jones, David/G-9588-2013; Pfister, Stefan/F-6860-2013; OI Jones, David/0000-0002-2036-5141; Pfister, Stefan/0000-0002-5447-5322; Jaeger, Natalie/0000-0002-9589-7580 FU NIH [NHGRI U54HG003067, R01CA109467, R01CA105607, P30 HD18655, R01 CA030002, CA050661, R01 NS046789, R01 CA154480, R25NS070682, R01CA148699]; St. Baldrick's Foundation Scholar Award; Beirne Faculty Scholar endowment and Center for Children's Brain Tumors at Stanford University; German Cancer Aid [109252]; BMBF ICGC-PedBrain project; HHMI; Pediatric Brain Tumor Foundation; Canadian Institutes of Health Research Fellowship; Hospital for Sick Children; Mullarkey Research Fund FX This work was supported by NIH grants NHGRI U54HG003067 to E. S. Lander (E. S., D. A., S. B. G., G. G., M. M.); R01CA109467(S. L. P., J.P.M.); R01CA105607 (H. G., T. M. R., M. M., S. L. P.); P30 HD18655 (S. L. P.); R01 CA030002 and CA050661 (T. M. R.); R01 NS046789 (G. R. C.); R01 CA154480 (P. T.); R25NS070682 (S. S.) and R01CA148699 (M. D. T.); St. Baldrick's Foundation Scholar Award and the Beirne Faculty Scholar endowment and Center for Children's Brain Tumors at Stanford University (Y.-J.C.); German Cancer Aid (109252) and the BMBF ICGC-PedBrain project (N.J., D.T.W.J., P. L., S. M. P.); HHMI (G. R. C.); the Pediatric Brain Tumor Foundation (M. D. T.); Canadian Institutes of Health Research Fellowship (T.J.P.); Restracomp funding from the Hospital for Sick Children (P.A.N.); and the Mullarkey Research Fund (S. L. P.). We thank Children's Oncology Group and the Cooperative Human Tissue Network for providing tumour samples, the staff of the Broad Institute Biological Samples, Genome Sequencing and Genetic Analysis Platforms for their assistance in genomic processing of samples and generating the sequencing data used in this analysis, K. Keho and M. Brown at Pacific Biosciences for technical support with sample barcoding methods, and L. Gaffney of Broad Institute Communications for assistance with figure layout and design. NR 29 TC 296 Z9 302 U1 1 U2 44 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 2 PY 2012 VL 488 IS 7409 BP 106 EP 110 DI 10.1038/nature11329 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 981ZE UT WOS:000307010700042 PM 22820256 ER PT J AU Schuur, JD Venkatesh, AK AF Schuur, Jeremiah D. Venkatesh, Arjun K. TI The Growing Role of Emergency Departments in Hospital Admissions SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Schuur, Jeremiah D.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Venkatesh, Arjun K.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency Progra, Boston, MA 02114 USA. [Schuur, Jeremiah D.; Venkatesh, Arjun K.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Schuur, JD (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. NR 5 TC 106 Z9 107 U1 0 U2 7 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 AUG 2 PY 2012 VL 367 IS 5 BP 391 EP 393 DI 10.1056/NEJMp1204431 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 981VZ UT WOS:000307001900002 PM 22784039 ER PT J AU Baeten, JM Donnell, D Ndase, P Mugo, NR Campbell, JD Wangisi, J Tappero, JW Bukusi, EA Cohen, CR Katabira, E Ronald, A Tumwesigye, E Were, E Fife, KH Kiarie, J Farquhar, C John-Stewart, G Kakia, A Odoyo, J Mucunguzi, A Nakku-Joloba, E Twesigye, R Ngure, K Apaka, C Tamooh, H Gabona, F Mujugira, A Panteleeff, D Thomas, KK Kidoguchi, L Krows, M Revall, J Morrison, S Haugen, H Emmanuel-Ogier, M Ondrejcek, L Coombs, RW Frenkel, L Hendrix, C Bumpus, NN Bangsberg, D Haberer, JE Stevens, WS Lingappa, JR Celum, C AF Baeten, J. M. Donnell, D. Ndase, P. Mugo, N. R. Campbell, J. D. Wangisi, J. Tappero, J. W. Bukusi, E. A. Cohen, C. R. Katabira, E. Ronald, A. Tumwesigye, E. Were, E. Fife, K. H. Kiarie, J. Farquhar, C. John-Stewart, G. Kakia, A. Odoyo, J. Mucunguzi, A. Nakku-Joloba, E. Twesigye, R. Ngure, K. Apaka, C. Tamooh, H. Gabona, F. Mujugira, A. Panteleeff, D. Thomas, K. K. Kidoguchi, L. Krows, M. Revall, J. Morrison, S. Haugen, H. Emmanuel-Ogier, M. Ondrejcek, L. Coombs, R. W. Frenkel, L. Hendrix, C. Bumpus, N. N. Bangsberg, D. Haberer, J. E. Stevens, W. S. Lingappa, J. R. Celum, C. CA Partners PrEP Study Team TI Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SUB-SAHARAN AFRICA; PREEXPOSURE PROPHYLAXIS; POSTEXPOSURE PROPHYLAXIS; SEXUAL TRANSMISSION; CLINICAL-TRIALS; VIRAL LOAD; THERAPY; METAANALYSIS; COUPLES AB Background Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. Methods We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens - once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo - and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. Results We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P = 0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. Conclusions Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.) C1 [Baeten, J. M.] Univ Washington, Dept Global Hlth, Int Clin Res Ctr, Seattle, WA 98104 USA. [Baeten, J. M.; Farquhar, C.; John-Stewart, G.; Coombs, R. W.; Lingappa, J. R.; Celum, C.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Baeten, J. M.; Farquhar, C.; John-Stewart, G.; Celum, C.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Coombs, R. W.; Frenkel, L.] Univ Washington, Dept Lab Med, Seattle, WA 98104 USA. [Frenkel, L.; Lingappa, J. R.] Univ Washington, Dept Pediat, Seattle, WA 98104 USA. [Donnell, D.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Ondrejcek, L.] DF Net Res, Seattle, WA USA. [Frenkel, L.] Seattle Childrens Hosp Res Inst, Seattle, WA USA. [Mugo, N. R.; Bukusi, E. A.; Kiarie, J.; Ngure, K.; Tamooh, H.] Univ Nairobi, Dept Obstet & Gynecol, Nairobi, Kenya. [Mugo, N. R.; Bukusi, E. A.; Kiarie, J.; Ngure, K.; Tamooh, H.] Kenyatta Natl Hosp, Nairobi, Kenya. [Bukusi, E. A.; Odoyo, J.] Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya. [Were, E.; Apaka, C.] Moi Univ, Dept Reprod Hlth, Eldoret, Kenya. [Campbell, J. D.] Ctr Dis Control & Prevent, Entebbe, Uganda. [Wangisi, J.; Kakia, A.; Mucunguzi, A.] Makerere Univ, AIDS Support Org, Kampala, Uganda. [Katabira, E.; Ronald, A.; Nakku-Joloba, E.; Gabona, F.] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Tumwesigye, E.; Twesigye, R.] Kabwohe Clin Res Ctr, Kabwohe, Uganda. [Tappero, J. W.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Bukusi, E. A.; Cohen, C. R.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Ronald, A.] Univ Manitoba, Dept Med, Winnipeg, MB, Canada. [Fife, K. H.] Indiana Univ, Dept Med, Indianapolis, IN USA. [Hendrix, C.; Bumpus, N. N.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Bangsberg, D.; Haberer, J. E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bangsberg, D.; Haberer, J. E.] Harvard Univ, Sch Med, Boston, MA USA. [Stevens, W. S.] Univ Witwatersrand, Dept Mol Med & Hematol, Johannesburg, South Africa. [Stevens, W. S.] Wits Hlth Consortium, Contract Lab Serv, Johannesburg, South Africa. RP Baeten, JM (reprint author), Univ Washington, Dept Global Hlth, Int Clin Res Ctr, Box 359927,325 9th Ave, Seattle, WA 98104 USA. EM jbaeten@uw.edu RI Hendrix, Craig/G-4182-2014; OI Hendrix, Craig/0000-0002-5696-8665; Ronald, Allan/0000-0002-5746-3490; Frenkel, Lisa M/0000-0001-9566-8959; Joloba, Moses/0000-0002-0334-9983; Donnell, Deborah/0000-0002-0587-7480 FU Bill and Melinda Gates Foundation [47674] FX Supported by a research grant (ID #47674) from the Bill and Melinda Gates Foundation. NR 40 TC 884 Z9 903 U1 14 U2 94 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 AUG 2 PY 2012 VL 367 IS 5 BP 399 EP 410 DI 10.1056/NEJMoa1108524 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 981VZ UT WOS:000307001900005 PM 22784037 ER PT J AU Shin, JJ Stinnett, S Page, J Randolph, GW AF Shin, Jennifer J. Stinnett, Sandra Page, John Randolph, Gregory W. TI Evidence-Based Medicine in Otolaryngology, Part 3: Everyday Probabilities: Diagnostic Tests with Binary Results SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE evidence-based medicine; diagnostic tests; sensitivity; specificity; positive predictive value; negative predictive value; likelihood ratio ID GENERAL-PRACTITIONERS; ACCURACY AB Recent studies have demonstrated that the majority of physicians cannot accurately determine the predictive values of diagnostic tests. Physicians must understand the predictive probabilities associated with diagnostic testing in order to convey accurate information to patients, a key aspect of evidence-based practice. While sensitivity and specificity are widely understood, predictive values require a further understanding of conditional probabilities, pretest probabilities, and the prevalence of disease. Therefore, this third installment of the series "Evidence-Based Medicine in Otolaryngology'' focuses on understanding the probabilities needed to accurately convey the results of dichotomous diagnostic tests in everyday practice. C1 [Shin, Jennifer J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Otolaryngol, Boston, MA 02114 USA. [Stinnett, Sandra] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Page, John] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Div Gen Otolaryngol & Thyroid Parathyroid Surg, Boston, MA 02114 USA. RP Shin, JJ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Div Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM jennifer_shin@meei.harvard.edu RI Shin, Jennifer/A-3169-2016 NR 14 TC 7 Z9 7 U1 1 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2012 VL 147 IS 2 BP 185 EP 192 DI 10.1177/0194599812447750 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 080VW UT WOS:000314273200001 PM 22588733 ER PT J AU Lee, LN Susarla, SM Henstrom, DK Hohman, MH Durand, ML Cheney, ML Hadlock, TA AF Lee, Linda N. Susarla, Srinivas M. Henstrom, Douglas K. Hohman, Marc H. Durand, Marlene L. Cheney, Mack L. Hadlock, Tessa A. TI Surgical Site Infections after Gracilis Free Flap Reconstruction for Facial Paralysis SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE gracilis free flap; facial paralysis; surgical site infection; perioperative antibiotics ID SURGERY; HEAD; CLINDAMYCIN AB Compared with other free tissue transfer procedures, the gracilis free muscle transfer (GFMT) for facial reanimation is unique in that the recipient site is typically uninvolved by malignancy or infection. In this study, the authors examined the incidence, bacteriology, and outcomes of surgical site infection (SSI) after gracilis free muscle transfer for facial reanimation. From 2003 to 2011, 105 patients underwent 107 GFMT operations, with 6 SSIs. All cases of infection occurred in patients receiving clindamycin, levofloxacin, and/or cefazolin perioperatively. None of the patients who received ampicillin-sulbactam developed an SSI. Surgical site cultures grew oral flora, including alpha-hemolytic streptococci, Haemophilus parainfluenzae, Fusobacterium and Neisseria species, and coagulase-negative staphylococci. Notably, there were no methicillin-resistant Staphylococcus aureus (MRSA) infections. These data may have implications for the optimal perioperative antibiotic choice in facial reanimation cases. Further study is needed to determine the ideal antibiotic regimen for this category of free flap surgeries. C1 [Lee, Linda N.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Lee, Linda N.; Hohman, Marc H.; Cheney, Mack L.; Hadlock, Tessa A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Susarla, Srinivas M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Susarla, Srinivas M.] Massachusetts Gen Hosp, Dept Oral Maxillofacial Surg, Boston, MA 02114 USA. [Henstrom, Douglas K.] Univ Iowa, Dept Otolaryngol, Facial Plast & Reconstruct Surg & Facial Nerve Ct, Iowa City, IA USA. [Hohman, Marc H.; Cheney, Mack L.; Hadlock, Tessa A.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Facial Nerve Ctr, Boston, MA 02114 USA. [Durand, Marlene L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis,Dept Med, Boston, MA 02114 USA. RP Lee, LN (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol,Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM Linda_Lee@meei.harvard.edu OI Susarla, Srinivas/0000-0003-0155-8260 NR 5 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2012 VL 147 IS 2 BP 245 EP 248 DI 10.1177/0194599812444262 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 080VW UT WOS:000314273200011 PM 22496103 ER PT J AU Zarraga, IGE Dougherty, CM MacMurdy, KS Raitt, MH AF Zarraga, Ignatius Gerardo E. Dougherty, Cynthia M. MacMurdy, Karen S. Raitt, Merritt H. TI The Effect of Spironolactone on Ventricular Tachyarrhythmias in Patients With Implantable Cardioverter-Defibrillators SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE antiarrhythmia agents; cardioversion; defibrillation; spironolactone; tachyarrhythmias ID RANDOMIZED ALDACTONE EVALUATION; CONGESTIVE-HEART-FAILURE; MYOCARDIAL-INFARCTION; SHOCKS; CARDIOMYOPATHY; MORTALITY; PREVENTS; THERAPY AB Background-Previous studies have suggested that aldosterone blockade can reduce the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with heart failure. The SPIronolactone to Reduce ICD Therapy (SPIRIT) trial was designed to test the hypothesis that spironolactone reduces the incidence of VT/VF in patients with implantable cardioverter-defibrillators (ICDs) who are at moderately high risk for recurrent VT/VF. Methods and Results-Ninety patients who had ICDs who were at moderately high risk for recurrent VT/VF and who were not candidates for spironolactone by current heart failure guidelines were randomized to receive spironolactone 25 mg daily or placebo in a double-blind fashion. All patients had previously received ICD therapy (shock or antitachycardia pacing) for VT/VF within 2 years of randomization or an ICD for secondary prevention of VT/VF within 6 months of randomization. The primary end point was time to first recurrence of VT/VF requiring ICD therapy. After a median follow-up of 35 months, the Kaplan-Meier probability estimates for VT/VF requiring ICD therapy were 68.7% in the placebo group and 84.7% in the spironolactone group. Compared with placebo, spironolactone was associated with a similar risk of VT/VF (hazard ratio, 1.01; 95% CI, 0.64-1.83; P=0.71). There was no significant difference between the median times to first VT/VF recurrence requiring ICD therapy in the 2 groups. Conclusions-In patients with ICDs who were at moderately high risk for recurrent VT/VF on account of a recent VT/VF event that was either sustained or treated by the ICD and who were not candidates for spironolactone by current heart failure guidelines, spironolactone did not delay the first recurrence of VT/VF or reduce the risk of recurrent VT/VF. (Circ Arrhythm Electrophysiol. 2012;5:739-747.) C1 [Zarraga, Ignatius Gerardo E.; MacMurdy, Karen S.; Raitt, Merritt H.] Portland VA Med Ctr, Div Cardiol, Portland, OR 97239 USA. [Zarraga, Ignatius Gerardo E.; MacMurdy, Karen S.; Raitt, Merritt H.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Dougherty, Cynthia M.] Univ Washington, Sch Nursing, Seattle, WA 98195 USA. RP Zarraga, IGE (reprint author), Portland VA Med Ctr, Div Cardiol, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM Ignatius.Zarraga@va.gov OI Raitt, Merritt/0000-0001-5638-7732 FU Department of Defense; Veterans Administration FX This work was supported by a grant from the Department of Defense and the Veterans Administration. NR 24 TC 3 Z9 3 U1 0 U2 1 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 AUG PY 2012 VL 5 IS 4 BP 739 EP 747 DI 10.1161/CIRCEP.112.970566 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071IE UT WOS:000313584500022 PM 22773022 ER PT J AU Friedman, DJ Altman, RK Orencole, M Picard, MH Ruskin, JN Singh, JP Heist, EK AF Friedman, Daniel J. Altman, Robert K. Orencole, Mary Picard, Michael H. Ruskin, Jeremy N. Singh, Jagmeet P. Heist, E. Kevin TI Predictors of Sustained Ventricular Arrhythmias in Cardiac Resynchronization Therapy SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE cardiomyopathy; heart failure; pacemakers; risk factors; tachyarrhythmias ID HEART-FAILURE; DEFIBRILLATOR IMPLANTATION; REVERSE; TRIAL; STIMULATION; DEATH; FIBRILLATION; ABLATION; INCREASE; SHOCK AB Background-Patients undergoing cardiac resynchronization therapy (CRT) are at high risk for ventricular arrhythmias (VAs), and risk stratification in this population remains poor. Methods and Results-This study followed 269 patients (left ventricular ejection fraction <35%; QRS >120 ms; New York Heart Association class III/IV) undergoing CRT with a defibrillator for 553 +/- 464 days after CRT with defibrillator implantation to assess for independent predictors of appropriate device therapy for VAs. Baseline medication use, medical comorbidities, and echocardiographic parameters were considered. The 4-year incidence of appropriate device therapy was 36%. A Cox proportional hazard model identified left ventricular end-systolic diameter >61 mm as an independent predictor in the entire population (hazard ratio [HR], 2.66; P=0.001). Those with left ventricular end-systolic diameter >61 mm had a 51% 3-year incidence of VA compared with a 26% incidence among those with a less dilated ventricle (P=0.001). Among patients with left ventricular end-systolic diameter <= 61 mm, multivariate predictors of appropriate therapy were absence of beta-blocker therapy (HR, 6.34; P<0.001), left ventricular ejection fraction <20% (HR, 4.22; P<0.001), and history of sustained VA (HR, 2.97; P=0.013). Early (<180 days after implant) shock therapy was found to be a robust predictor of hospitalization for heart failure (HR, 3.41; P<0.004) and mortality (HR, 5.16; P<0.001.) Conclusions-Among patients with CRT and a defibrillator, left ventricular end-systolic diameter >61 mm is a powerful predictor of VAs, and further risk stratification of those with less dilated ventricles can be achieved based on assessment of ejection fraction, history of sustained VA, and absence of beta-blocker therapy. (Circ Arrhythm Electrophysiol.2012;5:762-772.) C1 [Altman, Robert K.; Orencole, Mary; Ruskin, Jeremy N.; Singh, Jagmeet P.; Heist, E. Kevin] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Picard, Michael H.] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. [Friedman, Daniel J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Heist, EK (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, GRB 109,55 Fruit St, Boston, MA 02114 USA. EM kheist@partners.org OI Altman, Robert/0000-0002-1612-3561; Picard, Michael/0000-0002-9264-3243; Friedman, Daniel /0000-0001-5791-1954 FU Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award) [UL1 RR 025758]; Harvard University; Biotronik; Boston Scientific; Medtronic; St. Jude Medical; Biosense Webster FX This work was conducted with support from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic healthcare centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic healthcare centers or the National Institutes of Health.; Dr Singh reports serving as an advisor or consultant for Biotronik, Boston Scientific, Medtronic, Sorin, St. Jude Medical, Respicardia, and CardioInsight; serving as a speaker or a member of a speakers bureau for Biotronik, Boston Scientific, Sorin, and St. Jude Medical; and receiving grants for clinical research from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical. Dr Ruskin reports serving as an advisor or consultant for Astellas/Cardiome, Biosense Webster, CardioFocus, CardioInsight, CryoCath, Medtronic, Pfizer, Portola, and Third Rock Ventures; receiving fellowship support from Biosense Webster, Boston Scientific, Medronic, and St. Jude Medical; receiving honoraria from Med-IQ; and owning equity in Portola. Dr Heist reports serving as a consultant for Boston Scientific, Sorin, and St. Jude Medical; receiving research grants from Biotronik, Boston Scientific, and St. Jude Medical; and receiving honoraria from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical. The other authors have no conflicts to report. NR 32 TC 9 Z9 10 U1 0 U2 3 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 AUG PY 2012 VL 5 IS 4 BP 762 EP 772 DI 10.1161/CIRCEP.112.971101 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071IE UT WOS:000313584500025 PM 22787010 ER PT J AU Segal, AD Zelik, KE Klute, GK Morgenroth, DC Hahn, ME Orendurff, MS Adamczyk, PG Collins, SH Kuo, AD Czerniecki, JM AF Segal, Ava D. Zelik, Karl E. Klute, Glenn K. Morgenroth, David C. Hahn, Michael E. Orendurff, Michael S. Adamczyk, Peter G. Collins, Steven H. Kuo, Arthur D. Czerniecki, Joseph M. TI The effects of a controlled energy storage and return prototype prosthetic foot on transtibial amputee ambulation SO HUMAN MOVEMENT SCIENCE LA English DT Article DE Prosthesis; Amputation; Metabolic cost; Biomechanics; Rehabilitation ID BELOW-KNEE AMPUTEES; POWERED ANKLE EXOSKELETONS; LOWER-LIMB AMPUTATION; TO-STEP TRANSITIONS; HUMAN WALKING; MECHANICAL WORK; METABOLIC COST; BIOMECHANICAL ANALYSIS; SOUND LIMB; GAIT AB The lack of functional ankle musculature in lower limb amputees contributes to the reduced prosthetic ankle push-off, compensations at other joints and more energetically costly gait commonly observed in comparison to non-amputees. A variety of energy storing and return prosthetic feet have been developed to address these issues but have not been shown to sufficiently improve amputee biomechanics and energetic cost, perhaps because the timing and magnitude of energy return is not controlled. The goal of this study was to examine how a prototype microprocessor-controlled prosthetic foot designed to store some of the energy during loading and return it during push-off affects amputee gait. Unilateral transtibial amputees wore the Controlled Energy Storage and Return prosthetic foot (CESR), a conventional foot (CONV), and their previously prescribed foot (PRES) in random order. Three-dimensional gait analysis and net oxygen consumption were collected as participants walked at constant speed. The CESR foot demonstrated increased energy storage during early stance, increased prosthetic foot peak push-off power and work, increased prosthetic limb center of mass (COM) push-off work and decreased intact limb COM collision work compared to CONV and PRES. The biological contribution of the positive COM work for CESR was reduced compared to CONV and PRES. However, the net metabolic cost for CESR did not change compared to CONV and increased compared to PRES, which may partially reflect the greater weight, lack of individualized size and stiffness and relatively less familiarity for CESR and CONV. Controlled energy storage and return enhanced prosthetic push-off, but requires further design modifications to improve amputee walking economy. Published by Elsevier B.V. C1 [Segal, Ava D.; Klute, Glenn K.; Morgenroth, David C.; Hahn, Michael E.; Orendurff, Michael S.; Czerniecki, Joseph M.] VA Puget Sound Hlth Care Syst, RR&D Ctr, Dept Vet Affairs, Seattle, WA 98108 USA. [Klute, Glenn K.; Hahn, Michael E.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Klute, Glenn K.] Univ Washington, Dept Elect Engn, Seattle, WA 98195 USA. [Morgenroth, David C.; Czerniecki, Joseph M.] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Zelik, Karl E.; Adamczyk, Peter G.; Collins, Steven H.; Kuo, Arthur D.] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Adamczyk, Peter G.; Collins, Steven H.] Intelligent Prosthet Syst LLC, Ann Arbor, MI USA. RP Czerniecki, JM (reprint author), VA Puget Sound Hlth Care Syst, RR&D Ctr, Dept Vet Affairs, 1660 S Columbian Way, Seattle, WA 98108 USA. EM joseph.czerniecki@med.va.gov RI Kuo, Arthur/L-3359-2013; Adamczyk, Peter/P-5928-2014; OI Kuo, Arthur/0000-0001-5233-9709; Adamczyk, Peter/0000-0001-5374-7691; Morgenroth, David/0000-0002-0226-7775 FU NICHD NIH HHS [HD055706, R44 HD055706] NR 49 TC 19 Z9 19 U1 4 U2 47 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9457 EI 1872-7646 J9 HUM MOVEMENT SCI JI Hum. Mov. Sci. PD AUG PY 2012 VL 31 IS 4 BP 918 EP 931 DI 10.1016/j.humov.2011.08.005 PG 14 WC Neurosciences; Psychology; Psychology, Experimental; Sport Sciences SC Neurosciences & Neurology; Psychology; Sport Sciences GA 063BV UT WOS:000312971800014 PM 22100728 ER PT J AU Silver, DP Livingston, DM AF Silver, Daniel P. Livingston, David M. TI Mechanisms of BRCA1 Tumor Suppression SO CANCER DISCOVERY LA English DT Review ID DNA-DAMAGE RESPONSE; INACTIVE X-CHROMOSOME; BREAST-CANCER; MUTATION CARRIERS; OVARIAN CARCINOMAS; CELL FATE; XIST RNA; PROTEIN; REPAIR; RESISTANCE AB The p220 BRCA1 tumor suppressor protein has been implicated in multiple biochemical and biologic functions since its molecular cloning 18 years ago. Here, we discuss those functions most relevant for its tumor-suppressing activities with an emphasis on new findings. In particular, this review focuses on what is known of the activities of those BRCA1-binding partners that have tumor suppressor functions, on the reversion of mutant BRCA1 alleles concomitant with therapy resistance, on insights gained from studies of BRCA1 structure-function relationships, recent findings from animal models, and the potential role of BRCA1 in some nonhereditary tumors. From this information, a more detailed and refined picture of BRCA1 tumor suppression is beginning to emerge. Although key mysteries remain-such as why BRCA1 tumor suppression is focused on carcinomas of the breast and ovary-the pace of discovery is increasing. Significance: BRCA1 functions as a clinically important classical tumor suppressor in hereditary breast and ovarian cancer; here, we review progress in understanding how BRCA1 operates to suppress tumor formation. Cancer Discov; 2(8);679-84. (C) 2012 AACR. C1 [Silver, Daniel P.; Livingston, David M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Silver, Daniel P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Livingston, David M.] Dana Farber Canc Inst, Dept Genet, Boston, MA 02215 USA. RP Livingston, DM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave,SM 870, Boston, MA 02215 USA. EM david_livingston@dfci.harvard.edu FU Novartis; National Cancer Institute; Susan B. Komen Foundation for the Cure; Breast Cancer Research Foundation; Dana-Farber/Harvard SPORE in Breast Cancer [CA089393]; NCI; V Foundation; Cogan Family Foundation FX D.M. Livingston has a commercial research grant from Novartis and is a consultant/advisory board member for Novartis and Nextech Venture. No potential conflicts of interest were disclosed by the other author.; Some of the work cited in this article was supported by grants from the National Cancer Institute, from the Susan B. Komen Foundation for the Cure, by the Breast Cancer Research Foundation, by the Dana-Farber/Harvard SPORE in Breast Cancer (grant number CA089393), by a K08 grant from the NCI, by a V Foundation Grant, and by a Cogan Family Foundation award. NR 53 TC 40 Z9 40 U1 0 U2 29 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2012 VL 2 IS 8 BP 679 EP 684 DI 10.1158/2159-8290.CD-12-0221 PG 6 WC Oncology SC Oncology GA 048HU UT WOS:000311902800021 PM 22843421 ER PT J AU Genovese, G Ergun, A Shukla, SA Campos, B Hanna, J Ghosh, P Quayle, SN Rai, K Colla, S Ying, HQ Wu, CJ Sarkar, S Xiao, YH Zhang, JH Zhang, HL Kwong, L Dunn, K Wiedemeyer, WR Brennan, C Zheng, HW Rimm, DL Collins, JJ Chin, L AF Genovese, Giannicola Ergun, Ayla Shukla, Sachet A. Campos, Benito Hanna, Jason Ghosh, Papia Quayle, Steven N. Rai, Kunal Colla, Simona Ying, Haoqiang Wu, Chang-Jiun Sarkar, Sharmistha Xiao, Yonghong Zhang, Jianhua Zhang, Hailei Kwong, Lawrence Dunn, Katherine Wiedemeyer, Wolf Ruprecht Brennan, Cameron Zheng, Hongwu Rimm, David L. Collins, James J. Chin, Lynda TI microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF-beta Signaling in Glioblastoma SO CANCER DISCOVERY LA English DT Article ID INTEGRATED GENOMIC ANALYSIS; EXPRESSION PROFILES; IDH2 MUTATIONS; MESSENGER-RNA; IN-VIVO; CANCER; GLIOMA; PROGRESSION; PROGNOSIS; PTEN AB Leveraging The Cancer Genome Atlas (TCGA) multidimensional data in glioblastoma, we inferred the putative regulatory network between microRNA and mRNA using the Context Likelihood of Relatedness modeling algorithm. Interrogation of the network in context of defined molecular subtypes identified 8 microRNAs with a strong discriminatory potential between proneural and mesenchymal subtypes. Integrative in silico analyses, a functional genetic screen, and experimental validation identified miR-34a as a tumor suppressor in proneural subtype glioblastoma. Mechanistically, in addition to its direct regulation of platelet-derived growth factor receptor-alpha (PDGFRA), promoter enrichment analysis of context likelihood of relatedness-inferred mRNA nodes established miR-34a as a novel regulator of a SMAD4 transcriptional network. Clinically, miR-34a expression level is shown to be prognostic, where miR-34a low-expressing glioblastomas exhibited better overall survival. This work illustrates the potential of comprehensive multidimensional cancer genomic data combined with computational and experimental models in enabling mechanistic exploration of relationships among different genetic elements across the genome space in cancer. SIGNIFICANCE: We illustrate here that network modeling of complex multidimensional cancer genomic data can generate a framework in which to explore the biology of cancers, leading to discovery of new pathogenetic insights as well as potential prognostic biomarkers. Specifically in glioblastoma, within the context of the global network, promoter enrichment analysis of network edges uncovered a novel regulation of TGF-beta signaling via a Smad4 transcriptomic network by miR-34a. Cancer Discov; 2(8); 736-49. (C) 2012 AACR. C1 [Genovese, Giannicola; Rai, Kunal; Colla, Simona; Ying, Haoqiang; Wu, Chang-Jiun; Sarkar, Sharmistha; Kwong, Lawrence; Chin, Lynda] MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77054 USA. [Genovese, Giannicola; Shukla, Sachet A.; Campos, Benito; Ghosh, Papia; Quayle, Steven N.; Rai, Kunal; Colla, Simona; Ying, Haoqiang; Wu, Chang-Jiun; Sarkar, Sharmistha; Xiao, Yonghong; Zhang, Jianhua; Zhang, Hailei; Kwong, Lawrence; Dunn, Katherine; Zheng, Hongwu; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Ergun, Ayla; Collins, James J.] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA 02215 USA. [Ergun, Ayla; Collins, James J.] Boston Univ, Ctr BioDynam, Boston, MA 02215 USA. [Collins, James J.] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Zhang, Jianhua; Chin, Lynda] MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77054 USA. [Shukla, Sachet A.] Iowa State Univ, Dept Stat, Ames, IA USA. [Campos, Benito] Univ Heidelberg, Dept Neurosurg, Div Neurosurg Res, Heidelberg, Germany. [Hanna, Jason; Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Zhang, Hailei; Chin, Lynda] MIT, Eli & Edythe L Broad Inst, Cambridge, MA USA. [Zhang, Hailei; Chin, Lynda] Harvard Univ, Cambridge, MA 02138 USA. [Wiedemeyer, Wolf Ruprecht] Cedars Sinai Med Ctr, Womens Canc Program, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, Cold Spring Harbor, NY USA. [Zheng, Hongwu] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. RP Chin, L (reprint author), MD Anderson Canc Ctr, Dept Genom Med, 1901 East Rd,Rm 4SCR6-2080, Houston, TX 77054 USA. EM jcollins@engc.bu.edu; LChin@mdanderson.org OI Zheng, Hongwu/0000-0002-5823-4913; Brennan, Cameron/0000-0003-4064-8891 FU NIH [PO1 CA095616, U01 CA141508, U24 CA143845, 1K99CA160578-01, P01 CA95616]; Ben and Catherine Ivy Foundation; AIRC "Associazione Italiana per la Ricerca sul Cancro"; Robert A. and Renee E. Belfer foundation; GDAC [NIH U24 CA143845]; NIH; Canadian Institutes of Health Research; Charles A. King Trust; Terry Fox Foundation [2009-700118]; Ovarian Cancer Research Foundation FX This work is supported by funding from the NIH (PO1 CA095616, U01 CA141508, and U24 CA143845) and from the Ben and Catherine Ivy Foundation to L. Chin. J.J. Collins is an HHMI investigator. G. Genovese was supported by the AIRC "Associazione Italiana per la Ricerca sul Cancro" fellowship. S.A. Shukla was supported by The Robert A. and Renee E. Belfer foundation and by the GDAC grant (NIH U24 CA143845). P. Ghosh was supported by a NIH F32 fellowship. S.N. Quayle was supported by a fellowship from the Canadian Institutes of Health Research. K. Rai was supported by an NIH K99/R00 Pathway to Independence award (1K99CA160578-01) and Charles A. King Trust postdoctoral fellowship. K. Dunn was supported by the Terry Fox Foundation (#2009-700118). S. Sarkar was supported by a fellowship from the Ovarian Cancer Research Foundation. C. Brennan is supported by the NIH P01 CA95616 grant. NR 48 TC 54 Z9 56 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2012 VL 2 IS 8 BP 736 EP 749 DI 10.1158/2159-8290.CD-12-0111 PG 14 WC Oncology SC Oncology GA 048HU UT WOS:000311902800026 PM 22750848 ER PT J AU Cevasco, M Itani, KMF AF Cevasco, Marisa Itani, Kamal M. F. TI Ventral Hernia Repair with Synthetic, Composite, and Biologic Mesh: Characteristics, Indications, and Infection Profile SO SURGICAL INFECTIONS LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the Surgical-Infection-Society CY MAY 11-14, 2011 CL Palm Beach, FL SP Surg Infect Soc ID ABDOMINAL-WALL DEFECTS; ACELLULAR DERMAL MATRIX; COMPROMISED SURGICAL FIELD; SMALL-INTESTINAL SUBMUCOSA; LONG-TERM COMPLICATIONS; EXPANDED POLYTETRAFLUOROETHYLENE; POLYPROPYLENE MESH; INCISIONAL HERNIAS; LAPAROSCOPIC REPAIR; BACTERIAL ADHERENCE AB Background: A variety of mesh materials are available for ventral hernia repair (VHR), each with a unique set of characteristics. Surgeons are offered an ever-expanding selection of products, making a review of the available materials timely. Methods: Current surgical literature is reviewed to describe the different types of synthetic mesh, the indications for the use of each type, their relative risks of infection, and other benefits and shortcomings. We also review clinical studies demonstrating outcomes, efficacy, and use of the meshes in different surgical settings, including laparoscopic hernia repair and special situations such as infection or large abdominal wall defects. Results: Three main types of prosthetic mesh are available. Synthetic mesh, such as polypropylene (PP) or polyester, is characterized by high tensile strength and vigorous tissue ingrowth, but is unsuitable for intraabdominal placement because of its tendency to induce bowel adhesions. Composite, or barrier-coated, mesh is a dual-sided prosthetic having a synthetic parietal side to promote a strong repair and a visceral surface that repels tissue ingrowth and decreases adhesion formation. Biologic mesh is a collagen-based human, porcine, or bovine scaffold that may be implanted in the extra-or intra-peritoneal position. Biologic mesh is used frequently in the setting of infected or contaminated surgical incisions. Conclusions: Synthetic PP mesh is an appropriate, durable material for extra-peritoneal placement in uncomplicated, clean VHR. Expanded polytetrafluoroethylene and composite meshes are suitable for intraperitoneal placement during laparoscopic VHR. Biologic meshes may be appropriate for contaminated fields or other special situations, but there is no consensus on when or how to use them. C1 [Itani, Kamal M. F.] Boston Univ, Sch Med, Vet Affairs Boston Healthcare Syst, Boston, MA 02118 USA. [Cevasco, Marisa] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Itani, Kamal M. F.] Harvard Univ, Sch Med, Boston, MA USA. RP Itani, KMF (reprint author), VA Boston Healthcare Syst, Dept Surg, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM kitani@va.gov NR 78 TC 33 Z9 36 U1 2 U2 18 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-2964 EI 1557-8674 J9 SURG INFECT JI Surg. Infect. PD AUG PY 2012 VL 13 IS 4 BP 209 EP 215 DI 10.1089/sur.2012.123 PG 7 WC Infectious Diseases; Surgery SC Infectious Diseases; Surgery GA 047HP UT WOS:000311830500005 PM 22913337 ER PT J AU McGahan, AM AF McGahan, Anita M. TI Challenges of the Informal Economy for the Field of Management SO ACADEMY OF MANAGEMENT PERSPECTIVES LA English DT Article ID DYNAMIC CAPABILITIES; CREATIVE DESTRUCTION; ABSORPTIVE-CAPACITY; TRANSACTION COSTS; FIRMS; INNOVATION; INDUSTRY; PERSPECTIVE; ENTERPRISE; SURVIVAL AB The informal economy comprises business activities that are unregistered and unregulated but not otherwise illegal (Hart, 2006). Studying informal activity yields important insights for mainstream theories of management, pointing to areas for new theorizing on the boundaries of the firm, diversification, dynamic capabilities, absorptive capacity, property rights, governance, stakeholder theory, disruptive technology, innovation, and organizational legitimacy. I argue that research on this sector is not only an opportunity for management scholars but also essential to the continued relevance and vitality of management as a discipline. C1 [McGahan, Anita M.] Univ Toronto, Rotman Sch Management, Toronto, ON M5S 1A1, Canada. [McGahan, Anita M.] Harvard Univ, Munk Sch Global Affairs, Cambridge, MA 02138 USA. [McGahan, Anita M.] Harvard Univ, Inst Strategy & Competitiveness, Cambridge, MA 02138 USA. [McGahan, Anita M.] Massachusetts Gen Hosp, Div Global Hlth & Human Rights, Boston, MA 02114 USA. RP McGahan, AM (reprint author), Univ Toronto, Rotman Sch Management, Toronto, ON M5S 1A1, Canada. EM amcgahan@rotman.utoronto.ca NR 69 TC 19 Z9 20 U1 4 U2 43 PU ACAD MANAGEMENT PI BRIARCLIFF MANOR PA PACE UNIV, PO BOX 3020, 235 ELM RD, BRIARCLIFF MANOR, NY 10510-8020 USA SN 1558-9080 J9 ACAD MANAGE PERSPECT JI Acad. Manag. Perspect. PD AUG PY 2012 VL 26 IS 3 BP 12 EP 21 DI 10.5465/amp.2012.0104 PG 10 WC Business; Management SC Business & Economics GA 042GN UT WOS:000311459800002 ER PT J AU Royall, DR Palmer, RF Petrovitch, H Ross, GW Masaki, K White, LR AF Royall, Donald R. Palmer, Raymond F. Petrovitch, Helen Ross, G. Webster Masaki, Kamal White, Lon R. TI Modeling regional vulnerability to Alzheimer pathology SO NEUROBIOLOGY OF AGING LA English DT Article DE Old age; Neuropathology; Alzheimer's disease ID MILD COGNITIVE IMPAIRMENT; NEUROFIBRILLARY TANGLES; DEMENTIA SEVERITY; SPATIAL-PATTERNS; BRAIN PATHOLOGY; SENILE PLAQUES; DISEASE; AGE; AD; CRITERIA AB Latent growth curve (LGC) models estimate change over time in a cohort's serially obtained measurements. We have applied LGC techniques to a spatial distribution of Alzheimer's disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study. Neurofibrillary tangle (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. The gradient of spatial change in neuritic plaque (dNP), was significantly associated with that of neurofibrillary tangle (dNFT), but weakly and inversely (r = -0.12; p < 0.001). Both dNFT and dNP correlated significantly and inversely with Braak stage. Sixty-one percent of the variance in Braak stage was explained by dNFT independent of covariates. Only dNFT was significantly associated with longitudinal change in cognition. Only dNP was associated with apolipoprotein (APOE) e4 burden. This is the first application of LGC models to spatially-ordered data. The result is a quantification of the interindividual variation in the interregional vulnerability to Alzheimer's disease lesions. (C) 2012 Published by Elsevier Inc. C1 [Royall, Donald R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78284 USA. [Royall, Donald R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78284 USA. [Royall, Donald R.; Palmer, Raymond F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78284 USA. [Royall, Donald R.] S Texas Vet Hlth Syst, Audie L Murphy Div GRECC, San Antonio, TX USA. [Petrovitch, Helen] Pacific Hlth Res & Educ Inst, Honolulu, HI USA. [Ross, G. Webster] Honolulu Dept Vet Affairs, Honolulu, HI USA. [Masaki, Kamal; White, Lon R.] John A Burns Sch Med Kakaako, Dept Geriatr Med, Honolulu, HI USA. [Masaki, Kamal; White, Lon R.] HonoluluKuakini Med Ctr, Kuakini Med Ctr, Honolulu, HI USA. RP Royall, DR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. EM royall@uthscsa.edu FU National Institute of Neurological Disorders and Stroke (National Institutes of Health, USA) [NSO48123-01]; Julia and Van Buren Parr professorship in Aging and Geriatric Psychiatry FX DRR, RFP, and LRW were funded by National Institute of Neurological Disorders and Stroke (National Institutes of Health, USA), Grant No. NSO48123-01. DRR is supported by the Julia and Van Buren Parr professorship in Aging and Geriatric Psychiatry. HAAS neuropathological data were entirely generated by a team of 4 expert neuropathologists under leadership of Dr. William Markesbery (deceased), with the oversight of LRW, the HAAS Principal Investigator. Other members of the team were Dr. John Hardman (deceased), Dr. James Nelson (retired), and Dr. Daron Davis (who left the study for a clinical practice in 2001). NR 41 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2012 VL 33 IS 8 BP 1556 EP 1563 DI 10.1016/j.neurobiolaging.2011.05.028 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 969QN UT WOS:000306070800006 PM 21803455 ER PT J AU Bhattacharya, A Bokov, A Muller, FL Jernigan, AL Maslin, K Diaz, V Richardson, A Van Remmen, H AF Bhattacharya, Arunabh Bokov, Alex Muller, Florian L. Jernigan, Amanda L. Maslin, Keith Diaz, Vivian Richardson, Arlan Van Remmen, Holly TI Dietary restriction but not rapamycin extends disease onset and survival of the H46R/H48Q mouse model of ALS SO NEUROBIOLOGY OF AGING LA English DT Article DE Dietary-restriction; Rapamycin; H46R/H48Q; G93A; ALS ID GENETICALLY HETEROGENEOUS MICE; AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DEGENERATION; LIFE-SPAN; CALORIC RESTRICTION; G93A MOUSE; PROGRESSION; EXTENSION; TOXICITY; MTOR AB Dietary restriction (DR) and rapamycin (Rapa) have been shown to increase the lifespan of a variety of organisms leading to the speculation that these interventions increase lifespan through related mechanisms. However, both these interventions have a detrimental effect in the G93A mutant mouse model of amyotrophic lateral sclerosis (ALS). Our previous work indicated that different ALS SOD1 mutant mouse models differ in disease pathogenesis; therefore in this study we measured the effect of DR and Rapa in a second ALS mutant mouse model (the H46R/H48Q mutant). Interestingly, in mice expressing this mutant SOD1 protein, DR significantly delays disease onset and extends lifespan, while Rapa has no effect. These findings suggest that: (1) the effect of DR in ALS is not mediated through pathways common with Rapa, (2) the deleterious effect of DR and Rapa in the G93A ALS mouse model may not be universal to disease caused by all SOD1 mutations, and (3) the results reinforce our previous conclusions that the pathogenic mechanisms in G93A and H46R/H48Q mice are distinct. (C) 2012 Elsevier Inc. All rights reserved. C1 [Bhattacharya, Arunabh; Jernigan, Amanda L.; Maslin, Keith; Diaz, Vivian; Richardson, Arlan; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Bhattacharya, Arunabh; Muller, Florian L.; Richardson, Arlan; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78245 USA. [Bokov, Alex; Richardson, Arlan; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78245 USA. [Richardson, Arlan; Van Remmen, Holly] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. RP Van Remmen, H (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Res Pk Campus,15355 Lambda Dr, San Antonio, TX 78245 USA. EM vanremmen@uthscsa.edu FU Muscular Dystrophy Association [MDA 10047] FX This work was supported by the Muscular Dystrophy Association (Grant MDA 10047 to HVR). We thank Dr. David Borchelt for kindly providing the H46R/H48Q mutant mice. NR 21 TC 21 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2012 VL 33 IS 8 BP 1829 EP 1832 DI 10.1016/j.neurobiolaging.2011.06.002 PG 4 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 969QN UT WOS:000306070800032 PM 21763036 ER PT J AU Dusetzina, SB Alexander, GC Freedman, RA Huskamp, HA Keating, NL AF Dusetzina, Stacie B. Alexander, G. Caleb Freedman, Rachel A. Huskamp, Haiden A. Keating, Nancy L. TI Trends in Antidepressants and Tamoxifen Co-Prescribing among Women with Breast Cancer, 2004-2010 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Dusetzina, Stacie B.; Huskamp, Haiden A.; Keating, Nancy L.] Harvard Univ, Sch Med, Boston, MA USA. [Alexander, G. Caleb] Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. [Freedman, Rachel A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 10 BP 5 EP 5 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701010 ER PT J AU Yong, M Schenfeld, J Anthony, M Pariser, D Kimball, AB AF Yong, Mellissa Schenfeld, Jennifer Anthony, Mary Pariser, David Kimball, Alexa B. TI Malignancy and Infection Rates in Psoriasis Patients with or without Treatment and in a General Population in the US: 2005-2009 SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Yong, Mellissa; Schenfeld, Jennifer; Anthony, Mary] Amgen Inc, Ctr Observat Res, Thousand Oaks, CA 91320 USA. [Pariser, David] Virginia Clin Res Inc, Norfolk, VA USA. [Kimball, Alexa B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, Alexa B.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 83 BP 42 EP 42 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701083 ER PT J AU Gothe, H Saverno, K Gothe, RM Durdu, N Stefan, A Endel, G Biskupiak, JE Brixner, D Siebert, U AF Gothe, Holger Saverno, Kim Gothe, Raffaella Matteucci Durdu, Nimet Stefan, Andrea Endel, Gottfried Biskupiak, Joseph E. Brixner, Diana Siebert, Uwe TI Identification of COPD Patients in Epidemiological Studies Using Administrative Databases SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Gothe, Holger; Saverno, Kim; Gothe, Raffaella Matteucci; Durdu, Nimet; Brixner, Diana; Siebert, Uwe] UMIT, Dept Publ Hlth & HTA, Tyrol, Austria. [Gothe, Holger] Univ Dresden, Dresden Med Sch, Dept Publ Hlth, Dresden, Saxony, Germany. [Saverno, Kim; Biskupiak, Joseph E.; Brixner, Diana] Univ Utah, Outcomes Res Ctr, Dept Pharmacotherapy, Salt Lake City, UT USA. [Stefan, Andrea; Endel, Gottfried] Austrian Social Secur Inst, Main Assoc, Vienna, Austria. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 161 BP 78 EP 78 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701158 ER PT J AU Bateman, BT Hernandez-Diaz, S Huybrechts, K Palmsten, K Fischer, MA AF Bateman, Brian T. Hernandez-Diaz, Sonia Huybrechts, Krista Palmsten, Kristen Fischer, Michael A. TI Patterns of antihypertensive medication use in medicaid-eligible pregnant women SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Bateman, Brian T.; Huybrechts, Krista; Fischer, Michael A.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Bateman, Brian T.; Huybrechts, Krista; Fischer, Michael A.] Harvard Univ, Sch Med, Boston, MA USA. [Bateman, Brian T.; Palmsten, Kristen] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 362 BP 170 EP 170 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701350 ER PT J AU Lawler, EV Fonda, J Gagnon, DR Hermos, J Barber, C Miller, M AF Lawler, Elizabeth V. Fonda, Jennifer Gagnon, David R. Hermos, John Barber, Catherine Miller, Matthew TI Risk of Unintentional Overdose Following Outpatient Opioid Treatment for Pain SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Lawler, Elizabeth V.; Fonda, Jennifer; Gagnon, David R.; Hermos, John] VA Boston Healthcare Syst, MAVERIC, Boston, MA USA. [Lawler, Elizabeth V.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Barber, Catherine; Miller, Matthew] Harvard Univ, Sch Publ Hlth, Harvard Injury Control Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 368 BP 173 EP 173 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701356 ER PT J AU Fung, V Price, M Hsu, J AF Fung, Vicki Price, Mary Hsu, John TI Access, Benefit Design, and Antipsychotic Drugs in the Medicare Part D Program SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Fung, Vicki] Midatlantic Permanente Med Grp, Midatlantic Permanente Res Inst, Rockville, MD USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Price, Mary] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2012 VL 21 SU 3 SI SI MA 397 BP 188 EP 188 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 996YU UT WOS:000308131701385 ER PT J AU Payakachat, N Tilford, JM Kovacs, E Kuhlthau, K AF Payakachat, Nalin Tilford, J. Mick Kovacs, Erica Kuhlthau, Karen TI Autism spectrum disorders: a review of measures for clinical, health services and cost effectiveness applications SO EXPERT REVIEW OF PHARMACOECONOMICS & OUTCOMES RESEARCH LA English DT Review DE autism spectrum disorders; behavioral outcomes; children; clinical outcomes; economic evaluation; HRQL; preference-weighted scores ID QUALITY-OF-LIFE; PERVASIVE DEVELOPMENTAL DISORDERS; DIAGNOSTIC OBSERVATION SCHEDULE; REPORTED OUTCOMES MEASUREMENT; GENERIC CORE SCALES; CHILD HEALTH; PSYCHIATRIC-DISORDERS; REPETITIVE BEHAVIORS; ECONOMIC EVALUATIONS; ASPERGER-SYNDROME AB Autism spectrum disorders (ASDs) are characterized by impairments in social interaction, communication and behavioral functioning that can affect the health-related quality-of-life outcomes of the affected child and the family. ASDs have increased in prevalence, leading to a demand for improved understanding of the comparative effectiveness of different pharmacologic, behavioral, medical and alternative treatments for children as well as systems for providing services. This review describes outcome instruments that can be used for clinical, health services and cost effectiveness applications. There is a pressing need to identify the most appropriate instruments for measuring health-related quality-of-life outcomes in this population. Studies evaluating the cost effectiveness of interventions or treatments for children with ASDs using the cost per quality-adjusted life year metric are lacking. Researchers have the potential to contribute greatly to the field of autism by quantifying outcomes that can inform optimal treatment strategies. C1 [Payakachat, Nalin; Tilford, J. Mick] Univ Arkansas Med Sci, Div Pharmaceut Evaluat & Policy, Little Rock, AR 72205 USA. [Tilford, J. Mick] Univ Arkansas Med Sci, Dept Hlth Policy & Management, Little Rock, AR 72205 USA. [Kovacs, Erica] Columbia Univ, Dept Psychiat, New York, NY USA. [Kuhlthau, Karen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kuhlthau, Karen] Massachusetts Gen Hosp, Ctr Adolescent Hlth Policy, Boston, MA 02114 USA. RP Payakachat, N (reprint author), Univ Arkansas Med Sci, Div Pharmaceut Evaluat & Policy, Little Rock, AR 72205 USA. EM npayakachat@uams.edu FU National Institute of Mental Health [R01MH089466]; NIH through the Translational Research Institute at the University of Arkansas for Medical Sciences [1UL1RR029884] FX This project was supported by award number R01MH089466 from the National Institute of Mental Health with K Kuhlthau and JM Tilford serving as Principal Investigators. JM Tilford also received support from the NIH (Grant # 1UL1RR029884) through the Translational Research Institute at the University of Arkansas for Medical Sciences. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the NIH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 130 TC 12 Z9 12 U1 3 U2 31 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7167 J9 EXPERT REV PHARM OUT JI Expert Rev. Pharmacoecon. Outcomes Res. PD AUG PY 2012 VL 12 IS 4 BP 485 EP 503 DI 10.1586/ERP.12.29 PG 19 WC Health Care Sciences & Services; Health Policy & Services; Pharmacology & Pharmacy SC Health Care Sciences & Services; Pharmacology & Pharmacy GA 030GO UT WOS:000310559200018 PM 22971035 ER PT J AU Savoia, E Agboola, F Biddinger, PD AF Savoia, Elena Agboola, Foluso Biddinger, Paul D. TI Use of After Action Reports (AARs) to Promote Organizational and Systems Learning in Emergency Preparedness SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE lessons learned; after action report (AAR); knowledge management; organizational learning; emergency preparedness AB Many public health and healthcare organizations use formal knowledge management practices to identify and disseminate the experiences gained over time. The "lessons-learned" approach is one such example of knowledge management practice applied to the wider concept of organizational learning. In the field of emergency preparedness, the lessons-learned approach stands on the assumption that learning from experience improves practice and minimizes avoidable deaths and negative economic and social consequences of disasters. In this project, we performed a structured review of AARs to analyze how lessons learned from the response to real-incidents may be used to maximize knowledge management and quality improvement practices such as the design of public health emergency preparedness (PHEP) exercises. We chose as a source of data the "Lessons Learned Information Sharing (LLIS.gov)" system, a joined program of the U. S. Department of Homeland Security DHS and FEMA that serves as the national, online repository of lessons learned, best practices, and innovative ideas. We identified recurring challenges reported by various states and local public health agencies in the response to different types of incidents. We also strived to identify the limitations of systematic learning that can be achieved due to existing weaknesses in the way AARs are developed. C1 [Savoia, Elena] Harvard Univ, Sch Publ Hlth, Dept Biostat, Landmark Ctr, Boston, MA 02215 USA. [Savoia, Elena] Harvard Univ, Sch Publ Hlth, Landmark Ctr, Div Policy Translat & Leadership Dev, Boston, MA 02215 USA. [Savoia, Elena; Agboola, Foluso; Biddinger, Paul D.] Harvard Univ, Sch Publ Hlth, Div Policy Translat & Leadership Dev, Boston, MA 02115 USA. [Biddinger, Paul D.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Biddinger, Paul D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Savoia, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Landmark Ctr, 401 Pk Dr,3rd Floor E, Boston, MA 02215 USA. EM esavoia@hsph.harvard.edu; fagboola@hsph.harvard.edu; pbiddinger@partners.org FU U.S. Centers for Disease Control and Prevention (CDC) [5PO1TP000307-04] FX We acknowledge funding support from the U.S. Centers for Disease Control and Prevention (CDC) grant number 5PO1TP000307-04 Preparedness and Emergency Response Research Center-Linking Assessment to Measurement and Performance in Public Health Emergency Preparedness Exercises. The content of this publication as well as the views and discussions expressed in these paper are solely those of the authors and do not necessarily represent the views of any partner organizations, the CDC or the U.S. Department of Health and Human Services nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. NR 14 TC 18 Z9 18 U1 4 U2 16 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD AUG PY 2012 VL 9 IS 8 BP 2949 EP 2963 DI 10.3390/ijerph9082949 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 998MB UT WOS:000308242300026 PM 23066408 ER PT J AU Japuntich, SJ Regan, S Viana, J Tymoszczuk, J Reyen, M Levy, DE Singer, DE Park, ER Chang, YC Rigotti, NA AF Japuntich, Sandra J. Regan, Susan Viana, Joseph Tymoszczuk, Justyna Reyen, Michele Levy, Douglas E. Singer, Daniel E. Park, Elyse R. Chang, Yuchiao Rigotti, Nancy A. TI Comparative effectiveness of post-discharge interventions for hospitalized smokers: study protocol for a randomized controlled trial SO TRIALS LA English DT Article DE Smoking cessation; Hospitalization; Pharmacotherapy; Counseling; Randomized clinical trial; Interactive voice response ID INTERACTIVE VOICE RESPONSE; SMOKING-CESSATION INTERVENTION; FREE NICOTINE PATCHES; COST-EFFECTIVENESS; TOBACCO QUITLINE; HEART-DISEASE; PRIMARY-CARE; SYSTEM; MORTALITY; PROGRAM AB Background: A hospital admission offers smokers an opportunity to quit. Smoking cessation counseling provided in the hospital is effective, but only if it continues for more than one month after discharge. Providing smoking cessation medication at discharge may add benefit to counseling. A major barrier to translating this research into clinical practice is sustaining treatment during the transition to outpatient care. An evidence-based, practical, cost-effective model that facilitates the continuation of tobacco treatment after discharge is needed. This paper describes the design of a comparative effectiveness trial testing a hospital-initiated intervention against standard care. Methods/design: A two-arm randomized controlled trial compares the effectiveness of standard post-discharge care with a multi-component smoking cessation intervention provided for three months after discharge. Current smokers admitted to Massachusetts General Hospital who receive bedside smoking cessation counseling, intend to quit after discharge and are willing to consider smoking cessation medication are eligible. Study participants are recruited following the hospital counseling visit and randomly assigned to receive Standard Care or Extended Care after hospital discharge. Standard Care includes a recommendation for a smoking cessation medication and information about community resources. Extended Care includes up to three months of free FDA-approved smoking cessation medication and five proactive computerized telephone calls that use interactive voice response technology to provide tailored motivational messages, offer additional live telephone counseling calls from a smoking cessation counselor, and facilitate medication refills. Outcomes are assessed at one, three, and six months after hospital discharge. The primary outcomes are self-reported and validated seven-day point prevalence tobacco abstinence at six months. Other outcomes include short-term and sustained smoking cessation, post-discharge utilization of smoking cessation treatment, hospital readmissions and emergency room visits, and program cost per quit. Discussion: This study tests a disseminable smoking intervention model for hospitalized smokers. If effective and widely adopted, it could help to reduce population smoking rates and thereby reduce tobacco-related mortality, morbidity, and health care costs. Trial registration: United States Clinical Trials Registry NCT01177176. C1 [Japuntich, Sandra J.; Regan, Susan; Viana, Joseph; Tymoszczuk, Justyna; Reyen, Michele; Levy, Douglas E.; Singer, Daniel E.; Park, Elyse R.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Regan, Susan; Chang, Yuchiao; Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Gen Med Div, Boston, MA 02114 USA. [Japuntich, Sandra J.; Levy, Douglas E.; Park, Elyse R.; Rigotti, Nancy A.] Partners HealthCare, Mongan Inst Hlth Policy, Boston, MA USA. [Japuntich, Sandra J.; Regan, Susan; Levy, Douglas E.; Singer, Daniel E.; Park, Elyse R.; Chang, Yuchiao; Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. EM nrigotti@partners.org OI Regan, Susan/0000-0003-0940-2017 FU Nabi Biopharmaceuticals, Inc.; National Heart Lung and Blood Institute [RC1-HL099668-01] FX Dr. Rigotti has served as an unpaid consultant for Pfizer, Inc., and Free & Clear, Inc., regarding smoking cessation. Her institution has been funded by Nabi Biopharmaceuticals, Inc., to conduct trials of an investigational smoking cessation product. Drs. Singer, Japuntich, Regan, Levy, Park, Chang, Mr. Viana, Ms. Tymoszczuk, and Ms. Reyen have no conflicts of interest related to this project to report.; This study is funded by grant #RC1-HL099668-01 from the National Heart Lung and Blood Institute. We thank the MGH Tobacco Treatment Service counselors for their help with screening and recruitment (Beth Ewy, Kathleen McKool, Nancy McCleary, Jean Mizer, and Caitlin McCann) and Drs. Ryan Thompson and Lindsay Jubelt for their help in designing protocols for recruitment and intervention delivery in the hospital. We also acknowledge the assistance of many other members of the hospital staff (including floor nursing staff, case managers, responding clinicians and pharmacy staff) in aiding recruitment and medication delivery. NR 47 TC 7 Z9 7 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD AUG 1 PY 2012 VL 13 AR 124 DI 10.1186/1745-6215-13-124 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 032SB UT WOS:000310738300001 PM 22852832 ER PT J AU Weiss, AP Chang, G Rauch, SL Smallwood, JA Schechter, M Kosowsky, J Hazen, E Haimovici, F Gitlin, DF Finn, CT Orav, EJ AF Weiss, Anthony P. Chang, Grace Rauch, Scott L. Smallwood, Jennifer A. Schechter, Mark Kosowsky, Joshua Hazen, Eric Haimovici, Florina Gitlin, David F. Finn, Christine T. Orav, Endel J. TI Patient- and Practice-Related Determinants of Emergency Department Length of Stay for Patients With Psychiatric Illness SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID MEDICAL-CENTER; VISITS; SERVICE; TIME; VARIABLES; TRENDS; ABUSE AB Study objective: To identify patient and clinical management factors related to emergency department (ED) length of stay for psychiatric patients. Methods: This was a prospective study of 1,092 adults treated at one of 5 EDs between June 2008 and May 2009. Regression analyses were used to identify factors associated with ED length of stay and its 4 subcomponents. Secondary analyses considered patients discharged to home and those who were admitted or transferred separately. Results: The overall mean ED length of stay was 11.5 hours (median 8.2 hours). ED length of stay varied by discharge disposition, with patients discharged to home staying 8.6 hours (95% confidence interval 7.7 to 9.5 hours) and patients transferred to a hospital outside the system of care staying 15 hours (95% confidence interval 12.7 to 17.6 hours) on average. Older age and being uninsured were associated with increased ED length of stay, whereas race, sex, and homelessness had no association. Patients with a positive toxicology screen result for alcohol stayed an average of 6.2 hours longer than patients without toxicology screens, an effect observed primarily in the periods before disposition decision. Diagnostic imaging was associated with an average 3.2-hour greater length of stay, prolonging both early and late components of the ED stay. Restraint use had a similar effect, leading to a length of stay 4.2 hours longer than that of patients not requiring restraints. Conclusion: Psychiatric patients spent more than 11 hours in the ED on average when seeking care. The need for hospitalization, restraint use, and the completion of diagnostic imaging had the greatest effect on postassessment boarding time, whereas the presence of alcohol on toxicology screening led to delays earlier in the ED stay. Identification and sharing of best practices associated with each of these factors would provide an opportunity for improvement in ED care for this population. [Ann Emerg Med. 2012;60:162-171.] C1 [Weiss, Anthony P.; Chang, Grace; Rauch, Scott L.; Smallwood, Jennifer A.; Orav, Endel J.] Partners Psychiat & Mental Hlth, Div Hlth Serv Res, Boston, MA USA. [Weiss, Anthony P.; Chang, Grace; Rauch, Scott L.; Smallwood, Jennifer A.; Kosowsky, Joshua; Hazen, Eric; Haimovici, Florina; Gitlin, David F.; Orav, Endel J.] Harvard Univ, Sch Med, Boston, MA USA. [Weiss, Anthony P.; Hazen, Eric] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chang, Grace; Smallwood, Jennifer A.; Kosowsky, Joshua; Gitlin, David F.; Orav, Endel J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Schechter, Mark] N Shore Med Ctr, Salem, MA USA. [Hazen, Eric] Newton Wellesley Hosp, Newton, MA USA. [Haimovici, Florina] Faulkner Hosp, Jamaica Plain, MA USA. [Finn, Christine T.] Dartmouth Hitchcock Med Ctr, Hanover, NH USA. RP Weiss, AP (reprint author), Partners Psychiat & Mental Hlth, Div Hlth Serv Res, Boston, MA USA. EM aweiss@partners.org FU Partners Psychiatry and Mental Health Division of Health Services Research; [K24 AA 000289] 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 as per ICMJE conflict of interest guidelines (see www.icmje.org). This study was supported by the Partners Psychiatry and Mental Health Division of Health Services Research and K24 AA 000289 (Dr. Chang). Dr. Weiss has received honoraria from the National Lipid Association (nonprofit). NR 37 TC 29 Z9 29 U1 1 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 AUG PY 2012 VL 60 IS 2 BP 162 EP 171 DI 10.1016/j.annemergmed.2012.01.037 PG 10 WC Emergency Medicine SC Emergency Medicine GA 986DX UT WOS:000307322300009 PM 22555337 ER PT J AU Andruchow, JE Schuur, JD Raja, AS Kabrhel, C AF Andruchow, James E. Schuur, Jeremiah D. Raja, Ali S. Kabrhel, Christopher TI Don't Forget the 99% SO ANNALS OF EMERGENCY MEDICINE LA English DT Letter C1 [Andruchow, James E.; Schuur, Jeremiah D.; Raja, Ali S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Kabrhel, Christopher] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Andruchow, JE (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. OI Kabrhel, Christopher/0000-0002-8699-7176 NR 4 TC 1 Z9 1 U1 0 U2 1 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 AUG PY 2012 VL 60 IS 2 BP 242 EP 243 DI 10.1016/j.annemergmed.2012.01.034 PG 2 WC Emergency Medicine SC Emergency Medicine GA 986DX UT WOS:000307322300026 PM 22818375 ER PT J AU Alpert, MD Harvey, JD Lauer, WA Reeves, RK Piatak, M Carville, A Mansfield, KG Lifson, JD Li, WJ Desrosiers, RC Johnson, RP Evans, DT AF Alpert, Michael D. Harvey, Jackson D. Lauer, W. Anderson Reeves, R. Keith Piatak, Michael, Jr. Carville, Angela Mansfield, Keith G. Lifson, Jeffrey D. Li, Wenjun Desrosiers, Ronald C. Johnson, R. Paul Evans, David T. TI ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIV(mac)251 Challenge SO PLOS PATHOGENS LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; DEPENDENT CELLULAR CYTOTOXICITY; T-LYMPHOCYTE RESPONSES; RHESUS MACAQUES; VAGINAL CHALLENGE; ANTIBODY PROTECTION; VACCINE PROTECTION; IMMUNE-RESPONSES; ADULT MACAQUES; HIV TYPE-1 AB Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIV Delta nef, increased progressively over time, and was proportional to SIVDnef replication. Persistent infection with SIV Delta nef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIV(mac)251 challenge, measures of ADCC activity were higher among the SIV Delta nef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIV Delta nef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIV Delta nef. C1 [Alpert, Michael D.; Harvey, Jackson D.; Lauer, W. Anderson; Desrosiers, Ronald C.; Evans, David T.