FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Morone, NE Greco, CM Rollman, BL Moore, CG Lane, B Morrow, L Glynn, NW Delaney, J Albert, SM Weiner, DK AF Morone, Natalia E. Greco, Carol M. Rollman, Bruce L. Moore, Charity G. Lane, Bridget Morrow, Lisa Glynn, Nancy W. Delaney, Jill Albert, Steven M. Weiner, Debra K. TI The design and methods of the aging successfully with pain study SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Low back pain; Older adult; Mindfulness; Meditation; Randomized clinical trial ID LOW-BACK-PAIN; LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; SELF-REPORTED DISABILITY; STRESS REDUCTION PROGRAM; MINDFULNESS MEDITATION; OLDER-ADULTS; PSYCHOMETRIC PROPERTIES; SUBSEQUENT DISABILITY; CANCER OUTPATIENTS AB Chronic low back pain (CLBP) is widespread among older adults (>= 65 years) and is often treated inadequately. With a rapidly growing aging population, CLBP will increase and so will the demand for treatment. We believe that mind-body therapies can help to meet this demand. We present the methodology of a randomized, controlled clinical trial of 300 individuals with CLBP aged 65 years or older. The specific aims are, 1) to determine the effectiveness of a mindfulness meditation program in increasing function and reducing pain among older adults with CLBP, and 2) to evaluate the impact of mindfulness meditation on neuropsychological performance in older adults with CLBP. The intervention program is modeled on the Mindfulness-Based Stress Reduction Program (MBSR) and the control is adapted from the 10 Keys (TM) to Healthy Aging. We will measure self-reported and objectively measured physical function and include a variety of measures to assess pain intensity and pain interference and psychological function. Our primary hypothesis is that the MBSR program will be more effective than the 10 Keys (TM) program in increasing function and decreasing pain. The proposed study represents the first large, well-controlled, comprehensive examination of the effects of a mind-body program on older adults with chronic pain. Published by Elsevier Inc. C1 [Morone, Natalia E.; Rollman, Bruce L.; Moore, Charity G.; Lane, Bridget; Delaney, Jill] Univ Pittsburgh, Sch Med, Div Gen Internal Med, Ctr Res Hlth Care, Pittsburgh, PA USA. [Morone, Natalia E.; Weiner, Debra K.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Morone, Natalia E.; Rollman, Bruce L.; Moore, Charity G.; Weiner, Debra K.] Univ Pittsburgh, Sch Med, Clin & Translat Sci Inst, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Sch Med, Div Geriatr, Pittsburgh, PA USA. [Greco, Carol M.] Univ Pittsburgh, Sch Med, Dept Psychiat, Ctr Integrat Med,Med Ctr Shadyside, Pittsburgh, PA USA. [Glynn, Nancy W.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Albert, Steven M.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Behav & Community Hlth Sci, Pittsburgh, PA 15261 USA. RP Morone, NE (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM moronene@upmc.edu OI Moore, Charity/0000-0002-0060-0124; Albert, Steven/0000-0001-6786-9956; Glynn, Nancy/0000-0003-2265-0162 FU National Institute on Aging [R01 AG034078-01] FX This work was supported by a grant from the National Institute on Aging R01 AG034078-01. Clinical trials.gov identifier: NCT01405716. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 51 TC 6 Z9 7 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2012 VL 33 IS 2 BP 417 EP 425 DI 10.1016/j.cct.2011.11.012 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 901JA UT WOS:000300962000022 PM 22115971 ER PT J AU Lowery, JT Marcus, A Kinney, A Bowen, D Finkelstein, DM Horick, N Garrett, K Haile, R Sandler, R Ahnen, DJ AF Lowery, Jan T. Marcus, Al Kinney, Anita Bowen, Deborah Finkelstein, Dianne M. Horick, Nora Garrett, Kathleen Haile, Robert Sandler, Robert Ahnen, Dennis J. TI The Family Health Promotion Project (FHPP): Design and baseline data from a randomized trial to increase colonoscopy screening in high risk families SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Colonoscopy; High risk; Intervention; Randomized trial ID NONPOLYPOSIS COLORECTAL-CANCER; COLON-CANCER; OLDER-ADULTS; BEHAVIOR; SURVEILLANCE; RELATIVES; BARRIERS; MODEL; INDIVIDUALS; BELIEFS AB Colorectal cancer (CRC) is a significant cause of mortality and morbidity in the United States, much of which could be prevented through adequate screening. Consensus guidelines recommend that high-risk groups initiate screening earlier with colonoscopy and more frequently than average risk persons. However, a large proportion of high risk individuals do not receive regular colonoscopic screening. The Family Health Promotion Project (FHPP) is a randomized-controlled trial to test the effectiveness of a telephone-based counseling intervention to increase adherence to risk-appropriate colonoscopy screening in high risk individuals. Unaffected members of CRC families from two national cancer family registries were enrolled (n = 632) and randomized to receive either a single session telephone counseling intervention using Motivational Interviewing techniques or a minimal mail-out intervention. The primary endpoint, rate of colonoscopy screening, was assessed at 6, 12 and 24 months post-enrollment. In this paper, we describe the research design and telephone counseling intervention of the FHPP trial, and report baseline data obtained from the two high risk cohorts recruited into this trial. Results obtained at baseline confirm the need for interventions to promote colonoscopy screening among these high risk individuals, as well as highlighting several key opportunities for intervention, including increasing knowledge about risk-appropriate screening guidelines, and providing both tailored risk information and barriers counseling. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lowery, Jan T.; Marcus, Al; Garrett, Kathleen; Ahnen, Dennis J.] Univ Colorado, Ctr Canc, Div Canc Prevent & Control, Aurora, CO 80045 USA. [Lowery, Jan T.] Univ Colorado, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. [Kinney, Anita] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA. [Kinney, Anita] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Bowen, Deborah] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA USA. [Finkelstein, Dianne M.; Horick, Nora] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Finkelstein, Dianne M.; Horick, Nora] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Haile, Robert] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Sandler, Robert] Univ N Carolina, Chapel Hill, NC USA. [Ahnen, Dennis J.] Univ Colorado, Sch Med, Aurora, CO 80045 USA. [Ahnen, Dennis J.] Vet Adm Med Ctr, Dept Med, Aurora, CO USA. RP Lowery, JT (reprint author), Univ Colorado, Ctr Canc, Div Canc Prevent & Control, Anschutz Med Campus,Bldg 500,MS F-538,POB 6508, Aurora, CO 80045 USA. EM jan.lowery@ucdenver.edu FU National Cancer Institute [5R01CA68099] FX Funded by National Cancer Institute, Grant #5R01CA68099. NR 51 TC 8 Z9 8 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2012 VL 33 IS 2 BP 426 EP 435 DI 10.1016/j.cct.2011.11.005 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 901JA UT WOS:000300962000023 PM 22101228 ER PT J AU Grover, S Ashley, SW Raut, CP AF Grover, Shilpa Ashley, Stanley W. Raut, Chandrajit P. TI Small intestine gastrointestinal stromal tumors SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Review DE endoscopy; gastrointestinal stromal tumor; imatinib; sunitinib; surgery ID TYROSINE-KINASE INHIBITOR; FINE-NEEDLE-ASPIRATION; GUIDED TRUCUT BIOPSY; PHASE-II TRIAL; IMATINIB MESYLATE; C-KIT; GERMLINE MUTATION; IN-VITRO; DIFFERENTIAL-DIAGNOSIS; SUBEPITHELIAL MASSES AB Purpose of review To review the contemporary management of gastrointestinal stromal tumor (GIST), including endoscopy, surgery, and systemic therapy, highlighting the aspects unique to small intestinal tumors. Recent findings Tumor size, mitotic count, and site of origin are the three key prognostic factors, with mitotic count being the single strongest predictor of recurrence. Tumors arising in the small bowel have worse prognosis than those of comparable size and mitotic count arising in other organs. Endoscopy and endoscopic ultrasound-guided, fine-needle aspiration are key components in the diagnosis of GIST. The role of endoscopy in surveillance and resection remain investigational. Surgery, either open or laparoscopic, remains the only curative option, but recurrence rates are high. Adjuvant therapy with imatinib mesylate improves recurrence-free survival rates and may improve overall survival (OS) with longer duration of treatment. Neoadjuvant imatinib may play an important role in the management of patients with locally advanced disease. For patients with advanced disease, first-line imatinib and second-line sunitinib malate have improved progression-free and OS rates. Systemic treatment should be continued life-long or until treatment failure. Summary Advances in the last decade have dramatically changed the management and prognosis of patients with primary and advanced GIST. C1 [Ashley, Stanley W.; Raut, Chandrajit P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Grover, Shilpa] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Grover, Shilpa; Ashley, Stanley W.; Raut, Chandrajit P.] Harvard Univ, Sch Med, Boston, MA USA. [Grover, Shilpa; Ashley, Stanley W.; Raut, Chandrajit P.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Raut, CP (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM craut@partners.org NR 117 TC 18 Z9 22 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD MAR PY 2012 VL 28 IS 2 BP 113 EP 123 DI 10.1097/MOG.0b013e32834ec154 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898SW UT WOS:000300763100004 PM 22157511 ER PT J AU Friedman, ES Davis, LL Zisook, S Wisniewski, SR Trivedi, MH Fava, M Rush, AJ AF Friedman, Edward S. Davis, Lori L. Zisook, Sidney Wisniewski, Stephen R. Trivedi, Madhukar H. Fava, Maurizio Rush, A. John CA CO-MED Study Team TI Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: Results from the CO-MED trial SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Depression; Abuse; Suicide; Combination treatment severity; Response; Remission ID MEASUREMENT-BASED CARE; STAR-ASTERISK-D; DIAGNOSTIC SCREENING QUESTIONNAIRE; REPORT QIDS-SR; SELF-REPORT; MAJOR DEPRESSION; QUICK INVENTORY; PSYCHOMETRIC EVALUATION; PSYCHIATRIC-DISORDERS; CLINICAL-PRACTICE AB The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0-10) [N=81], moderate (11-15) [N=238], severe (16-20) [N=260] and very severe (21-27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severe group versus 1/5-1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/- 1.99 suicide attempts in the severe group versus 0.0 +/- 0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbidities (e.g. [at p<.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9% of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p<.03). These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity. (C) 2011 Elsevier B.V. and ECNP. All rights reserved. C1 [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Davis, Lori L.] VA Med Ctr, Res & Dev Serv, Tuscaloosa, AL USA. [Davis, Lori L.] Univ Alabama, Sch Med, Dept Psychiat, Birmingham, AL USA. [Zisook, Sidney] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Zisook, Sidney] VA San Diego Hlth Care Syst, San Diego, CA USA. [Wisniewski, Stephen R.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rush, A. John] Duke NUS, Off Clin Sci, Singapore, Singapore. RP Friedman, ES (reprint author), 3811 OHara St, Pittsburgh, PA 15213 USA. EM friedmane@upmc.