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Immunobiol, Southborough, MA 01772 USA. [Reeves, R. Keith; Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Carville, Angela; Mansfield, Keith G.] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Pathol, Southborough, MA 01772 USA. [Li, Wenjun] Univ Massachusetts, Sch Med, Worcester, MA USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. RP Alpert, MD (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Immunobiol, Southborough, MA 01772 USA. EM david_evans@hms.harvard.edu RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU National Institutes of Health [AI071306, AI063993, RR000168/OD01103]; American Recovery and Reinvestment Act (ARRA) [3P01AI071306-04S1]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was supported by grants AI071306, AI063993, and RR000168/OD01103 from the National Institutes of Health, and supplement 3P01AI071306-04S1 from the American Recovery and Reinvestment Act (ARRA) of 2009, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. DTE is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 60 Z9 60 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2012 VL 8 IS 8 AR e1002890 DI 10.1371/journal.ppat.1002890 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 002TI UT WOS:000308558000060 PM 22927823 ER PT J AU Lebreton, F van Schaik, W Sanguinetti, M Posteraro, B Torelli, R Le Bras, F Verneuil, N Zhang, XL Giard, JC Dhalluin, A Willems, RJL Leclercq, R Cattoir, V AF Lebreton, Francois van Schaik, Willem Sanguinetti, Maurizio Posteraro, Brunella Torelli, Riccardo Le Bras, Florian Verneuil, Nicolas Zhang, Xinglin Giard, Jean-Christophe Dhalluin, Anne Willems, Rob J. L. Leclercq, Roland Cattoir, Vincent TI AsrR Is an Oxidative Stress Sensing Regulator Modulating Enterococcus faecium Opportunistic Traits, Antimicrobial Resistance, and Pathogenicity SO PLOS PATHOGENS LA English DT Article ID ORGANIC HYDROPEROXIDE STRESS; GRAM-POSITIVE BACTERIA; STAPHYLOCOCCUS-AUREUS; GALLERIA-MELLONELLA; HYDROGEN-PEROXIDE; BACILLUS-SUBTILIS; VIRULENCE DETERMINANTS; COLLAGEN ADHESIN; BETA-LACTAMS; MARR FAMILY AB Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses in microorganisms. Here, we identified an oxidative stress sensor and response regulator in the important multidrug-resistant nosocomial pathogen Enterococcus faecium belonging to the MarR family and called AsrR (antibiotic and stress response regulator). The AsrR regulator used cysteine oxidation to sense the hydrogen peroxide which results in its dissociation to promoter DNA. Transcriptome analysis showed that the AsrR regulon was composed of 181 genes, including representing functionally diverse groups involved in pathogenesis, antibiotic and antimicrobial peptide resistance, oxidative stress, and adaptive responses. Consistent with the upregulated expression of the pbp5 gene, encoding a low-affinity penicillin-binding protein, the asrR null mutant was found to be more resistant to beta-lactam antibiotics. Deletion of asrR markedly decreased the bactericidal activity of ampicillin and vancomycin, which are both commonly used to treat infections due to enterococci, and also led to over-expression of two major adhesins, acm and ecbA, which resulted in enhanced in vitro adhesion to human intestinal cells. Additional pathogenic traits were also reinforced in the asrR null mutant including greater capacity than the parental strain to form biofilm in vitro and greater persistance in Galleria mellonella colonization and mouse systemic infection models. Despite overexpression of oxidative stress-response genes, deletion of asrR was associated with a decreased oxidative stress resistance in vitro, which correlated with a reduced resistance to phagocytic killing by murine macrophages. Interestingly, both strains showed similar amounts of intracellular reactive oxygen species. Finally, we observed a mutator phenotype and enhanced DNA transfer frequencies in the asrR deleted strain. These data indicate that AsrR plays a major role in antimicrobial resistance and adaptation for survival within the host, thereby contributes importantly to the opportunistic traits of E. faecium. C1 [Lebreton, Francois; Le Bras, Florian; Giard, Jean-Christophe; Dhalluin, Anne; Leclercq, Roland; Cattoir, Vincent] Univ Caen Basse Normandie, EA4655, Team Antibioresistance, Sch Med, Caen, France. [van Schaik, Willem; Zhang, Xinglin; Willems, Rob J. L.] Univ Med Ctr Utrecht, Dept Med Microbiol, Utrecht, Netherlands. [Sanguinetti, Maurizio; Torelli, Riccardo] Univ Cattolica Sacro Cuore, Inst Microbiol, I-00168 Rome, Italy. [Posteraro, Brunella] Univ Cattolica Sacro Cuore, Inst Hyg, I-00168 Rome, Italy. [Verneuil, Nicolas] Univ Caen Basse Normandie, EA4655, Team Stress & Virulence, Caen, France. [Leclercq, Roland; Cattoir, Vincent] Univ Hosp Caen, Dept Microbiol, Caen, France. RP Lebreton, F (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. EM cattoir-v@chu-caen.fr RI Willems, Rob/E-3681-2010; OI Posteraro, Brunella/0000-0002-1663-7546; Sanguinetti, Maurizio/0000-0002-9780-7059 FU 7th Framework European Program "Translational Research On Combating Antimicrobial Resistance" (TROCAR); European Union [LSHE-CT-2007-037410]; NWO-VENI [916.86.044] FX This work was supported in part by the 7th Framework European Program "Translational Research On Combating Antimicrobial Resistance" (TROCAR). FL obtained an EMBO short-term fellowship as part of this project. WvS, XZ and RJLW are funded through the European Union Sixth Framework Programme "Approaches to Control multi-resistant Enterococci (ACE): Studies on molecular ecology, horizontal gene transfer, fitness and prevention" under contract LSHE-CT-2007-037410. WvS is also funded by an NWO-VENI grant (916.86.044). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 91 TC 20 Z9 21 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2012 VL 8 IS 8 AR e1002834 DI 10.1371/journal.ppat.1002834 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 002TI UT WOS:000308558000012 PM 22876178 ER PT J AU Stanley, SA Grant, SS Kawate, T Iwase, N Shimizu, M Wivagg, C Silvis, M Kazyanskaya, E Aquadro, J Golas, A Fitzgerald, M Dai, HQ Zhang, LX Hung, DT AF Stanley, Sarah A. Grant, Sarah Schmidt Kawate, Tomohiko Iwase, Noriaki Shimizu, Motohisa Wivagg, Carl Silvis, Melanie Kazyanskaya, Edward Aquadro, John Golas, Aaron Fitzgerald, Michael Dai, Huanqin Zhang, Lixin Hung, Deborah T. TI Identification of Novel Inhibitors of M. tuberculosis Growth Using Whole Cell Based High-Throughput Screening SO ACS CHEMICAL BIOLOGY LA English DT Article ID MYCOBACTERIUM-BOVIS BCG; BENZOTHIAZINONES; EPIPOLYTHIODIOXOPIPERAZINES; SMEGMATIS; MEMBRANE; DORMANT; MMPL3; DPRE1; MICE AB Despite the urgent need for new antitubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new targets will be required. Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery. We find that conducting primary screens using model mycobacterial species may limit the potential for identifying new inhibitors with efficacy against M. tuberculosis. In addition, we confirm the importance of developing in vitro assay conditions that are reflective of in vivo biology for maximizing the proportion of hits from whole cell screening that are likely to have activity in vivo. Finally, we describe the identification and characterization of two novel inhibitors that target steps in M. tuberculosis cell wall biosynthesis. The first is a novel benzimidazole that targets mycobacterial membrane protein large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. The second is a nitro-triazole that inhibits decaprenylphosphoryl-beta-D-ribose 2'-epimerase (DprE1), an epimerase required for cell wall biosynthesis. These proteins are both among the small number of new targets that have been identified by forward chemical genetics using resistance generation coupled with genome sequencing. This suggests that methodologies currently employed for screening and target identification may lead to a bias in target discovery and that alternative methods should be explored. C1 [Stanley, Sarah A.; Grant, Sarah Schmidt; Kawate, Tomohiko; Iwase, Noriaki; Shimizu, Motohisa; Wivagg, Carl; Silvis, Melanie; Kazyanskaya, Edward; Aquadro, John; Golas, Aaron; Fitzgerald, Michael; Hung, Deborah T.] Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Stanley, Sarah A.; Grant, Sarah Schmidt; Kawate, Tomohiko; Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Stanley, Sarah A.; Grant, Sarah Schmidt; Kawate, Tomohiko; Hung, Deborah T.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Stanley, Sarah A.; Grant, Sarah Schmidt; Kawate, Tomohiko; Wivagg, Carl; Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Dai, Huanqin; Zhang, Lixin] Chinese Acad Sci, Inst Microbiol, Beijing 100080, Peoples R China. RP Hung, DT (reprint author), Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM hung@molbio.mgh.harvard.edu OI Wivagg, Carl/0000-0001-9617-7625; Silvis, Melanie/0000-0002-0732-9744 FU Novartis; Helen Hay Whitney Foundation; NIH [K08AI085033]; Chinese Academy of Science; Bill and Melinda Gates Foundation; NIH Molecular Libraries Production Centers Network (MLPCN) FX We thank L. Verplank, N. Tolliday, J. Bittker, and the Broad Institute Chemical Biology platform for technical assistance, data management, and advice on assay development; B. Birren, C. Nussbaum, C. Russ, and the Broad Institute Genome Sequencing and Analysis Platform for technical assistance and data analysis for genome sequencing; R. Goldman, B. Laughon, T. Parker, the NIAID, and TAACF/SRI for providing the 1113 compound set; E. Rubin, J. Gomez, and A. Stern for helpful discussion and advice throughout the project; K. Gordon for technical assistance. S.A.S. gratefully acknowledges Novartis and the Helen Hay Whitney Foundation for funding. S.S.G. gratefully acknowledges the NIH for funding (K08AI085033). This work was supported through funding from the Chinese Academy of Science to S.A.S. and the Bill and Melinda Gates Foundation to D.T.H. This work was also supported by the NIH Molecular Libraries Production Centers Network (MLPCN; www.mli.nih.gov), which funded primary screening of a 215,110-compound library against M. tuberculosis strain H37Rv at Southern Research Institute. NR 29 TC 107 Z9 109 U1 2 U2 49 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD AUG PY 2012 VL 7 IS 8 BP 1377 EP 1384 DI 10.1021/cb300151m PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 988YE UT WOS:000307526600010 PM 22577943 ER PT J AU Lundby, A Lage, K Weinert, BT Bekker-Jensen, DB Secher, A Skovgaard, T Kelstrup, CD Dmytriyev, A Choudhary, C Lundby, C Olsen, JV AF Lundby, Alicia Lage, Kasper Weinert, Brian T. Bekker-Jensen, Dorte B. Secher, Anna Skovgaard, Tine Kelstrup, Christian D. Dmytriyev, Anatoliy Choudhary, Chunaram Lundby, Carsten Olsen, Jesper V. TI Proteomic Analysis of Lysine Acetylation Sites in Rat Tissues Reveals Organ Specificity and Subcellular Patterns SO CELL REPORTS LA English DT Article ID PROTEIN COMPLEXES; GENE-EXPRESSION; DNA-BINDING; PHOSPHORYLATION; NETWORKS; QUANTIFICATION; IDENTIFICATION; HOMEOSTASIS; ACTIVATION; DISORDERS AB Lysine acetylation is a major posttranslational modification involved in a broad array of physiological functions. Here, we provide an organ-wide map of lysine acetylation sites from 16 rat tissues analyzed by high-resolution tandem mass spectrometry. We quantify 15,474 modification sites on 4,541 proteins and provide the data set as a web-based database. We demonstrate that lysine acetylation displays site-specific sequence motifs that diverge between cellular compartments, with a significant fraction of nuclear sites conforming to the consensus motifs G-AcK and AcK-P. Our data set reveals that the subcellular acetylation distribution is tissue-type dependent and that acetylation targets tissue-specific pathways involved in fundamental physiological processes. We compare lysine acetylation patterns for rat as well as human skeletal muscle biopsies and demonstrate its general involvement in muscle contraction. Furthermore, we illustrate that acetylation of fructose-bisphosphate aldolase and glycerol-3-phosphate dehydrogenase serves as a cellular mechanism to switch off enzymatic activity. C1 [Lundby, Alicia; Lage, Kasper; Weinert, Brian T.; Bekker-Jensen, Dorte B.; Secher, Anna; Skovgaard, Tine; Kelstrup, Christian D.; Dmytriyev, Anatoliy; Choudhary, Chunaram; Olsen, Jesper V.] Univ Copenhagen, Fac Hlth Sci, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, DK-2200 Copenhagen N, Denmark. [Lundby, Alicia] Danish Natl Res Fdn Ctr Cardiac Arrhythmia, DK-2200 Copenhagen N, Denmark. [Lundby, Alicia; Lage, Kasper] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Lage, Kasper] Massachusetts Gen Hosp, Pediat Surg Res Lab, Boston, MA 02114 USA. [Lage, Kasper] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Secher, Anna] Novo Nordisk AS, DK-2760 Malov, Denmark. [Lundby, Carsten] Univ Zurich, Dept Physiol, Zurich Ctr Integrat Human Physiol, CH-8057 Zurich, Switzerland. RP Olsen, JV (reprint author), Univ Copenhagen, Fac Hlth Sci, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. EM jesper.olsen@cpr.ku.dk RI Lundby, Alicia/H-3322-2013; OI Lundby, Alicia/0000-0002-1612-6041; Weinert, Brian/0000-0002-1335-9915; Olsen, Jesper/0000-0002-4747-4938; Kelstrup, Christian Dahl/0000-0003-4647-1425 FU Seventh Framework Programme of the European Union [262067-PRIME-XS]; research career programme Sapere Aude from The Danish Council for Independent Research for Medical Sciences FX We thank all members of the Department for Proteomics at the Center for Protein Research for scientific discussions and Dr. Nikolai Nordsborg for help with collecting human samples. The Center for Protein Research is partly supported by a generous donation from the Novo Nordisk Foundation. This work was supported by the Seventh Framework Programme of the European Union (Contract no. 262067-PRIME-XS) and the research career programme Sapere Aude from The Danish Council for Independent Research for Medical Sciences (to A. L. and J. V. O.). A. L. and J. V. O. designed all of the experiments, A. S. and C. L. coordinated animal and human sample handling, respectively, A. L. completed all sample preparation, A. L. performed MS analysis, B. T. W. provided input on SCX fractionation, C. D. K. provided input on Q Exactive measurements, K. L. generated protein interaction networks, D. B. B.-J. and T. S. performed enzyme experiments, A. D. made the MySQL database, A. L. and J. V. O. performed data analysis, B. T. W. and C. C. provided input on manuscript, and A. L. and J. V. O. wrote the paper. NR 48 TC 177 Z9 180 U1 2 U2 39 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG PY 2012 VL 2 IS 2 BP 419 EP 431 DI 10.1016/j.celrep.2012.07.006 PG 13 WC Cell Biology SC Cell Biology GA 019CR UT WOS:000309715100020 PM 22902405 ER PT J AU Block, GA Wheeler, DC Persky, MS Kestenbaum, B Ketteler, M Spiegel, DM Allison, MA Asplin, J Smits, G Hoofnagle, AN Kooienga, L Thadhani, R Mannstadt, M Wolf, M Chertow, GM AF Block, Geoffrey A. Wheeler, David C. Persky, Martha S. Kestenbaum, Bryan Ketteler, Markus Spiegel, David M. Allison, Matthew A. Asplin, John Smits, Gerard Hoofnagle, Andrew N. Kooienga, Laura Thadhani, Ravi Mannstadt, Michael Wolf, Myles Chertow, Glenn M. TI Effects of Phosphate Binders in Moderate CKD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GROWTH-FACTOR 23; CORONARY-ARTERY CALCIUM; SERUM PHOSPHATE; CARDIOVASCULAR-DISEASE; PHOSPHORUS BINDERS; VITAMIN-D; PROGRESSION; MORTALITY; FGF23 AB Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain. C1 [Block, Geoffrey A.; Persky, Martha S.; Smits, Gerard; Kooienga, Laura] Denver Nephrol, Denver, CO 80230 USA. [Wheeler, David C.] UCL, Sch Med, Ctr Nephrol, London W1N 8AA, England. [Kestenbaum, Bryan; Hoofnagle, Andrew N.] Univ Washington, Seattle, WA 98195 USA. [Ketteler, Markus] Klinikum Coburg, Nephrol Klin, Coburg, Germany. [Spiegel, David M.] Univ Colorado, Denver, CO 80202 USA. [Allison, Matthew A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Asplin, John] Litholink Corp, Chicago, IL USA. [Thadhani, Ravi; Mannstadt, Michael] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Thadhani, Ravi; Mannstadt, Michael] Harvard Univ, Sch Med, Boston, MA USA. [Wolf, Myles] Univ Miami, Miami, FL USA. [Chertow, Glenn M.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. RP Block, GA (reprint author), Denver Nephrol, 130 Rampart Way,Suite 300B, Denver, CO 80230 USA. EM ga-block@denverneph.net OI Allison, Matthew/0000-0003-0777-8272 FU Shire, Inc.; Fresenius NA; Genzyme, Inc.; Denver Nephrologists, PC; Novartis, Inc.; Davita, Inc.; Amgen; Roche; Cytochroma; CMD; Genzyme; Abbott; Keryx; Waters; National Institutes of Health; Shire; National Institute of Diabetes and Digestive and Kidney Diseases; Reata FX Funding for this investigator-initiated study was provided by Shire, Inc., Fresenius NA, Genzyme, Inc., Denver Nephrologists, PC, Novartis, Inc., and Davita, Inc.; G.A.B. has received research grants from Amgen, Roche, Cytochroma, and CMD; received honoraria from Genzyme; has been on advisory boards or a consultant for Amgen, Genzyme, KAI, Ardelyx, and Mitsubishi; and was a Medical Director for Davita. D.C.W. received research grants from Genzyme and Abbott and honoraria from Amgen, Fresenius, and Shire; and has been on the advisory board for KAI. M.S.P. has consulted for KAI. B.K. has received a research grant from Amgen. M.K. has received research grants from Amgen and Abbott; honoraria from Amgen, Abbott, Genzyme, FMC, Medice, and Shire; and payment for development of educational presentations from Amgen and Abbott; and has been a consultant for Amgen, Abbott, Genzyme, FMC, Medice, and Shire. D.M.S. has received research grants from Amgen and Keryx and honoraria from Amgen and Sanofi; has been on advisory boards for Affymax, Amgen, and Sanofi; and has been a consultant for Amgen. J.A. has been an employee of LabCorp and a consultant for Oxthera Corp.. N.H. has received research grants from Waters and has been a consultant for Onconome. R.T. has received a research grant from Abbott; has been a consultant for Fresenius North America and Mitsubishi Tanabe; and has received honoraria from Shire. M.W. has received research grants from National Institutes of Health, Shire, Amgen, and Genzyme; has received honoraria from Abbott, Genzyme, and Shire; and has been a consultant for Abbott, Genzyme, Luitpold, Mitsubishi, Cytochroma, Biotrends, Ardelyx, and Astellas. G.M.C. has received a research grant from National Institute of Diabetes and Digestive and Kidney Diseases, Amgen, and Reata; and has been an advisor for Ardelyx. M.A.A., G.S., L.K., and M.M. have nothing to disclose. NR 32 TC 168 Z9 180 U1 0 U2 29 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2012 VL 23 IS 8 BP 1407 EP 1415 DI 10.1681/ASN.2012030223 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 020BL UT WOS:000309783500018 PM 22822075 ER PT J AU Maruyama, N Takahashi, F Uno, H Takeuchi, M AF Maruyama, Nami Takahashi, Fumiaki Uno, Hajime Takeuchi, Masahiro TI Predicting Binary Outcomes Using Trajectory Classes SO STATISTICS IN BIOPHARMACEUTICAL RESEARCH LA English DT Article DE EM algorithm; Longitudinal data; Mixture distribution, Prediction; ROC curve; Trajectory ID SMOKING-CESSATION; EM ALGORITHM; MODEL; TRIALS AB In longitudinal data, the interest often lies in the repeatedly measured variable itself. However, in some situations, the changing pattern of the variable over time may contain information about a separate outcome variable. In such a situation, longitudinal data provide the opportunity to develop predictive models of subsequent observations of the separate outcome variable given current data for an individual. In particular, longitudinally changing patterns of repeated measurements of a variable, or trajectories, measured up to time t can be used to predict an outcome measure or event that occurs after time t. We propose a predictive model based on latent classes of trajectories, which is fitted using the expectation-maximization (EM) algorithm, and show how to get model estimates with other covariates in the model. Applications of our methodology are demonstrated through an example of a smoking cessation trial. C1 [Maruyama, Nami] Pfizer Japan Inc, Clin Statisticians, Tokyo 1518589, Japan. [Takahashi, Fumiaki; Takeuchi, Masahiro] Kitasato Univ, Grad Sch, Dept Biostat, Tokyo 1088641, Japan. [Uno, Hajime] Harvard Univ, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Uno, Hajime] Harvard Univ, Dept Biostat, Boston, MA 02115 USA. RP Maruyama, N (reprint author), Pfizer Japan Inc, Clin Statisticians, Tokyo 1518589, Japan. EM nami.maruyama@pfizer.com NR 27 TC 0 Z9 0 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 1946-6315 J9 STAT BIOPHARM RES JI Stat. Biopharm. Res. PD AUG PY 2012 VL 4 IS 3 BP 284 EP 292 DI 10.1080/19466315.2011.646912 PG 9 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 019PC UT WOS:000309750800007 ER PT J AU Ha, J Yoo, H Tearney, GJ Bouma, BE AF Ha, Jinyong Yoo, Hongki Tearney, Guillermo J. Bouma, Brett E. TI Compensation of motion artifacts in intracoronary optical frequency domain imaging and optical coherence tomography SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Motion artifacts; Image compensation; OCT; OFDI ID MICROSCOPY; ADVANTAGE AB Intracoronary optical coherence tomography and optical frequency domain imaging (OFDI) have been utilized for two-dimensional and three-dimensional imaging of vascular microanatomy. Image quality and the spatial accuracy of multidimensional reconstructions, however, can be degraded due to artifacts resulting from relative motion between the intracoronary catheter and the vessel wall. To track the relative motion of a catheter with regard to the vessel, a motion tracking system was incorporated with a standard OFDI system by using wavelength division multiplexing techniques. Motion of the vessel was acquired by a frequency shift of the backscattered light caused by the Doppler effect. A single monochromatic beam was utilized for tracking the relative longitudinal displacements of a catheter-based fiber probe with regard to the vessel. Although two tracking beams are, in general, required to correct for longitudinal motion artifacts, the accurate reconstruction in a longitudinal view was achieved by the Doppler frequency information of a single beam. Our results demonstrate that the single beam based motion tracking scheme is a cost-effective, practical approach to compensating for longitudinal distortions due to cardiac dynamics, thus leading to accurate quantitative analysis of 3D intracoronary OFDI. C1 [Ha, Jinyong; Yoo, Hongki; Tearney, Guillermo J.; Bouma, Brett E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Bouma, BE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, 40 Blossom St,BAR 701, Boston, MA 02114 USA. EM bouma@helix.mgh.harvard.edu RI Yoo, Hongki/B-6421-2013 OI Yoo, Hongki/0000-0001-9819-3135 FU National Institutes of Health [R33 CA125560, R01 HL076398]; Terumo Medical Corporation FX This research was supported in part by the National Institutes of Health (grants R33 CA125560 and R01 HL076398), and Terumo Medical Corporation. NR 9 TC 5 Z9 5 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD AUG PY 2012 VL 28 IS 6 BP 1299 EP 1304 DI 10.1007/s10554-011-9953-8 PG 6 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 016VH UT WOS:000309547300004 PM 21993895 ER PT J AU Koontz, AM Worobey, LA Rice, IM Collinger, JL Boninger, ML AF Koontz, Alicia M. Worobey, Lynn A. Rice, Ian M. Collinger, Jennifer L. Boninger, Michael L. TI Comparison Between Overground and Dynamometer Manual Wheelchair Propulsion SO JOURNAL OF APPLIED BIOMECHANICS LA English DT Article DE biomechanics; kinetics; spinal cord injury ID SPINAL-CORD-INJURY; PUSHRIM FORCES; BIOMECHANICS; ERGOMETER; KINETICS; TERRAIN; WALKING; LEVEL AB Laboratory-based simulators afford many advantages for studying physiology and biomechanics; however, they may not perfectly mimic wheelchair propulsion over natural surfaces. The goal of this study was to compare kinetic and temporal parameters between propulsion overground on a tile surface and on a dynamometer. Twenty-four experienced manual wheelchair users propelled at a self-selected speed on smooth, level tile and a dynamometer while kinetic data were collected using an instrumented wheel. A Pearson correlation test was used to examine the relationship between propulsion variables obtained on the dynamometer and the overground condition. Ensemble resultant force and moment curves were compared using cross-correlation and qualitative analysis of curve shape. User biomechanics were correlated (R ranging from 0.41 to 0.83) between surfaces. Overall, findings suggest that although the dynamometer does not perfectly emulate overground propulsion, wheelchair users were consistent with the direction and amount of force applied, the time peak force was reached, push angle, and their stroke frequency between conditions. C1 [Koontz, Alicia M.; Worobey, Lynn A.; Rice, Ian M.; Collinger, Jennifer L.; Boninger, Michael L.] US Dept Vet Affairs, Human Engn Res Labs, Rehabil Res & Dev Ctr, Pittsburgh, PA USA. [Koontz, Alicia M.; Worobey, Lynn A.; Collinger, Jennifer L.; Boninger, Michael L.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Koontz, Alicia M.; Rice, Ian M.; Collinger, Jennifer L.; Boninger, Michael L.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Boninger, Michael L.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Koontz, Alicia M.; Worobey, Lynn A.; Rice, Ian M.; Collinger, Jennifer L.; Boninger, Michael L.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Koontz, AM (reprint author), US Dept Vet Affairs, Human Engn Res Labs, Rehabil Res & Dev Ctr, Pittsburgh, PA USA. OI Worobey, Lynn/0000-0001-8795-6061; Boninger, Michael/0000-0001-6966-919X FU National Institutes of Health [1 R03 HD049735-01A1]; Department of Veterans Affairs [B6252R]; Human Engineering Research Laboratories, VA Pittsburgh Healthcare System FX This material is based in part upon work supported by the National Institutes of Health (Grant Number: 1 R03 HD049735-01A1) and by the Department of Veterans Affairs (Project Number: B6252R). The study sponsors had no involvement in study design, collection, analysis, and interpretation of data, writing of the manuscript, or decision to submit the manuscript for publication. This material is the result of work supported with resources and the use of facilities at the Human Engineering Research Laboratories, VA Pittsburgh Healthcare System. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 27 TC 6 Z9 6 U1 1 U2 6 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, PO BOX 5076, CHAMPAIGN, IL 61820-2200 USA SN 1065-8483 J9 J APPL BIOMECH JI J. Appl. Biomech. PD AUG PY 2012 VL 28 IS 4 BP 412 EP 419 PG 8 WC Engineering, Biomedical; Sport Sciences SC Engineering; Sport Sciences GA 017DC UT WOS:000309569300007 PM 22085811 ER PT J AU Gonzalez, L Chen, A Lin, PH Pisimisis, G Barshes, NR Bechara, CF Kougias, P AF Gonzalez, L. Chen, A. Lin, P. H. Pisimisis, G. Barshes, N. R. Bechara, C. F. Kougias, P. TI Latest recanalization techniques for complex superficial femoral artery occlusions SO JOURNAL OF CARDIOVASCULAR SURGERY LA English DT Article DE Femoral artery; Coronary occlusion; Surgical procedures, minimally invasive ID SINGLE-CENTER EXPERIENCE; TRUE LUMEN REENTRY; CONTROLLED BLUNT MICRODISSECTION; SUBINTIMAL ANGIOPLASTY; OUTBACK CATHETER; DEVICE; DISSECTION AB Complex, long segment lesions of the superficial femoral artery (SFA) are common, occurring in 40% of patients with peripheral vascular disease. In particular, chronic total occlusions (CTOs) continue to pose a challenge in the endovascular management of SFA disease. Several conventional wire and catheter based techniques have been described including subintimal recanalization and retrograde techniques. In addition, advances in endovascular technology have led to the development of a series of new devices aimed specifically at facilitating the crossing of long segment SFA occlusions or establishing re-entry of the true lumen. Here we present an overview of the minimally invasive techniques used to recanalize CTOs of the SFA and the latest specialized devices available for both recanalization and re-entry, as well as a summary of the literature supporting their application. C1 [Pisimisis, G.; Barshes, N. R.; Bechara, C. F.; Kougias, P.] Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. [Gonzalez, L.; Chen, A.; Lin, P. H.; Pisimisis, G.; Barshes, N. R.; Bechara, C. F.; Kougias, P.] Baylor Coll Med, Houston, TX 77030 USA. RP Kougias, P (reprint author), Houston VAMC, Michael E DeBakey Dept Surg, 2002 Holcombe Blvd,OCL-112, Houston, TX 77030 USA. EM pkougias@bcm.eclu NR 19 TC 2 Z9 3 U1 0 U2 2 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0021-9509 J9 J CARDIOVASC SURG JI J. Cardiovasc. Surg. PD AUG PY 2012 VL 53 IS 4 BP 487 EP 494 PG 8 WC Cardiac & Cardiovascular Systems; Surgery; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Surgery GA 017EI UT WOS:000309572500010 PM 22854529 ER PT J AU Karakis, I Chiappa, KH San Luciano, M Sassower, KC Stakes, JW Cole, AJ AF Karakis, Ioannis Chiappa, Keith H. San Luciano, Marta Sassower, Kenneth C. Stakes, John W. Cole, Andrew J. TI The Utility of Routine EEG in the Diagnosis of Sleep Disordered Breathing SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Electroencephalogram; EEG; Sleep disordered breathing; Sleep apnea ID APNEA SYNDROME; EPILEPSY; POPULATION; SEIZURES AB Sleep disordered breathing (SDB) is a common medical condition. Its manifestations of snoring, nocturnal choking, arousals, and sleep fragmentation can lead to excessive daytime sleepiness, neuropsychological slowing, lapses of consciousness, and accidents that can be misinterpreted as epileptic phenomena. Moreover, patients with documented epilepsy commonly exhibit similar symptomatology because of the undiagnosed coexistence of sleep apnea. Therefore, a large proportion of patients referred to the electroencephalogram (EEG) laboratory primarily to confirm or refute the diagnosis of epilepsy could suffer from latent sleep apnea and the routine EEG has the potential to divulge it. We retrospectively evaluated the reporting of sleep apnea symptomatology (snoring, choking, gasping/deep breath, apnea, desaturation, excessive drowsiness) in routine inpatient and outpatient adult EEG studies performed in our institution over the past 12 years (39,130 studies, approximately half of which recorded at least early stages of sleep). Comparisons were performed with the medical records to ascertain the coexistence of objectively diagnosed SDB with polysomnography before or after the EEG study and the importance of reporting variations in assisting with the diagnosis. Two illustrative examples are provided. Sixty-nine EEG studies were identified, performed primarily to confirm, or refute the diagnosis of epilepsy. The mean age of the subjects at EEG was 64 years (range 30-89), and 55 (80%) were male. 36% of them suffered from known epilepsy. Snoring was the most commonly reported sign in 48 (70%) of the studies, followed by arousals in 29 (42%), apnea in 16 (23%), excessive drowsiness in 13 (19%), gasping/deep breath in 9 (13%), and desaturation in 7 (10%). A sleep disorder was suggested in 25 (36%) of the interpretations and a direct recommendation for a sleep study was made in 22 of them (32%). This interpretation was included in the impression of the report in 21 (30%) of the cases, in the detail in 20 (30%) of the cases and in both in 28 (40%). Only 14 (20%) patients underwent polysomnography, and all of them were formally diagnosed with SDB. Seven (50%) of them were diagnosed with obstructive sleep apnea, 2 (14%) with central sleep apnea, 3 (22%) with both, 1 (7%) with upper airways resistance syndrome, and 1 (7%) with primary snoring. From these 14 patients, 9 (64%) were diagnosed with a sleep study performed after the EEG, 4 (29%) before the EEG interpretation, and 1 (7%) had a repeat study after the EEG. In the logistic regression model applied, with the exception of the presence of arousals (odds ratio = 4.63, P = 0.033), none of the aforementioned symptomatology or the reporting of suspicion for SDB or the location (impression vs. detail) of the reporting showed a statistically significant association with the completion of a sleep study. Routine EEG offers a unique opportunity of direct clinical observation along with electrophysiologic and cardiorespiratory monitoring. When sleep is recorded, it can help identify clinical and electrographic features of sleep apnea and prompt confirmation with a polysomnogram in the appropriate clinical context. It can therefore serve as a valuable, adjunctive tool for the diagnosis of SDB. Our data highlight that potential but unveil its decreased use in the neurology community. Increased awareness is required by the EEG technologists, interpreting neurologists, and referring physicians, regarding reporting and using sleep apnea features on the EEG. C1 [Karakis, Ioannis; Chiappa, Keith H.; Sassower, Kenneth C.; Stakes, John W.; Cole, Andrew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Epilepsy Serv,Dept Neurol, Boston, MA 02114 USA. [San Luciano, Marta] SUNY Downstate Coll Med, Suny Downstate Med Ctr, Dept Neurol, Brooklyn, NY USA. [Sassower, Kenneth C.; Stakes, John W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Sleep Div,Dept Neurol, Boston, MA 02114 USA. RP Karakis, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Epilepsy Serv,Dept Neurol, 55 Fruit St,Wang 735, Boston, MA 02114 USA. EM ikarakis@partners.org NR 38 TC 3 Z9 3 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0736-0258 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD AUG PY 2012 VL 29 IS 4 BP 333 EP 338 DI 10.1097/WNP.0b013e31826244ae PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 016VC UT WOS:000309546700007 PM 22854767 ER PT J AU Danna, CH Zhang, XC Khatri, A Bent, AF Ronald, PC Ausubel, FM AF Danna, Cristian H. Zhang, Xue-Cheng Khatri, Ashok Bent, Andrew F. Ronald, Pamela C. Ausubel, Frederick M. TI FLS2-Mediated Responses to Ax21-Derived Peptides: Response to the Mueller et al. Commentary SO PLANT CELL LA English DT Letter C1 [Danna, Cristian H.; Zhang, Xue-Cheng; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Danna, Cristian H.; Zhang, Xue-Cheng; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Khatri, Ashok] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bent, Andrew F.] Univ Wisconsin, Dept Plant Pathol, Madison, WI 53706 USA. [Ronald, Pamela C.] Univ Calif Davis, Dept Plant Pathol, Davis, CA 95616 USA. [Ronald, Pamela C.] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. RP Danna, CH (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RI Bent, Andrew/E-5391-2016 OI Bent, Andrew/0000-0001-6610-9525 FU NIGMS NIH HHS [R37 GM048707, R37-GM48707] NR 3 TC 4 Z9 4 U1 0 U2 12 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD AUG PY 2012 VL 24 IS 8 BP 3174 EP 3176 DI 10.1105/tpc.112.099275 PG 3 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 016RJ UT WOS:000309536600007 PM 22923675 ER PT J AU Lee, H Khatri, A Plotnikov, JM Zhang, XC Sheen, J AF Lee, Horim Khatri, Ashok Plotnikov, Julia M. Zhang, Xue-Cheng Sheen, Jen TI Complexity in Differential Peptide-Receptor Signaling: Response to Segonzac et al. and Mueller et al. Commentaries SO PLANT CELL LA English DT Letter ID ARABIDOPSIS-THALIANA; KINASE; SHOOT; PERCEPTION; FLAGELLIN; IMMUNITY; CLAVATA3; FLS2 C1 [Lee, Horim; Plotnikov, Julia M.; Zhang, Xue-Cheng; Sheen, Jen] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Lee, Horim; Plotnikov, Julia M.; Zhang, Xue-Cheng; Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Lee, Horim; Plotnikov, Julia M.; Zhang, Xue-Cheng; Sheen, Jen] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Khatri, Ashok] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Lee, H (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. FU NIGMS NIH HHS [R01 GM060493, R01 GM070567] NR 29 TC 7 Z9 7 U1 0 U2 10 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD AUG PY 2012 VL 24 IS 8 BP 3177 EP 3185 DI 10.1105/tpc.112.099259 PG 9 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 016RJ UT WOS:000309536600008 PM 22923676 ER PT J AU Dai, TH Gupta, A Murray, CK Vrahas, MS Tegos, GP Hamblin, MR AF Dai, Tianhong Gupta, Asheesh Murray, Clinton K. Vrahas, Mark S. Tegos, George P. Hamblin, Michael R. TI Blue light for infectious diseases: Propionibacterium acnes, Helicobacter pylori, and beyond? SO DRUG RESISTANCE UPDATES LA English DT Review DE Blue light; Infectious disease; Drug resistance; Intracellular porphyrins; Reactive oxygen species; Wound healing; Microbial signaling ID NARROW-SPECTRUM LIGHT; ANTIMICROBIAL PHOTODYNAMIC THERAPY; STAPHYLOCOCCUS-AUREUS INFECTION; BIPHASIC DOSE-RESPONSE; MRSA IN-VITRO; VISIBLE-LIGHT; HIGH-INTENSITY; PORPHYROMONAS-GINGIVALIS; ENVIRONMENTAL DECONTAMINATION; FUSOBACTERIUM-NUCLEATUM AB Blue light, particularly in the wavelength range of 405-470 nm, has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. In addition, it is commonly accepted that blue light is much less detrimental to mammalian cells than ultraviolet irradiation, which is another light-based antimicrobial approach being investigated. In this review, we discussed the blue light sensing systems in microbial cells, antimicrobial efficacy of blue light, the mechanism of antimicrobial effect of blue light, the effects of blue light on mammalian cells, and the effects of blue light on wound healing. It has been reported that blue light can regulate multi-cellular behavior involving cell-to-cell communication via blue light receptors in bacteria, and inhibit biofilm formation and subsequently potentiate light inactivation. At higher radiant exposures, blue light exhibits a broad-spectrum antimicrobial effect against both Gram-positive and Gram-negative bacteria. Blue light therapy is a clinically accepted approach for Propionibacterium acnes infections. Clinical trials have also been conducted to investigate the use of blue light for Helicobacter pylori stomach infections and have shown promising results. Studies on blue light inactivation of important wound pathogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa have also been reported. The mechanism of blue light inactivation of P. acnes, H. pylori, and some oral bacteria is proved to be the photo-excitation of intracellular porphyrins and the subsequent production of cytotoxic reactive oxygen species. Although it may be the case that the mechanism of blue light inactivation of wound pathogens (e.g., S. aureus, P. aeruginosa) is the same as that of P. acnes, this hypothesis has not been rigorously tested. Limited and discordant results have been reported regarding the effects of blue light on mammalian cells and wound healing. Under certain wavelengths and radiant exposures, blue light may cause cell dysfunction by the photo-excitation of blue light sensitizing chromophores, including flavins and cytochromes, within mitochondria or/and peroxisomes. Further studies should be performed to optimize the optical parameters (e.g., wavelength, radiant exposure) to ensure effective and safe blue light therapies for infectious disease. In addition, studies are also needed to verify the lack of development of microbial resistance to blue light. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Dai, Tianhong; Gupta, Asheesh; Tegos, George P.; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Dai, Tianhong; Gupta, Asheesh; Tegos, George P.; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Gupta, Asheesh] Def Inst Physiol & Allied Sci, Delhi 110054, India. [Murray, Clinton K.] Brooke Army Med Ctr, Infect Dis Serv, Ft Sam Houston, TX 78234 USA. [Vrahas, Mark S.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Tegos, George P.] Univ New Mexico, Sch Med, Dept Pathol, Albuquerque, NM 87131 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR 414,40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU NIAID NIH HHS [R01 AI050875] NR 79 TC 58 Z9 65 U1 3 U2 42 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD AUG PY 2012 VL 15 IS 4 BP 223 EP 236 DI 10.1016/j.drup.2012.07.001 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 013US UT WOS:000309332000003 PM 22846406 ER PT J AU Siket, MS Edlow, JA AF Siket, Matthew S. Edlow, Jonathan A. TI Transient ischemic Attack Reviewing the Evolution of the Definition, Diagnosis, Risk Stratification, and Management for the Emergency Physician SO EMERGENCY MEDICINE CLINICS OF NORTH AMERICA LA English DT Review DE Transient ischemic attack; Emergency medicine; Risk stratification; Diagnosis; Management ID EARLY STROKE RISK; PERIPHERAL VASCULAR-DISEASE; TISSUE-BASED DEFINITION; SHORT-TERM PROGNOSIS; C-REACTIVE PROTEIN; ABCD(2) SCORE; MINOR STROKE; COMPUTED-TOMOGRAPHY; RECURRENT STROKE; URGENT TREATMENT AB A transient ischemic attack (TIA) is an episode of reversible neurologic deficit caused by temporary focal central nervous system hypoperfusion. TIA is a medical emergency. Because patients with TIA in the emergency department (ED) have a high risk for stroke within the next 48 hours, it is imperative for the clinician to recognize this golden opportunity to prevent a disabling stroke. This article reviews our conceptual understanding of TIA, its definition, diagnosis, ways to stratify stroke risk, the acute management and disposition in the ED, and the potential future role of diagnostic biomarkers. C1 [Edlow, Jonathan A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Emergency Med, Sch Med, Boston, MA 02215 USA. [Siket, Matthew S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Edlow, JA (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Emergency Med, Sch Med, Boston, MA 02215 USA. EM jedlow@bidmc.harvard.edu NR 137 TC 11 Z9 12 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0733-8627 EI 1558-0539 J9 EMERG MED CLIN N AM JI Emerg. Med. Clin. N. Am. PD AUG PY 2012 VL 30 IS 3 BP 745 EP + DI 10.1016/j.emc.2012.05.001 PG 27 WC Emergency Medicine SC Emergency Medicine GA 016DM UT WOS:000309497600010 PM 22974647 ER PT J AU Caceres, JA Goldstein, JN AF Caceres, J. Alfredo Goldstein, Joshua N. TI Intracranial Hemorrhage SO EMERGENCY MEDICINE CLINICS OF NORTH AMERICA LA English DT Article DE Intracranial hemorrhage; Acute stroke; Intracerebral hemorrhage; Subarachnoid hemorrhage ID ANEURYSMAL SUBARACHNOID HEMORRHAGE; SPONTANEOUS INTRACEREBRAL HEMORRHAGE; PREDICTS HEMATOMA EXPANSION; ACUTE CEREBRAL-HEMORRHAGE; ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; PROTHROMBIN COMPLEX CONCENTRATE; HEALTH-CARE PROFESSIONALS; BLOOD-PRESSURE REDUCTION; ANGIOGRAPHY IN-PLACE; FRESH-FROZEN PLASMA AB Intracranial hemorrhage refers to any bleeding within the intracranial vault, including the brain parenchyma and surrounding meningeal spaces. This article focuses on the acute diagnosis and management of primary nontraumatic intracerebral hemorrhage and subarachnoid hemorrhage in the emergency department. C1 [Goldstein, Joshua N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Caceres, J. Alfredo] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 01940 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 01940 USA. RP Goldstein, JN (reprint author), Harvard Univ, Sch Med, 25 Shattuck St, Boston, MA 02115 USA. EM jgoldstein@partners.org RI Goldstein, Joshua/H-8953-2016 FU NINDS NIH HHS [K23 NS059774] NR 160 TC 4 Z9 4 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 0733-8627 J9 EMERG MED CLIN N AM JI Emerg. Med. Clin. N. Am. PD AUG PY 2012 VL 30 IS 3 BP 771 EP + DI 10.1016/j.emc.2012.06.003 PG 25 WC Emergency Medicine SC Emergency Medicine GA 016DM UT WOS:000309497600011 PM 22974648 ER PT J AU De Luca, G Gibson, CM Huber, K Dudek, D Cutlip, D Zeymer, U Gyongyosi, M Bellandi, F Noc, M Arntz, HR Maioli, M Secco, GG Zorman, S Gabriel, HM Emre, A Rakowski, T van't Hof, AWJ AF De Luca, Giuseppe Gibson, C. Michael Huber, Kurt Dudek, Dariusz Cutlip, Donald Zeymer, Uwe Gyongyosi, Maryann Bellandi, Francesco Noc, Marko Arntz, Hans-Richard Maioli, Mauro Secco, Gioel Gabrio Zorman, Simona Gabriel, H. Mesquita Emre, Ayse Rakowski, Tomasz van't Hof, Arnoud W. J. CA EGYPT Cooperation TI Time-related impact of distal embolisation on myocardial perfusion and survival among patients undergoing primary angioplasty with glycoprotein IIb-IIIa inhibitors: insights from the EGYPT cooperation SO EUROINTERVENTION LA English DT Article DE primary angioplasty; distal embolisation; time-to-treatment ID PERCUTANEOUS CORONARY INTERVENTION; META-REGRESSION ANALYSIS; ST-SEGMENT RESOLUTION; NO-REFLOW PHENOMENON; RANDOMIZED-TRIALS; MECHANICAL REVASCULARIZATION; RISK PROFILE; INFARCT SIZE; REPERFUSION; METAANALYSIS AB Aims: Considerable interest has been focused in recent years on the role of distal embolisation as a major deteminant of impaired reperfusion after primary angioplasty for STEMI. The aim of the current study was to evaluate in a large cohort of STEMI patients undergoing primary angioplasty with glycoprotein (Gp) IIb-IIIa inhibitors, whether the impact of distal embolisation on myocardial perfusion and survival may depend on time-to-treatment. Methods and results: Our population is represented by 1,182 patients undergoing primary angioplasty for STEMI included in the EGYPT database. Patients were grouped according to time-to-treatment (<3 hours, 3-6 hours, >6 hours). Distal embolisation was defined as an abrupt "cutoff" in the main vessel or one of the coronary branches of the infarct-related artery, distal to the angioplasty site. Myocardial perfusion was evaluated by angiography or ST-segment resolution, whereas infarct size was estimated by using peak creatine kinase (CK) and CK-MB. Follow-up data were collected between 30 days and one year after primary angioplasty. Distal embolisation was observed in 132 patients (11.1%) and tended to occur more frequently in late presenters (p=0.067). Patients with distal embolisation less often had post-procedural Thrombolysis In Myocardial Infarction (TIMI) 3 flow (p<0.001), post-procedural myocardial blush grade (MBG) 2-3 (p<0.001), complete ST-segment resolution (p=0.021) and larger infarct size (p=0.012). Distal embolisation was associated with a significantly higher mortality (9.2% vs. 2.7%, heart rate [HR] [95% CI]=3.41 [1.73-6.71], p<0.0001). The impact of distal embolisation on myocardial perfusion and survival persisted for all time intervals. Conclusions: This study showed that among STEMI patients treated with Gp IIb-IIIa inhibitors, the negative impact of distal embolisation on myocardial perfusion and mortality is independent of the time from symptom onset to balloon angioplasty. C1 [De Luca, Giuseppe; Secco, Gioel Gabrio] Eastern Piedmont Univ, Maggiore della Carita Hosp, Div Cardiol, I-28100 Novara, Italy. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, TIMI Study Grp, Boston, MA 02215 USA. [Huber, Kurt] Wilhelminenspital Stadt Wien, Dept Med Cardiol & Emergency Med 3, Vienna, Austria. [Dudek, Dariusz; Rakowski, Tomasz] Jagiellonian Univ, Inst Cardiol, Dept Cardiol 2, Krakow, Poland. [Cutlip, Donald] Beth Israel Deaconess Med Ctr, Intervent Cardiol Sect, Boston, MA 02215 USA. [Zeymer, Uwe] Herzzentrum Ludwigshafen, Div Cardiol, Ludwigshafen, Germany. [Gyongyosi, Maryann] Med Univ Vienna, Dept Cardiol, Vienna, Austria. [Bellandi, Francesco; Maioli, Mauro] Prato Hosp, Div Cardiol, Prato, Italy. [Noc, Marko; Zorman, Simona] Univ Med Ctr, Ctr Intens Internal Med, Ljubljana, Slovenia. [Arntz, Hans-Richard] Charite Univ Klinikum Campus Benjamin Franklin, Med Klin Kardiol & Pulmol 2, Berlin, Germany. [Gabriel, H. Mesquita] Hosp Santa Maria, Div Cardiol, Lisbon, Portugal. [Emre, Ayse] Siyami Ersek Thorac & Cardiovasc Surg Ctr, Istanbul, Turkey. [van't Hof, Arnoud W. J.] Hosp Weezenlanden, Div Cardiol, Zwolle, Netherlands. RP De Luca, G (reprint author), Eastern Piedmont Univ, Maggiore della Carita Hosp, Div Cardiol, I-28100 Novara, Italy. EM giuseppe.deluca@maggioreosp.novara.it NR 32 TC 3 Z9 3 U1 0 U2 1 PU EUROPA EDITION PI TOULOUSE CEDEX 6 PA 5, RUE SAINT-PANTALEON, BP 61508, TOULOUSE CEDEX 6, 31015, FRANCE SN 1774-024X J9 EUROINTERVENTION JI EuroIntervention PD AUG PY 2012 VL 8 IS 4 BP 470 EP 476 DI 10.4244/EIJV8I4A74 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 015HG UT WOS:000309436400012 PM 22917731 ER PT J AU Khitri, MR Mills, MD Ying, GS Davidson, SL Quinn, GE AF Khitri, Monica R. Mills, Monte D. Ying, Gui-Shuang Davidson, Stefanie L. Quinn, Graham E. TI Visual acuity outcomes in pediatric glaucomas SO JOURNAL OF AAPOS LA English DT Article ID CHILDHOOD GLAUCOMA; GRATING ACUITY; CHILDREN; CATARACT AB PURPOSE To evaluate and compare the visual acuity prognosis in the various pediatric glaucoma subtypes and to determine risk factors for vision loss. METHODS The medical records of pediatric glaucoma patients from 2000 to 2010 at Children's Hospital of Philadelphia were retrospectively reviewed. Visual acuities, surgeries, glaucoma subtype, and etiology of vision impairment were recorded. Univariate and multivariate analyses were performed to determine the risk factors for visual impairment. RESULTS A total of 133 eyes (36.8% primary congenital glaucoma, 28.6% aphakic glaucoma, 12.0% glaucoma associated with anterior segment dysgenesis, 12.0% Sturge-Weber glaucoma) of 88 patients were included. At last follow-up (median length, 5 years), 46.6% eyes achieved excellent (>= 20/70) visual acuity. Of the glaucoma subtypes, primary congenital glaucoma conferred the best visual prognosis, with 69.4% eyes with excellent (>= 20/70) visual acuity at final follow-up. Factors most associated with visual impairment (<20/200) were unilateral disease, multiple surgeries, poor vision at diagnosis, and other ocular comorbidities. The most common primary etiology for vision impairment was amblyopia (54.9%). CONCLUSIONS Patients with glaucoma early in life appear to have a better visual acuity prognosis than previously reported, with those with primary congenital glaucoma faring better than other glaucoma subtypes. Recognition of risk factors for visual impairment can better guide clinical management and counseling of patients. (J AAPOS 2012;16:376-381) C1 [Khitri, Monica R.; Mills, Monte D.; Ying, Gui-Shuang; Davidson, Stefanie L.; Quinn, Graham E.] Childrens Hosp Philadelphia, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19104 USA. RP Khitri, MR (reprint author), Philadelphia VA Med Ctr, 3900 Woodland Ave, Philadelphia, PA 19104 USA. EM monica.ralli@gmail.com NR 14 TC 8 Z9 8 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD AUG PY 2012 VL 16 IS 4 BP 376 EP 381 DI 10.1016/j.jaapos.2012.05.007 PG 6 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 016FT UT WOS:000309503600014 PM 22929453 ER PT J AU Ball, LJ Fager, S Fried-Oken, M AF Ball, Laura J. Fager, Susan Fried-Oken, Melanie TI Augmentative and Alternative Communication for People with Progressive Neuromuscular Disease SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE AAC; Amyotrophic lateral sclerosis; Duchenne muscular dystrophy; Myotonic muscular dystrophy; Spinal muscular atrophy; Communication; Assistive technology ID AMYOTROPHIC-LATERAL-SCLEROSIS; BRAIN-COMPUTER INTERFACE; QUALITY STANDARDS SUBCOMMITTEE; SPEECH RECOGNITION; PRACTICE PARAMETER; SEVERE DYSARTHRIA; AMERICAN ACADEMY; AAC TECHNOLOGY; ALS PATIENTS; IMPAIRMENT AB Individuals with progressive neuromuscular disease often experience complex communication needs and consequently find that interaction using their natural speech may not sufficiently meet their daily needs. Increasingly, assistive technology advances provide accommodations for and/or access to communication. Assistive technology related to communication is referred to as augmentative and alternative communication (AAC). The nature of communication challenges in progressive neuromuscular diseases can be as varied as the AAC options currently available. AAC systems continue to be designed and implemented to provide targeted assistance based on an individual's changing needs. C1 [Ball, Laura J.] Massachusetts Gen Hosp, Inst Hlth Profess Commun Sci & Disorders, Boston, MA 02129 USA. [Fager, Susan] Madonna Rehabil Hosp, Inst Rehabil Sci & Engn, Commun Ctr, Lincoln, NE 68506 USA. [Fried-Oken, Melanie] Oregon Hlth & Sci Univ, BME, ENT, Portland, OR 97239 USA. RP Ball, LJ (reprint author), Massachusetts Gen Hosp, Inst Hlth Profess Commun Sci & Disorders, 36 1st Ave, Boston, MA 02129 USA. EM ljball9134@gmail.com NR 46 TC 6 Z9 6 U1 8 U2 49 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 EI 1558-1381 J9 PHYS MED REH CLIN N JI Phys. Med. Rehabil. Clin. N. Am. PD AUG PY 2012 VL 23 IS 3 BP 689 EP + DI 10.1016/j.pmr.2012.06.003 PG 12 WC Rehabilitation SC Rehabilitation GA 016DZ UT WOS:000309499000012 PM 22938882 ER PT J AU Min, C Shao, HL Liong, M Yoon, TJ Weissleder, R Lee, H AF Min, Changwook Shao, Huilin Liong, Monty Yoon, Tae-Jong Weissleder, Ralph Lee, Hakho TI Mechanism of Magnetic Relaxation Switching Sensing SO ACS NANO LA English DT Article DE magnetic relaxation switching; magnetic nanoparticles; NMR; biosensors ID DIFFUSION-LIMITED AGGREGATION; MRI CONTRAST AGENTS; NANOPARTICLES; PROTEINS; MODEL; NANOBIOTECHNOLOGY; SPHERES; BLOOD; CELLS AB Magnetic relaxation switching (MRSw) assays that employ target-induced aggregation (or disaggregation) of magnetic nanoparticles (MNPs) can be used to detect a wide range of biomolecules. The precise working mechanisms, however, remain poorly understood, often leading to confounding interpretation. We herein present a systematic and comprehensive characterization of MRSw sensing. By using different types of MNPs with varying physical properties, we analyzed the nature and transverse relaxation modes for MRSw detection. The study found that clustered MNPs are universally in a diffusion-limited fractal state (dimension of similar to 2.4). Importantly, a new model for transverse relaxation was constructed that accurately recapitulates observed MRSw phenomena and predicts the MRSw detection sensitivities and dynamic ranges. C1 [Min, Changwook; Shao, Huilin; Liong, Monty; Yoon, Tae-Jong; Weissleder, Ralph; Lee, Hakho] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [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, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; hlee@mgh.harvard.edu FU Agency for Science, Technology and Research, Singapore; NIH [2R01EB004626, U01-HL080731, U54-CA119349, T32-CA79443] FX The authors thank N. Sergeyev for providing cross-linked dextran-coated iron oxide nanoparticles. H. S. acknowledges financial support from the B.S.-Ph.D. National Science Scholarship awarded by the Agency for Science, Technology and Research, Singapore. This work was supported in part by NIH grants (2R01EB004626, U01-HL080731, U54-CA119349, and T32-CA79443). NR 33 TC 38 Z9 38 U1 7 U2 61 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD AUG PY 2012 VL 6 IS 8 BP 6821 EP 6828 DI 10.1021/nn301615b PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 995DU UT WOS:000307988900035 PM 22762250 ER PT J AU Ghoshhajra, BB Engel, LC Major, GP Goehler, A Techasith, T Verdini, D Do, S Liu, B Li, XH Sala, M Kim, MS Blankstein, R Prakash, P Sidhu, MS Corsini, E Banerji, D Wu, D Abbara, S Truong, Q Brady, TJ Hoffmann, U Kalra, M AF Ghoshhajra, Brian Burns Engel, Leif-Christopher Major, Gyoengyi Petra Goehler, Alexander Techasith, Tust Verdini, Daniel Do, Synho Liu, Bob Li, Xinhua Sala, Michiel Kim, Mi Sung Blankstein, Ron Prakash, Priyanka Sidhu, Manavjot S. Corsini, Erin Banerji, Dahlia Wu, David Abbara, Suhny Quynh Truong Brady, Thomas J. Hoffmann, Udo Kalra, Manudeep TI Evolution of Coronary Computed Tomography Radiation Dose Reduction at a Tertiary Referral Center SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Cardiac computed tomography; Coronary artery disease; Dose-savings methods; Radiation dose; Scan protocols ID DUAL-SOURCE CT; SHOOT MODE; MAGNETIC-RESONANCE; IMAGE QUALITY; HIGH-PITCH; ANGIOGRAPHY; EXPOSURE; ACCURACY; PROTOCOL; CRITERIA AB PURPOSE: We aimed to assess the temporal change in radiation doses from coronary computed tomography angiography (CCTA) during a 6-year period. High CCTA radiation doses have been reduced by multiple technologies that, if used appropriately, can decrease exposures significantly. METHODS: A total of 1277 examinations performed from 2005 to 2010 were included. Univariate and multivariable regression analysis of patient- and scan-related variables was performed with estimated radiation dose as the main outcome measure. RESULTS: Median doses decreased by 74.8% (P < .001), from 13.1 millisieverts (mSv) (interquartile range 9.3-14.7) in period 1 to 3.3 mSv (1.8-6.7) in period 4. Factors associated with greatest dose reductions (P < .001) were all most frequently applied in period 4: axial-sequential acquisition (univariate: -8.0 mSv [-9.7 to -7.9]), high-pitch helical acquisition (univariate: -8.8 mSv [-9.3 to -7.9]), reduced tube voltage (100 vs 120 kV) (univariate: -6.4 mSv [-7.4 to -5.4]), and use of automatic exposure control (univariate: -5.3 mSv [-6.2 to -4.4]). CONCLUSIONS: CCTA radiation doses were reduced 74.8% through increasing use of dose-saving measures and evolving scanner technology. (C) 2012 Elsevier Inc. All rights reserved. center dot The American Journal of Medicine (2012) 125, 764-772 C1 [Ghoshhajra, Brian Burns; Engel, Leif-Christopher; Major, Gyoengyi Petra; Goehler, Alexander; Techasith, Tust; Verdini, Daniel; Do, Synho; Sala, Michiel; Sidhu, Manavjot S.; Corsini, Erin; Banerji, Dahlia; Wu, David; Abbara, Suhny; Quynh Truong; Brady, Thomas J.