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU NIMH [MH-9008, NO1MH90003]; Aspect Medical Systems; AstraZeneca; Bristol-Myers Squibb; Cyberonics; Indevus; Medtronics; Northstar; Novartis; Pfizer; Sanofi-Aventis; Wyeth-Ayerst; Repligen; Abbott Laboratories, Inc.; Bristol-Myers Squibb Company (BMS); Eisai Pharmaceuticals; Janssen; VA, NIMH, Shire; Southwestern Oncology Group, Department of Defense (DoD); American Foundation for Suicide Prevention; Department of Veterans Affairs; PamLab; Advanced Neuromodulation Systems; Best Practice Project Management; Bristol-Myers Squibb/Otsuka; Forest Pharmaceuticals; Gerson Lehrman Group; GlaxoSmithKline; Jazz Pharmaceuticals; Magellan Health Services; Merck Company; Neuronetics; Novartis Pharmaceuticals; Ono Pharmaceuticals; Organon; Otsuka Pharmaceuticals; Transcept Pharmaceuticals; Urban Institute; Cyberonics Inc.; Stanley Medical Research Institute; Forest Laboratories; Otsuka; Guilford Publications; Healthcare Technology Systems FX The authors are entirely responsible for the scientific content of this paper. This study was supported and funded by NIMH grant MH-9008. We would also like to acknowledge the editorial support of Jon Kilner, MS, MA (Pittsburgh, PA). We acknowledge the administrative support of the Research and Development Services at the participating VA Medical Centers.; Edward S. Friedman M.D. has received grant/research support from Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb, Cyberonics, Indevus, Medtronics, Northstar, Novartis, Pfizer, Sanofi-Aventis, Wyeth-Ayerst, Repligen; and has served on the speakers bureaus or Advisory Boards for AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Wyeth-Ayerst, Bristol-Myers Squibb. Royalties: Springer.; Lori L. Davis M.D. Research support (no personal income received from these grants): Abbott Laboratories, Inc.; AstraZeneca; Bristol-Myers Squibb Company (BMS); Eisai Pharmaceuticals; Janssen; VA, NIMH, Shire; AstraZeneca; Southwestern Oncology Group, Department of Defense (DoD). Advisory/Consulting: Cyberonics; Abbott; Shire; Constella; Eli Lilly. Speaking: Abbott Laboratories; Cyberonics; Sanofi-Aventis; AstraZeneca. Equity Holdings (exclude mutual funds/blinded trusts): Pfizer (until 2009). Royalty/patent, other income: None.; Sidney Zisook, M.D. has received grant support from National Institute of Mental Health, American Foundation for Suicide Prevention, the Department of Veterans Affairs and PamLab.; John Rush, M.D., has received consultant fees from Advanced Neuromodulation Systems, AstraZeneca, Best Practice Project Management, Bristol-Myers Squibb/Otsuka, Cyberonics, Forest Pharmaceuticals, Gerson Lehrman Group, GlaxoSmithKline, Jazz Pharmaceuticals, Magellan Health Services, Merck & Company, Neuronetics, Novartis Pharmaceuticals, Ono Pharmaceuticals, Organon, Otsuka Pharmaceuticals, Pamlab, Pfizer, Transcept Pharmaceuticals, Urban Institute and Wyeth-Ayerst; speaking fees from Cyberonics Inc., Forest Laboratories, GlaxoSmithKline and Otsuka; royalties from Guilford Publications, and Healthcare Technology Systems, and research support from National Institute of Mental Health and the Stanley Medical Research Institute. He has owned shares of stock in Pfizer.; This study was supported and funded by NIMH grant NO1MH90003. NR 46 TC 12 Z9 13 U1 1 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2012 VL 22 IS 3 BP 183 EP 199 DI 10.1016/j.euroneuro.2011.07.010 PG 17 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 902BK UT WOS:000301013400002 PM 21920711 ER PT J AU Vallet, S Witzens-Harig, M Jaeger, D Podar, K AF Vallet, Sonia Witzens-Harig, Mathias Jaeger, Dirk Podar, Klaus TI Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE angiogenesis; birth defects; cereblon; immunomodulation; lenalidomide; multiple myeloma; myelodysplastic syndromes; pomalidomide; thalidomide ID DIAGNOSED MULTIPLE-MYELOMA; LOW-DOSE DEXAMETHASONE; STEM-CELL TRANSPLANTATION; NATURAL-KILLER-CELL; PHASE-II TRIAL; LENALIDOMIDE PLUS DEXAMETHASONE; SINGLE-AGENT LENALIDOMIDE; NECROSIS-FACTOR-ALPHA; NON-HODGKINS-LYMPHOMA; MYELODYSPLASTIC SYNDROMES AB Introduction: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs (R))] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies. Areas covered: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies. Expert opinion: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival. C1 [Vallet, Sonia; Witzens-Harig, Mathias; Jaeger, Dirk; Podar, Klaus] Heidelberg Univ, Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Vallet, Sonia; Witzens-Harig, Mathias; Jaeger, Dirk; Podar, Klaus] German Canc Res Ctr, Heidelberg, Germany. [Witzens-Harig, Mathias] Heidelberg Univ, Dept Hematol & Oncol, Heidelberg, Germany. [Podar, Klaus] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Podar, Klaus] Harvard Univ, Sch Med, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. RP Podar, K (reprint author), Heidelberg Univ, Natl Ctr Tumor Dis NCT, Heidelberg, Germany. NR 186 TC 7 Z9 7 U1 3 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD MAR PY 2012 VL 13 IS 4 BP 473 EP 494 DI 10.1517/14656566.2012.656091 PG 22 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 894UB UT WOS:000300451400003 PM 22324734 ER PT J AU Souter, I Dimitriadis, I Thatcher, ML Petrozza, JC Wright, DL AF Souter, Irene Dimitriadis, Irene Thatcher, Maria L. Petrozza, John C. Wright, Diane L. TI The Prognostic Significance of An Elevated Day-3 FSH in Young Women (<= 35 Years) Undergoing In-Vitro Fertilization (IVF) SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT 60th Annual Meeting of the Pacific-Coast-Reproductive-Society CY APR 18-22, 2012 CL CA SP Pacific Coast Reproduct Soc C1 [Souter, Irene; Dimitriadis, Irene; Thatcher, Maria L.; Petrozza, John C.; Wright, Diane L.] Massachusetts Gen Hosp, Fertil Ctr, Dept Ob Gyn, 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 J9 FERTIL STERIL JI Fertil. Steril. PD MAR PY 2012 VL 97 IS 3 SU S PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 900GX UT WOS:000300876000030 ER PT J AU Chang, TE Jing, YH Yeung, AS Brenneman, SK Kalsekar, I Hebden, T McQuade, R Baer, L Kurlander, JL Watkins, AK Siebenaler, JA Fava, M AF Chang, Trina E. Jing, Yonghua Yeung, Albert S. Brenneman, Susan K. Kalsekar, Iftekhar Hebden, Tony McQuade, Robert Baer, Lee Kurlander, Jonathan L. Watkins, Angela K. Siebenaler, Jean A. Fava, Maurizio TI Effect of communicating depression severity on physician prescribing patterns: findings from the Clinical Outcomes in MEasurement-based Treatment (COMET) trial SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Depressive disorder; Primary health care; Self-report; Questionnaires; Prescribing pattern ID STAR-ASTERISK-D; COMORBIDITY SURVEY REPLICATION; PRIMARY-CARE; COLLABORATIVE CARE; RANDOMIZED-TRIAL; UNITED-STATES; DOUBLE-BLIND; AUGMENTATION; DISORDER; PSYCHIATRISTS AB Objective: In this secondary analysis from the Clinical Outcomes in MEasurement-based Treatment trial (COMET), we evaluated whether providing primary care physicians with patient-reported feedback regarding depression severity affected pharmacological treatment patterns. Method: Intervention-arm physicians received their patients' 9-item Patient Health Questionnaire scores monthly. Odds of having no change in antidepressant treatment during the 6-month study period were calculated. Relationships between depression symptom status (partial or nonresponse) at month 3 and treatment changes in months 3 through 6 were assessed. Results: Among 503 intervention and 412 usual care (UC) patients with major depressive disorder, most received antidepressant monotherapy at baseline (79.4% UC vs. 88.4% intervention; P=.047). Few switched their baseline antidepressant (17.4%), increased their dose (12.4%) or augmented with a second medication (2%). Odds of having no change in antidepressant therapy did not differ significantly between study arms (odds ratio 1.21; 95% confidence interval 0.78-1.88; P=.392). Few month 3 partial or nonresponders had a regimen change over the following 3 months; the study arms did not differ significantly (partial responders: 4.1% UC vs. 7.7% intervention; P=.429; nonresponders: 14.6% UC vs. 15.9% intervention; P=.888). Conclusions: Among depressed patients treated in primary care, little active management was observed. The lack of treatment modification for the majority of partial and nonresponders was notable. (C) 2012 Elsevier Inc. All rights reserved. C1 [Chang, Trina E.; Yeung, Albert S.; Baer, Lee; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Chang, Trina E.; Baer, Lee; Fava, Maurizio] Massachusetts Gen Hosp, Clin Trials Network & Inst, Boston, MA 02114 USA. [Jing, Yonghua; Kalsekar, Iftekhar; Hebden, Tony] Bristol Myers Squibb Co, Plainsboro, NJ 08536 USA. [Brenneman, Susan K.; Kurlander, Jonathan L.; Watkins, Angela K.] OptumInsight, Eden Prairie, MN 55344 USA. [McQuade, Robert] Otsuka Pharmaceut Dev & Commercializat Inc, Princeton, NJ 08540 USA. [Siebenaler, Jean A.] OptumInsight, Cincinnati, OH 45069 USA. RP Chang, TE (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. EM techang@partners.org FU Bristol-Myers Squibb (Princeton, NJ); Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan); Bristol-Myers Squibb FX This study was funded by Bristol-Myers Squibb (Princeton, NJ) and Otsuka Pharmaceutical Co, Ltd (Tokyo, Japan). The authors thank Elizabeth J. Davis, PhD (medical writing, OptumInsight), Mia Eisenbart (OptumInsight Site Management Center), Ross Baker, PhD (Otsuka Pharmaceutical), Edward Kim, MD (formerly of Bristol-Myers Squibb), Kurt Kroenke, MD (Regenstrief Institute, Inc.; Indiana University School of Medicine), and Michael Klinkman, MS, MD (University of Michigan Department of Family Medicine). Dr. Chang has received research support from companies with an interest in depression treatment. Drs. Jing, Kalsekar, and Hebden are employees of Bristol-Myers Squibb. Drs. Yeung and Baer have no institutional or financial relationships that pose a conflict of interest. Dr. Brenneman, Mr. Kurlander, Ms. Watkins, and Dr. Siebenaler are employees of OptumInsight (formerly Innovus), an independent research organization contracted by Bristol-Myers Squibb to conduct the study. Dr. McQuade is an employee of Otsuka. Pharmaceutical Co, Ltd. Dr. Fava has received research support from or served as a consultant to companies with an interest in depression treatment. Presented in part at NCDEU 2011, Boca Raton, June 13-16, 2011. NR 36 TC 16 Z9 16 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAR-APR PY 2012 VL 34 IS 2 BP 105 EP 112 DI 10.1016/j.genhosppsych.2011.12.003 PG 8 WC Psychiatry SC Psychiatry GA 902ET UT WOS:000301022100001 PM 22264654 ER PT J AU Sadasivam, S Duan, SH DeCaprio, JA AF Sadasivam, Subhashini Duan, Shenghua DeCaprio, James A. TI The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression SO GENES & DEVELOPMENT LA English DT Article DE DREAM complex; Myb-MuvB complex; B-Myb; FoxM1; ChIP sequencing; cell cycle ID CELL-CYCLE PROGRESSION; REPRESSOR COMPLEX; TRANSCRIPTIONAL NETWORK; TERMINAL DOMAIN; DREAM COMPLEX; G(2)/M GENES; S-PHASE; PROTEIN; PHOSPHORYLATION; IDENTIFICATION AB Cell cycle progression is dependent on two major waves of gene expression. Early cell cycle gene expression occurs during G1/S to generate factors required for DNA replication, while late cell cycle gene expression begins during G2 to prepare for mitosis. Here we demonstrate that the MuvB complex-comprised of LIN9, LIN37, LIN52, LIN54, and RBBP4-serves an essential role in three distinct transcription complexes to regulate cell cycle gene expression. The MuvB complex, together with the Rb-like protein p130, E2F4, and DP1, forms the DREAM complex during quiescence and represses expression of both early and late genes. Upon cell cycle entry, the MuvB complex dissociates from p130/DREAM, binds to B-Myb, and reassociates with the promoters of late genes during S phase. MuvB and B-Myb are required for the subsequent recruitment of FoxM1 to late gene promoters during G2. The MuvB complex remains bound to FoxM1 during peak late cell cycle gene expression, while B-Myb binding is lost when it undergoes phosphorylation-dependent, proteasome-mediated degradation during late S phase. Our results reveal a novel role for the MuvB complex in recruiting B-Myb and FoxM1 to promote late cell cycle gene expression and in regulating cell cycle gene expression from quiescence through mitosis. C1 [Sadasivam, Subhashini; DeCaprio, James A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Sadasivam, Subhashini; DeCaprio, James A.] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02215 USA. [Duan, Shenghua] Dana Farber Canc Inst, Ctr Canc Computat Biol, Boston, MA 02215 USA. RP DeCaprio, JA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM james_decaprio@dfci.harvard.edu FU Public Health Service [P01CA050661, RO1CA93804, R01CA63113]; Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute FX We thank Eric McIntush (Bethyl Laboratories) for antibodies. We thank the Microarray Core and the Center for Cancer Computational Biology (CCCB) at Dana-Farber Cancer Institute for excellent assistance with expression profiling and ChIP-seq, respectively. We thank all members of the DeCaprio laboratory, N. Dyson (Massachusetts General Hospital), and W. Tansey (Vanderbilt University) for discussions. We thank N. Dyson and W. Wei (Beth Israel Deaconess Medical Center) for critically reading the manuscript. S. D. thanks S. Bentink and B. Haibe-Kains (Dana-Farber Cancer Institute) for discussions. We thank M. Correll (CCCB) for critically reviewing the bioinformatics analysis presented here. We thank Dustin Holloway (CCCB) for the bioinformatics analysis on FoxM1 and CHR motifs. This work was supported in part by Public Health Service grants P01CA050661, RO1CA93804, and R01CA63113 to J.A.D., and a research grant from the Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute to S. S. S. S. designed and performed all of the experiments, analyzed data, and wrote the paper; S. D. performed bioinformatics analysis and helped with generating Figures 2 and 3; and J.A.D. designed experiments, gave conceptual advice, and wrote the paper. NR 55 TC 79 Z9 82 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD MAR 1 PY 2012 VL 26 IS 5 BP 474 EP 489 DI 10.1101/gad.181933.111 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 904KZ UT WOS:000301196100007 PM 22391450 ER PT J AU Graham-Jones, P Jain, SH Friedman, CP Marcotte, L Blumenthal, D AF Graham-Jones, Pierce Jain, Sachin H. Friedman, Charles P. Marcotte, Leah Blumenthal, David TI The Need To Incorporate Health Information Technology Into Physicians' Education And Professional Development SO HEALTH AFFAIRS LA English DT Article AB Nationwide, as physicians and health care systems adopt electronic health records, health information technology is becoming integral to the practice of medicine. But current medical education and professional development curricula do not systematically prepare physicians to use electronic health records and the data these systems collect. We detail how training in meaningful use of electronic health records could be incorporated into physician training, from medical school, through licensure and board certification, to continuing medical education and the maintenance of licensure and board certification. We identify six near-term opportunities for professional organizations to accelerate the integration of health information technology into their requirements. C1 [Graham-Jones, Pierce] US Dept HHS, Beacon Community Program, Off Natl Coordinator Hlth Informat Technol, Washington, DC 20201 USA. [Jain, Sachin H.] Harvard Univ, Sch Business, Inst Strategy & Competitiveness, Boston, MA 02163 USA. [Friedman, Charles P.] Univ Michigan, Sch Informat, Hlth Informat Program, Ann Arbor, MI 48109 USA. [Friedman, Charles P.] Univ Michigan, Sch Publ Hlth, Hlth Informat Program, Ann Arbor, MI 48109 USA. [Marcotte, Leah] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blumenthal, David] Partners HealthCare Syst, Massachusetts Gen Hosp, Boston, MA USA. [Blumenthal, David] Harvard Univ, Sch Med, Boston, MA USA. RP Graham-Jones, P (reprint author), US Dept HHS, Beacon Community Program, Off Natl Coordinator Hlth Informat Technol, Washington, DC 20201 USA. EM pierce.graham-jones@hhs.gov NR 22 TC 17 Z9 17 U1 0 U2 16 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD MAR PY 2012 VL 31 IS 3 BP 481 EP 487 DI 10.1377/hlthaff.2011.0423 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 904UQ UT WOS:000301223800004 PM 22392658 ER PT J AU Zen, AL Whooley, MA Zhao, SJ Cohen, BE AF Zen, Angelica L. Whooley, Mary A. Zhao, Shoujun Cohen, Beth E. TI Post-Traumatic Stress Disorder is Associated With Poor Health Behaviors: Findings From the Heart and Soul Study SO HEALTH PSYCHOLOGY LA English DT Article DE posttraumatic stress disorder; health behaviors; smoking; physical activity; medication adherence ID PHYSICAL-ACTIVITY; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; MEDICATION ADHERENCE; DEPRESSIVE SYMPTOMS; CONSTRUCT-VALIDITY; PROBLEM DRINKING; RISK; NONADHERENCE; VETERANS AB Objective: Posttraumatic stress disorder (PTSD) results in substantial disability, including increased risk of cardiovascular disease (CVD). Poor health behaviors are major risk factors for initial and recurrent CVD events. Therefore, this study investigated whether PTSD is associated with poor health behaviors in patients with CVD. Method: Cross-sectional study of 1,022 men and women with CVD. PTSD was assessed with the Computerized Diagnostic Interview Schedule for DSM-IV. Physical activity, medication adherence and smoking history were determined by self-report questionnaires. Multivariate logistic and linear regression models were used to evaluate the association of PTSD with health behaviors. Results: Of the 1,022 participants, 95 (9%) had PTSD. PTSD was associated with significantly higher rates of physical inactivity in terms of overall exercise (OR 1.6, 95% CI [1.0-2.6]; p = .049), light exercise (OR 1.7, 95% CI [1.0-2.9]; p = .045), and self-rated level of exercise compared to others of their age and sex (OR 1.8, 95% CI [1.0-3.0]; p = .047). Participants with PTSD were more likely to report medication nonadherence, including forgetting medications (OR 1.8, 95% CI [1.0-3.3]; p = .04) or skipping medications (OR 1.7, 95% CI [1.1-2.9]; p = .03). Participants with PTSD also reported a greater smoking history (beta 6.4 pack years, 95% CI [1.8-10.9]; p = .006), which remained significant after adjustment for depression and income. Conclusions: Among patients with heart disease, those with PTSD were more likely to report physical inactivity, medication nonadherence and smoking. The majority of these associations were explained by adjustment for comorbid depression and lower income. C1 [Whooley, Mary A.; Cohen, Beth E.] San Francisco VA Med Ctr, Dept Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. [Zen, Angelica L.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Whooley, Mary A.; Cohen, Beth E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Zhao, Shoujun] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. RP Cohen, BE (reprint author), San Francisco VA Med Ctr, Dept Vet Affairs Med Ctr, Gen Internal Med Sect, Box 111A1, San Francisco, CA 94121 USA. EM beth.cohen@va.gov RI Schueter, nicos/A-3625-2014 FU NIH/NHLBI [K23 HL 094765-01]; Department of Defense/NCIRE [DAMD17-03-1-0532, W81XWH-05-2-0094]; Irene Perstein Foundation; Department of Veterans Affairs, Washington, DC; National Heart Lung and Blood Institute, Bethesda, MD [R01 HL079235]; American Federation for Aging Research, New York, NY; Robert Wood Johnson Foundation, Princeton, NJ; Ischemia Research and Education Foundation, South San Francisco, CA; Nancy Kirwan Heart Research Fund, San Francisco, CA FX The authors do not have any conflicts of interest. Preliminary data for this article was presented as an abstract at the American Geriatrics Society, 2010 meeting. Dr. Cohen was supported by NIH/NHLBI grant K23 HL 094765-01, Department of Defense/NCIRE grant DAMD17-03-1-0532, W81XWH-05-2-0094, and a grant from the Irene Perstein Foundation. The Heart and Soul Study was funded by the Department of Veterans Affairs, Washington, DC, the National Heart Lung and Blood Institute (R01 HL079235), Bethesda, MD, the American Federation for Aging Research (Paul Beeson Scholars Program), New York, NY, the Robert Wood Johnson Foundation (Faculty Scholars Program), Princeton, NJ, the Ischemia Research and Education Foundation, South San Francisco, CA, and the Nancy Kirwan Heart Research Fund, San Francisco, CA. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of any of these funding agencies. The funding organizations were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. NR 43 TC 51 Z9 51 U1 1 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD MAR PY 2012 VL 31 IS 2 BP 194 EP 201 DI 10.1037/a0025989 PG 8 WC Psychology, Clinical; Psychology SC Psychology GA 907BM UT WOS:000301392800009 PM 22023435 ER PT J AU Shi, Y Meeker, WQ AF Shi, Ying Meeker, William Q. TI Bayesian Methods for Accelerated Destructive Degradation Test Planning SO IEEE TRANSACTIONS ON RELIABILITY LA English DT Article DE Compromise plan; general equivalence theorem; large-sample approximation; log-location-scale distribution; optimum plan ID OPTIMAL EXPERIMENTAL-DESIGN AB Accelerated Destructive Degradation Tests (ADDTs) provide timely product reliability information in practical applications. This paper describes Bayesian methods for ADDT planning under a class of nonlinear degradation models with one accelerating variable. We use a Bayesian criterion based on the estimation precision of a specified failure-time distribution quantile at use conditions to find optimum test plans. A large-sample approximation for the posterior distribution provides a useful simplification to the planning criterion. The general equivalence theorem (GET) is used to verify the global optimality of the numerically optimized test plans. Optimum plans usually provide insight for constructing compromise plans which tend to be more robust, and practically useful. We present a numerical example with a log-location-scale distribution to illustrate the Bayesian test planning methods, and to investigate the effects of the prior distribution and sample size on test planning results. C1 [Shi, Ying] San Francisco VA Med Ctr, No Calif Inst Res & Educ, San Francisco, CA 94121 USA. [Meeker, William Q.] Iowa State Univ, Dept Stat, Ames, IA 50011 USA. RP Shi, Y (reprint author), San Francisco VA Med Ctr, No Calif Inst Res & Educ, San Francisco, CA 94121 USA. EM ying.shi2@va.gov; wqmeeker@iastate.edu NR 16 TC 17 Z9 19 U1 3 U2 24 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9529 J9 IEEE T RELIAB JI IEEE Trans. Reliab. PD MAR PY 2012 VL 61 IS 1 BP 245 EP 253 DI 10.1109/TR.2011.2170115 PG 9 WC Computer Science, Hardware & Architecture; Computer Science, Software Engineering; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 904LP UT WOS:000301198500028 ER PT J AU Palacios, E Franke, M Munoz, M Hurtado, R Dallman, R Chalco, K Guerra, D Mestanza, L Llaro, K Bonilla, C Sebastian, J Bayona, J Lyzigos, M Anger, H Shin, S AF Palacios, E. Franke, M. Munoz, M. Hurtado, R. Dallman, R. Chalco, K. Guerra, D. Mestanza, L. Llaro, K. Bonilla, C. Sebastian, J. Bayona, J. Lyzigos, M. Anger, H. Shin, S. TI HIV-positive patients treated for multidrug-resistant tuberculosis: clinical outcomes in the HAART era SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article DE HIV; multidrug-resistant tuberculosis; resource-poor settings; antiretroviral therapy; clinical outcomes ID NEW-YORK-CITY; VIRUS-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; DRUG-RESISTANCE; ADVERSE EVENTS; RISK-FACTORS; SURVIVAL; PREDICTORS; TARGETS; IMPACT AB SETTING: Multidrug-resistant tuberculosis (MDR-TB) and the human immunodeficiency virus (HIV) pose two of the greatest threats to global tuberculosis (TB) control. Given expanding global access to antiretroviral therapy (ART) and second-line TB drugs, more data are needed on experiences treating MDR-TB and HIV co-infection in resource-poor settings. OBJECTIVE: To describe the clinical characteristics, management, outcomes, and factors associated with survival among HIV-positive individuals receiving treatment for MDR-TB. DESIGN: This was a retrospective case series of 52 HIV-positive individuals receiving treatment for MDR-TB in Lima, Peru. We used Cox proportional hazards regression models to identify risk factors for mortality. RESULTS: A total of 31 (57%) of the cohort died on treatment, with the majority of deaths due to MDR-TB. Low baseline weight predicted a three-fold increased rate of death (aHR 3.1, 95%CI 1.5-6.7), while individuals receiving highly active ART experienced a significantly lower rate of death compared to those who were not (aHR 0.4, 95 %CI 0.2-0.9). CONCLUSION: Early ART is likely a key component of effective MDR-TB management in co-infected individuals. C1 [Shin, S.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. [Palacios, E.; Munoz, M.; Chalco, K.; Guerra, D.; Mestanza, L.; Llaro, K.; Bayona, J.; Anger, H.] Socios Salud, Sucursal Peru, Lima, Peru. [Franke, M.; Shin, S.] Harvard Univ, Sch Med, Boston, MA USA. [Hurtado, R.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Dallman, R.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Bonilla, C.] Minist Salud, Natl TB Program, Lima, Peru. [Sebastian, J.] Minist Salud, Peruvian HIV Program, Lima, Peru. [Lyzigos, M.] Univ Michigan, Sch Med, Ann Arbor, MI USA. RP Shin, S (reprint author), Brigham & Womens Hosp, Div Global Hlth Equ, 7th Floor,FXB Bldg,651 Huntington Ave, Boston, MA 02115 USA. EM sshin@partners.org NR 40 TC 23 Z9 23 U1 0 U2 6 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD MAR PY 2012 VL 16 IS 3 BP 348 EP 354 DI 10.5588/ijtld.11.0473 PG 7 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 903DY UT WOS:000301097500012 PM 22640448 ER PT J AU Camargo, CA AF Camargo, Carlos A., Jr. TI Potter Stewart and the definition of anaphylaxis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE Anaphylaxis ID EMERGENCY-DEPARTMENT VISITS; REPEAT EPINEPHRINE TREATMENTS; ALLERGIC REACTIONS; FOOD; MULTICENTER; ORGANIZATION C1 [Camargo, Carlos A., Jr.] Harvard Univ, Div Rheumatol Allergy & Immunol, Dept Med, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Dept Emergency Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Camargo, CA (reprint author), Harvard Univ, Div Rheumatol Allergy & Immunol, Dept Med, Massachusetts Gen Hosp,Med Sch, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org NR 16 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2012 VL 129 IS 3 BP 753 EP 754 DI 10.1016/j.jaci.2012.01.030 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 904IW UT WOS:000301189300021 PM 22285277 ER PT J AU Walsh, J Arora, M Hosenfeld, C Ladabaum, U Kuppermann, M Knight, SJ AF Walsh, Judith Arora, Millie Hosenfeld, Christina Ladabaum, Uri Kuppermann, Miriam Knight, Sara J. TI Preferences for Genetic Testing to Identify Hereditary Colorectal Cancer: Perspectives of High-Risk Patients, Community Members, and Clinicians SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Colorectal cancer screening; Preferences; Focus groups ID BREAST-CANCER; COLON-CANCER; ATTITUDES; KNOWLEDGE; SUSCEPTIBILITY; PERCEPTIONS; WOMEN; INDIVIDUALS; ASSOCIATION; RELATIVES AB The aim of this study was to establish key characteristics that patients, consumers, and health professionals value regarding genetic testing (GT) and personalized medicine using the example of GT for hereditary Lynch syndrome. We conducted a series of focus groups with individuals recruited from a clinic that follows those at high risk for hereditary cancer, individuals recruited from the community, physicians, and genetic counselors. Participants were presented with clinical scenarios about Lynch syndrome testing and asked to identify characteristics that they perceived as important in making decisions about GT. Forty-two participants (19 community members, 8 high-risk and cancer patients, 3 genetic counselors, and 8 physicians) participated. Among community members and patients, the most frequently discussed considerations were the personal impact of GT and family impact, respectively. Among physicians, the most frequently discussed topic was the characteristics of genomic services (e.g., test invasiveness); among genetic counselors, the most frequently discussed topic was evidence and recommendations. A variety of test characteristics were important in decision making about GT. High-risk patients, community members, and health care providers had different priorities. Health care professionals should be aware of differences between their own considerations about GT and those that are important to patients. C1 [Walsh, Judith] UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94115 USA. [Walsh, Judith; Arora, Millie] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA USA. [Hosenfeld, Christina] Univ Calif San Francisco, Dept Pharm, San Francisco, CA USA. [Ladabaum, Uri] Stanford Univ, Div Gastroenterol, Palo Alto, CA 94304 USA. [Kuppermann, Miriam] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA USA. [Kuppermann, Miriam] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Knight, Sara J.] San Francisco VA Med Ctr, San Francisco, CA USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Knight, Sara J.] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA. RP Walsh, J (reprint author), UCSF Womens Hlth Clin Res Ctr, 1635 Divisadero Suite 600, San Francisco, CA 94115 USA. EM Judith.Walsh@ucsf.edu NR 26 TC 8 Z9 8 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2012 VL 27 IS 1 BP 112 EP 119 DI 10.1007/s13187-011-0286-z PG 8 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 895IU UT WOS:000300490600019 PM 22131063 ER PT J AU Pagan, JA Brown, CJ Asch, DA Armstrong, K Bastida, E Guerra, C AF Pagan, Jose A. Brown, Cynthia J. Asch, David A. Armstrong, Katrina Bastida, Elena Guerra, Carmen TI Health Literacy and Breast Cancer Screening among Mexican American Women in South Texas SO JOURNAL OF CANCER EDUCATION LA English DT Article DE Mammography; Mexican American; Health literacy ID HISPANIC WOMEN; MAMMOGRAPHY; DISPARITIES; LATINAS; CARE AB Breast cancer is the main cause of cancer deaths for Hispanic women. This study analyzes the role of functional health literacy on mammography screening behavior and adherence of Hispanic women. Survey data from 722 Mexican American women age 40 and over residing in the Lower Rio Grande Valley of Texas in 2008 were used to estimate logistic regression models to assess the role of functional health literacy on mammography screening behavior and adherence. About 51% of survey respondents had a functional health literacy level deemed as inadequate or marginally functional. After adjusting for other factors, women with adequate health literacy levels were more likely to report to have ever had a mammogram (odds ratio [OR] = 2.92; 95% confidence interval [CI] = 1.62-5.28), to have had a mammogram within the last 2 years (OR = 1.70; 95% CI = 1.14-2.53) or to have had one within the last year (OR = 2.30; 95% CI = 1.54-3.43), compared to women with inadequate or marginally adequate functional health literacy levels. Inadequate/marginal functional health literacy is strongly associated with lower mammography screening. Large improvements in breast cancer control in this population may come from either basic advances in health literacy or by tailored approaches to help women with low literacy navigate local health care systems. C1 [Pagan, Jose A.] Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Dept Hlth Management & Policy, Ft Worth, TX 76107 USA. [Pagan, Jose A.; Asch, David A.; Armstrong, Katrina] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Brown, Cynthia J.] Univ Texas Pan Amer, Coll Business Adm, Dept Econ & Finance, Edinburg, TX 78541 USA. [Asch, David A.; Armstrong, Katrina; Guerra, Carmen] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Bastida, Elena] Florida Int Univ, Robert Stempel Coll Publ Hlth & Social Work, Dept Hlth Promot & Dis Prevent, Miami, FL 33199 USA. RP Pagan, JA (reprint author), Univ N Texas, Hlth Sci Ctr, Sch Publ Hlth, Dept Hlth Management & Policy, 3500 Camp Bowie Blvd, Ft Worth, TX 76107 USA. EM jose.pagan@unthsc.edu OI Asch, David/0000-0002-7970-286X NR 23 TC 13 Z9 13 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD MAR PY 2012 VL 27 IS 1 BP 132 EP 137 DI 10.1007/s13187-011-0239-6 PG 6 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 895IU UT WOS:000300490600021 PM 21573944 ER PT J AU Lopez-Jimenez, F Kramer, VC Masters, B Stuart, PW Mullooly, C Hinshaw, L Haas, L Warwick, K AF Lopez-Jimenez, Francisco Kramer, Valerie Carroll Masters, Barbara Stuart, Patricia (Mickey) W. Mullooly, Cathy Hinshaw, Ling Haas, Linda Warwick, Kathy TI Recommendations for Managing Patients With Diabetes Mellitus in Cardiopulmonary Rehabilitation AN AMERICAN ASSOCIATION OF CARDIOVASCULAR AND PULMONARY REHABILITATION STATEMENT SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Article DE cardiopulmonary rehabilitation; diabetes mellitus; scientific review; blood glucose monitoring; exercise ID CORONARY-ARTERY-DISEASE; CARDIAC REHABILITATION; GLYCEMIC CONTROL; MYOCARDIAL-INFARCTION; SCIENTIFIC STATEMENT; PREVENTION PROGRAMS; METABOLIC SYNDROME; HEART-ASSOCIATION; BETA-BLOCKER; TASK-FORCE AB Diabetes mellitus is a highly prevalent condition in patients participating in cardiopulmonary rehabilitation. However, research and subsequent guidelines specifically applicable to patients with diabetes, participating in cardiopulmonary rehabilitation, are limited. Recognizing this limitation, the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) initiated this statement, with the goal of developing a template that incorporated recommendations provided in the AACVPR Core Components and the American Association of Diabetes Educators 7 Self-Care Behaviors. This statement describes key processes regarding evaluation, interventions, and expected outcomes in each of the core components for the management of patients with diabetes in a cardiopulmonary rehabilitation program. C1 [Lopez-Jimenez, Francisco; Hinshaw, Ling] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Kramer, Valerie Carroll] Northwestern Univ, Evanston Hosp, NorthShore Univ HealthSyst, Evanston, IL 60201 USA. [Masters, Barbara] Protestant Mem Med Ctr, Belleville, IL USA. [Stuart, Patricia (Mickey) W.] Diabet Educ & Etc LLC, Vicksburg, MS USA. [Mullooly, Cathy] Novo Nordisk Inc, Boston, MA USA. [Haas, Linda] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Haas, Linda] VHA Off Nursing Serv, Washington, DC USA. [Warwick, Kathy] Profess Nutr Consultants LLC, Jackson, MS USA. RP Kramer, VC (reprint author), 709 Newgate, Prospect Heights, IL 60070 USA. EM valeriekramer@comcast.net OI Hinshaw, Ling/0000-0002-6103-8294 NR 47 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-7501 J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD MAR-APR PY 2012 VL 32 IS 2 BP 101 EP 112 DI 10.1097/HCR.0b013e31823be0bc PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 901EG UT WOS:000300943900006 PM 22198371 ER PT J AU Banerji, V Frumm, SM Ross, KN Li, LS Schinzel, AC Hahn, CK Kakoza, RM Chow, KT Ross, L Alexe, G Tolliday, N Inguilizian, H Galinsky, I Stone, RM DeAngelo, DJ Roti, G Aster, JC Hahn, WC Kung, AL Stegmaier, K AF Banerji, Versha Frumm, Stacey M. Ross, Kenneth N. Li, Loretta S. Schinzel, Anna C. Hahn, Cynthia K. Kakoza, Rose M. Chow, Kwan T. Ross, Linda Alexe, Gabriela Tolliday, Nicola Inguilizian, Haig Galinsky, Ilene Stone, Richard M. DeAngelo, Daniel J. Roti, Giovanni Aster, Jon C. Hahn, William C. Kung, Andrew L. Stegmaier, Kimberly TI The intersection of genetic and chemical genomic screens identifies GSK-3 alpha as a target in human acute myeloid leukemia SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID GLYCOGEN-SYNTHASE KINASE-3; NF-KAPPA-B; THERAPEUTIC TARGET; CELL-GROWTH; STEM-CELLS; LITHIUM; INHIBITION; GSK-3; AML; NEUTROPENIA AB Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3 alpha (GSK-3 alpha) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3 alpha induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3 alpha-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3 beta has been well studied in cancer development, these studies support a role for GSK-3 alpha in AML. C1 [Banerji, Versha; Frumm, Stacey M.; Li, Loretta S.; Hahn, Cynthia K.; Kakoza, Rose M.; Chow, Kwan T.; Ross, Linda; Alexe, Gabriela; Inguilizian, Haig; Roti, Giovanni; Kung, Andrew L.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Banerji, Versha; Frumm, Stacey M.; Li, Loretta S.; Hahn, Cynthia K.; Kakoza, Rose M.; Chow, Kwan T.; Ross, Linda; Alexe, Gabriela; Inguilizian, Haig; Roti, Giovanni; Kung, Andrew L.; Stegmaier, Kimberly] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Ross, Kenneth N.; Schinzel, Anna C.; Tolliday, Nicola; Hahn, William C.; Stegmaier, Kimberly] Broad Inst MIT, Cambridge, MA USA. [Ross, Kenneth N.; Schinzel, Anna C.; Tolliday, Nicola; Hahn, William C.; Stegmaier, Kimberly] Harvard Univ, Cambridge, MA 02138 USA. [Schinzel, Anna C.; Galinsky, Ilene; Stone, Richard M.; DeAngelo, Daniel J.; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM kimberly_stegmaier@dfci.harvard.edu FU National Cancer Institute [R01 CA140292]; American Cancer Society; ASH Fellow Scholar Award in Clinical/Translational Research; Howard Hughes Medical Institute; Smith Family New Investigator Award; Boston Foundation; CancerCare Manitoba; CancerCare Manitoba Foundation; University of Manitoba; Terry Fox Foundation through National Cancer Institute of Canada FX We thank Serena Silver, Jen Grenier, and David Root for RNAi screening guidance and the Chemical Biology Platform at the Broad Institute. We thank all of the patients who contributed invaluable primary samples. We thank Alexandre Puissant, Annie Carlton, and Jacob Berchuck for their technical advice and assistance. This work was supported by the National Cancer Institute (R01 CA140292) (to K. Stegmaier), the American Cancer Society (to K. Stegmaier), an ASH Fellow Scholar Award in Clinical/Translational Research (to K. Stegmaier), Howard Hughes Medical Institute (to K. Stegmaier and L.S. Li), a Smith Family New Investigator Award supported by the Richard Allan Barry Fund at the Boston Foundation (to K. Stegmaier), CancerCare Manitoba (to V. Banerji), CancerCare Manitoba Foundation (to V. Banerji), the University of Manitoba (to V. Banerji), and the Terry Fox Foundation through an award from the National Cancer Institute of Canada (to V. Banerji). NR 48 TC 34 Z9 36 U1 2 U2 13 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2012 VL 122 IS 3 BP 935 EP 947 DI 10.1172/JCI46465 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 902EN UT WOS:000301021500019 PM 22326953 ER PT J AU Lengerova, M Kocmanova, I Racil, Z Hrncirova, K Pospisilova, S Mayer, J Najvar, LK Wiederhold, NP Kirkpatrick, WR Patterson, TF AF Lengerova, Martina Kocmanova, Iva Racil, Zdenek Hrncirova, Kristyna Pospisilova, Sarka Mayer, Jiri Najvar, Laura K. Wiederhold, Nathan P. Kirkpatrick, William R. Patterson, Thomas F. TI Detection and Measurement of Fungal Burden in a Guinea Pig Model of Invasive Pulmonary Aspergillosis by Novel Quantitative Nested Real-Time PCR Compared with Galactomannan and (1,3)-beta-D-Glucan Detection SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; EXPERIMENTAL MURINE ASPERGILLOSIS; ENZYME-IMMUNOASSAY; FUMIGATUS; DIAGNOSIS; SERUM; DNA; SEQUENCE; RELEASE AB We developed and assessed the diagnostic value of a novel quantitative nested real-time (QNRT) PCR assay targeting the internal transcribed spacer region of ribosomal DNA (rDNA) in a guinea pig model of invasive pulmonary aspergillosis. Groups of 5 immunosuppressed animals that were infected using an aerosol chamber with Aspergillus fumigatus conidia were humanely terminated 1 h postinoculation and at days 3, 5, 7, and 11 postchallenge, and lung tissue, bronchoalveolar lavage (BAL) fluid, whole blood, and serum samples were collected. The QNRT PCR results obtained with the serum and BAL fluid were compared to those achieved with galactomannan and (1 -> 3)-beta-D-glucan assays. High fungal burden levels were detected by QNRT PCR in both lung tissue and BAL fluid in all infected animals at each time point, and the sensitivity of each assay in BAL fluid was 100% by day 3 and remained so through the remainder of the study. The sensitivity of detection of fungi in whole blood and serum samples was significantly lower, and some samples remained negative by all three assays despite the advanced stage of the infection. From these data, we can conclude that this novel QNRT PCR method was highly sensitive for the detection of A. fumigatus from different types of samples in this model. In addition, BAL fluid samples appeared to be the most suitable for the early diagnosis of invasive pulmonary aspergillosis. When testing serum, the use of a combination of available assays may increase the possibility of early detection of this opportunistic mycosis. C1 [Lengerova, Martina; Kocmanova, Iva; Racil, Zdenek; Hrncirova, Kristyna; Pospisilova, Sarka; Mayer, Jiri] Masaryk Univ, Dept Internal Med Hematooncol, Fac Med, Brno, Czech Republic. [Lengerova, Martina; Kocmanova, Iva; Racil, Zdenek; Hrncirova, Kristyna; Pospisilova, Sarka; Mayer, Jiri] Univ Hosp Brno, Brno, Czech Republic. [Lengerova, Martina; Pospisilova, Sarka; Mayer, Jiri] Masaryk Univ, CEITEC Cent European Inst Technol, Brno, Czech Republic. [Najvar, Laura K.; Wiederhold, Nathan P.; Kirkpatrick, William R.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Najvar, Laura K.; Kirkpatrick, William R.; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Wiederhold, Nathan P.