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Ghoshhajra, Brian Burns; Engel, Leif-Christopher; Major, Gyoengyi Petra; Goehler, Alexander; Techasith, Tust; Verdini, Daniel; Do, Synho; Sala, Michiel; Sidhu, Manavjot S.; Corsini, Erin; Banerji, Dahlia; Wu, David; Abbara, Suhny; Quynh Truong; Brady, Thomas J.; Hoffmann, Udo] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ghoshhajra, Brian Burns; Engel, Leif-Christopher; Major, Gyoengyi Petra; Goehler, Alexander; Techasith, Tust; Verdini, Daniel; Do, Synho; Liu, Bob; Li, Xinhua; Sala, Michiel; Kim, Mi Sung; Prakash, Priyanka; Sidhu, Manavjot S.; Corsini, Erin; Banerji, Dahlia; Wu, David; Abbara, Suhny; Quynh Truong; Brady, Thomas J.; Hoffmann, Udo; Kalra, Manudeep] Harvard Univ, Sch Med, Boston, MA USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. RP Ghoshhajra, BB (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM bghoshhajra@partners.org FU National Institutes of Health [1T32 HL076136]; Radiological Society of North America [RF0908] FX Drs Ghoshhajra, Blankstein, and Goehler received funding from National Institutes of Health 1T32 HL076136. Dr Ghoshhajra received funding from Radiological Society of North America RF0908. Partners Healthcare Institutional Review Board specifically approved the waiver of consent for this study. NR 30 TC 21 Z9 21 U1 2 U2 2 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 AUG PY 2012 VL 125 IS 8 BP 764 EP 772 DI 10.1016/j.amjmed.2011.10.036 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 978LE UT WOS:000306741300020 PM 22703931 ER PT J AU Padula, AM Pressman, AR Vittinghoff, E Grady, D Neuhaus, J Ackerson, L Rudd, P Avins, AL AF Padula, Amy M. Pressman, Alice R. Vittinghoff, Eric Grady, Deborah Neuhaus, John Ackerson, Lynn Rudd, Peter Avins, Andrew L. TI Placebo Adherence and Mortality in the Heart and Estrogen/Progestin Replacement Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Adherence; Double-blind clinical trials; Placebo ID MYOCARDIAL-INFARCTION; TRIAL; ASSOCIATION; SURVIVAL; THERAPY; WOMEN; DEATH; RISK AB BACKGROUND: Analyses from double-blind randomized trials have reported lower mortality among participants who were more adherent to placebo compared with those who were less adherent. We explored this phenomenon by analyzing data from the placebo arm of the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, double-blind, placebo-controlled trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the HERS. Secondary aims included assessment of the association between placebo adherence and cause-specific morbidity and mortality. METHODS: Participants with "higher placebo adherence" were defined as having taken at least 75% of their placebo study medication during each individual's participation in the study, whereas those with "lower placebo adherence" took less than 75%. The primary outcome was in-study all-cause mortality. RESULTS: More adherent participants had significantly lower total mortality compared with less adherent participants (hazard ratio, 0.52; 95% confidence interval, 0.29-0.93). Adjusting for available confounders did not change the magnitude or significance of the estimates. Analyses revealed that the association of higher adherence and mortality might be explained, in part, by time-dependent confounding. CONCLUSIONS: Analyses of the HERS data support a strong association between adherence to placebo study medication and mortality. Although probably not due to simple confounding by healthy lifestyle factors, the underlying mechanism for the association remains unclear. Further analyses of this association are necessary to explain this observation. (C) 2012 Elsevier Inc. All rights reserved. center dot The American Journal of Medicine (2012) 125, 804-810 C1 [Padula, Amy M.; Rudd, Peter] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Padula, Amy M.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Pressman, Alice R.; Ackerson, Lynn; Avins, Andrew L.] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Vittinghoff, Eric; Neuhaus, John; Avins, Andrew L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Grady, Deborah; Avins, Andrew L.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Grady, Deborah; Avins, Andrew L.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Padula, AM (reprint author), Stanford Univ, Sch Med, Dept Med, Off Bldg,1265 Welsh Rd, Stanford, CA 94305 USA. EM ampadula@stanford.edu FU National Heart, Lung, and Blood Institute [R01 HL081195]; Wyeth-Ayerst Research FX Supported by a grant from the National Heart, Lung, and Blood Institute (R01 HL081195). The HERS was conducted and supported by Wyeth-Ayerst Research. The manuscript does not necessarily reflect the opinions or views of the HERS investigators or Wyeth-Ayerst Research. NR 13 TC 4 Z9 5 U1 1 U2 3 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 AUG PY 2012 VL 125 IS 8 BP 804 EP 810 DI 10.1016/j.amjmed.2012.02.014 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 978LE UT WOS:000306741300025 PM 22840666 ER PT J AU Hutchens, MP Fujiyoshi, T Komers, R Herson, PS Anderson, S AF Hutchens, Michael P. Fujiyoshi, Tetsuhiro Komers, Radko Herson, Paco S. Anderson, Sharon TI Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE ischemia-reperfusion injury; renal ischemia; acute renal failure; acute kidney injury; oxygen-glucose deprivation; cardiac arrest; cardiopulmonary resuscitation; gender; sex; estrogen; estradiol ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CRITICALLY-ILL PATIENTS; HEAT-SHOCK PROTEINS; ACUTE KIDNEY INJURY; CARDIOPULMONARY-RESUSCITATION; REPLACEMENT THERAPY; SIZE-SELECTIVITY; SERUM CREATININE; RECEPTOR-ALPHA; CARDIAC-ARREST AB Hutchens MP, Fujiyoshi T, Komers R, Herson PS, Anderson S. Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo. Am J Physiol Renal Physiol 303:F377-F385, 2012. First published May 23, 2012; doi:10.1152/ajprenal.00354.2011.-Emerging evidence suggests that renal endothelial function may be altered in ischemia-reperfusion injury. Acute kidney injury is sexually dimorphic, and estrogen protects renal tubular function after experimental ischemic injury. This study tested the hypothesis that during ischemia-reperfusion, estrogen alters glomerular endothelial function to prevent hyperpermeability. Glomerular endothelial cells were exposed to 8-h oxygen-glucose deprivation (OGD) followed by 4- and 8-h reoxygenation-glucose repletion. After 4-h reoxygenation-glucose repletion, transendothelial permeability to Ficoll-70 was reduced, and transendothelial resistance increased, by 17 beta-estradiol vs. vehicle treatment during OGD (OGD-vehicle: 91.0 +/- 11.8%, OGD-estrogen: 102.6 +/- 10.8%, P < 0.05). This effect was reversed by coadministration of G protein-coupled receptor 30 (GPR30) antagonist G15 with 17 beta-estradiol (OGD-estrogen-G15: 89.5 +/- 6.9, P < 0.05 compared with 17 beta-estradiol). To provide preliminary confirmation of this result in vivo, Ficoll-70 was administered to mice 24 h after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Blood urea nitrogen (BUN) and serum creatinine (SCr) in these mice were elevated within 12 h following CA/CPR and reduced at 24 h by pretreatment with 17 beta-estradiol (BUN/SCr 17 beta-estradiol: 34 +/- 19/0.2 +/- 0.1 vehicle: 92 +/- 49/0.5 +/- 0.3, n = 8-12, P < 0.05). Glomerular sieving of Ficoll 70 was increased by CA/CPR within 2 h of injury and 17 beta-estradiol treatment (theta; 17 beta-estradiol: 0.74 +/- 0.26 vs. vehicle: 1.05 +/- 0.53, n = 14-15, P < 0.05). These results suggest that estrogen reduces postischemic glomerular endothelial hyperpermeability at least in part through GPR30 and that estrogen may regulate post CA/CPR glomerular permeability in a similar fashion in vivo. C1 [Hutchens, Michael P.; Fujiyoshi, Tetsuhiro; Herson, Paco S.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Komers, Radko; Anderson, Sharon] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Dept Internal Med, Portland, OR 97239 USA. [Anderson, Sharon] Portland VA Med Ctr, Med Serv, Portland, OR USA. RP Hutchens, MP (reprint author), Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, HRC 5N,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM hutchenm@ohsu.edu OI Hutchens, Michael/0000-0001-8583-1812 FU NIDDK [DK090754-01] FX This work was supported in part by NIDDK Grant DK090754-01 (to M. P. Hutchens). NR 48 TC 26 Z9 26 U1 0 U2 6 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 AUG PY 2012 VL 303 IS 3 BP F377 EP F385 DI 10.1152/ajprenal.00354.2011 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 984ZA UT WOS:000307231300009 PM 22622457 ER PT J AU Pejo, E Cotten, JF Kelly, EW Ge, RL Cuny, GD Laha, JK Liu, JF Lin, XJ Raines, DE AF Pejo, Ervin Cotten, Joseph F. Kelly, Elizabeth W. Ge, Ri Le Cuny, Gregory D. Laha, Joydev K. Liu, Jifeng Lin, Xiang Jie Raines, Douglas E. TI In Vivo and In Vitro Pharmacological Studies of Methoxycarbonyl-Carboetomidate SO ANESTHESIA AND ANALGESIA LA English DT Article ID RAPID-SEQUENCE INTUBATION; ADRENOCORTICAL-FUNCTION; ETOMIDATE; INDUCTION; SUPPRESSION; INHIBITION; ANESTHESIA; PROPOFOL; ANALOG; AGENT AB BACKGROUND: We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-Pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11 beta-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate. METHODS: MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC50) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on yaminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. RESULTS: MOC-carboetomidate's octanol:water partition coefficient was 3300 +/- 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 +/- 180, 15,000 +/- 3700, and 190 +/- 25, respectively. MOC-carboetomidate's EC50, for LORR in tadpoles was 9 1 mu M and its EC50 for LORR in rats was 13 +/- 5 mg/kg. At 13 mu M, MOC-carboetomidate enhanced GABAA receptor currents by 400% +/- 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 +/- 1 vs 15 +/- 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. CONCLUSIONS: MOC-carboetomidate is a GABA, receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function. (Anesth Analg 2012;115:297-304) C1 [Cuny, Gregory D.; Laha, Joydev K.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Liu, Jifeng; Lin, Xiang Jie] Aberjona Labs Inc, Beverly, MA USA. [Pejo, Ervin; Cotten, Joseph F.; Kelly, Elizabeth W.; Ge, Ri Le; Raines, Douglas E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Raines, DE (reprint author), Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM draines@partners.org FU NIDA NIH HHS [R21 DA029253-02, R21 DA029253, R21 DA029253-01]; NIGMS NIH HHS [R01 GM087316-01A1, R01 GM087316-03, R01 GM087316-02, K08 GM083216, R01 GM087316] NR 23 TC 13 Z9 15 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2012 VL 115 IS 2 BP 297 EP 304 DI 10.1213/ANE.0b013e3182320559 PG 8 WC Anesthesiology SC Anesthesiology GA 978TU UT WOS:000306769500015 PM 21965364 ER PT J AU Ge, RL Pejo, E Haburcak, M Husain, SS Forman, SA Raines, DE AF Ge, Ri Le Pejo, Ervin Haburcak, Marian Husain, S. Shaukat Forman, Stuart A. Raines, Douglas E. TI Pharmacological Studies of Methoxycarbonyl Etomidate's Carboxylic Acid Metabolite SO ANESTHESIA AND ANALGESIA LA English DT Article ID REMIFENTANIL; PHARMACODYNAMICS; PHARMACOKINETICS; ANALOG AB BACKGROUND: Methoxycarbonyl etomidate (MOC-etomidate) is a rapidly metabolized and ultrashort-acting etomidate analog that does not produce prolonged adrenocortical suppression after bolus administration. Its metabolite (MOC-ECA) is a carboxylic acid whose pharmacology is undefined. We hypothesized that MOC-ECA possesses significantly lower pharmacological activity than MOC-etomidate, accounting for the latter's very brief duration of hypnotic action and inability to produce prolonged adrenocortical suppression after bolus administration. To test this hypothesis, we compared the potencies of MOC-ECA and MOC-etomidate in 3 biological assays. METHODS: The hypnotic potency of MOC-ECA was assessed in tadpoles using a loss-of-righting reflexes assay. The gamma-aminobutyric acid type A (GABA(A)) receptor modulatory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to directly activate alpha(1)(L264T))beta(2)gamma(2L) GABAA receptors. The adrenocortical inhibitory potencies of MOC-ECA and MOC-etomidate were compared by defining the concentrations of each required to inhibit in vitro codisol production by adrenocortical cells. RESULTS: MOC-ECA's 50% effective concentration for loss-of-righting reflexes in tadpoles was 2.8 +/- 0.64 mM as compared with a previously reported value of 8 +/- 2 mu M for MOC-etomidate. The 50% effective concentrations for direct activation of GABA(A) receptors were 3.5 +/- 0.63 mM for MOC-ECA versus 10 +/- 2.5 mu M for MOC-etomidate. The half-maximal inhibitory concentration for inhibiting in vitro cortisol production by adrenocortical cells was 30 +/- 7 mu M for MOC-ECA versus 0.10 +/- 0.02 mu M for MOC-etomidate. CONCLUSIONS: In all 3 biological assays, MOC-ECA's potency was approximately 300-fold lower than that of MOC-etomidate. (Anesth Analg 2012;115:305-8) C1 [Ge, Ri Le; Pejo, Ervin; Haburcak, Marian; Husain, S. Shaukat; Forman, Stuart A.; Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM draines@partners.org OI Haburcak, Marian/0000-0003-0662-0756 FU National Institutes of Health, Bethesda, MD [R01-GM087316, R21-DA029253]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA FX Supported by grants R01-GM087316 and R21-DA029253 from the National Institutes of Health, Bethesda, MD, and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA. NR 12 TC 15 Z9 16 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2012 VL 115 IS 2 BP 305 EP 308 DI 10.1213/ANE.0b013e318239c6ca PG 4 WC Anesthesiology SC Anesthesiology GA 978TU UT WOS:000306769500016 PM 22052979 ER PT J AU Itani, KMF Biswas, P Reisman, A Bhattacharyya, H Baruch, AM AF Itani, Kamal M. F. Biswas, Pinaki Reisman, Arlene Bhattacharyya, Helen Baruch, Alice M. TI Clinical Efficacy of Oral Linezolid Compared With Intravenous Vancomycin for the Treatment of Methicillin-Resistant Staphylococcus aureus-Complicated Skin and Soft Tissue Infections: A Retrospective, Propensity Score-Matched, Case-Control Analysis SO CLINICAL THERAPEUTICS LA English DT Article DE complicated skin and soft tissue infections; linezolid; methicillin-resistant Staphylococcus aureus; vancomycin ID LENGTH-OF-STAY; ECONOMIC OUTCOMES; MRSA AB Background: Linezolid is 100% bioavailable in oral and intravenous formulations. In a recent prospective, randomized, open-label, comparator-controlled, multicenter, phase 4 clinical trial in adults with complicated skin and soft tissue infections (cSSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA), linezolid achieved clinical and microbiologic success comparable to appropriately dosed intravenous vancomycin. Although patients were randomly assigned to receive linezolid or vancomycin, the protocol allowed patients to start therapy using oral or intravenous linezolid on the basis of investigator discretion and patient ability to tolerate oral medication. Objective: The objective of this study was to assess the efficacy and tolerability of linezolid when administered orally in adults with cSSTI caused by MRSA. In this retrospective analysis, we examined data collected from the aforementioned trial to compare outcomes in patients who received either oral linezolid or intravenous vancomycin therapy. Methods: This study analyzed outcomes in patients who received treatment for 7 to 14 days with either oral linezolid (600 mg q12h; n = 95) or intravenous vancomycin (15 mg/kg q12h, adjusted for creatinine clearance and trough concentration; n = 210). By design, these groups were not randomized. Propensity score matching on baseline variables was used to balance these groups by identifying a comparable group of patients who received vancomycin therapy and comparing them with patients who received oral linezolid therapy. Clinical and microbiologic success rates at the end of treatment and the end of the study (EOS) were then directly compared between the groups using matched-pair logistic regression. The tolerability of the 2 treatments (within this matched group) was also described. Results: Ninety-two patients with well-matched baseline characteristics were included in each treatment group. At EOS, the odds ratio for clinical success of oral linezolid therapy vs intravenous vancomycin therapy was 4.0 (95% CI, 1.3-12.0; P = 0.01), and the odds ratio for microbiologic success at EOS was,2.7 (95% CI, 1.2-5.7; P = 0.01). Overall rates of adverse events in each group were consistent with reported safety profiles for each drug. Conclusion: A favorable clinical cure rate was achieved with oral linezolid therapy when compared with intravenous vancomycin therapy in propensity score matched patients with cSSTI proved to be caused by MRSA. ClinicalTrials.gov Identifier: NCT00087490. (Clin Ther. 2012;34:1667-1673) Published by Elsevier HS Journals, Inc. C1 [Itani, Kamal M. F.] VA Boston Healthcare Syst, Boston, MA 02132 USA. [Biswas, Pinaki] Pfizer Inc, Collegeville, PA USA. [Reisman, Arlene; Bhattacharyya, Helen; Baruch, Alice M.] Pfizer Inc, New York, NY USA. RP Itani, KMF (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, Boston, MA 02132 USA. EM kitani@va.gov FU Pfizer Inc.; Merck Co, Inc; Trius Therapeutics, Inc. FX This study was funded by Pfizer Inc. The authors thank Drs. Dan Meyer and Jack Mardekian for their insightful suggestions on the statistical methods and Dr. H. Preston Holley for helpful comments on an earlier version of this manuscript. Drs. Itani and Baruch designed and executed the protocol for the original study (NCT00087490) and formulated the clinical hypotheses and analyses in this article. Dr. Bhattacharyya, Ms. Reisman and Dr. Biswas designed and implemented the protocol of the study and performed the statistical analysis. All authors participated in interpretation of the results and in the writing, review and approval of the manuscript. Editorial support was provided by H. Christian and E.M. Wells of PAR-EXEL International and by A. Seth and E. Parr of UBC Scientific Solutions.; This study was funded by Pfizer Inc (the sponsor). The execution of the design, data collection and medical monitoring was conducted by the sponsor or its designated representatives. The analysis, interpretation of the data, preparation, review and approval of this manuscript was performed by all authors and supported by the sponsor. Dr. Itani has received institutional research support from Pfizer Inc, Merck & Co, Inc, and Trius Therapeutics, Inc. Dr. Biswas, Ms. Reisman, and Dr. Bhattacharyya are employees of Pfizer Inc. Dr. Baruch was an employee of Pfizer Inc when this study was performed. The authors have indicated that they have no other conflicts of interest regarding the content of this article. NR 16 TC 13 Z9 14 U1 1 U2 7 PU ELSEVIER PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0149-2918 J9 CLIN THER JI Clin. Ther. PD AUG PY 2012 VL 34 IS 8 BP 1667 EP 1673 DI 10.1016/j.clinthera.2012.06.018 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 992QI UT WOS:000307794400002 PM 22770644 ER PT J AU McCarthy, MM Ching, SN Whittington, MA Kopell, N AF McCarthy, Michelle M. Ching, ShiNung Whittington, Miles A. Kopell, Nancy TI Dynamical changes in neurological diseases and anesthesia SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID PARKINSONS-DISEASE; SUBTHALAMIC NUCLEUS; GAMMA OSCILLATIONS; BASAL GANGLIA; GENERAL-ANESTHESIA; BETA-OSCILLATIONS; PATHOLOGICAL SYNCHRONIZATION; SCHIZOPHRENIA; RHYTHM; INTERNEURONS AB Dynamics of neuronal networks can be altered in at least two ways: by changes in connectivity, that is, the physical architecture of the network, or changes in the amplitudes and kinetics of the intrinsic and synaptic currents within and between the elements making up a network. We argue that the latter changes are often overlooked as sources of alterations in network behavior when there are also structural (connectivity) abnormalities present; indeed, they may even give rise to the structural changes observed in these states. Here we look at two clinically relevant states (Parkinson's disease and schizophrenia) and argue that non-structural changes are important in the development of abnormal dynamics within the networks known to be relevant to each disorder. We also discuss anesthesia, since it is entirely acute, thus illustrating the potent effects of changes in synaptic and intrinsic membrane currents in the absence of structural alteration. In each of these, we focus on the role of changes in GABAergic function within microcircuits, stressing literature within the last few years. C1 [McCarthy, Michelle M.; Ching, ShiNung; Kopell, Nancy] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Ching, ShiNung] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ching, ShiNung] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Whittington, Miles A.] Newcastle Univ, Sch Med, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RP Kopell, N (reprint author), Boston Univ, Dept Math & Stat, 111 Cummington St, Boston, MA 02215 USA. EM nk@math.bu.edu FU NINDS NIH HHS [R01 NS067199] NR 86 TC 12 Z9 12 U1 1 U2 15 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD AUG PY 2012 VL 22 IS 4 BP 693 EP 703 DI 10.1016/j.conb.2012.02.009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 013UK UT WOS:000309331200018 PM 22446010 ER PT J AU Calabro, FJ Vaina, LM AF Calabro, F. J. Vaina, L. M. TI Interaction of cortical networks mediating object motion detection by moving observers SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE Object motion; Self-motion; fMRI; Connectivity ID HUMAN VISUAL-CORTEX; VENTRAL INTRAPARIETAL AREA; LATERAL OCCIPITAL COMPLEX; SUPERIOR TEMPORAL AREA; SURFACE-BASED ANALYSIS; OPTIC FLOW STIMULI; HUMAN BRAIN; RESPONSE SELECTIVITY; PERCEPTUAL DECISION; FUNCTIONAL-ANALYSIS AB The task of parceling perceived visual motion into self- and object motion components is critical to safe and accurate visually guided navigation. In this paper, we used functional magnetic resonance imaging to determine the cortical areas functionally active in this task and the pattern connectivity among them to investigate the cortical regions of interest and networks that allow subjects to detect object motion separately from induced self-motion. Subjects were presented with nine textured objects during simulated forward self-motion and were asked to identify the target object, which had an additional, independent motion component toward or away from the observer. Cortical activation was distributed among occipital, intra-parietal and fronto-parietal areas. We performed a network analysis of connectivity data derived from partial correlation and multivariate Granger causality analyses among functionally active areas. This revealed four coarsely separated network clusters: bilateral V1 and V2; visually responsive occipito-temporal areas, including bilateral LO, V3A, KO (V3B) and hMT; bilateral VIP, DIPSM and right precuneus; and a cluster of higher, primarily left hemispheric regions, including the central sulcus, post-, pre- and sub-central sulci, pre-central gyrus, and FEF. We suggest that the visually responsive networks are involved in forming the representation of the visual stimulus, while the higher, left hemisphere cluster is involved in mediating the interpretation of the stimulus for action. Our main focus was on the relationships of activations during our task among the visually responsive areas. To determine the properties of the mechanism corresponding to the visual processing networks, we compared subjects' psychophysical performance to a model of object motion detection based solely on relative motion among objects and found that it was inconsistent with observer performance. Our results support the use of scene context (e.g., eccentricity, depth) in the detection of object motion. We suggest that the cortical activation and visually responsive networks provide a potential substrate for this computation. C1 [Calabro, F. J.; Vaina, L. M.] Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA. [Vaina, L. M.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Vaina, L. M.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Vaina, LM (reprint author), Boston Univ, Dept Biomed Engn, Brain & Vis Res Lab, Boston, MA 02215 USA. EM vaina@bu.edu OI Calabro, Finnegan/0000-0002-8092-3942 FU NIH [RO1NS064100]; National Center for Research Resources (NCRR), National Institutes of Health; NCRR [S10RR021110] FX This work was supported by NIH grant RO1NS064100 to L.M.V. We thank Victor Solo for discussions regarding models of functional connectivity and our subjects for participating in the psychophysical and fMRI experiments. This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41RR14075, a P41 Regional Resource supported by the Biomedical Technology Program of the National Center for Research Resources (NCRR), National Institutes of Health. This work also involved the use of instrumentation supported by the NCRR Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant number S10RR021110. NR 67 TC 7 Z9 7 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD AUG PY 2012 VL 221 IS 2 BP 177 EP 189 DI 10.1007/s00221-012-3159-8 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 985GL UT WOS:000307251300007 PM 22811215 ER PT J AU Beecher, B Glassner, P Malchau, H Kwon, YM AF Beecher, Benjamin Glassner, Philip Malchau, Henrik Kwon, Young-Min TI A concise minimum eight year follow-up of proximally porous-coated tapered titanium femoral stem in primary total hip arthroplasty SO INTERNATIONAL ORTHOPAEDICS LA English DT Article ID CEMENTLESS; REPLACEMENT; COMPONENT; 5-YEAR; PROSTHESIS; FIXATION; IMPLANT; YOUNGER; AGE AB Our goal was to assess clinical and radiographic outcomes using a second-generation circumferentially proximally porous-coated titanium alloy stem at a minimum of eight years of follow-up. Ninety-one hips (80 patients) with Fibre Metal Taper (FMT, Zimmer Inc, Warsaw, IN, USA) femoral stems implanted between May 1998 and April 2002 were followed prospectively and re-evaluated at a minimum of eight years postoperatively. The median patient age was 56 (range 34-78) years, with 40 women and 40 men. Radiographic data and clinical follow-up using Harris Hip Score (HHS) and EuroQol (EQ)-5D outcome measures were evaluated. Mean follow-up was 9.61 (range 8-12.3) years. At the time of the most recent follow-up, the mean HHS was 85.8 (range 46-100) points, mean EQ-5D Weighted Health State Index was 0.76 (range 0.05-1.00), and mean EQ-5D Visual Analogue Score was 80 (range 24-100). All stems were biologically stable, with all hips having osseous ingrowth. One stem was revised due to early periprosthetic fracture with stem subsidence. No hip had diaphyseal osteolysis. To our knowledge, the data presented here represent the longest clinical follow-up of this second-generation cementless, proximally porous-coated femoral stem. The stems were found to perform well clinically and radiographically beyond the first five years previously reported in the literature. Patients had high levels of satisfaction and function, and osseous fixation occurred reliably without evidence of distal osteolysis. C1 [Beecher, Benjamin; Malchau, Henrik; Kwon, Young-Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. [Glassner, Philip] Hunterdon Orthoped Inst, Flemington, NJ USA. RP Beecher, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. EM brbeecher@partners.org OI Malchau, Henrik/0000-0002-4291-2441 NR 26 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 J9 INT ORTHOP JI Int. Orthop. PD AUG PY 2012 VL 36 IS 8 BP 1561 EP 1565 DI 10.1007/s00264-012-1515-8 PG 5 WC Orthopedics SC Orthopedics GA 985EM UT WOS:000307246200003 PM 22410972 ER PT J AU Choi, HR Burke, D Malchau, H Kwon, YM AF Choi, Ho-Rim Burke, Dennis Malchau, Henrik Kwon, Young-Min TI Utility of tibial tubercle osteotomy in the setting of periprosthetic infection after total knee arthroplasty SO INTERNATIONAL ORTHOPAEDICS LA English DT Article ID FIXATION TECHNIQUES; 2-STAGE REVISION; VALGUS KNEE; REPLACEMENT; EXPOSURE; SPACER; ACCESS AB This study reports radiographic and clinical treatment outcomes of tibial tubercle osteotomy (TTO) used for two-stage revision total knee arthroplasty (TKA) in the setting of periprosthetic infection. Thirty-six patients with 51 TTOs used for infected TKA were retrospectively analysed from 2000 to 2010. In 15 of 36 patients, TTO was used in a sequential manner during both first and second stage procedures. The mean follow-up period was 57 months (range seven-126 months). The mean pre-operative range of knee motion was 40A degrees (range 10-90A degrees), and at latest follow-up it was 92A degrees (range 50-140A degrees). The Knee Society knee scores and function scores were 47 and 9 pre-operatively and 82 and 72 at latest follow-up, respectively. Bony union was achieved in all cases except one nonunion of an avulsion fragment of the osteotomy segment without functional deterioration. TTO can be a useful extensile surgical approach for treatment of infected TKA with satisfactory clinical and radiographic outcomes. C1 [Choi, Ho-Rim; Burke, Dennis; Malchau, Henrik; Kwon, Young-Min] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Harris Orthoped Lab, Boston, MA 02114 USA. RP Kwon, YM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Harris Orthoped Lab, Boston, MA 02114 USA. EM kwon.young-min@mgh.harvard.edu OI Malchau, Henrik/0000-0002-4291-2441 NR 25 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0341-2695 J9 INT ORTHOP JI Int. Orthop. PD AUG PY 2012 VL 36 IS 8 BP 1609 EP 1613 DI 10.1007/s00264-012-1541-6 PG 5 WC Orthopedics SC Orthopedics GA 985EM UT WOS:000307246200010 PM 22581352 ER PT J AU Lee, HS Hattori, T Park, EY Stevenson, W Chauhan, SK Dana, R AF Lee, Hyun Soo Hattori, Takaaki Park, Eun Young Stevenson, William Chauhan, Sunil K. Dana, Reza TI Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OCULAR-SURFACE; EPITHELIAL-CELLS; DENDRITIC CELLS; ISCHEMIA/REPERFUSION INJURY; AUTOIMMUNE-DISEASE; MD-2 EXPRESSION; MOUSE MODEL; TLR4; IMMUNITY; PATHWAYS AB PURPOSE. To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED). METHODS. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1 beta, IL-6, TNF, and CCL2), corneal infiltration of CD11b(+) antigen-presenting cells, and lymph node frequency of mature MHC-IIhi CD11b(+) cells were assessed. RESULTS. The epithelial cells of normal corneas expressed TLR4 intracellularly; however, DED significantly increased the cell surface expression of TLR4. Similarly, flow cytometric analysis of stromal cells revealed a significant increase in the expression of TLR4 proteins by DED-induced corneas as compared with normal corneas. DED increased the mRNA expression of TLR4 in corneal stromal cells, but not epithelial cells. TLR4 inhibition decreased the severity of CFS and significantly reduced the mRNA expression of IL-1 beta, IL-6, and TNF. Furthermore, TLR4 inhibition significantly reduced the corneal infiltration of CD11b(+) cells and the lymph node frequency of MHC-IIhi CD11b(+) cells. CONCLUSIONS. These results suggest that DED increases the corneal expression of TLR4 and that TLR4 participates in the inflammatory response to ocular surface desiccating stress. (Invest Ophthalmol Vis Sci. 2012;53:5632-5640) DOI: 10.1167/iovs.12-9547 C1 [Lee, Hyun Soo; Hattori, Takaaki; Park, Eun Young; Stevenson, William; Chauhan, Sunil K.; Dana, Reza] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Lee, Hyun Soo] Catholic Univ Korea, Seoul St Marys Hosp, Coll Med, Dept Ophthalmol, Seoul, South Korea. RP Dana, R (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU National Eye Institute/National Institutes of Health [EY-20889] FX Supported in part by National Eye Institute/National Institutes of Health Grant EY-20889. NR 50 TC 23 Z9 26 U1 0 U2 6 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2012 VL 53 IS 9 BP 5632 EP 5640 DI 10.1167/iovs.12-9547 PG 9 WC Ophthalmology SC Ophthalmology GA 004QE UT WOS:000308695400068 PM 22789921 ER PT J AU Deus, HF Prud'hommeaux, E Miller, M Zhao, J Malone, J Adamusiak, T McCusker, J Das, S Serra, PR Fox, R Marshall, MS AF Deus, Helena F. Prud'hommeaux, Eric Miller, Michael Zhao, Jun Malone, James Adamusiak, Tomasz McCusker, Jim Das, Sudeshna Serra, Philippe Rocca Fox, Ronan Marshall, M. Scott TI Translating standards into practice - One Semantic Web API for Gene Expression SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Semantic Web technologies; Genomics; Transcriptomics; Pharmacogenomics; Microarrays; Linked Data ID MICROARRAY DATA; BIOMEDICAL INVESTIGATIONS; DATA INTEGRATION; ONTOLOGIES; ANNOTATION; BIOLOGY; INFORMATION; GENOMICS; MIAME AB Sharing and describing experimental results unambiguously with sufficient detail to enable replication of results is a fundamental tenet of scientific research. In today's cluttered world of "-omics" sciences, data standards and standardized use of terminologies and ontologies for biomedical informatics play an important role in reporting high-throughput experiment results in formats that can be interpreted by both researchers and analytical tools. Increasing adoption of Semantic Web and Linked Data technologies for the integration of heterogeneous and distributed health care and life sciences (HCLSs) datasets has made the reuse of standards even more pressing; dynamic semantic query federation can be used for integrative bioinformatics when ontologies and identifiers are reused across data instances. We present here a methodology to integrate the results and experimental context of three different representations of microarray-based transcriptomic experiments: the Gene Expression Atlas, the W3C BioRDF task force approach to reporting Provenance of Microarray Experiments, and the HSCI blood genomics project. Our approach does not attempt to improve the expressivity of existing standards for genomics but, instead, to enable integration of existing datasets published from microarray-based transcriptomic experiments. SPARQL Construct is used to create a posteriori mappings of concepts and properties and linking rules that match entities based on query constraints. We discuss how our integrative approach can encourage reuse of the Experimental Factor Ontology (EFO) and the Ontology for Biomedical Investigations (OBIs) for the reporting of experimental context and results of gene expression studies. (C) 2012 Elsevier Inc. All rights reserved. C1 [Deus, Helena F.; Fox, Ronan] Natl Univ Ireland, Digital Enterprise Res Inst, Galway, Ireland. [Prud'hommeaux, Eric] MIT, World Wide Web Consortium W3C, Cambridge, MA 02139 USA. [Miller, Michael] Inst Syst Biol, Seattle, WA USA. [Zhao, Jun] Univ Oxford, Image Bioinformat Res Grp, Oxford, England. [Malone, James; Adamusiak, Tomasz] European Bioinformat Inst, Cambridge, England. [McCusker, Jim] Rensselaer Polytech Inst, Tetherless World Constellat, Troy, NY 12181 USA. [Das, Sudeshna] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Das, Sudeshna] Harvard Univ, Sch Med, Boston, MA USA. [Serra, Philippe Rocca] Univ Oxford, Oxford E Res Ctr, Oxford, England. [Marshall, M. Scott] Univ Amsterdam, Leiden Univ Med Ctr, NL-1012 WX Amsterdam, Netherlands. [Marshall, M. Scott] Univ Amsterdam, Inst Informat, NL-1012 WX Amsterdam, Netherlands. RP Deus, HF (reprint author), Natl Univ Ireland, Digital Enterprise Res Inst, Galway, Ireland. EM helena.deus@deri.org; eric@w3.org; mmiller@systemsbiology.org; jun.zhao@zoo.ox.ac.uk; malone@ebi.ac.uk; tomasz@ebi.ac.uk; james.mccusker@yale.edu; sudeshna_das@harvard.edu; proccaserra@gmail.com; ronan.fox@deri.org; marshall@science.uva.nl OI Adamusiak, Tomasz/0000-0002-0746-2916; Zhao, Jun/0000-0001-6935-9028; Prud'hommeaux, Eric/0000-0003-1775-9921 FU EU Project GRANATUM [270139] FX We thankfully acknowledge Aidan Hogan, Jonas Almeida and Helen Parkinson for fruitful discussions. We also would like to acknowledge IO Informatics for providing a license to their software Sentient Knowledge Explorer, used to create Figs. 2-4. We thank Kei-Hoi Cheung for his previous chairmanship of the BioRDF taskforce and his initiative to represent expression study results for neurodegenerative diseases. H.F.D. was supported by EU Project GRANATUM (Ref. 270139). NR 43 TC 7 Z9 7 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD AUG PY 2012 VL 45 IS 4 SI SI BP 782 EP 794 DI 10.1016/j.jbi.2012.03.002 PG 13 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 998RN UT WOS:000308258200021 PM 22449719 ER PT J AU Bouhaddou, O Cromwell, T Davis, M Maulden, S Hsing, N Carlson, D Cockle, J Hoang, C Fischetti, L AF Bouhaddou, Omar Cromwell, Tim Davis, Mike Maulden, Sarah Hsing, Nelson Carlson, David Cockle, Jennifer Hoang, Catherine Fischetti, Linda TI Translating standards into practice: Experience and lessons learned at the Department of Veterans Affairs SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE Standards adoption; Reference implementation; Standards Life Cycle; Interoperability; Likelihood of Adoption Scale; Health information technology AB The increased need for interoperable electronic health records in health care organizations underscores the importance of standards. The US Department of Veterans Affairs (VA) has a long history of developing and adopting various types of health care data standards. The authors present in detail their experience in this domain. A formal organization within VA is responsible for helping to develop and implement standards. This group has produced a Standards Life Cycle (SLC) process endorsed by VA key business and information technology (IT) stakeholders. It coordinates the identification, description, and implementation of standards aligned with VA business requirements. In this paper, we review the adoption of four standards in the categories of security and privacy, terminology, health information exchange, and modeling tools; emphasizing the implementation approach used in each. In our experience, adoption is facilitated by internal staff with expertise in standards development and adoption. Use of processes such as an SLC and tools such as an enterprise requirement repository help formally track and ensure that IT development and acquisition incorporate these standards. An organization should adopt standards that are aligned with its business priorities and favor those that are more readily implementable. To assist with this final point, we offer a standard "Likelihood of Adoption Scale," which changes as standards specifications evolve from PDF documents only, to PDF documents with construction and testing tools, to fully functional reference implementations. (C) 2012 Elsevier Inc. All rights reserved. C1 [Bouhaddou, Omar; Cromwell, Tim; Davis, Mike; Maulden, Sarah; Hsing, Nelson; Carlson, David; Cockle, Jennifer; Hoang, Catherine; Fischetti, Linda] US Dept Vet Affairs, Washington, DC USA. RP Bouhaddou, O (reprint author), POB 3351, Rancho Santa Fe, CA 92067 USA. EM omar.bouhaddou@va.gov NR 19 TC 5 Z9 5 U1 1 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD AUG PY 2012 VL 45 IS 4 SI SI BP 813 EP 823 DI 10.1016/j.jbi.2012.01.003 PG 11 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 998RN UT WOS:000308258200023 PM 22285982 ER PT J AU Aronis, KN Foo, JP Chamberland, JP Mantzoros, CS AF Aronis, Konstantinos N. Foo, Joo-Pin Chamberland, John P. Mantzoros, Christos S. TI Secretion Patterns of Circulating Osteoprotegerin and Response to Acute and Chronic Energy Deprivation in Young Healthy Adults SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID METHIONYL HUMAN LEPTIN; TYPE-2 DIABETIC-PATIENTS; HUMAN PHYSIOLOGY; SERUM OSTEOPROTEGERIN; CLINICAL-IMPLICATIONS; CIRCADIAN VARIATION; ANOREXIA-NERVOSA; BONE-RESORPTION; SOLUBLE RANKL; HIGH-RISK AB Introduction: Osteoprotegerin (OPGN) is a bone-remodeling marker that is associated with various metabolic and vascular complications. Cross-sectional studies in humans have demonstrated an inverse association between leptin, a marker of energy sufficiency, and OPGN. The physiology of OPGN has not been fully elucidated to date. We thus aim to elucidate 1) whether OPGN levels exhibit any gender dimorphism or day/night secretion pattern; and 2) whether there is any effect of acute and/or chronic energy deprivation on its circulating levels and whether such effects are mediated through leptin. Materials and Methods: Study A: To evaluate OPGN secretion patterns and OPGN response to acute energy deprivation, we studied 12 healthy subjects under three different conditions for 72 h-in the isocaloric fed state, and during a fasting state with administration of either placebo or metreleptin in replacement doses. Blood samples were obtained every 15 min and pooled hourly during the last 24 h of the study. Study B: To evaluate the effect of chronic energy deprivation on OPGN secretion, we measured its levels in 14 obese subjects before and during weight loss after bariatric surgery. Results: OPGN levels exhibited a statistically significant (P < 0.01), albeit clinically limited in magnitude, day/night variation pattern in both genders (R-2 = 14.68%; 10.7-14.8% reduction with lower levels around 1600-1800 h; P < 0.01). Males had lower OPGN levels compared to females (1.81 +/- 0.04 vs. 3.65 +/- 0.07 pmol/liter; P < 0.001). Three days of fasting with either placebo or metreleptin administration did not change OPGN levels. OPGN levels did not change during bariatric surgery-induced weight loss. Conclusions: OPGN levels are lower in men and exhibit a statistically significant, albeit clinically limited in magnitude, day/night secretion pattern. Neither acute nor chronic energy deprivation leading to significant weight loss has any effects on OPGN levels. Nomenclature Comment: Use of the terms "circadian" and "day/night variation" is meant as follows: Circadian pattern is a functional term that implies a rhythm that has been proven to be regulated by the innate circadian apparatus (anatomical and/or molecular). Conversely, day/night variation pattern is a descriptive term that refers to serum levels that vary during a day, usually in a periodic fashion. It is not known whether this variation is an innate property of the organ that secretes this hormone or whether it is determined by exogenous factors. (J Clin Endocrinol Metab 97: 2765-2772, 2012) C1 [Aronis, Konstantinos N.; Foo, Joo-Pin; Chamberland, John P.; Mantzoros, Christos S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol,Dept Internal Med, Boston, MA 02215 USA. [Aronis, Konstantinos N.; Chamberland, John P.; Mantzoros, Christos S.] Harvard, Sch Med, VA Boston Healthcare Syst, Sect Endocrinol,Dept Internal Med, Boston, MA 02215 USA. RP Mantzoros, CS (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, 330 Brookline Ave,Stoneman 816, Boston, MA 02215 USA. EM cmantzor@bidmc.harvard.edu RI Aronis, Konstantinos/F-3586-2012 OI Aronis, Konstantinos/0000-0001-7189-8434 FU Harvard Clinical and Translational Science Center [M01-RR-01032-328840]; National Institutes of Health; National Center for Research Resources; National Institute of Diabetes and Digestive and Kidney Diseases [DK058785, DK079929, DK081913]; National Institute on Aging [AG032030] FX The project described was supported by Grant M01-RR-01032-328840 to the Harvard Clinical and Translational Science Center, from the National Institutes of Health, National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources, the National Institutes of Health, or the VA Administration. Funding was also received from the National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK058785, DK079929, and DK081913) and the National Institute on Aging (Grant AG032030). Metreleptin was provided by Amylin Inc., which had no role in the conduct of the study, collection, management, analysis, and interpretation of the data, or the preparation, review, or approval of the manuscript. NR 47 TC 0 Z9 0 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2012 VL 97 IS 8 BP 2765 EP 2772 DI 10.1210/jc.2012-1618 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 987ZI UT WOS:000307457400061 PM 22563105 ER PT J AU Mostaghel, EA Lin, DW Amory, JK Wright, JL Marck, BT Nelson, PS Matsumoto, AM Bremner, WJ Page, ST AF Mostaghel, Elahe A. Lin, Daniel W. Amory, John K. Wright, Jonathan L. Marck, Brett T. Nelson, Peter S. Matsumoto, Alvin M. Bremner, William J. Page, Stephanie T. TI Impact of Male Hormonal Contraception on Prostate Androgens and Androgen Action in Healthy Men: A Randomized, Controlled Trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TESTOSTERONE REPLACEMENT; ORAL TESTOSTERONE; OLDER MEN; CANCER; FINASTERIDE; CASTRATION; TISSUE; HYPERPLASIA; DUTASTERIDE; DIHYDROTESTOSTERONE AB Context: Male hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health. Objective: The objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action. Design: This was a single-blind, randomized, placebo-controlled study. Setting: The study was conducted at an academic medical center. Participants: 32 healthy men aged 25-55 yr participated in the study. Intervention: Interventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10. Main Outcome Measures: Serum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured. Results: Thirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm. Conclusions: MHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed. (J Clin Endocrinol Metab 97: 2809-2817, 2012) C1 [Page, Stephanie T.] Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98195 USA. [Mostaghel, Elahe A.; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol & Clin Res, Seattle, WA 98109 USA. [Lin, Daniel W.; Wright, Jonathan L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Lin, Daniel W.; Wright, Jonathan L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Marck, Brett T.; Matsumoto, Alvin M.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Marck, Brett T.; Matsumoto, Alvin M.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Seattle, WA 98108 USA. RP Page, ST (reprint author), Univ Washington, Sch Med, Div Metab Endocrinol & Nutr, Dept Med, Box 357138,1959 NE Pacific St, Seattle, WA 98195 USA. EM page@u.washington.edu FU National Institutes of Health through National Institute of Aging Grants [K23-AG027238, RO1-AG037603A]; Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant [U54-HD-42454]; National Cancer Institute Grant [K23 CA122820-01]; Pacific Northwest Prostate Cancer SPORE Grant [P50-CA097186]; Damon Runyon-Genentech Clinical Investigator Award [CI-40-08]; Prostate Cancer Foundation; GlaxoSmithKline; Abbott Pharmaceuticals FX This work was supported by the National Institutes of Health through National Institute of Aging Grants K23-AG027238 and RO1-AG037603A, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant U54-HD-42454, the National Cancer Institute Grant K23 CA122820-01, and the Pacific Northwest Prostate Cancer SPORE Grant P50-CA097186 E.A.M. was also supported by a Damon Runyon-Genentech Clinical Investigator Award CI-40-08 and the Prostate Cancer Foundation. NR 34 TC 8 Z9 8 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2012 VL 97 IS 8 BP 2809 EP 2817 DI 10.1210/jc.2012-1536 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 987ZI UT WOS:000307457400066 PM 22659250 ER PT J AU Tepper, PG Randolph, JF McConnell, DS Crawford, SL El Khoudary, SR Joffe, H Gold, EB Zheng, HY Bromberger, JT Sutton-Tyrrell, K AF Tepper, Ping G. Randolph, John F., Jr. McConnell, Daniel S. Crawford, Sybil L. El Khoudary, Samar R. Joffe, Hadine Gold, Ellen B. Zheng, Huiyong Bromberger, Joyce T. Sutton-Tyrrell, Kim TI Trajectory Clustering of Estradiol and Follicle-Stimulating Hormone during the Menopausal Transition among Women in the Study of Women's Health across the Nation (SWAN) SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FINAL MENSTRUAL PERIOD; ADIPOSE-TISSUE; SAS PROCEDURE; PATTERNS; ESTROGEN; OBESITY; CYCLE; AGE; PERIMENOPAUSE; GONADOTROPIN AB Context: Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. Objective: The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. Design: The Study of Women's Health Across the Nation is a longitudinal observational study of the menopausal transition. Setting: Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. Participants: Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. Main Outcome Measures: Annual serum E2 and FSH levels anchored to final menstrual period were measured. Results: Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. Conclusions: E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition. (J Clin Endocrinol Metab 97: 2872-2880, 2012) C1 [Tepper, Ping G.; El Khoudary, Samar R.; Sutton-Tyrrell, Kim] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Bromberger, Joyce T.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol & Psychiat, Pittsburgh, PA 15261 USA. [Randolph, John F., Jr.] Univ Michigan, Sch Publ Hlth, Div Reprod Endocrinol & Infertil, Ann Arbor, MI 48109 USA. [McConnell, Daniel S.; Zheng, Huiyong] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Crawford, Sybil L.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. [Joffe, Hadine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Womens Mental Hlth, Boston, MA 02114 USA. [Gold, Ellen B.] Univ Calif Davis, Sch Med, Dept Publ Hlth Sci, Davis, CA 95616 USA. RP Tepper, PG (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM tepperp@edc.pitt.edu OI El Khoudary Abushaban, Samar/0000-0003-2913-0821 FU National Institutes of Health, Department of Health and Human Services, through the National Institute on Aging; National Institute of Nursing Research; National Institutes of Health Office of Research on Women's Health [NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495] FX The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health, Department of Health and Human Services, through the National Institute on Aging, the National Institute of Nursing Research, and the National Institutes of Health Office of Research on Women's Health (Grants NR004061, AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, and AG012495). NR 38 TC 24 Z9 24 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2012 VL 97 IS 8 BP 2872 EP 2880 DI 10.1210/jc.2012-1422 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 987ZI UT WOS:000307457400073 PM 22659249 ER PT J AU Chan, YM Butler, JP Sidhoum, VF Pinnell, NE Seminara, SB AF Chan, Yee-Ming Butler, James P. Sidhoum, Valerie F. Pinnell, Nancy E. Seminara, Stephanie B. TI Kisspeptin Administration to Women: A Window into Endogenous Kisspeptin Secretion and GnRH Responsiveness across the Menstrual Cycle SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; INTERPULSE INTERVAL SEQUENCE; PITUITARY-GONADAL AXIS; MONKEY MACACA-MULATTA; HYPOGONADOTROPIC HYPOGONADISM; HYPOTHALAMIC AMENORRHEA; HUMAN METASTIN-45-54; RECEPTOR GPR54; FEMALE RAT; LH AB Context: Kisspeptin is the most powerful known stimulus of GnRH-induced LH secretion across mammalian species. However, the effects of kisspeptin are just being explored, and the dynamics of kisspeptin responsiveness across the menstrual cycle are incompletely understood. Objective: The objective of the study was to characterize the effects of kisspeptin on GnRH secretion in healthy women in different phases of the menstrual cycle. Participants and Intervention: Ten women in the early follicular phase, three women in the late follicular (preovulatory) phase, and 14 women in the midluteal phase received a bolus of kisspeptin 112-121 0.24 nmol/kg iv. An additional four women in the early to midfollicular phase received kisspeptin 112-121 0.72 nmol/kg iv. Results: The response to kisspeptin varied depending on the phase of the menstrual cycle. LH pulses were observed immediately after kisspeptin administration in all luteal and preovulatory women. However, only half the womenin the early follicular phase had unambiguous kisspeptin responses. Increasing the kisspeptin dose did not increase the LH response in early to midfollicular phase women. Kisspeptin did not appear to reset the GnRH pulse generator in women as it does in men. Conclusions: Differences in responses to exogenous kisspeptin across the menstrual cycle suggest that kisspeptin tone is higher in the early follicular phase compared with other cycle phases. The mechanisms that determine the timing of GnRH pulse generation in men and women appear to be distinct. (J Clin Endocrinol Metab 97: E1458-E1467, 2012) C1 [Chan, Yee-Ming; Sidhoum, Valerie F.; Pinnell, Nancy E.; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Harvard Reprod Sci Ctr, Boston, MA 02114 USA. [Chan, Yee-Ming; Sidhoum, Valerie F.; Pinnell, Nancy E.; Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Childrens Hosp, Div Endocrinol, Dept Med, Boston, MA 02115 USA. [Butler, James P.] Brigham & Womens Hosp, Div Sleep Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Chan, YM (reprint author), Massachusetts Gen Hosp, Dept Med, Harvard Reprod Sci Ctr, 55 Fruit St,BHX 5, Boston, MA 02114 USA. EM ymchan@partners.org FU Eunice Kennedy Shriver National Institute for Child Health and Human Development [R01 HD43341]; Harvard Catalyst; Harvard Clinical and Translational Science Center; National Center for Research Resources; National Center for Advancing Translational Sciences; National Institutes of Health Award [UL1 RR 025758]; Harvard University; Charles A. King Trust; Career Development Award from Children's Hospital Boston FX This work was supported by Grant R01 HD43341 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development and Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic health care centers). Y.-M.C. was supported by a Charles A. King Trust postdoctoral fellowship and a Career Development Award from Children's Hospital Boston. NR 44 TC 30 Z9 30 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2012 VL 97 IS 8 BP E1458 EP E1467 DI 10.1210/jc.2012-1282 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 987ZI UT WOS:000307457400013 PM 22577171 ER PT J AU Hermanstyne, KA Bangsberg, DR Hennessey, K Weinbaum, C Hahn, JA AF Hermanstyne, Keith A. Bangsberg, David R. Hennessey, Karen Weinbaum, Cindy Hahn, Judith A. TI The association between use of non-injection drug implements and hepatitis C virus antibody status in homeless and marginally housed persons in San Francisco SO JOURNAL OF PUBLIC HEALTH LA English DT Article DE epidemiology; liver disorders; public health ID HIV-INFECTED MEN; NEW-YORK-CITY; UNITED-STATES; RISK-FACTORS; BLOOD-DONORS; VIRAL-HEPATITIS; B-VIRUS; PREVALENCE; POPULATION; SEX AB Background Up to 17 000 persons in the USA became infected with hepatitis C virus (HCV) in 2007, and many cases have unknown transmission routes. To date research on transmission of HCV via shared implements used to snort or smoke non-injection drugs has been : inconclusive. Methods We tested stored sera for HCV antibodies (anti-HCV) in a large population-based study of homeless and marginally housed persons in San Francisco. We examined the association between sharing implements used for snorting and smoking drugs and anti-HCV while controlling for sociodemographic variables in those who denied ever injecting drugs (n = 430). We also examined the association of anti-HCV status with history of incarceration, tattoo and piercing history, sexual history and alcohol consumption. Results Seventeen percent of our sample was anti-HCV positive. We found no statistically significant associations with sharing implements used to smoke or snort drugs with anti-HCV status in our various multivariate models. There was a statistically significant negative association between ever snorting cocaine and anti-HCV status (adjusted odds ratio: 0.39; 95% confidence interval: 0.21-0.73). There were no other statistically significant associations with any other measured covariates in multivariate analyses. Conclusions Our findings suggest that sharing implements to snort or smoke drugs is not a significant risk factor for anti-HCV-positive status. C1 [Hermanstyne, Keith A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. [Hennessey, Karen; Weinbaum, Cindy] Ctr Dis Control & Prevent, Atlanta, GA 30033 USA. [Hahn, Judith A.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. RP Hermanstyne, KA (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave,Box 0984, San Francisco, CA 94143 USA. EM keith.hermanstyne@ucsf.edu FU National Institutes of Mental Health [54907, K-24 87227] FX We thank the National Institutes of Mental Health for funding provided by the National Institutes of Mental Health Grant 54907 and additional support received by David R. Bangsberg from the National Institutes of Mental Health Grant K-24 87227. NR 55 TC 5 Z9 5 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-3842 J9 J PUBLIC HEALTH-UK JI J. Public Health PD AUG PY 2012 VL 34 IS 3 BP 330 EP 339 DI 10.1093/pubmed/fds018 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 006XX UT WOS:000308854200006 PM 22451327 ER PT J AU Sevick, MA Korytkowski, M Stone, RA Piraino, B Ren, DX Sereika, S Wang, YY Steenkiste, A Burke, LE AF Sevick, Mary Ann Korytkowski, Mary Stone, Roslyn A. Piraino, Beth Ren, Dianxu Sereika, Susan Wang, Yuanyuan Steenkiste, Ann Burke, Lora E. TI Biophysiologic Outcomes of the Enhancing Adherence in Type 2 Diabetes (ENHANCE) Trial SO JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS LA English DT Article DE Diabetes mellitus, type 2; Chronic kidney disease; Computers, hand-held; Personal digital assistant; Randomized clinical trial ID GLOMERULAR-FILTRATION-RATE; GLYCEMIC CONTROL; GLUCOSE; METAANALYSIS AB Background Behavioral research to improve lifestyle in broadly defined populations of patients with type 2 diabetes is limited. Objective We evaluated a behavioral intervention featuring technology-based self-monitoring on biophysiologic outcomes of glycemic control and markers of cardiovascular risk Design In this single-site, randomized clinical trial, participants were stratified by good and poor glycemic control (glycated hemoglobin <8% or >= 8%) and absence or presence of kidney disease, (estimated glomerular filtration rate >= 60 or <60 mL/min) and randomized within strata. Measurements were obtained at 0, 3, and 6 months. Participants/setting Self-referred, community-dwelling adults with type 2 diabetes mellitus. Intervention The intervention group received Social Cognitive Theory-based counseling paired with technology-based self-monitoring, and results were compared with an attention control group. Main outcome measures Glycated hemoglobin, fasting serum glucose, lipid levels, blood pressure, weight, body mass index, and waist circumference were evaluated. Statistical analyses performed Mean differences within and between randomization groups were compared over time. Intervention effects over time were estimated using random intercept models. Results Two hundred ninety-six subjects were randomized, 256(86.5%) completed 3-month and 246 (83.1%) completed 6-month assessments. Glycated hemoglobin was reduced in the intervention group by 0.5% at 3 months and 0.6% at 6 months (P<0.001 for each), and the control group by 0.3% (P<0.001) at 3 months and 0.2% (P<0.05) at 6 months; but between-group differences were not significant. In those with baseline glycated hemoglobin >= 8% and estimated glomerular filtration rate >= 60 mL/min, glycated hemoglobin was reduced in the intervention group by 1.5% at 3 months and 1.8% at 6 months (P<0.001 for each), and the control group by 0.9% (P<0.001) at 3 months and 0.8% (P<0.05) at 6 months; but between-group differences were not significant. In random intercept models, the estimated reduction in glycated hemoglobin of 0.29% was not significant. Conclusions Two behavioral approaches to improving general lifestyle management in individuals with type 2 diabetes mellitus were effective in improving glycemic control, but no significant between-group differences were observed. J Acad Nutr Diet. 2012;112:1147-1157. C1 [Sevick, Mary Ann] VA Pittsburgh Healthcare Syst, Ctr Res & Promot, Pittsburgh, PA 15213 USA. [Sevick, Mary Ann] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, Pittsburgh, PA 15213 USA. [Sevick, Mary Ann; Korytkowski, Mary] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. [Stone, Roslyn A.; Burke, Lora E.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Ren, Dianxu; Burke, Lora E.] Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15213 USA. [Wang, Yuanyuan] INC Res, Philadelphia, PA USA. [Steenkiste, Ann] Vet Res Fdn Pittsburgh, Pittsburgh, PA USA. RP Sevick, MA (reprint author), VA Pittsburgh Healthcare Syst, Ctr Res & Promot, Suite 600,230 McKee Pl, Pittsburgh, PA 15213 USA. EM sevick@pitt.edu OI Piraino, Beth/0000-0001-5061-0841 FU National Institutes of Health; National Institutes of Health/National Institute of Nursing Research [NR-R01008792]; National Institutes of Health/National Center for Research Resources [CTSA-UL1-RR024153, GCRC-M01-RR000056] FX M. Korytkowski serves as a consultant to Eli Lilly and Company, and also serves as a grant reviewer to Pfizer, Inc. M. A. Sevick and L. E. Burke have received grants from the National Institutes of Health to carry out separate protocols involving self-management interventions involving PDA-based self-monitoring. None of the other authors reported any financial conflicts of interest.; This work was supported by the following grants: National Institutes of Health/National Institute of Nursing Research no. NR-R01008792, National Institutes of Health/National Center for Research Resources no. CTSA-UL1-RR024153, and National Institutes of Health/National Center for Research Resources no. GCRC-M01-RR000056. Clinical trials.gov identifier: NCT00222846. The sponsors initially approved the study concept and protocol, required regular updates regarding protocol accrual and data safety and monitoring, and provided funds to the participating organization. The sponsor did not have any role in the analysis or interpretation of data or in the preparation, review, or approval of the manuscript. NR 21 TC 9 Z9 9 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 2212-2672 J9 J ACAD NUTR DIET JI J. Acad. Nutr. Diet. PD AUG PY 2012 VL 112 IS 8 BP 1147 EP 1157 DI 10.1016/j.jand.2012.05.008 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 986CJ UT WOS:000307318100006 PM 22818724 ER PT J AU Ma, XZ Singh, A Fay, J Boland, G Sahani, DV AF Ma, Xiaozhou Singh, Anand Fay, Joseph Boland, Giles Sahani, Dushyant V. TI Comparison of Dual-Syringe and Syringeless Power Injectors in Outpatient MDCT Practice: Impact on the Operator's Performance, CT Workflow, and Operation Cost SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE CT; dual-syringe power injector; syringeless power injector; contrast media; outpatient; workflow ID COMPUTED-TOMOGRAPHY; UNITED-STATES; TRENDS; EXTRAVASATION; WORKLOAD AB Purpose: The purpose of this study was to compare enhancement quality, performance efficiency, technologists' satisfaction, and operation costs between 2 different power injectors (Pis) in an outpatient setting. Methods: In this prospective study, 275 consecutive outpatients (135 men, 140 women) scheduled for contrast-enhanced CT (CECT) were randomized and scanned using either of 2 multidetector CT scanners (16 adjacently placed detectors) fitted with a dual-syringe contrast injector or a syringeless contrast injector. The corresponding CECT studies were subjectively reviewed by 2 radiologists in consensus to rate the quality of contrast enhancement in each study. The equipment preparation time (contrast media [CM], saline loading), releasing time (unloading of saline and CM), and CM wastage incurred for each PI were recorded by one operator. Technologists' satisfaction with the use of the PIs was rated on a 10-point scale. Statistical analyses were performed using Student's t tests. Results: A total of 140 patients were examined using the dual-syringe system, and 135 with the syringeless system, and CECT examination quality was comparable for both PI systems (P>.05). Equipment preparation time and releasing time per examination for dual-syringe and syringeless PIs were 139 +/- 39 and 32 +/- 14 seconds and 48 +/- 31 and 8 +/- 3 seconds, respectively (P <.00]). On average, 11 mL CM wastage per examination was observed with the dual-syringe PI and 0 mL with the syringeless PI (P < .001). Technologists had higher satisfaction with the syringeless PI than the dual-syringe system (9.3 vs 6.3, P < .01). Because of improved efficiency, 2.6 additional patients per day were examined in the room using the syringeless PI. Conclusion: Given comparable CECT examination quality, the syringeless PI was more user-friendly and improved outpatient CT workflow and CT throughput while allowing 11-mL CM saving per examination compared with the dual-syringe injector. C1 [Ma, Xiaozhou; Singh, Anand; Fay, Joseph; Boland, Giles; Sahani, Dushyant V.] Harvard Univ, Sch Med,Massachusetts Gen Hosp Imaging, Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Harvard Univ, Sch Med,Massachusetts Gen Hosp Imaging, Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 20 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD AUG PY 2012 VL 9 IS 8 BP 578 EP 582 DI 10.1016/j.jacr.2012.04.007 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 988XY UT WOS:000307526000015 PM 22863467 ER PT J AU Moonis, G Cunnane, MB Emerick, K Curtin, H AF Moonis, Gul Cunnane, Mary Beth Emerick, Kevin Curtin, Hugh TI Patterns of Perineural Tumor Spread in Head and Neck Cancer SO MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA LA English DT Article DE Perineural tumor spread; Trigeminal nerve; Facial nerve; Adenoid cystic carcinoma; Skin cancer metastases ID NERVE; EXTENSION; ANATOMY AB Perineural tumor spread (PNS) is a mode of neoplastic spread whereby tumor cells use neural conduits to escape the borders of a primary tumor. MRI is generally favored over CT for evaluating PNS, and findings include obliteration of fat within skull base foramina, enlargement and enhancement of the involved nerves, and enlargement and destruction of the bony foramina. Careful examination of the entire course of the nerve allows detection of skip lesions. Recognition of the complete extent of PNS is crucial for correct treatment because it facilitates both surgical and radiotherapy targeting of entire extent of disease. C1 [Moonis, Gul] Massachusetts Eye & Ear Infirm, Dept Radiol, Beth Israel Deaconess Med Ctr, Boston, MA 02114 USA. [Moonis, Gul] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Emerick, Kevin] Massachusetts Eye & Ear Infirm, Dept Otorhinolaryngol, Boston, MA 02114 USA. RP Moonis, G (reprint author), Massachusetts Eye & Ear Infirm, Dept Radiol, Beth Israel Deaconess Med Ctr, Boston, MA 02114 USA. EM gmoonis@bidmc.harvard.edu NR 15 TC 9 Z9 9 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1064-9689 J9 MAGN RESON IMAGING C JI Magn. Reson. Imaging Clin. N. Am. PD AUG PY 2012 VL 20 IS 3 BP 435 EP + DI 10.1016/j.mric.2012.05.006 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 010FL UT WOS:000309080000004 PM 22877950 ER PT J AU Lim, E Metzger, O Winer, EP AF Lim, Elgene Metzger-Filho, Otto Winer, Eric P. TI The Natural History of Hormone Receptor-Positive Breast Cancer SO ONCOLOGY-NEW YORK LA English DT Article ID INTERNATIONAL EXPERT CONSENSUS; ESTROGEN-RECEPTOR; ADJUVANT TREATMENT; PRIMARY THERAPY; RANDOMIZED-TRIALS; ENDOCRINE THERAPY; GENE-EXPRESSION; CLINICAL-TRIALS; TUMOR-CELLS; BONE-MARROW AB Approximately 70% of human breast tumors express hormone receptors (HRs), comprising the estrogen receptor (ER) and/or progesterone receptor (PR). The ER is the primary transcription factor driving oncogenesis in HR-positive (HR+) breast cancers; it is both a target of, and predictor of response to, antiestrogen therapy. Unlike in other breast cancer subtypes, more than half of all disease recurrences in HR+ breast cancer occur 6 years or more after diagnosis, particularly following 5 years of adjuvant anti-estrogen therapy. Late relapses in HR+ breast cancer thus represent a significant clinical challenge. There is considerable molecular and clinical heterogeneity underlying HR+ breast cancers, and a limited understanding of the mechanisms underlying treatment resistance and late relapse. In this review, we describe the long natural history of HR+ breast cancer and discuss relapse patterns in relation to their clinicopathological and molecular characteristics. We highlight the relationship between tumor relapse and anti-estrogen therapy resistance, and we describe the concept of tumor dormancy. Finally, we review novel translational research strategies utilizing preclinical models and patient tumor samples, and current clinical strategies that address this increasingly common challenge in breast cancer. C1 [Lim, Elgene; Metzger-Filho, Otto; Winer, Eric P.] Dana Farber Canc Inst, Div Womens Canc, Boston, MA 02115 USA. RP Lim, E (reprint author), Dana Farber Canc Inst, Div Womens Canc, Boston, MA 02115 USA. NR 51 TC 36 Z9 38 U1 1 U2 12 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 AUG PY 2012 VL 26 IS 8 BP 688 EP + PG 8 WC Oncology SC Oncology GA 994EO UT WOS:000307913900001 PM 22957400 ER PT J AU Duda, DG Willett, CG AF Duda, Dan G. Willett, Christopher G. TI Going Beyond Systemic Fluoropyrimidines With Radiation Therapy for Rectal Cancer: What Should Be the Priority? SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID TOTAL MESORECTAL EXCISION; PREOPERATIVE RADIOTHERAPY; PHASE-II; CHEMORADIATION; BEVACIZUMAB; CETUXIMAB C1 [Duda, Dan G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Willett, Christopher G.] Duke Univ, Med Ctr, Div Radiat Oncol, Durham, NC 27710 USA. RP Duda, DG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. FU NCI NIH HHS [P01 CA080124, R01-CA159258, P01-CA080124, R01 CA159258] NR 22 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 AUG PY 2012 VL 26 IS 8 BP 741 EP 743 PG 3 WC Oncology SC Oncology GA 994EO UT WOS:000307913900008 PM 22957407 ER PT J AU Berry, DL Wang, Q Halpenny, B Hong, FX AF Berry, Donna L. Wang, Qian Halpenny, Barbara Hong, Fangxin TI Decision preparation, satisfaction and regret in a multi-center sample of men with newly diagnosed localized prostate cancer SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE Prostate cancer; Randomized trial; Internet; Decision making ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; VALIDATION; SURVIVORS; CHOICE; SCALE; AID AB Objective: To describe relationships between use of the Personal Patient Profile-Prostate (P3P) decision support system and patient characteristics, and perceived preparation for decision making (PrepDM), satisfaction and decisional regret in the context of prostate cancer treatment choice. Methods: 494 men with localized prostate cancer (LPC) were randomized to receive the P3P intervention or usual care and completed pre-treatment, 1-month and 6-month outcome measures. Multivariable linear regression models were fit for each outcome. Results: Physician consult visits prior to enrollment, race/ethnicity, and use of clinic-provided books were significant predictors of perceived PrepDM at 1 month. Prior Internet use and PrepDM significantly predicted 6-month decision satisfaction. Decisional regret was significantly predicted by demographics, anxiety, PrepDM score, and EPIC bowel domain score at 6 months. Use of P3P did not predict any outcome. Conclusion: While the P3P intervention did not significantly affect the outcomes, pre-enrollment information and preparation were strong predictors of the 1- and 6-month outcomes. Decision regret was significantly influenced by personal characteristics and post-treatment symptoms/side effects. Practice implications: Information received and used between biopsy and the treatment options consult visit is likely to make a difference in decision satisfaction. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Berry, Donna L.; Halpenny, Barbara] Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, Boston, MA 02215 USA. [Berry, Donna L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wang, Qian; Hong, Fangxin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Berry, DL (reprint author), Dana Farber Canc Inst, Phyllis F Cantor Ctr Res Nursing & Patient Care S, 450 Brookline Ave,LW-518, Boston, MA 02215 USA. EM donna_berry@dfci.harvard.edu FU National Institutes of Health, National Institute of Nursing Research [R01NR009692] FX This work was funded by National Institutes of Health, National Institute of Nursing Research, R01NR009692. NR 31 TC 18 Z9 18 U1 4 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD AUG PY 2012 VL 88 IS 2 BP 262 EP 267 DI 10.1016/j.pec.2012.04.002 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 994EW UT WOS:000307914700016 PM 22608696 ER PT J AU Nicolay, BN Dyson, NJ AF Nicolay, Brandon N. Dyson, Nicholas J. TI It's All in the Timing: Too Much E2F Is a Bad SO PLOS GENETICS LA English DT Editorial Material ID S-PHASE; DNA-DAMAGE; CHECKPOINT; EXPRESSION; APOPTOSIS C1 [Nicolay, Brandon N.; Dyson, Nicholas J.] Massachusetts Gen Hosp, Canc Res Ctr, Charlestown, MA 02129 USA. RP Nicolay, BN (reprint author), Massachusetts Gen Hosp, Canc Res Ctr, Charlestown, MA 02129 USA. EM DYSON@helix.mgh.harvard.edu FU NCI NIH HHS [R01 CA064402, F32 CA165856, CA64402, CA155202] NR 10 TC 0 Z9 0 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2012 VL 8 IS 8 AR e1002909 DI 10.1371/journal.pgen.1002909 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 002JX UT WOS:000308529300061 PM 22916039 ER PT J AU Pollin, TI Isakova, T Jablonski, KA de Bakker, PIW Taylor, A McAteer, J Pan, Q Horton, ES Delahanty, LM Altshuler, D Shuldiner, AR Goldberg, RB Florez, JC Franks, PW AF Pollin, Toni I. Isakova, Tamara Jablonski, Kathleen A. de Bakker, Paul I. W. Taylor, Andrew McAteer, Jarred Pan, Qing Horton, Edward S. Delahanty, Linda M. Altshuler, David Shuldiner, Alan R. Goldberg, Ronald B. Florez, Jose C. Franks, Paul W. CA Diabet Prevention Program Res Grp TI Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program SO PLOS GENETICS LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; DENSITY-LIPOPROTEIN CHOLESTEROL; GENOME-WIDE ASSOCIATION; HEPATIC LIPASE GENE; CONFIDENCE-INTERVALS; POWER CALCULATIONS; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; CORONARY EVENTS; COMMON VARIANTS AB Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1x10(-17)). Except for total HDL particles (r = -0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07-0.17, P=5x10(-5)-1x10(-19)). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (beta = +0.87, SEE +/- 0.22 mg/dl/allele, P=8x10(-5), P-interaction = 0.02) in the lifestyle intervention group, but not in the placebo (beta = +0.20, SEE +/- 0.22 mg/dl/allele, P = 0.35) or metformin (beta = -0.03, SEE +/- 0.22 mg/dl/allele, P = 0.90; P-interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (beta = +0.30, SEE +/- 0.012 ln nmol/L/allele, P = 0.01, P-interaction = 0.01) but not in the placebo (beta = 20.002, SEE +/- 0.008 ln nmol/L/allele, P = 0.74) or metformin (beta = +0.013, SEE +/- 0.008 nmol/L/allele, P = 0.12; P-interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss. C1 [Pollin, Toni I.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Pollin, Toni I.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Genet & Genom Med, Baltimore, MD 21201 USA. [Isakova, Tamara] Univ Miami, Dept Med, Leonard M Miller Sch Med, Div Nephrol & Hypertens, Miami, FL USA. [Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [de Bakker, Paul I. W.; Taylor, Andrew; McAteer, Jarred; Altshuler, David; Florez, Jose C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.; Altshuler, David] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr Utrecht, Dept Epidemiol, Utrecht, Netherlands. [Taylor, Andrew; McAteer, Jarred; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Horton, Edward S.; Delahanty, Linda M.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Horton, Edward S.; Delahanty, Linda M.; Altshuler, David; Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Delahanty, Linda M.] Massachusetts Gen Hosp, Diabet Clin, Boston, MA 02114 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Goldberg, Ronald B.] Univ Miami, Leonard M Miller Sch Med, Div Endocrinol Diabet & Metab, Lipid Disorders Clin, Miami, FL USA. [Goldberg, Ronald B.] Univ Miami, Diabet Res Inst, Leonard M Miller Sch Med, Miami, FL USA. [Franks, Paul W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, Paul W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Pollin, TI (reprint author), Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. EM paul.franks@med.lu.se RI Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Uwaifo, Gabriel/M-2361-2016; OI Altshuler, David/0000-0002-7250-4107; Kahn, Steven/0000-0001-7307-9002; de Bakker, Paul/0000-0001-7735-7858; Uwaifo, Gabriel/0000-0002-6962-9304; Allison, David/0000-0003-3566-9399; Kriska, Andrea/0000-0002-3522-0869; orchard, trevor/0000-0001-9552-3215; Shamoon, Harry/0000-0002-5014-5211; Franks, Paul/0000-0002-0520-7604; Lachin, John/0000-0001-9838-2841 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health; NIDDK; Indian Health Service; Office of Research on Minority Health; National Institute of Child Health and Human Development; National Institute on Aging; Centers for Disease Control and Prevention; Office of Research on Women's Health; American Diabetes Association; Doris Duke Charitable Foundation; NIH [K23DK087858]; Physician Scientist Development Award by the Massachusetts General Hospital; Swedish Research Council; Swedish Heart-Lung Foundation; Pahlssons Foundation; Novo Nordisk Foundation; NIH; Pfizer; Bristol Myers Squibb; GSK; Roche; [R01 DK072041] FX The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan, Health O Meter, Hoechst Marion Roussel, Merck-Medco Managed Care, Merck, Nike Sports Marketing, Slim Fast Foods, and Quaker Oats donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices, Matthews Media Group, and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of centers, investigators, and staff is shown in the Acknowledgments. Genetics research in the DPP and the work reported in this manuscript was supported in part by R01 DK072041 to DA, JCF, KAJ, TIP, and ARS (PWF was an unpaid co-investigator) and by a Doris Duke Charitable Foundation Distinguished Scientist Clinical Award to DA. TI was supported by NIH grant K23DK087858. JCF is supported by a Physician Scientist Development Award by the Massachusetts General Hospital and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. PWF was supported by the Swedish Research Council, Swedish Heart-Lung Foundation, Pahlssons Foundation, and Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; TIP has been a consultant for Isis Pharmaceuticals. TI has received a research grant from NIDDK and honoraria from Shire and Genzyme and has been a consultant for Shire. KAJ (the DPP Genetics Program) has a research grant from NIH. DA has received a research grant from Pfizer and honoraria from academic non-profit (e. g. talks) and has been a consultant for Eisai, MPM Capital, and NanoString. ARS has a NIH research grant. RBG has a research grant from NIH for this study; speaker honoraria from Merck; other research support from Bristol Myers Squibb, GSK, and Roche; and small consultant activities. JCF has received consulting honoraria from Daiichi-Sankyo and AstraZeneca. PWF has received speaking honoraria from Novo Nordisk and other academic/non-profit organisations. NR 46 TC 17 Z9 17 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2012 VL 8 IS 8 AR e1002895 DI 10.1371/journal.pgen.1002895 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 002JX UT WOS:000308529300051 PM 22951888 ER PT J AU Sorrells, S Carbonneau, S Harrington, E Chen, AT Hast, B Milash, B Pyati, U Major, MB Zhou, Y Zon, LI Stewart, RA Look, AT Jette, C AF Sorrells, Shelly Carbonneau, Seth Harrington, Erik Chen, Aye T. Hast, Bridgid Milash, Brett Pyati, Ujwal Major, Michael B. Zhou, Yi Zon, Leonard I. Stewart, Rodney A. Look, A. Thomas Jette, Cicely TI Ccdc94 Protects Cells from Ionizing Radiation by Inhibiting the Expression of p53 SO PLOS GENETICS LA English DT Article ID DNA-DAMAGE RESPONSE; BCL-2 FAMILY-MEMBERS; SACCHAROMYCES-CEREVISIAE; ATAXIA-TELANGIECTASIA; NEXT-GENERATION; DANIO-RERIO; ZEBRAFISH; APOPTOSIS; REPAIR; PSO4 AB DNA double-strand breaks (DSBs) represent one of the most deleterious forms of DNA damage to a cell. In cancer therapy, induction of cell death by DNA DSBs by ionizing radiation (IR) and certain chemotherapies is thought to mediate the successful elimination of cancer cells. However, cancer cells often evolve to evade the cytotoxicity induced by DNA DSBs, thereby forming the basis for treatment resistance. As such, a better understanding of the DSB DNA damage response (DSB-DDR) pathway will facilitate the design of more effective strategies to overcome chemo-and radioresistance. To identify novel mechanisms that protect cells from the cytotoxic effects of DNA DSBs, we performed a forward genetic screen in zebrafish for recessive mutations that enhance the IR-induced apoptotic response. Here, we describe radiosensitizing mutation 7 (rs7), which causes a severe sensitivity of zebrafish embryonic neurons to IR-induced apoptosis and is required for the proper development of the central nervous system. The rs7 mutation disrupts the coding sequence of ccdc94, a highly conserved gene that has no previous links to the DSB-DDR pathway. We demonstrate that Ccdc94 is a functional member of the Prp19 complex and that genetic knockdown of core members of this complex causes increased sensitivity to IR-induced apoptosis. We further show that Ccdc94 and the Prp19 complex protect cells from IR-induced apoptosis by repressing the expression of p53 mRNA. In summary, we have identified a new gene regulating a dosage-sensitive response to DNA DSBs during embryonic development. Future studies in human cancer cells will determine whether pharmacological inactivation of CCDC94 reduces the threshold of the cancer cell apoptotic response. C1 [Sorrells, Shelly; Harrington, Erik; Hast, Bridgid; Stewart, Rodney A.; Jette, Cicely] Univ Utah, Dept Oncol Sci, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Carbonneau, Seth; Pyati, Ujwal; Look, A. Thomas] Harvard Univ, Sch Med, Boston, MA USA. [Carbonneau, Seth; Pyati, Ujwal; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Chen, Aye T.; Zon, Leonard I.] Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. [Hast, Bridgid; Major, Michael B.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. RP Sorrells, S (reprint author), Univ Utah, Dept Oncol Sci, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. EM Thomas_Look@dfci.harvard.edu; Cicely.Jette@hci.utah.edu OI Major, Michael/0000-0002-6753-8513; Stewart, Rodney/0000-0003-1220-1830 FU NIH [NIH K01 DK074555, NIH 3R01CA119066]; Huntsman Cancer Institute/Huntsman Cancer Foundation; [P30 CA042014]; [NS058608] FX Support for this work was provided by NIH grant NIH K01 DK074555 (CJ), the Huntsman Cancer Institute/Huntsman Cancer Foundation (CJ, RAS, SS, EH), P30 CA042014 (BM), NIH 3R01CA119066 (ATL, UP, SC), and NS058608 (RAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 11 Z9 13 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2012 VL 8 IS 8 AR e1002922 DI 10.1371/journal.pgen.1002922 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 002JX UT WOS:000308529300071 PM 22952453 ER PT J AU Tanwar, PS Kaneko-Tarui, T Zhang, LH Tanaka, Y Crum, CP Teixeira, JM AF Tanwar, Pradeep S. Kaneko-Tarui, Tomoko Zhang, Lihua Tanaka, Yoshihiro Crum, Christopher P. Teixeira, Jose M. TI Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1 SO PLOS GENETICS LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; FEMALE REPRODUCTIVE-TRACT; BASEMENT-MEMBRANE COMPONENTS; OF-THE-LITERATURE; TUMOR-SUPPRESSOR; TUBEROUS SCLEROSIS; BETA-CATENIN; CONDITIONAL DELETION; ANNULAR TUBULES; SOMATIC-CELLS AB Germline mutations of the Liver Kinase b1 (LKB1/STK11) tumor suppressor gene have been linked to Peutz-Jeghers Syndrome (PJS), an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. We have conditionally deleted Lkb1 in Mullerian duct mesenchyme-derived cells of the female reproductive tract and observed expansion of the stromal compartment and hyperplasia and/or neoplasia of adjacent epithelial cells throughout the reproductive tract with paratubal cysts and adenomyomas in oviducts and, eventually, endometrial cancer. Examination of the proliferation marker phospho-histone H3 and mammalian Target Of Rapamycin Complex 1 (mTORC1) pathway members revealed increased proliferation and mTORC1 activation in stromal cells of both the oviduct and uterus. Treatment with rapamycin, an inhibitor of mTORC1 activity, decreased tumor burden in adult Lkb1 mutant mice. Deletion of the genes for Tuberous Sclerosis 1 (Tsc1) or Tsc2, regulators of mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1-deleted stroma contributes to the phenotype. Loss of PTEN, an upstream regulator of mTORC1 signaling, along with Lkb1 deletion significantly increased tumor burden in uteri and induced tumorigenesis in the cervix and vagina. These studies show that LKB1/TSC1/TSC2/mTORC1 signaling in mesenchymal cells is important for the maintenance of epithelial integrity and suppression of carcinogenesis in adjacent epithelial cells. Because similar changes in the stromal population are also observed in human oviductal/ovarian adenoma and endometrial adenocarcinoma patients, we predict that dysregulated mTORC1 activity by upstream mechanisms similar to those described in these model systems contributes to the pathogenesis of these human diseases. C1 [Tanwar, Pradeep S.; Kaneko-Tarui, Tomoko; Zhang, Lihua; Tanaka, Yoshihiro; Teixeira, Jose M.] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Tanwar, Pradeep S.] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW 2308, Australia. [Crum, Christopher P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Womens & Perinatal Pathol, Boston, MA 02115 USA. RP Tanwar, PS (reprint author), Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU NICHD [HD052701]; Vincent Memorial Research Funds FX This work was supported by funding from NICHD (HD052701) and by Vincent Memorial Research Funds to JMT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 20 Z9 21 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2012 VL 8 IS 8 AR e1002906 DI 10.1371/journal.pgen.1002906 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 002JX UT WOS:000308529300058 PM 22916036 ER PT J AU Voight, BF Kang, HM Ding, J Palmer, CD Sidore, C Chines, PS Burtt, NP Fuchsberger, C Li, YM Erdmann, J Frayling, TM Heid, IM Jackson, AU Johnson, T Kilpelainen, TO Lindgren, CM Morris, AP Prokopenko, I Randall, JC Saxena, R Soranzo, N Speliotes, EK Teslovich, TM Wheeler, E Maguire, J Parkin, M Potter, S Rayner, NW Robertson, N Stirrups, K Winckler, W Sanna, S Mulas, A Nagaraja, R Cucca, F Barroso, I Deloukas, P Loos, RJF Kathiresan, S Munroe, PB Newton-Cheh, C Pfeufer, A Samani, NJ Schunkert, H Hirschhorn, JN Altshuler, D McCarthy, MI Abecasis, GR Boehnke, M AF Voight, Benjamin F. Kang, Hyun Min Ding, Jun Palmer, Cameron D. Sidore, Carlo Chines, Peter S. Burtt, Noel P. Fuchsberger, Christian Li, Yanming Erdmann, Jeanette Frayling, Timothy M. Heid, Iris M. Jackson, Anne U. Johnson, Toby Kilpelaeinen, Tuomas O. Lindgren, Cecilia M. Morris, Andrew P. Prokopenko, Inga Randall, Joshua C. Saxena, Richa Soranzo, Nicole Speliotes, Elizabeth K. Teslovich, Tanya M. Wheeler, Eleanor Maguire, Jared Parkin, Melissa Potter, Simon Rayner, N. William Robertson, Neil Stirrups, Kathleen Winckler, Wendy Sanna, Serena Mulas, Antonella Nagaraja, Ramaiah Cucca, Francesco Barroso, Ines Deloukas, Panos Loos, Ruth J. F. Kathiresan, Sekar Munroe, Patricia B. Newton-Cheh, Christopher Pfeufer, Arne Samani, Nilesh J. Schunkert, Heribert Hirschhorn, Joel N. Altshuler, David McCarthy, Mark I. Abecasis, Goncalo R. Boehnke, Michael TI The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; QT INTERVAL DURATION; COMMON VARIANTS; SUSCEPTIBILITY LOCI; HAPLOTYPE MAP; IDENTIFIES 13; HUMAN HEIGHT; RISK; METAANALYSIS AB Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits. C1 [Speliotes, Elizabeth K.; Maguire, Jared; Parkin, Melissa; Winckler, Wendy; Kathiresan, Sekar; Newton-Cheh, Christopher; Hirschhorn, Joel N.; Altshuler, David] Broad Inst Harvard, Cambridge, MA 02142 USA. [Speliotes, Elizabeth K.; Maguire, Jared; Parkin, Melissa; Winckler, Wendy; Kathiresan, Sekar; Newton-Cheh, Christopher; Hirschhorn, Joel N.; Altshuler, David] MIT, Cambridge, MA 02139 USA. [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Kang, Hyun Min; Sidore, Carlo; Fuchsberger, Christian; Li, Yanming; Jackson, Anne U.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Ding, Jun; Nagaraja, Ramaiah] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Palmer, Cameron D.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Sidore, Carlo; Sanna, Serena; Cucca, Francesco] CNR, Ist Ric Genet & Biomed, Monserrato, Italy. [Sidore, Carlo; Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Chines, Peter S.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Nord Ctr Cardiovasc Res, D-23538 Lubeck, Germany. [Frayling, Timothy M.] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England. [Heid, Iris M.] Univ Hosp Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Heid, Iris M.] Inst Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Johnson, Toby; Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med, London, England. [Kilpelaeinen, Tuomas O.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Lindgren, Cecilia M.; Morris, Andrew P.; Prokopenko, Inga; Randall, Joshua C.; Rayner, N. William; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Prokopenko, Inga; Rayner, N. William; Robertson, Neil; McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Saxena, Richa; Kathiresan, Sekar; Newton-Cheh, Christopher; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, Richa] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Soranzo, Nicole; Wheeler, Eleanor; Potter, Simon; Rayner, N. William; Stirrups, Kathleen; Barroso, Ines; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Barroso, Ines] Univ Cambridge, Metab Res Labs, Addenbrookes Hosp, Inst Metab Sci, Cambridge, England. [Kathiresan, Sekar; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar; Newton-Cheh, Christopher; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Pfeufer, Arne] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne] Deutsch Forsch Zentrum Gesundheit & Umwelt, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Pfeufer, Arne] EURAC Ctr Biomed, Bolzano, Italy. [Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Coronary Artery Di, Leicester, Leics, England. [Hirschhorn, Joel N.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. RP Voight, BF (reprint author), Broad Inst Harvard, Cambridge, MA 02142 USA. EM altshuler@molbio.mgh.harvard.edu; mark.mccarthy@drl.ox.ac.uk; goncalo@umich.edu; boehnke@umich.edu RI Erdmann, Jeanette/P-7513-2014; Deloukas, Panos/B-2922-2013; Pfeufer, Arne/B-6634-2013; Ding, Jun/G-3918-2011; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Prokopenko, Inga/H-3241-2014; OI Erdmann, Jeanette/0000-0002-4486-6231; Soranzo, Nicole/0000-0003-1095-3852; Wheeler, Eleanor/0000-0002-8616-6444; Deloukas, Panos/0000-0001-9251-070X; sanna, serena/0000-0002-3768-1749; Fuchsberger, Christian/0000-0002-5918-8947; Johnson, Toby/0000-0002-5998-3270; Altshuler, David/0000-0002-7250-4107; Prokopenko, Inga/0000-0003-1624-7457; Mulas, Antonella/0000-0002-6856-1483; Sidore, Carlo/0000-0001-7504-7477; Abecasis, Goncalo/0000-0003-1509-1825 FU National Institutes of Health [HG000376, HG005214, HG005581, DK062370, NO1-AG-1-2109]; Wellcome Trust [098051]; British Heart Foundation; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease FX Support from the National Institutes of Health (HG000376, HG005214, HG005581, DK062370, NO1-AG-1-2109), the Wellcome Trust (098051), the British Heart Foundation, and the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 214 Z9 216 U1 0 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2012 VL 8 IS 8 AR e1002793 DI 10.1371/journal.pgen.1002793 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 002JX UT WOS:000308529300001 PM 22876189 ER PT J AU Vilardaga, JP Gardella, TJ Wehbi, VL Feinstein, TN AF Vilardaga, Jean-Pierre Gardella, Thomas J. Wehbi, Vanessa L. Feinstein, Timothy N. TI Non-canonical signaling of the PTH receptor SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID PARATHYROID-HORMONE RECEPTOR; BETA-ADRENERGIC-RECEPTOR; PROTEIN-KINASE-C; PTH/PTHRP RECEPTOR; LIGAND-BINDING; BETA(2)-ADRENERGIC RECEPTORS; BETA-2-ADRENERGIC RECEPTOR; POSTMENOPAUSAL WOMEN; COUPLED RECEPTORS; PEPTIDE LIGANDS AB The classical model of arrestin-mediated desensitization of cell-surface G-protein-coupled receptors (GPCRs) is thought to be universal. However, this paradigm is incompatible with recent reports that the parathyroid hormone (PTH) receptor (PTHR), a crucial GPCR for bone and mineral ion metabolism, sustains G(s) activity and continues to generate cAMP for prolonged periods after ligand washout; during these periods the receptor is observed mainly in endosomes, associated with the bound ligand, Gs and beta-arrestins. In this review we discuss possible molecular mechanisms underlying sustained signaling by the PTHR, including modes of signal generation and attenuation within endosomes, as well as the biological relevance of such non-canonical signaling. C1 [Vilardaga, Jean-Pierre; Wehbi, Vanessa L.; Feinstein, Timothy N.] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. [Gardella, Thomas J.] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Gardella, Thomas J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Vilardaga, JP (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. EM jpv@pitt.edu OI Feinstein, Timothy/0000-0002-9801-9708 FU National Institutes of Health [R01 DK087688] FX This work was supported by the National Institutes of Health (grant award R01 DK087688 to J-P.V.). NR 70 TC 26 Z9 26 U1 1 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2012 VL 33 IS 8 BP 423 EP 431 DI 10.1016/j.tips.2012.05.004 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 011EK UT WOS:000309147300003 PM 22709554 ER PT J AU Hosoya, Y Shiraishi, T Ando, S Miyazaki, M Garcia-Godoy, F AF Hosoya, Yumiko Shiraishi, Takanobu Ando, Susumu Miyazaki, Masashi Garcia-Godoy, Franklin TI Effects of polishing on surface roughness and gloss of S-PRG filled flowable resin composite SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID COLOR; SYSTEMS; SIZE; WEAR AB Purpose: To evaluate the effects of polishing on surface roughness (Ra, mu m) and gloss of different shades of a surface pre-reacted glass-ionomer (S-PRG) filled flowable resin composite. Methods: Resin disks of 15 mm diameter and 2 mm thickness and final polish with 3000-grit SiC paper (#3000), super fine cut diamond point (FG) and Super-Snap mini-disk red (SNAP) were made with Beautifil Flow Plus (shades: A2, A2O, Inc). The surface roughness and gloss were measured 1-week after curing. Data was analyzed with ANOVA and Fisher's PLSD with alpha=0.05. Results: The order of Ra differed among the composite shades. For all shades in all polishing groups, the Ra was over 0.5 mu m. For all shades, the gloss of the #3000 group was significantly higher than that of the FG and SNAP groups with no significant difference between the FG and SNAP groups except for the A2O shade. For A2O shade, the gloss of the SNAP group was significantly higher than that of the FG group. (Am J Dent 2012;25:227-230). C1 [Hosoya, Yumiko] Nagasaki Univ, Grad Sch Biomed Sci, Course Med & Dent Sci, Unit Translat Med,Dept Pediat Dent, Nagasaki 8528588, Japan. [Shiraishi, Takanobu] Nagasaki Univ, Grad Sch Biomed Sci, Course Med & Dent Sci, Unit Translat Med,Dept Dent & Biomed Mat Sci, Nagasaki 8528588, Japan. [Ando, Susumu; Miyazaki, Masashi] Nihon Univ, Sch Dent, Dept Operat Dent, Tokyo 101, Japan. [Garcia-Godoy, Franklin] Univ Tennessee, Coll Dent, Biosci Res Ctr, Memphis, TN USA. [Garcia-Godoy, Franklin] Forsyth Ctr, Cambridge, MA USA. RP Hosoya, Y (reprint author), Nagasaki Univ, Grad Sch Biomed Sci, Course Med & Dent Sci, Unit Translat Med,Dept Pediat Dent, Nagasaki 8528588, Japan. EM hosoya@nagasaki-u.ac.jp NR 21 TC 0 Z9 0 U1 0 U2 3 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 AUG PY 2012 VL 25 IS 4 BP 227 EP 230 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 005DZ UT WOS:000308732000008 PM 23082387 ER PT J AU Barata, JS Casagrande, L Pitoni, CM de Araujo, FB Garcia-Godoy, F Groismann, S AF Barata, Juliana Sarmento Casagrande, Luciano Pitoni, Carla Moreira de Araujo, Fernando Borba Garcia-Godoy, Franklin Groismann, Sonia TI Influence of gaps in adhesive restorations in the development of secondary caries lesions: An in situ evaluation SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID COMPOSITE RESTORATIONS; GLASS-IONOMER; AMALGAM RESTORATIONS; FLUORIDE; VITRO; REPLACEMENT; INHIBITION; REASONS; VIVO; AGE AB Purpose: To investigate in situ the influence of gaps in the development of secondary caries lesion in adhesive restorations. Methods: 10 volunteers utilized intra-oral appliances, containing three human dental blocks (enamel and dentin), representing the three different groups (two restored, one sound): (1) restored with resin composite using the total acid etch adhesive technique (37% H3PO4 + Single Bond + Z250); (2) restored with resin composite but without acid etching (Single Bond + Z250); (3) and sound blocks (control group). The dental blocks (n=30) were randomly positioned inside the intra-oral appliances, and covered by a porous tissue (gabardine base) to induce a cariogenic biofilm. The volunteers used the appliances 24 hours daily for a 28-day period, removing just during meals and oral hygiene. Eight times a day, a 20% sucrose solution was dripped onto the blocks. Five minutes later, the appliance was washed with distilled water and replaced in the oral environment. After the experimental period, the dental blocks were removed from the appliance and examined by visual examination to detect the presence or the absence of an active carious lesion (kappa= 0.89). Posteriorly, they were prepared for the polarized light microscopy examination, which was performed to describe enamel surface characteristics on the restored and unrestored blocks with active caries lesion (kappa= 1). Results: The visual examination demonstrated that almost all (29/30) of the blocks showed non-cavitated active caries lesion on the enamel surface. The microscopic evaluation showed non-cavitated caries lesions on enamel surfaces for all groups. In the restored blocks (with and without the total etch technique), the demineralization was first identified as an outer lesion that follows the enamel prism directions, and in some cases, reached the cavity walls. The results showed that caries lesion development adjacent to the restoration was determined by the cariogenic challenge of the oral environment, instead of the restoration adhesive quality, and the wall lesion was determined by the prism orientation, regardless of the presence of gaps. (Am J Dent 2012;25:244-248). C1 [Casagrande, Luciano] Univ Fed Rio Grande do Sul, Dept Pediat Dent, Sch Dent, BR-90035003 Porto Alegre, RS, Brazil. [Barata, Juliana Sarmento; Pitoni, Carla Moreira] Private Practice, Porto Alegre, RS, Brazil. [Garcia-Godoy, Franklin] Univ Tennessee, Ctr Hlth Sci, Coll Dent, Memphis, TN 38163 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Cambridge, MA USA. [Groismann, Sonia] Univ Fed Rio de Janeiro, Sch Dent, BR-21941 Rio De Janeiro, Brazil. RP Casagrande, L (reprint author), Univ Fed Rio Grande do Sul, Dept Pediat Dent, Sch Dent, Ramiro Barcelos 2492, BR-90035003 Porto Alegre, RS, Brazil. EM luciano.casagrande@ufrgs.br OI Araujo, Fernando/0000-0001-6471-5564 NR 30 TC 6 Z9 6 U1 1 U2 4 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 AUG PY 2012 VL 25 IS 4 BP 244 EP 248 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 005DZ UT WOS:000308732000012 PM 23082391 ER PT J AU Ryou, M Hazan, R Rahme, L Thompson, CC AF Ryou, Marvin Hazan, Ronen Rahme, Laurence Thompson, Christopher C. TI An Ex Vivo Bacteriologic Study Comparing Antiseptic Techniques for Natural Orifice Translumenal Endoscopic Surgery (NOTES) via the Gastrointestinal Tract SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Antiseptic technique; Sterility; Natural orifice translumenal endoscopic surgery; NOTES; Endoluminal surgery; Transgastric surgery; Transcolonic surgery; Transvaginal surgery; Chlorhexidine; Povidone ID FINE-NEEDLE-ASPIRATION; EUS-GUIDED FNA; POVIDONE-IODINE; PORCINE MODEL; ANTIBIOTIC-PROPHYLAXIS; COLORECTAL SURGERY; CHLORHEXIDINE; COMPLICATIONS; PREVENTION; INFECTION AB NOTES via the gastrointestinal tract raises the specter of intra-peritoneal infection. Various anti-microbial techniques have been employed in animal and human survival studies, including saline lavage, intravenous and topical antibiotics, and povidone-iodine, although there is a paucity of data regarding their general effectiveness. To assess the effectiveness of existing sterilization techniques for NOTES by quantifying and speciating colony-forming units (CFUs) before and after treatment. Ex vivo animal studies; bacteriological study. Stomachs and distal colons were harvested en bloc from ten fasted adult white pigs following euthanasia. Half received cefazolin 1 g intravenously prior to killing. Multiple tissue samples were obtained from each resected organ. Each tissue sample was then assigned to one of five treatment arms: (1) normal saline, (2) Betadine, (3) cefazolin/metronidazole suspension, (4) chlorhexidine, (5) no treatment. Fifteen samples were used per arm. After treatment, the mucosal surface of each sample was swabbed and inoculated in normal saline, followed by serial dilutions, which were then plated onto sheep's blood agar plates and incubated under aerobic and anaerobic conditions. CFUs were quantified and speciated. Median bacterial density was estimated to be 8.0 x 10(5) CFUs/ml (stomach) and 1.9 x 10(6) CFUs/ml (colon). The predominant organisms were Escherichia coli (stomach) and both E. coli and Enterococcus sp. (colon). Saline and antibiotic suspension lavages caused a 1-log reduction in stomach and colon. Betadine/chlorhexidine lavage resulted in a 4-log reduction. Intravenous antibiotics alone resulted in a 4-log reduction. Combining intravenous antibiotics and either Betadine or chlorhexidine decreased counts to the 10(1) level. By Kruskal-Wallis method, differences were statistically significant (p = 0.001). The use of intravenous antibiotics in addition to topical Betadine or chlorhexidine effectively reduced microbial burden in both gastric and colonic mucosa in this porcine model to the 10(1) level. C1 [Ryou, Marvin; Thompson, Christopher C.] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Hazan, Ronen; Rahme, Laurence] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Hazan, Ronen; Rahme, Laurence] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Thompson, CC (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. EM christopher_thompson@hms.harvard.edu FU Olympus; Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR) FX This study was supported by a grant from Olympus and the Natural Orifice Surgery Consortium for Assessment and Research (NOSCAR). The authors would also like to thank Rie Maurer for her assistance with statistical analysis. NR 34 TC 5 Z9 5 U1 1 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2012 VL 57 IS 8 BP 2130 EP 2136 DI 10.1007/s10620-012-2126-3 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 980YM UT WOS:000306930100022 PM 22447433 ER PT J AU Walensky, LD AF Walensky, Loren D. TI Interview with Loren D Walensky SO FUTURE MEDICINAL CHEMISTRY LA English DT Editorial Material C1 [Walensky, Loren D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Walensky, Loren D.] Childrens Hosp Boston, Boston, MA 02215 USA. RP Walensky, LD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Mayer Bldg,Room 664,450 Brookline Ave, Boston, MA 02215 USA. EM loren_walensky@dfci.harvard.edu NR 0 TC 1 Z9 1 U1 0 U2 7 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD AUG PY 2012 VL 4 IS 12 SI SI BP 1537 EP 1539 DI 10.4155/FMC.12.86 PG 3 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 008LV UT WOS:000308959400007 PM 22917243 ER PT J AU Brown, AK Mandelkern, MA Farahi, J Robertson, C Ghahremani, DG Sumerel, B Moallem, N London, ED AF Brown, Amira K. Mandelkern, Mark A. Farahi, Judah Robertson, Chelsea Ghahremani, Dara G. Sumerel, Brittany Moallem, Nathasha London, Edythe D. TI Sex differences in striatal dopamine D-2/D-3 receptor availability in smokers and non-smokers SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE D-2 receptors; dopamine; [F-18]fallypride; nicotine dependence; PET; sex differences ID REFERENCE TISSUE MODEL; TRANSPORTER AVAILABILITY; NICOTINE DEPENDENCE; BRAIN; REGISTRATION; F-18-FALLYPRIDE; SPECT AB In previous research, nicotine-dependent men exhibited lower putamen D-2/D-3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D-2/D-3 dopamine-receptor availability, using positron emission tomography with [F-18]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex x smoking interactions were observed in the caudate nuclei and putamen. Post-hoc t tests showed that male smokers had significantly lower D-2/D-3 dopamine-receptor availability than female smokers (-17% caudate, -21% putamen) and male non-smokers (-15% caudate, -16% putamen). Female smokers did not differ from non-smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D-2/D-3 receptor down-regulation in men but not women. C1 [London, Edythe D.] Univ Calif Los Angeles, Semel Inst Neurosci & Biobehav Sci, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90045 USA. [Brown, Amira K.; Mandelkern, Mark A.; Farahi, Judah] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mandelkern, Mark A.] UC Irvine, Dept Phys, Irvine, CA USA. [Robertson, Chelsea; London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90045 USA. [London, Edythe D.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90045 USA. RP London, ED (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Biobehav Sci, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza,Rm C8-831, Los Angeles, CA 90045 USA. EM elondon@mednet.ucla.edu FU NIH [R01 DA020726, R01 DA015179, P20 DA022539]; Marjorie Green Family Trust; UCLA FX This research was supported by NIH grants R01 DA020726, R01 DA015179 and P20 DA022539. Additional funding was provided by endowments from the Thomas P. and Katherine K. Pike Chair in Addiction Studies and the Marjorie Green Family Trust. The authors thank Dr Buyean Lee and Shruthi Chakrapani for data acquisition, Ms Julia Keighley for assisting with data organization and Dr Babak Ardekani for technical assistance with the ART image registration software library.; Dr Edythe London has tobacco-related research other than that reported here, supported by a contract between Philip Morris USA and UCLA. The authors have no other potential conflicts of interest. NR 24 TC 32 Z9 32 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD AUG PY 2012 VL 15 IS 7 BP 989 EP 994 DI 10.1017/S1461145711001957 PG 6 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 984KB UT WOS:000307187400012 PM 22243762 ER PT J AU Shera, CA Bergevin, C AF Shera, Christopher A. Bergevin, Christopher TI Obtaining reliable phase-gradient delays from otoacoustic emission data SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID BRAIN-STEM RESPONSES; STIMULUS-FREQUENCY; COHERENT REFLECTION; MIDDLE-EAR; TRAVELING-WAVES; COCHLEAR MODEL; FINE-STRUCTURE; LATENCY; CHINCHILLA; PROPAGATION AB Reflection-source otoacoustic emission phase-gradient delays are widely used to obtain noninvasive estimates of cochlear function and properties, such as the sharpness of mechanical tuning and its variation along the length of the cochlear partition. Although different data-processing strategies are known to yield different delay estimates and trends, their relative reliability has not been established. This paper uses in silico experiments to evaluate six methods for extracting delay trends from reflection-source otoacoustic emissions (OAEs). The six methods include both previously published procedures (e. g., phase smoothing, energy-weighting, data exclusion based on signal-to-noise ratio) and novel strategies (e. g., peak-picking, all-pass factorization). Although some of the methods perform well (e. g., peak-picking), others introduce substantial bias (e. g., phase smoothing) and are not recommended. In addition, since standing waves caused by multiple internal reflection can complicate the interpretation and compromise the application of OAE delays, this paper develops and evaluates two promising signal-processing strategies, the first based on time-frequency filtering using the continuous wavelet transform and the second on cepstral analysis, for separating the direct emission from its subsequent reflections. Altogether, the results help to resolve previous disagreements about the frequency dependence of human OAE delays and the sharpness of cochlear tuning while providing useful analysis methods for future studies. (C) 2012 Acoustical Society of America. [http://dx.doi.org/10.1121/1.4730916] C1 [Shera, Christopher A.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. [Bergevin, Christopher] Columbia Univ, Dept Otolaryngol Head & Neck Surg, New York, NY 10032 USA. RP Shera, CA (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. EM shera@epl.meei.harvard.edu FU NIDCD, National Institutes of Health [R01 DC003687] FX We thank Carolina Abdala, John Guinan, Radha Kalluri, Sarah Verhulst, and the anonymous reviewers for helpful comments on the manuscript. Work supported by Grant No. R01 DC003687 from the NIDCD, National Institutes of Health. NR 50 TC 17 Z9 17 U1 1 U2 3 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD AUG PY 2012 VL 132 IS 2 BP 927 EP 943 DI 10.1121/1.4730916 PG 17 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 010FD UT WOS:000309079200052 PM 22894215 ER PT J AU Gallun, FJ Diedesch, AC Beasley, R AF Gallun, Frederick J. Diedesch, Anna C. Beasley, Robertson TI Impacts of age on memory for auditory intensity SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID ATTENTIONAL BLINK; INFORMATIONAL MASKING; TEMPORAL DISCRIMINATION; VISUAL-ATTENTION; DELAYED MASKING; TONAL PATTERNS; COMPONENTS; SEQUENCES; SPEECH; IDENTIFICATION AB It is hypothesized that older listeners are more likely than younger listeners to be impaired when asked to make intensity judgments about target tones embedded in rapidly presented auditory sequences. This study examined this hypothesis by asking listeners ranging in age from 19 to 74 yr to make judgments of intensity based on narrowband noise bursts varying in frequency and intensity. In two experiments, listeners made intensity judgments of target bursts alone or embedded in sequences of bursts. In the first experiment, one of four fixed sequences was presented and had to be identified. In the second experiment, pre- or post-trial bursts acted as cues that identified the frequency of the target burst in the sequence. In both experiments, intensity discrimination thresholds for single bursts were good predictors of performance with sequences and were little affected by age. Significant negative relationships between age and accuracy were observed when single sequences had to be identified or a post-trial cue was used, but no age effects were apparent when a pre-trial cue was used. These data are interpreted as being consistent with previous suggestions that the aging process results in a decline in auditory memory capacity and/or internally generated selective attention. [http://dx.doi.org/10.1121/1.4731235] C1 [Gallun, Frederick J.; Diedesch, Anna C.; Beasley, Robertson] Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res NCRAR, Portland, OR 97239 USA. [Gallun, Frederick J.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97239 USA. RP Gallun, FJ (reprint author), Portland VA Med Ctr, VA RR&D Natl Ctr Rehabil Auditory Res NCRAR, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM Frederick.Gallun@va.gov RI Gallun, Frederick/G-3792-2012 OI Gallun, Frederick/0000-0002-4145-2199 FU Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service (VA RR&D Career Development II Award) [C4963W]; NIH/NIDCD [R03 DC08395] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service (VA RR&D Career Development II Award C4963W to F.J.G.) and by NIH/NIDCD (R03 DC08395 to F.J.G.). Facilities and equipment support was also provided by the VA RR&D National Center for Rehabilitative Auditory Research. The authors are extremely grateful to Marjorie Leek for help with the sensitivity analysis, to Stephen Fausti for guidance, to Matthew Marble, Kelly Reavis, Marc Caldwell, and Erin Connor for help with data collection, to Marilyn Dille and Julia Fitzer for discussions of design issues, and of course to our listeners. Two anonymous reviewers gave very helpful comments on previous versions of the manuscript and one of the anonymous reviewers provided an especially useful analysis of the Eguchi and Hirsh (1969) method of calculating listener sensitivity, the core insights of which are described in the Appendix. The opinions and assertions presented are private views of the authors and are not to be construed as official or as necessarily reflecting the views of the Department of Veterans Affairs. NR 40 TC 0 Z9 0 U1 0 U2 4 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD AUG PY 2012 VL 132 IS 2 BP 944 EP 956 DI 10.1121/1.4731235 PG 13 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 010FD UT WOS:000309079200053 PM 22894216 ER PT J AU Hershman, JM Valente, W Saji, M AF Hershman, Jerome M. Valente, William Saji, Motoyasu TI Leonard D. Kohn, 1935-2012 In Memoriam SO THYROID LA English DT Biographical-Item C1 [Hershman, Jerome M.] Vet Adm Greater Los Angeles Healthcare Syst, Dept Endocrinol, Los Angeles, CA USA. [Hershman, Jerome M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Valente, William] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Valente, William] Interthyr Res Fdn, Baltimore, MD USA. [Saji, Motoyasu] Ohio State Univ, Dept Internal Med, Div Endocrinol, Columbus, OH 43210 USA. RP Hershman, JM (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jhershmn@ucla.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD AUG PY 2012 VL 22 IS 8 BP 863 EP 864 DI 10.1089/thy.2012.2208.obit PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 984KK UT WOS:000307188300018 ER PT J AU Lutz, CT Quinn, LS AF Lutz, Charles T. Quinn, LeBris S. TI Sarcopenia, obesity, and natural killer cell immune senescence in aging: Altered cytokine levels as a common mechanism SO AGING-US LA English DT Review DE Skeletal muscle; adipose tissue; Sarcopenia; obesity; immunity; natural killer lymphocytes; aging ID IL-15 RECEPTOR-ALPHA; TUMOR-NECROSIS-FACTOR; HUMAN NK CELLS; ADIPOSE-TISSUE; IN-VIVO; SKELETAL-MUSCLE; GROWTH-FACTOR; TNF-ALPHA; INTERLEUKIN-15 RECEPTOR; METABOLIC SYNDROME AB Human aging is characterized by both physical and physiological frailty. A key feature of frailty, sarcopenia is the age-associated decline in skeletal muscle mass, strength, and endurance that characterize even the healthy elderly. Increases in adiposity, particularly in visceral adipose tissue, are almost universal in aging individuals and can contribute to sarcopenia and insulin resistance by increasing levels of inflammatory cytokines known collectively as adipokines. Aging also is associated with declines in adaptive and innate immunity, known as immune senescence, which are risk factors for cancer and all-cause mortality. The cytokine interleukin-15 (IL-15) is highly expressed in skeletal muscle tissue and declines in aging rodent models. IL-15 inhibits fat deposition and insulin resistance, is anabolic for skeletal muscle in certain situations, and is required for the development and survival of natural killer (NK) lymphocytes. We review the effect that adipokines and myokines have on NK cells, with special emphasis on IL-15. We posit that increased adipokine and decreased IL-15 levels during aging constitute a common mechanism for sarcopenia, obesity, and immune senescence. C1 [Lutz, Charles T.] Univ Kentucky, Dept Pathol & Lab Med, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA. [Lutz, Charles T.] Univ Kentucky, Lucille P Markey Canc Ctr, Lexington, KY 40536 USA. [Quinn, LeBris S.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Quinn, LeBris S.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Quinn, LeBris S.] Seattle Inst Biomed & Clin Res, Seattle, WA 98108 USA. RP Lutz, CT (reprint author), Univ Kentucky, Dept Pathol & Lab Med, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA. EM ctlutz2@uky.edu FU NIH [AI50656, AG040542]; National Center for Advancing Translational Sciences [UL1TR000117]; Department of Veterans Affairs [BX001026] FX Supported by NIH AI50656, AG040542, and the National Center for Advancing Translational Sciences, UL1TR000117 (CTL) and Merit Review #BX001026 from the Department of Veterans Affairs (LSQ), and use of resources and facilities at VA Puget Sound Health Care System. We thank Craig Horbinski, Michael Cibull, and Ahmad Al-Attar for help with figures and Charlotte Peterson for insightful discussions. NR 140 TC 48 Z9 52 U1 1 U2 17 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 AUG PY 2012 VL 4 IS 8 BP 535 EP 546 PG 12 WC Cell Biology SC Cell Biology GA 002ZX UT WOS:000308579000004 PM 22935594 ER PT J AU Trivedi, RB Bryson, CL Udris, E Au, DH AF Trivedi, Ranak B. Bryson, Chris L. Udris, Edmunds Au, David H. TI The Influence of Informal Caregivers on Adherence in COPD Patients SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Self-management; Chronic illness; Dyads ID SMOKING-CESSATION INTERVENTION; OBSTRUCTIVE PULMONARY-DISEASE; QUALITY-OF-LIFE; MEDICAL-TREATMENT; CLINICAL-TRIAL; UNITED-STATES; LUNG HEALTH; METAANALYSIS; MORTALITY; SUPPORT AB Background Contributions of informal caregivers to adherence among chronic obstructive pulmonary disease (COPD) patients remain understudied. Purpose This study aims to evaluate the association between caregiver presence and adherence to medical recommendations among COPD patients. Methods Three hundred and seventy-four COPD patients were asked whether they had a caregiver. Medication adherence was assessed using pharmacy refill data. Smoking status was based on patient self-report. One-way ANOVAs and chi-square analyses were performed controlling for age and number of illnesses. Results Compared with the "no caregiver" group, antihypertensive medications adherence was higher in the "spousal caregiver" (0.68 vs. 0.81; 95% CI=0.04 and 0.22) and "non-spousal caregiver" (0.68 vs. 0.80; 95% CI=0.03 and 0.22) groups; long-acting beta agonist adherence was higher in the "spousal caregiver" group (0.60 vs. 0.80; 95% CI=0.05 and 0.43). Patients in the "spousal caregiver" group had fewer current smokers compared with the "no caregiver" (chi(2)=16.08; p<0.001) and "non-spousal caregiver" (chi(2)=05.07; p<0.05) groups; those in the "non-spousal caregiver" group reported fewer smokers than the "no caregiver" group (chi(2)=4.54; p<0.05). Conclusions Caregivers, especially spouses, may improve adherence in COPD. Future interventions may target patients without caregivers to optimize COPD management. C1 [Trivedi, Ranak B.] Univ Washington, Dept Hlth Serv, Seattle, WA 98101 USA. [Trivedi, Ranak B.; Bryson, Chris L.; Udris, Edmunds; Au, David H.] VA Puget Sound Hlth Care Syst, NW Hlth Serv Res & Dev HSR&D, Ctr Excellence, Seattle, WA USA. [Bryson, Chris L.; Au, David H.] Univ Washington, Dept Med, Seattle, WA 98101 USA. RP Trivedi, RB (reprint author), Univ Washington, Dept Hlth Serv, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM ranak.trivedi@va.gov NR 29 TC 21 Z9 22 U1 1 U2 17 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 AUG PY 2012 VL 44 IS 1 BP 66 EP 72 DI 10.1007/s12160-012-9355-8 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 006MG UT WOS:000308822700010 PM 22422104 ER PT J AU Fernandez, SM Lopez-Cuenca, A Januzzi, JL Mateo-Martinez, A Sanchez-Martinez, M Parra-Pallares, S Orenes-Pinero, E Romero-Aniorte, AI Valdes-Chavarri, M Marin, F AF Manzano Fernandez, S. Lopez-Cuenca, A. Januzzi, J. L. Mateo-Martinez, A. Sanchez-Martinez, M. Parra-Pallares, S. Orenes-Pinero, E. Romero-Aniorte, A. I. Valdes-Chavarri, M. Marin, F. TI Beta-trace protein and cystatin C for the prediction of mortality in non ST segment elevation acute coronary syndromes SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Manzano Fernandez, S.; Lopez-Cuenca, A.; Mateo-Martinez, A.; Sanchez-Martinez, M.; Parra-Pallares, S.; Orenes-Pinero, E.; Romero-Aniorte, A. I.; Valdes-Chavarri, M.; Marin, F.] Univ Hosp Virgen De La Arrixaca, Murcia, Spain. [Januzzi, J. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 6 EP 6 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012400014 ER PT J AU Tawakol, A Mani, V Niesor, EJ Suchankova, G Kallend, D Fuster, V Rudd, JHF Farkouh, ME Rader, D Fayad, ZA AF Tawakol, A. Mani, V. Niesor, E. J. Suchankova, G. Kallend, D. Fuster, V. Rudd, J. H. F. Farkouh, M. E. Rader, D. Fayad, Z. A. TI Increased cholesterol efflux is associated with reductions in arterial wall area and inflammation as assessed by MR and FDG-PET imaging in humans: analysis of the dal-PLAQUE study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Tawakol, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tawakol, A.] Harvard Univ, Sch Med, Boston, MA USA. [Fuster, V.] Mt Sinai Sch Med, Cardiovasc Inst, New York, NY USA. [Niesor, E. J.; Suchankova, G.; Kallend, D.] F Hoffmann La Roche & Co Ltd, Pharma Div, CH-4002 Basel, Switzerland. [Rudd, J. H. F.] Univ Cambridge, Div Cardiovasc Med, Cambridge, England. [Farkouh, M. E.] Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Farkouh, M. E.] Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Rader, D.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. RI Mani, Venkatesh/B-8939-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 36 EP 37 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401062 ER PT J AU Piccini, JP Stevens, S Patel, MP Singer, DE Breithardt, G Hankey, GJ Halperins, JL Mahaffey, KW Fox, KAA Califf, RM AF Piccini, J. P. Stevens, S. Patel, M. P. Singer, D. E. Breithardt, G. Hankey, G. J. Halperins, J. L. Mahaffey, K. W. Fox, K. A. A. Califf, R. M. CA ROCKET AF Executive Comm TI Independent predictors of mortality in patients with non-valvular atrial fibrillation: results from ROCKET AF SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Piccini, J. P.; Stevens, S.; Patel, M. P.; Mahaffey, K. W.] Duke Univ, Duke Clin Res Inst, Med Ctr, Durham, NC 27706 USA. [Singer, D. E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Breithardt, G.] Hosp Univ Munster, Munster, Germany. [Hankey, G. J.] Univ Western Australia, Royal Perth Hosp, Perth, WA 6009, Australia. [Halperins, J. L.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Fox, K. A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Fox, K. A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Califf, R. M.] Duke Univ, Med Ctr, Duke Translat Med Inst, Durham, NC 27706 USA. RI Hankey, Graeme /H-4968-2014 OI Hankey, Graeme /0000-0002-6044-7328 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 56 EP 57 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401134 ER PT J AU Grapsa, J Afilalo, J Dawson, D Cabrita, IZ Jakaj, G Punjabi, PP Nihoyannopoulos, P AF Grapsa, J. Afilalo, J. Dawson, D. Cabrita, I. Z. Jakaj, G. Punjabi, P. P. Nihoyannopoulos, P. TI Geometrical characterization of tricuspid valve remodeling with real time 3D echocardiography in patients undergoing mitral valve surgery: translational study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Grapsa, J.; Dawson, D.; Cabrita, I. Z.; Jakaj, G.; Punjabi, P. P.; Nihoyannopoulos, P.] Hammersmith Hosp, London, England. [Afilalo, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 67 EP 68 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401177 ER PT J AU Bossone, E Korach, A Fattori, R Hughes, GC Tsai, TT Montgomery, DG Eagle, KA Nienaber, CA Isselbacher, EM Suzuki, T AF Bossone, E. Korach, A. Fattori, R. Hughes, G. C. Tsai, T. T. Montgomery, D. G. Eagle, K. A. Nienaber, C. A. Isselbacher, E. M. Suzuki, T. CA Int Registry Acute Aortic TI Racial differences in acute aortic dissection: insights from the International Registry of Acute Aortic Dissection SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Bossone, E.] Univ Hosp San Giovanni di Dio & Ruggi dAragona, Salerno, Italy. [Korach, A.] Hadassah Hebrew Univ, Med Ctr, Jerusalem, Israel. [Fattori, R.] SantOrsola Malpighi Polyclin, Bologna, Italy. [Hughes, G. C.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Tsai, T. T.] Univ Colorado Denver, Aurora, CO USA. [Montgomery, D. G.; Eagle, K. A.] Univ Michigan, Ann Arbor, MI 48109 USA. [Nienaber, C. A.] Univ Hosp Rostock, Rostock, Germany. [Isselbacher, E. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Suzuki, T.] Univ Tokyo, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 82 EP 83 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401235 ER PT J AU Achenbach, S Schuhbaeck, A Hoffmann, U Abbara, S Aulbach, P Berman, D Lell, M Daniel, WG Hamm, C Hausleiter, J AF Achenbach, S. Schuhbaeck, A. Hoffmann, U. Abbara, S. Aulbach, P. Berman, D. Lell, M. Daniel, W. G. Hamm, C. Hausleiter, J. TI Influence of heart rate on the accuracy of dual source CT for coronary stenosis detection in patients with intermediate likelihood of disease: results of the international multicenter MEDIC trial SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Achenbach, S.; Lell, M.] Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. [Schuhbaeck, A.; Daniel, W. G.; Hamm, C.] Univ Giessen, Med Clin 1, Giessen, Germany. [Hoffmann, U.; Abbara, S.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Cardiac MRI PET CT Prog, Boston, MA 02115 USA. [Aulbach, P.] Siemens Healthcare, Forchheim, Germany. [Berman, D.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Hausleiter, J.] German Heart Ctr, Clin Heart & Circulatory Dis, D-8000 Munich, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 93 EP 93 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401275 ER PT J AU Waters, DD Ho, JE Shah, SJ Demicco, DA Breazna, A AF Waters, D. D. Ho, J. E. Shah, S. J. Demicco, D. A. Breazna, A. TI Do changes in HDL-C after increasing the dose of atorvastatin have prognostic significance? SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 25-29, 2012 CL Munchen, GERMANY SP European Soc Cardiol (ESC) C1 [Waters, D. D.] San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Waters, D. D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ho, J. E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Shah, S. J.] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL 60611 USA. [Demicco, D. A.; Breazna, A.] Pfizer Inc, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2012 VL 33 SU 1 BP 134 EP 135 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 995MO UT WOS:000308012401434 ER EF