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. RP Lengerova, M (reprint author), Masaryk Univ, Dept Internal Med Hematooncol, Fac Med, Brno, Czech Republic. EM mlengerova@fnbrno.cz RI Lengerova, Martina/E-1038-2012; Pospisilova, Sarka/D-7200-2012 FU Ministry of Health of the Czech Republic [NS10442-3/2009, NS10441-3/2009]; Ministry of Industry and Trade of the Czech Republic [FR-TI2/254]; NIH/NIAID [N01-AI-30041] FX This study was supported in part by grants from the Ministry of Health of the Czech Republic (NS10442-3/2009, NS10441-3/2009), the Ministry of Industry and Trade of the Czech Republic (FR-TI2/254), and NIH/NIAID contract N01-AI-30041. NR 28 TC 17 Z9 20 U1 3 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 602 EP 608 DI 10.1128/JCM.05356-11 PG 7 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800011 PM 22189110 ER PT J AU Campbell, JD Lewis, JS McElmeel, ML Fulcher, LC Jorgensen, JH AF Campbell, Jennifer D. Lewis, James S., II McElmeel, M. Leticia Fulcher, Letitia C. Jorgensen, James H. TI Detection of Favorable Oral Cephalosporin-Clavulanate Interactions by In Vitro Disk Approximation Susceptibility Testing of Extended-Spectrum- Beta-Lactamase-Producing Members of the Enterobacteriaceae SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID ESCHERICHIA-COLI; PHARMACOKINETICS; COMBINATION; VOLUNTEERS; ACID; COMMUNITY; EMERGENCE AB Extended-spectrum-beta-lactamase (ESBL)-producing members of the Enterobacteriaceae are often resistant to multiple drug classes, making therapy of urinary infections with oral antibiotics difficult. Previously it was shown that amoxicillin-clavulanate can provide clavulanate inhibition of ESBLs and protect an oral cephalosporin present in combination when tested by broth microdilution. This study has shown that disk approximation testing could detect favorable cephalosporin-clavulanate interactions among a group of 101 previously characterized members of the Enterobacteriaceae with CTX-M, SHV, or TEM ESBLs. C1 [McElmeel, M. Leticia; Fulcher, Letitia C.; Jorgensen, James H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Campbell, Jennifer D.] S Texas Vet Healthcare Syst, San Antonio, TX USA. [Campbell, Jennifer D.; Lewis, James S., II] Univ Texas Austin, Coll Pharm, Pharmacotherapy Div, Austin, TX 78712 USA. [Campbell, Jennifer D.; Lewis, James S., II] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Lewis, James S., II] Univ Hlth Syst, San Antonio, TX USA. RP Jorgensen, JH (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. EM jorgensen@uthscsa.edu NR 18 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 1023 EP 1026 DI 10.1128/JCM.06248-11 PG 4 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800070 PM 22170910 ER PT J AU Issa, NC Koo, S Lynch, RC Gay, C Hammond, SP Baden, LR Ghobrial, IM Finkelman, MA Marty, FM AF Issa, Nicolas C. Koo, Sophia Lynch, Robert C. Gay, Charline Hammond, Sarah P. Baden, Lindsey R. Ghobrial, Irene M. Finkelman, Malcolm A. Marty, Francisco M. TI Serum Galactomannan and (1 -> 3)-beta-D-Glucan Assays for Patients with Multiple Myeloma and Waldenstrom's Macroglobulinemia SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; BETA-D-GLUCAN; EARLY-DIAGNOSIS; ASPERGILLOSIS; EPIDEMIOLOGY; RECIPIENTS; LEUKEMIA; PLASMA AB We assessed the performance of galactomannan and (1 -> 3)-beta-D-glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1 -> 3)-beta-D-glucan assays were not falsely elevated in any patient. (1 -> 3)-beta-D-glucan assay results were uninterpretable in 24% of patients. Patients with IgG levels of >2,000 mg/dl had higher odds of uninterpretable (1 -> 3)-beta-D-glucan results. C1 [Issa, Nicolas C.; Koo, Sophia; Lynch, Robert C.; Gay, Charline; Hammond, Sarah P.; Baden, Lindsey R.; Ghobrial, Irene M.; Marty, Francisco M.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Issa, Nicolas C.; Koo, Sophia; Hammond, Sarah P.; Baden, Lindsey R.; Ghobrial, Irene M.; Marty, Francisco M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Issa, Nicolas C.; Koo, Sophia; Hammond, Sarah P.; Baden, Lindsey R.; Ghobrial, Irene M.; Marty, Francisco M.] Harvard Univ, Sch Med, Boston, MA USA. [Finkelman, Malcolm A.] Associates Cape Cod Inc, E Falmouth, MA USA. RP Issa, NC (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM nissa@partners.org OI Koo, Sophia/0000-0002-4973-7439 NR 21 TC 2 Z9 3 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2012 VL 50 IS 3 BP 1054 EP 1056 DI 10.1128/JCM.06295-11 PG 3 WC Microbiology SC Microbiology GA 901WB UT WOS:000300997800078 PM 22170932 ER PT J AU Wortzel, HS Strom, LA Anderson, AC Maa, EH Spitz, M AF Wortzel, Hal S. Strom, Laura A. Anderson, Alan C. Maa, Edward H. Spitz, Mark TI Disrobing Associated with Epileptic Seizures and Forensic Implications SO JOURNAL OF FORENSIC SCIENCES LA English DT Article DE forensic science; forensic medicine; forensic psychiatry; seizures; epilepsy; behavioral medicine ID VIOLENCE AB Little is known about the clinical aspects and medico-legal consequences of disrobing in the context of epileptic seizures. Seizure-related disrobing may occur either as an ictal automatism or during the postictal period. Some patients may experience a seizure while already in the unclothed state, engage in ictal wandering, and thereby appear in public in the nude. Two cases involving disrobing associated with seizures captured via video-monitored electroencephalography are offered. An additional case reveals the legal consequences endured by one patient who experienced a nocturnal seizure and began wandering in an unclothed state. Collectively, these cases illustrate the medical reality of seizure-related disrobing and the related adverse effects on patients quality of life. Disrobing associated with epileptic seizures carries the potential for serious legal consequences if not properly identified as an ictal phenomenon. C1 [Wortzel, Hal S.] Denver Vet Hosp, VISN MIRECC 19, Denver, CO 80220 USA. [Wortzel, Hal S.; Anderson, Alan C.] Dept Psychiat, Neurobehav Disorders Program, Aurora, CO 80045 USA. [Strom, Laura A.; Anderson, Alan C.; Maa, Edward H.; Spitz, Mark] Dept Neurol, Aurora, CO 80045 USA. [Strom, Laura A.; Anderson, Alan C.; Maa, Edward H.; Spitz, Mark] Denver Vet Hosp, Div Neurol, Denver, CO 80220 USA. RP Wortzel, HS (reprint author), Denver VA Hosp, VISN MIRECC 19, 1055 Clermont St, Denver, CO 80220 USA. EM hal.wortzel@ucdenver.edu NR 10 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-1198 J9 J FORENSIC SCI JI J. Forensic Sci. PD MAR PY 2012 VL 57 IS 2 BP 550 EP 552 DI 10.1111/j.1556-4029.2011.01995.x PG 3 WC Medicine, Legal SC Legal Medicine GA 897XY UT WOS:000300696400039 PM 22150773 ER PT J AU Hoshida, Y Fuchs, BC Tanabe, KK AF Hoshida, Yujin Fuchs, Bryan C. Tanabe, Kenneth K. TI Genomic risk of hepatitis C-related hepatocellular carcinoma SO JOURNAL OF HEPATOLOGY LA English DT Editorial Material ID GROWTH-FACTOR GENE; FUNCTIONAL POLYMORPHISM; SUSCEPTIBILITY LOCUS; WIDE ASSOCIATION; CIRRHOSIS; PROGRESSION; FIBROSIS AB To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P < 1 x 10(-5)) in the genome-wide association study were further genotyped in 673 cases and 2596 controls. We found a previously unidentified locus in the 5' flanking region of MICA on 6p21.33 (rs2596542, P(combined) = 4.21 x 10(-13), odds ratio = 1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P = 0.61) but is significantly associated with progression from CHC to HCC (P = 3.13 x 10(-8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P = 1.38 x 10(-13)). (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Hoshida, Yujin] Broad Inst Massachusetts Inst Technol, Canc Program, Cambridge, MA USA. [Hoshida, Yujin] Harvard Univ, Cambridge, MA 02138 USA. [Fuchs, Bryan C.; Tanabe, Kenneth K.] Harvard Med Sch, Boston, MA USA. [Fuchs, Bryan C.; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. RP Hoshida, Y (reprint author), Broad Inst Massachusetts Inst Technol, Canc Program, Cambridge, MA USA. EM hoshida@broadinstitute.org; ktanabe@partners.org NR 11 TC 10 Z9 10 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2012 VL 56 IS 3 BP 729 EP 730 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 904TQ UT WOS:000301221200032 PM 21963516 ER PT J AU Madaras-Kelly, KJ Remington, RE Fan, VS Sloan, KL AF Madaras-Kelly, Karl J. Remington, Richard E. Fan, Vincent S. Sloan, Kevin L. TI Predicting antibiotic resistance to community-acquired pneumonia antibiotics in culture-positive patients with healthcare-associated pneumonia SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID IN-VITRO ACTIVITY; STAPHYLOCOCCUS-AUREUS; RISK-FACTORS; INFECTION; FLUOROQUINOLONE; SUSCEPTIBILITY; COLONIZATION; GUIDELINES; MANAGEMENT; BACTERIA AB OBJECTIVE: To develop and validate a model to predict resistance to community-acquired pneumonia antibiotics (CAP-resistance) among patients with healthcare-associated pneumonia (HCAP), and to compare the model's predictive performance to a model including only guideline-defined criteria for HCAP. DESIGN: Retrospective cohort study. SETTING: Six Veterans Affairs Medical Centers in the northwestern United States. PATIENTS: Culture-positive inpatients with HCAP. MEASUREMENTS: Patients were identified based upon guideline-defined criteria for HCAP. Relevant cultures obtained within 48 hours of admission were assessed to determine bacteriology and antibiotic susceptibility. Medical records for the year preceding admission were assessed to develop predictive models of CAP-resistance with logistic regression. The predictive performance of cohort-developed and guideline-defined models was compared. RESULTS: CAP-resistant organisms were identified in 118 of 375 culture-positive patients. Of guideline-defined criteria, CAP-resistance was associated (odds ratio (OR) [95% confidence interval (CI)]) with: admission from nursing home (2.6 [1.6-4.4]); recent antibiotic exposure (1.7 [1.0-2.8]); and prior hospitalization (1.6 [1.0-2.6]). In the cohort-developed model, CAP-resistance was associated with: admission from nursing home or recent nursing home discharge (2.3 [1.4-3.8]); positive methicillin-resistant Staphylococcus aureus (MRSA) history within 90 days of admission (6.4 [2.6-17.8]) or 91-365 days (2.3 [0.9-5.9]); cephalosporin exposure (1.8 [1.12.9]); recent infusion therapy (1.9 [1.0-3.5]); diabetes (1.7 [1.0-2.8]); and intensive care unit (ICU) admission (1.6 [1.0-2.6]). Area under the receiver operating characteristic curve (aROC [95% CI]) for the cohort-developed model (0.71 [0.65-0.77]) was significantly higher than for the guideline-defined model (0.63 [0.57-0.69]) (P = 0.01). CONCLUSIONS: Select guideline-defined criteria predicted CAP-resistance. A cohort-developed model based primarily on prior MRSA history, nursing home residence, and specific antibiotic exposures provided improved prediction of CAP-resistant organisms in HCAP. Journal of Hospital Medicine 2012; 7: 195-202 (C) 2011 Society of Hospital Medicine. C1 [Madaras-Kelly, Karl J.] Vet Affairs Med Ctr, Clin Pharm Serv 119A, Boise, ID 83702 USA. [Remington, Richard E.] Vet Affairs Med Ctr, Res Serv, Boise, ID 83702 USA. [Fan, Vincent S.] Vet Affairs Puget Sound Hlth Care Syst, Med Serv, Seattle, WA USA. [Madaras-Kelly, Karl J.; Remington, Richard E.] Idaho State Univ, Coll Pharm, Dept Pharm Practice & Adm Sci, Meridian, ID USA. [Fan, Vincent S.] Univ Washington, Sch Med, Dept Pulm & Crit Care Med, Seattle, WA USA. RP Madaras-Kelly, KJ (reprint author), Vet Affairs Med Ctr, Clin Pharm Serv 119A, 500 W Ft St, Boise, ID 83702 USA. EM KMK@pharmacy.isu.edu FU Idaho State University [RO3AI074894-01A2]; Department of Veterans Affairs; National Institutes of Health FX Karl J. Madaras-Kelly is employed full time by Idaho State University. The National Institute of Allergy and Infectious Diseases provided salary support for this study paid through Idaho State University (grant RO3AI074894-01A2). The National Institute of Allergy and Infectious Diseases provided payment for statistical services on this study to Richard E. Remington, sub-contracted through Idaho State University (grant RO3AI074894-01A2). Vincent S. Fan is employed full time by the Department of Veterans Affairs, and receives grant support unrelated to the study from the Department of Veterans Affairs and the National Institutes of Health. He serves as a consultant for Uptake Medical Corporation. Kevin L. Sloan has no conflicts of interest to report. NR 31 TC 15 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD MAR PY 2012 VL 7 IS 3 BP 195 EP 202 DI 10.1002/jhm.942 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 901QY UT WOS:000300983100006 PM 22038859 ER PT J AU Freund, K Weckmann, MT Casarett, DJ Swanson, K Brooks, MK Broderick, A AF Freund, Katherine Weckmann, Michelle T. Casarett, David J. Swanson, Kristi Brooks, Mary Kay Broderick, Ann TI Hospice eligibility in patients who died in a tertiary care center SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article DE communication; palliative care; patient education ID END-OF-LIFE; PALLIATIVE CARE; NURSING-HOMES; NEAR-DEATH; DISCUSSIONS; HEALTH; CANCER; LENGTH; EXPENDITURES; ASSOCIATIONS AB BACKGROUND: Hospice is a service that patients, families, and physicians find beneficial, yet a majority of patients die without receiving hospice care. Little is known about how many hospitalized patients are hospice eligible at the time of hospitalization. METHODS: Retrospective chart review was used to examine all adult deaths (n = 688) at a tertiary care center during 2009. Charts were selected for full review if the death was nontraumatic and the patient had a hospital admission within 12 months of the terminal admission. The charts were examined for hospice eligibility based on medical criteria, evidence of a hospice discussion, and hospice enrollment. RESULTS: Two hundred nine patients had an admission in the year preceding the terminal admission and a nontraumatic death. Sixty percent were hospice eligible during the penultimate admission. Hospice discussions were documented in 14% of the hospice-eligible patients. Patients who were hospice eligible had more subspecialty consults on the penultimate admission compared to those not hospice eligible (P = 0.016), as well as more overall hospitalizations in the 12 months preceding their terminal admission (P = 0.0003), and fewer days between their penultimate admission and death (P = 0.001). CONCLUSION: The majority of terminally ill inpatients did not have a documented discussion of hospice with their care provider. Educating physicians to recognize the stepwise decline of most illnesses and hospice admission criteria will facilitate a more informed decision-making process for patients and their families. A consistent commitment to offer hospice earlier than the terminal admission would increase access to community or home-based care, potentially increasing quality of life. Journal of Hospital Medicine 2012; 7: 218-223. (C) 2011 Society of Hospital Medicine. C1 [Weckmann, Michelle T.; Swanson, Kristi] Univ Iowa, Carver Coll Med, Dept Family Med, Iowa City, IA 52242 USA. [Weckmann, Michelle T.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. [Casarett, David J.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Casarett, David J.] Philadelphia Vet Affairs Ctr Hlth Equ Res & Promo, Ctr Bioeth, Inst Aging, Philadelphia, PA USA. [Brooks, Mary Kay] Univ Iowa Hosp & Clin, Off Clin Qual Safety & Performance Improvement, Iowa City, IA 52242 USA. [Broderick, Ann] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. RP Weckmann, MT (reprint author), Univ Iowa, Carver Coll Med, Dept Family Med, 01102 PFP, Iowa City, IA 52242 USA. EM michelle-weckmann@uiowa.edu FU University of Iowa Carver College of Medicine [NIH 2-T35-HL007485-31] FX Support for this research was provided by the University of Iowa Carver College of Medicine, Medical Student Summer Research Fellowship Program (NIH 2-T35-HL007485-31). None of the authors have any financial conflicts of interest to report. NR 30 TC 10 Z9 10 U1 3 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD MAR PY 2012 VL 7 IS 3 BP 218 EP 223 DI 10.1002/jhm.975 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 901QY UT WOS:000300983100009 PM 22086609 ER PT J AU Nikolaou, VA Stratigos, AJ Flaherty, KT Tsao, H AF Nikolaou, Vasiliki A. Stratigos, Alexander J. Flaherty, Keith T. Tsao, Hensin TI Melanoma: New Insights and New Therapies SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID STAGE IV MELANOMA; PHASE-II TRIAL; METASTATIC MELANOMA; MALIGNANT-MELANOMA; IMATINIB MESYLATE; THERAPEUTIC TARGET; ANTISENSE THERAPY; CLINICAL-EFFICACY; TUMOR PROGRESSION; INDUCED APOPTOSIS AB Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. However, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. The discovery of BRAF mutations in melanoma created the first opportunity to develop oncogene-directed therapy in this disease and led to the development of compounds that inhibit aberrant BRAF activity. A decade later, vemurafenib, an orally available and well-tolerated selective BRAF inhibitor, ushered in a new era of molecular treatments for advanced disease. Additional targets have been identified, and novel agents that impact on various signaling pathways or modulate the immune system hold the promise of a whole new therapeutic landscape for patients with metastatic melanoma. One of the major thrusts in melanoma therapy is now focused on understanding and targeting the network of signal transduction pathways and on attacking elements that underlie the tumor's propensity for growth and chemoresistance. In this article, we review the novel targeted anticancer approaches that are under consideration in melanoma treatment. C1 [Tsao, Hensin] Massachusetts Gen Hosp, Wellman Ctr Photomed, MGH Canc Ctr, Dept Dermatol, Boston, MA 02114 USA. [Nikolaou, Vasiliki A.; Stratigos, Alexander J.] Univ Athens, Sch Med, Andreas Sygros Hosp, Dermatooncol Unit,Dept Dermatol, GR-11527 Athens, Greece. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, MGH Canc Ctr, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org FU Cephalon; National Institutes of Health [K24 CA149202]; American Skin Association; Melanoma Research Alliance; MGH FX K.T.F. has been a consultant at Roche/Genentech and GlaxoSmithKline. H.T. has been a consultant for Genentech, SciBASE, and Quest, and has received research funding from Cephalon. There is no conflict with the publicly reported research in this article. The other authors state no conflict of interest.; This scholarly activity was made possible in part by grants from the National Institutes of Health (K24 CA149202 to H.T.), the American Skin Association (to H.T.), and the Melanoma Research Alliance (to K.T.F and H.T.), and by generous donors to the MGH Millennium Melanoma Fund on behalf of melanoma research. NR 88 TC 72 Z9 75 U1 2 U2 33 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 MAR PY 2012 VL 132 IS 3 BP 854 EP 863 DI 10.1038/jid.2011.421 PN 2 PG 10 WC Dermatology SC Dermatology GA 893RW UT WOS:000300374100013 PM 22217739 ER PT J AU Zhu, YC Chabriat, H Godin, O Dufouil, C Rosand, J Greenberg, SM Smith, EE Tzourio, C Viswanathan, A AF Zhu, Yi-Cheng Chabriat, Hugues Godin, Ophelia Dufouil, Carole Rosand, Jonathan Greenberg, Steven M. Smith, Eric E. Tzourio, Christophe Viswanathan, Anand TI Distribution of white matter hyperintensity in cerebral hemorrhage and healthy aging SO JOURNAL OF NEUROLOGY LA English DT Article DE Intercerebral hemorrhage; White matter hyperintensity; Cerebral amyloid angiopathy ID LOBAR INTRACEREBRAL HEMORRHAGE; AMYLOID ANGIOPATHY; COGNITIVE DECLINE; LESIONS; DISEASE; MRI; POPULATION; VOLUMES; RISK AB We compared the severity of white matter T2-hyperintensities (WMH) in the frontal lobe and occipital lobe using a visual MRI score in 102 patients with lobar intracerebral hemorrhage (ICH) diagnosed with possible or probable cerebral amyloid angiopathy (CAA), 99 patients with hypertension-related deep ICH, and 159 normal elderly subjects from a population-based cohort. The frontal-occipital (FO) gradient was used to describe the difference in the severity of WMH between the frontal lobe and occipital lobe. A higher proportion of subjects with obvious occipital dominant WMH (FO gradient a parts per thousand currency signa'2) was found among patients with lobar ICH than among healthy elderly subjects (FO gradient a parts per thousand currency signa'2: 13.7 vs. 5.7%, p = 0.03). Subjects with obvious occipital dominant WMH were more likely to have more WMH (p = 0.0006) and a significantly higher prevalence of the apolipoprotein E epsilon 4 allele (45.8% vs. 19.4%, p = 0.04) than those who had obvious frontal dominant WMH. This finding is consistent with the relative predilection of CAA for posterior brain regions, and suggests that white matter lesions may preferentially occur in areas of greatest vascular pathology. C1 [Greenberg, Steven M.; Smith, Eric E.; Viswanathan, Anand] Harvard Univ, Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Dept Neurol,Stroke Res Ctr,Med Sch, Boston, MA 02114 USA. [Zhu, Yi-Cheng] Beijing Union Med Coll Hosp, Dept Neurol, Beijing, Peoples R China. [Zhu, Yi-Cheng; Chabriat, Hugues] CHU Lariboisiere, Assistance Publ Hop Paris, Dept Neurol, INSERM,U740, Paris, France. [Zhu, Yi-Cheng; Godin, Ophelia; Dufouil, Carole; Tzourio, Christophe] INSERM, Neuroepidemiol U708, Paris, France. [Godin, Ophelia; Dufouil, Carole; Tzourio, Christophe] Univ Paris 06, Paris, France. [Rosand, Jonathan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. RP Viswanathan, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Dept Neurol,Stroke Res Ctr,Med Sch, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM aviswanathan1@partners.org RI Dufouil, Carole/J-4968-2012; Tzourio, christophe/B-4015-2009; Chabriat, Hugues/G-5699-2010; OI Tzourio, christophe/0000-0002-6517-2984; Chabriat, Hugues/0000-0001-8436-6074; Smith, Eric/0000-0003-3956-1668 FU French Chinese Foundation for Science and Applications (FFCSA); China Scholarship Council (CSC); Association de Recherche en Neurologie Vasculaire (ARNEVA); EISAI; French National Research Agency (ANR); Sanofi-Synthelabo; Merck-Sharp; Dohm; Lundbeck; Servier; Johnson and Johnson FX Yi-Cheng Zhu is funded by the French Chinese Foundation for Science and Applications (FFCSA), the China Scholarship Council (CSC), and the Association de Recherche en Neurologie Vasculaire (ARNEVA). Carole Dufouil has received consulting fees from EISAI. Christophe Tzourio has received investigator initiated research funding from the French National Research Agency (ANR) and has received fees from Sanofi-Synthelabo for participation on a data safety monitoring board and from Merck-Sharp & Dohm for participation on a scientific committee. Hugues Chabriat has already received fees from Eisai, Lundbeck, Servier and Johnson and Johnson companies for participating on data safety and scientific committees in studies unrelated to the present study. NR 19 TC 21 Z9 22 U1 0 U2 4 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD MAR PY 2012 VL 259 IS 3 BP 530 EP 536 DI 10.1007/s00415-011-6218-3 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 904GW UT WOS:000301183500017 PM 21877206 ER PT J AU Duhaime, AC Holshouser, B Hunter, JV Tong, K AF Duhaime, Ann-Christine Holshouser, Barbara Hunter, Jill V. Tong, Karen TI Common Data Elements for Neuroimaging of Traumatic Brain Injury: Pediatric Considerations SO JOURNAL OF NEUROTRAUMA LA English DT Article DE CT; common data elements; MRI; pediatrics; traumatic brain injury ID CLOSED HEAD-INJURY; THERAPEUTIC PROCEDURES; WHITE-MATTER; MATURATION; CHILDREN; CT; ADOLESCENCE; GUIDELINES; MANAGEMENT; CHILDHOOD AB As part of the Traumatic Brain Injury Common Data Elements project, a large-scale effort to define common data elements across a variety of domains, including neuroimaging, special considerations for pediatric patients were introduced. This article is an extension of that initial work, in which pediatric-specific pathoanatomical entities, technical considerations, interpretation paradigms, and safety considerations were reviewed. The goal of this review was to outline differences and specific information relevant to optimal performance and proper interpretation of neuroimaging in pediatric patients with traumatic brain injury. The long-range goal of this project is to facilitate data sharing as well as to provide critical infrastructure for potential clinical trials in this major public health area. C1 [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Holshouser, Barbara] Loma Linda Univ, Sch Med, Dept Radiol, Loma Linda, CA USA. [Hunter, Jill V.] Texas Childrens Hosp, Baylor Coll Med, Dept Neuroradiol, Houston, TX 77030 USA. [Tong, Karen] Loma Linda Univ, Med Ctr, Loma Linda, CA USA. RP Duhaime, AC (reprint author), Massachusetts Gen Hosp, 15 Parkman St,Wang 331, Boston, MA 02114 USA. EM aduhaime@partners.org FU National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS); United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR) FX We gratefully acknowledge the valuable contributions of Ramona Hicks for providing the impetus as well as the organization and format for this project and for assistance with manuscript preparation. This project was jointly supported by the National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS) and the United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR). NR 27 TC 10 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2012 VL 29 IS 4 BP 629 EP 633 DI 10.1089/neu.2011.1927 PG 5 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 901SQ UT WOS:000300987500002 PM 21671798 ER PT J AU Miller, AC Odenkirchen, J Duhaime, AC Hicks, R AF Miller, A. Cate Odenkirchen, Joanne Duhaime, Ann-Christine Hicks, Ramona TI Common Data Elements for Research on Traumatic Brain Injury: Pediatric Considerations SO JOURNAL OF NEUROTRAUMA LA English DT Article DE assessment tools; bioinformatics; CDE; clinical trials; database; meta-analysis; pediatrics; rehabilitation; research; TBI ID PSYCHOLOGICAL HEALTH; OUTCOME MEASURES; WORKING GROUP; RECOMMENDATIONS AB Traumatic brain injury (TBI) is a significant global health problem, with a notably high incidence in children and adolescents. Despite the prevalence of TBI and the disabilities that often follow, research on which to base effective treatment is limited by several challenges, including but not limited to the complexity and heterogeneity of TBI. Even when rigorous methods are employed, the utility of the research may be limited by difficulties in comparing findings across studies resulting from the use of different measures to assess similar TBI study variables. Standardization of definitions and data elements is an important step toward accelerating the process of data sharing that will ultimately lead to a stronger evidence base for treatment advances. To address this need, recommendations for common data elements (CDEs) for research on TBI were developed through a 2009 national initiative. To ensure that the TBI CDE recommendations are relevant to pediatric populations, the National Institute on Disability and Rehabilitation Research (NIDRR) and the National Institute of Neurological Disorders and Stroke (NINDS) called for a review of the original recommendations. Following the process used for the original initiative, multidisciplinary work groups composed of pediatric TBI experts were formed (Demographics and Clinical Assessment; Biomarkers; Neuroimaging; and Outcomes Assessment). Recommendations for modifications and additions to the original CDEs were developed by the work groups, vetted at a 2010 workshop and further refined in preparation for publication. The pediatric considerations for TBI CDEs are described in a series of articles in this journal. This article describes the efforts leading to this pediatric CDE initiative and the CDE review and development process. It concludes with general recommendations for future iterations of the CDE initiative. C1 [Miller, A. Cate] US Dept Educ, Natl Inst Disabil & Rehabil Res, Washington, DC 20202 USA. [Odenkirchen, Joanne; Hicks, Ramona] NINDS, NIH, Bethesda, MD 20892 USA. [Duhaime, Ann-Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Miller, AC (reprint author), US Dept Educ, Natl Inst Disabil & Rehabil Res, 400 Maryland Ave SW, Washington, DC 20202 USA. EM cate.miller@ed.gov FU National Institute for Disability and Rehabilitation Research of the United States Department of Education (NIDRR/DoE); National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS/NIH) FX We gratefully acknowledge the working group members and chairpersons for their dedication of time and expertise to this initiative. Support for the workshop came from the National Institute for Disability and Rehabilitation Research of the United States Department of Education (NIDRR/DoE) and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS/NIH) NR 14 TC 6 Z9 6 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2012 VL 29 IS 4 BP 634 EP 638 DI 10.1089/neu.2011.1932 PG 5 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 901SQ UT WOS:000300987500003 PM 22091862 ER PT J AU Hunter, JV Wilde, EA Tong, KA Holshouser, BA AF Hunter, Jill V. Wilde, Elisabeth A. Tong, Karen A. Holshouser, Barbara A. TI Emerging Imaging Tools for Use with Traumatic Brain Injury Research SO JOURNAL OF NEUROTRAUMA LA English DT Article DE adults; children; CT; MRI; neuroimaging; TBI ID DIFFUSE AXONAL INJURY; MAGNETIC-RESONANCE-SPECTROSCOPY; CEREBRAL-BLOOD-FLOW; CONTROLLED CORTICAL IMPACT; PROTON MR SPECTROSCOPY; COMMON DATA ELEMENTS; WHITE-MATTER INJURY; CENTRAL-NERVOUS-SYSTEM; WORKING-MEMORY LOAD; SEVERE HEAD TRAUMA AB This article identifies emerging neuroimaging measures considered by the inter-agency Pediatric Traumatic Brain Injury (TBI) Neuroimaging Workgroup. This article attempts to address some of the potential uses of more advanced forms of imaging in TBI as well as highlight some of the current considerations and unresolved challenges of using them. We summarize emerging elements likely to gain more widespread use in the coming years, because of 1) their utility in diagnosis, prognosis, and understanding the natural course of degeneration or recovery following TBI, and potential for evaluating treatment strategies; 2) the ability of many centers to acquire these data with scanners and equipment that are readily available in existing clinical and research settings; and 3) advances in software that provide more automated, readily available, and cost-effective analysis methods for large scale data image analysis. These include multi-slice CT, volumetric MRI analysis, susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), arterial spin tag labeling (ASL), functional MRI (fMRI), including resting state and connectivity MRI, MR spectroscopy (MRS), and hyperpolarization scanning. However, we also include brief introductions to other specialized forms of advanced imaging that currently do require specialized equipment, for example, single photon emission computed tomography (SPECT), positron emission tomography (PET), encephalography (EEG), and magnetoencephalography (MEG)/magnetic source imaging (MSI). Finally, we identify some of the challenges that users of the emerging imaging CDEs may wish to consider, including quality control, performing multi-site and longitudinal imaging studies, and MR scanning in infants and children. C1 [Hunter, Jill V.] Texas Childrens Hosp, Dept Pediat Radiol, Houston, TX 77030 USA. [Hunter, Jill V.; Wilde, Elisabeth A.] Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. [Hunter, Jill V.; Wilde, Elisabeth A.] Baylor Coll Med, Dept Phys Med Rehabil & Neurol, Houston, TX 77030 USA. [Wilde, Elisabeth A.] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Tong, Karen A.; Holshouser, Barbara A.] Loma Linda Univ, Sch Med, Dept Radiol, Loma Linda, CA USA. RP Hunter, JV (reprint author), Texas Childrens Hosp, Dept Pediat Radiol, 6621 Fannin St,W1120, Houston, TX 77030 USA. EM jhunter@bcm.edu FU National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS); United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR); Department of Veterans' Affairs; United States Department of Defense FX This project was jointly supported by the National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS), the United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR), the Department of Veterans' Affairs, and the United States Department of Defense. NR 196 TC 50 Z9 52 U1 7 U2 38 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2012 VL 29 IS 4 BP 654 EP 671 DI 10.1089/neu.2011.1906 PG 18 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 901SQ UT WOS:000300987500005 PM 21787167 ER PT J AU McCauley, SR Wilde, EA Anderson, VA Bedell, G Beers, SR Campbell, TF Chapman, SB Ewing-Cobbs, L Gerring, JP Gioia, GA Levin, HS Michaud, LJ Prasad, MR Swaine, BR Turkstra, LS Wade, SL Yeates, KO AF McCauley, Stephen R. Wilde, Elisabeth A. Anderson, Vicki A. Bedell, Gary Beers, Sue R. Campbell, Thomas F. Chapman, Sandra B. Ewing-Cobbs, Linda Gerring, Joan P. Gioia, Gerard A. Levin, Harvey S. Michaud, Linda J. Prasad, Mary R. Swaine, Bonnie R. Turkstra, Lyn S. Wade, Shari L. Yeates, Keith O. TI Recommendations for the Use of Common Outcome Measures in Pediatric Traumatic Brain Injury Research SO JOURNAL OF NEUROTRAUMA LA English DT Article DE children; infants; outcome assessment, TBI ID CLOSED-HEAD-INJURY; VERBAL-LEARNING-TEST; QUALITY-OF-LIFE; TEST-CHILDRENS VERSION; DIFFICULTIES-QUESTIONNAIRE SDQ; MOTOR FUNCTION MEASURE; PORTLAND ADAPTABILITY INVENTORY; FUNCTIONAL INDEPENDENCE MEASURE; BEHAVIOR RATING INVENTORY; POST-CONCUSSIVE SYMPTOMS AB This article addresses the need for age-relevant outcome measures for traumatic brain injury (TBI) research and summarizes the recommendations by the inter-agency Pediatric TBI Outcomes Workgroup. The Pediatric Workgroup's recommendations address primary clinical research objectives including characterizing course of recovery from TBI, prediction of later outcome, measurement of treatment effects, and comparison of outcomes across studies. Consistent with other Common Data Elements (CDE) Workgroups, the Pediatric TBI Outcomes Workgroup adopted the standard three-tier system in its selection of measures. In the first tier, core measures included valid, robust, and widely applicable outcome measures with proven utility in pediatric TBI from each identified domain including academics, adaptive and daily living skills, family and environment, global outcome, health-related quality of life, infant and toddler measures, language and communication, neuropsychological impairment, physical functioning, psychiatric and psychological functioning, recovery of consciousness, social role participation and social competence, social cognition, and TBI-related symptoms. In the second tier, supplemental measures were recommended for consideration in TBI research focusing on specific topics or populations. In the third tier, emerging measures included important instruments currently under development, in the process of validation, or nearing the point of published findings that have significant potential to be superior to measures in the core and supplemental lists and may eventually replace them as evidence for their utility emerges. C1 [McCauley, Stephen R.] Baylor Coll Med, Cognit Neurosci Lab, Dept Phys Med & Rehabil, Houston, TX 77030 USA. [McCauley, Stephen R.; Wilde, Elisabeth A.; Levin, Harvey S.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [McCauley, Stephen R.; Levin, Harvey S.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [McCauley, Stephen R.; Wilde, Elisabeth A.; Levin, Harvey S.] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Wilde, Elisabeth A.] Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. [Anderson, Vicki A.] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Bedell, Gary] Tufts Univ, Dept Occupat Therapy, Medford, MA 02155 USA. [Beers, Sue R.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Campbell, Thomas F.] Univ Texas Dallas, Callier Ctr Commun Disorders, Commun Disorders Sch Behav & Brain Sci, Dallas, TX 75235 USA. [Chapman, Sandra B.] Univ Texas Dallas, Ctr BrainHlth Behav & Brain Sci, Dallas, TX 75235 USA. [Ewing-Cobbs, Linda; Prasad, Mary R.] Univ Texas Hlth Sci Ctr Houston, Childrens Learning Inst, Houston, TX USA. [Ewing-Cobbs, Linda; Prasad, Mary R.] Univ Texas Hlth Sci Ctr Houston, Dept Psychiat & Behav Sci, Houston, TX USA. [Gerring, Joan P.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Gerring, Joan P.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Gioia, Gerard A.] George Washington Univ, Sch Med, Dept Pediat, Washington, DC 20052 USA. [Gioia, Gerard A.] George Washington Univ, Sch Med, Dept Psychiat, Washington, DC 20052 USA. [Michaud, Linda J.; Wade, Shari L.] Univ Cincinnati, Dept Phys Med & Rehabil, Cincinnati, OH USA. [Michaud, Linda J.; Wade, Shari L.] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. [Michaud, Linda J.; Wade, Shari L.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Swaine, Bonnie R.] Univ Montreal, Ecole Readaptat, Ctr Interdisciplinary Rehabil Res CRIR, Montreal, PQ, Canada. [Turkstra, Lyn S.] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Turkstra, Lyn S.] Univ Wisconsin, Dept Communicat Disorders & Neurol Surg, Madison, WI USA. [Yeates, Keith O.] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. [Yeates, Keith O.] Nationwide Childrens Hosp, Res Inst, Ctr Biobehav Hlth, Columbus, OH USA. RP McCauley, SR (reprint author), Baylor Coll Med, Cognit Neurosci Lab, Dept Phys Med & Rehabil, 1709 Dryden Rd,Suite 1200,BCM635, Houston, TX 77030 USA. EM mccauley@bcm.edu OI Yeates, Keith/0000-0001-7680-2892 FU National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS); United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR) FX This project was jointly supported by the National Institutes of Health (National Institute of Neurological Disorders and Stroke; NIH/NINDS) and the United States Department of Education/National Institute on Disability and Rehabilitation Research (DOE/NIDRR). NR 298 TC 60 Z9 60 U1 9 U2 32 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD MAR PY 2012 VL 29 IS 4 BP 678 EP 705 DI 10.1089/neu.2011.1838 PG 28 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 901SQ UT WOS:000300987500007 PM 21644810 ER PT J AU Subramanian, A Timberlake, M Mittakanti, H Lara, M Brandt, ML AF Subramanian, Anuradha Timberlake, Matthew Mittakanti, Harsha Lara, Michael Brandt, Mary L. TI Novel Educational Approach for Medical Students: Improved Retention Rates Using Interactive Medical Software Compared with Traditional Lecture-Based Format SO JOURNAL OF SURGICAL EDUCATION LA English DT Article DE web-based; surgical education; interactive tool AB BACKGROUND: Mannequin and computer-based simulators are useful for the practice of patient management, physical procedures, and competency. However, they are ineffective in teaching clinical medicine. StepStone Interactive Medical Software (SS) is a web-based medical learning modality that provides the user with a highly focused set of evaluative and interventional tasks to treat memorable virtual patients in a visual case-based format. OBJECTIVE: To determine whether the SS learning modality is superior to traditional lecture format in medical student learning and retention. METHODS: After Institutional Review Board (IRB) approval was obtained and the consents were signed, 30 third-year medical students were assigned randomly to 2 groups of 15 students each: The control group received two 30-minute PowerPoint lectures (Microsoft Corporation, Redmond, Washington) about torsades de pointes (TdP) and pulseless electrical activity (PEA), and the SS group was given 1 hour to review 2 SS cases teaching TdP and PEA. A preintervention test was given to assess their baseline knowledge. An immediate postintervention test was given to both groups. Twenty-two clays later, a long-term retention test was administered. The results were analyzed using a Student t test for continuous variables. RESULTS: The mean scores for the preintervention test in the control and SS groups were 44.9 +/- 3% and 44.1 +/- 2%, respectively (p = 0.41). The mean scores for the postintervention test in the control and SS groups were 61.7 +/- 2% and 86.7 +/- 2%, respectively (p < 0.001). Improvement from baseline knowledge was calculated, and the mean improvement was 16.8 +/- 3% in the control group and 42.5 +/- 2% in the SS group (p < 0.001). The long-term retention test revealed the mean scores of 55.8 +/- 3% in the control group and 70.1 +/- 3% in the SS group (p < 0.001). Long-term improvement from baseline knowledge was calculated and the control group improved by 10.9 +/- 4%, whereas the SS group improved by 26 +/- 3% (p = 0.002). CONCLUSIONS: The SS learning modality demonstrated a significant improvement in student learning retention compared to traditional didactic lecture format. SS is an effective web-based medical education tool. (J Surg 69:253-256. (C) 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.) C1 [Subramanian, Anuradha] Baylor Coll Med, Michael E DeBakey Dept Surg, VA Med Ctr, Houston, TX 77030 USA. RP Subramanian, A (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, VA Med Ctr, 2002 Holcombe Blvd,OCL 112, Houston, TX 77030 USA. EM asubrama@bcm.edu NR 6 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-7204 J9 J SURG EDUC JI J. Surg. Educ. PD MAR-APR PY 2012 VL 69 IS 2 BP 253 EP 256 DI 10.1016/j.jsurg.2011.12.007 PG 4 WC Education, Scientific Disciplines; Surgery SC Education & Educational Research; Surgery GA 906AD UT WOS:000301316400023 PM 22365876 ER PT J AU Hammerness, PG AF Hammerness, Paul G. TI Cardiovascular Events and Methylphenidate Use in Taiwan Reply SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Letter ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; YOUNG-ADULTS; CHILDREN; ADOLESCENTS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hammerness, PG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM phammerness@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2012 VL 51 IS 3 BP 325 EP 326 DI 10.1016/j.jaac.2011.12.012 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 902IG UT WOS:000301031200012 ER PT J AU Niewczas, MA Gohda, T Skupien, J Smiles, AM Walker, WH Rosetti, F Cullere, X Eckfeldt, JH Doria, A Mayadas, TN Warram, JH Krolewski, AS AF Niewczas, Monika A. Gohda, Tomohito Skupien, Jan Smiles, Adam M. Walker, William H. Rosetti, Florencia Cullere, Xavier Eckfeldt, John H. Doria, Alessandro Mayadas, Tanya N. Warram, James H. Krolewski, Andrzej S. TI Circulating TNF Receptors 1 and 2 Predict ESRD in Type 2 Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; CORONARY-HEART-DISEASE; FACTOR-ALPHA; INFLAMMATORY CYTOKINES; RENAL-FUNCTION; RISK; MELLITUS; MARKERS; NEPHROPATHY; WOMEN AB Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria. C1 [Niewczas, Monika A.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. [Niewczas, Monika A.; Gohda, Tomohito; Skupien, Jan; Doria, Alessandro; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Niewczas, Monika A.] Med Univ Warsaw, Dept Immunol Transplantol & Internal Dis, Warsaw, Poland. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. [Rosetti, Florencia; Cullere, Xavier; Mayadas, Tanya N.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Eckfeldt, John H.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU Juvenile Diabetes Research Foundation [1-2008-1018, 3-2009-397]; National Institutes of Health [DK041526, DK067638, DK077111]; American Diabetes Association mentor-based fellowship [7-03-MN-28]; Uehara Memorial Foundation; Yasuhiko Tomino, Juntendo University, Tokyo, Japan; CONACYT Fundacion Mexico FX This study was supported by a Juvenile Diabetes Research Foundation research grant (1-2008-1018) and grants from the National Institutes of Health (DK041526 and DK067638) to ASK.; an American Diabetes Association mentor-based fellowship (7-03-MN-28) to MAN.; a grant from the Uehara Memorial Foundation and a personal grant from Yasuhiko Tomino, Juntendo University, Tokyo, Japan, to T.G.; a Juvenile Diabetes Research Foundation fellowship grant (3-2009-397) to J.S.; grants from the National Institutes of Health to T.N.M. (DK077111 and HL065095) and X.C. (KO1 AR054984); and a graduate student fellowship from CONACYT Fundacion Mexico en Harvard to F.R. NR 36 TC 125 Z9 130 U1 3 U2 10 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 MAR PY 2012 VL 23 IS 3 BP 507 EP 515 DI 10.1681/ASN.2011060627 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 904OD UT WOS:000301206900018 PM 22266663 ER PT J AU Gohda, T Niewczas, MA Ficociello, LH Walker, WH Skupien, J Rosetti, F Cullere, X Johnson, AC Crabtree, G Smiles, AM Mayadas, TN Warram, JH Krolewski, AS AF Gohda, Tomohito Niewczas, Monika A. Ficociello, Linda H. Walker, William H. Skupien, Jan Rosetti, Florencia Cullere, Xavier Johnson, Amanda C. Crabtree, Gordon Smiles, Adam M. Mayadas, Tanya N. Warram, James H. Krolewski, Andrzej S. TI Circulating TNF Receptors 1 and 2 Predict Stage 3 CKD in Type 1 Diabetes SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; SERUM CYSTATIN-C; RENAL-FUNCTION DECLINE; FOLLOW-UP; ALPHA; NEPHROPATHY; GENERATION; KIDNEY; CELLS; RISK AB Elevated plasma concentrations of TNF receptors 1 and 2 (TNFR1 and TNFR2) predict development of ESRD in patients with type 2 diabetes without proteinuria, suggesting these markers may contribute to the pathogenesis of renal decline. We investigated whether circulating markers of the TNF pathway determine GFR loss among patients with type 1 diabetes. We followed two cohorts comprising 628 patients with type 1 diabetes, normal renal function, and no proteinuria. Over 12 years, 69 patients developed estimated GFR less than 60 mL/min per 1.73 m(2) (16 per 1000 person-years). Concentrations of TNFR1 and TNFR2 were strongly associated with risk for early renal decline. Renal decline was associated only modestly with total TNF alpha concentration and appeared unrelated to free TNFa. The cumulative incidence of estimated GFR less than 60 mL/min per 1.73 m(2) for patients in the highest TNFR2 quartile was 60% after 12 years compared with 5%-19% in the remaining quartiles. In Cox proportional hazards analysis, patients with TNFR2 values in the highest quartile were threefold more likely to experience renal decline than patients in the other quartiles (hazard ratio, 3.0; 95% confidence interval, 1.7-5.5). The risk associated with high TNFR1 values was slightly less than that associated with high TNFR2 values. TNFR levels were unrelated to baseline free TNF alpha level and remained stable over long periods within an individual. In conclusion, early GFR loss in patients with type 1 diabetes without proteinuria is strongly associated with circulating TNF receptor levels but not TNF alpha levels (free or total). C1 [Krolewski, Andrzej S.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. [Gohda, Tomohito; Niewczas, Monika A.; Ficociello, Linda H.; Skupien, Jan; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. [Niewczas, Monika A.] Med Univ Warsaw, Dept Immunol Transplantol & Internal Dis, Warsaw, Poland. [Rosetti, Florencia; Cullere, Xavier; Mayadas, Tanya N.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU JDRF [1-2008-1018, 3-2009-397]; National Institutes of Health [DK077111, HL065095, DK041526, DK067638]; Uehara Memorial Foundation; Yasuhiko Tomino (Juntendo University, Tokyo, Japan); American Diabetes Association [7-03-MN-28]; CONACyT Fundacion Mexico FX This study was supported by JDRF Research Grant 1-2008-1018 and Grants DK041526 and DK067638 from the National Institutes of Health to A.S.K., a grant from the Uehara Memorial Foundation to T.G., a personal grant from Yasuhiko Tomino (Juntendo University, Tokyo, Japan) to T.G., an American Diabetes Association mentor-based fellowship (7-03-MN-28) to M.A.N., a JDRF fellowship grant (3-2009-397) to J.S., National Institutes of Health Grants DK077111 and HL065095 to T.N.M. and KO1 AR054984 to X.C., and a graduate student fellowship from CONACyT Fundacion Mexico en Harvard to F.R. NR 35 TC 99 Z9 102 U1 3 U2 5 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 MAR PY 2012 VL 23 IS 3 BP 516 EP 524 DI 10.1681/ASN.2011060628 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 904OD UT WOS:000301206900019 PM 22266664 ER PT J AU Roth, AJ Brown, MC Smith, RN Badhwar, AK Parente, O Chung, HC Bunch, DO McGregor, JG Hogan, SL Hu, YC Yang, JJ Berg, EA Niles, J Jennette, JC Preston, GA Falk, RJ AF Roth, Aleeza J. Brown, Michael C. Smith, Rex Neal Badhwar, Anshul K. Parente, Oscar Chung, Hyun Chul Bunch, Donna O'Dell McGregor, JulieAnne G. Hogan, Susan L. Hu, Yichun Yang, Jia-Jin Berg, Elisabeth A. Niles, John Jennette, J. Charles Preston, Gloria A. Falk, Ronald J. TI Anti-LAMP-2 Antibodies Are Not Prevalent in Patients With Antineutrophil Cytoplasmic Autoantibody Glomerulonephritis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CRESCENTIC GLOMERULONEPHRITIS; SYSTEMIC VASCULITIS; ANCA; GRANULOCYTES; PATHOGENESIS; H-LAMP-2 AB Lysosomal membrane protein 2 (LAMP-2) is a target of antineutrophil cytoplasmic autoantibodies (ANCA) in addition to the more commonly known targets proteinase 3 and myeloperoxidase. The prevalence of anti-LAMP-2 antibodies and their relationship to disease in ANCA glomerulonephritis are not well described. We measured anti-LAMP-2 reactivity in 680 sera samples (two academic centers) from patients with ANCA glomerulonephritis (n=329); those with ANCA-negative glomerulonephritis (n=104); those with fimbriated, gram-negative Escherichia coli urinary tract infection (n=104); disease controls (n=19); and healthy volunteers (n=124). With levels in healthy controls used to define a reference range, anti-LAMP-2 reactivity was present in 21% of ANCA sera from two of the centers; reactivity was present in 16% of the control group with urinary tract infection. Western blotting and immunofluorescence microscopy did not verify positivity. Titers of anti-myeloperoxidase and anti-proteinase 3 antibodies were 1500-fold and 10,000-fold higher than anti-LAMP-2 titers, respectively. There was no correlation between anti-LAMP-2 antibodies and disease activity. Furthermore, Wistar Kyoto rats injected with anti-LAMP-2 antibodies did not develop glomerulonephritis. In conclusion, antibodies that react with LAMP-2 may exist at very low titers in a minority of patients with ANCA disease. These data do not support a mechanistic relationship between anti-LAMP-2 antibodies and ANCA glomerulonephritis. C1 [Roth, Aleeza J.; Brown, Michael C.; Badhwar, Anshul K.; Parente, Oscar; Chung, Hyun Chul; Bunch, Donna O'Dell; McGregor, JulieAnne G.; Hogan, Susan L.; Hu, Yichun; Yang, Jia-Jin; Berg, Elisabeth A.; Jennette, J. Charles; Preston, Gloria A.; Falk, Ronald J.] Univ N Carolina, Kidney Ctr, Dept Med, Div Nephrol & Hypertens, Chapel Hill, NC 27599 USA. [Roth, Aleeza J.; Jennette, J. Charles; Preston, Gloria A.; Falk, Ronald J.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Smith, Rex Neal; Niles, John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Roth, AJ (reprint author), Univ N Carolina, Kidney Ctr, Dept Med, Div Nephrol & Hypertens, CB 7155,5009 Burnett Womack Bldg, Chapel Hill, NC 27599 USA. EM ajroth@med.unc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health [2PO1DK]; National Institutes of Health Training from the National Institute for Environmental Health Sciences [T32 ES 07017]; Howard Hughes Medical Institute (HHMI); HHMI through the Med FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health Grant 2PO1DK, National Institutes of Health Training Grant T32 ES 07017 from the National Institute for Environmental Health Sciences, and the Howard Hughes Medical Institute (HHMI) Med into Grad Scholar, supported in part by a grant to the University of North Carolina at Chapel Hill from HHMI through the Med into Grad Initiative. NR 15 TC 58 Z9 66 U1 1 U2 3 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 MAR PY 2012 VL 23 IS 3 BP 545 EP 555 DI 10.1681/ASN.2011030273 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 904OD UT WOS:000301206900022 PM 22021709 ER PT J AU Lombardi, JV Cambria, RP Nienaber, CA Chiesa, R Teebken, O Lee, A Mossop, P Bharadwaj, P AF Lombardi, Joseph V. Cambria, Richard P. Nienaber, Christoph A. Chiesa, Roberto Teebken, Omke Lee, Anthony Mossop, Peter Bharadwaj, Priya CA STABLE Investigators TI Prospective multicenter clinical trial (STABLE) on the endovascular treatment of complicated type B aortic dissection using a composite device design SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT Vascular Annual Meeting of the Society-for-Vascular-Surgery (SVS)/Plenary Session of William Von Liebig Forum/36th Annual Spring Meeting of the Peripheral-Vascular-Surgery-Society CY JUN 15-18, 2011 CL Chicago, IL SP Soc Vasc Surg (SVS), Peripheral Vasc Surg Soc ID STENT-GRAFT PLACEMENT; ANEURYSM REPAIR; INTERNATIONAL REGISTRY; MANAGEMENT; DISEASES; SOCIETY AB Objective: This study evaluates the safety and effectiveness of a unique composite thoracic endovascular aneurysm repair (TEVAR) construct (proximal stent graft and distal bare metal stent) for the treatment of patients with complicated type B aortic dissection (cTBAD). Methods: In this prospective, single-arm, multicenter study, patients with cTBAD were treated with an endovascular system consisting of proximal TX2 thoracic stent grafts and distal bare metal dissection stents (Zenith Dissection Endovascular System; Cook Medical, Bloomington, Ind). Indications for enrollment were branch vessel malperfusion, impending rupture, aortic diameter >= 40 mm, rapid aortic expansion, and persistent pain or hypertension despite maximum medical therapy. One-year follow-up results, including clinical and radiographic (computerized tomography [ CT] and X-ray) evaluation, were available for this report. Results: Ten centers enrolled 40 patients (70% men; mean age 58 years old) between December 2007 and August 2009. The onset of symptoms was acute (<= 14 days) in 24 patients (60%), subacute (15-30 days) in six patients (15%), and chronic (31-90 days) in 10 patients (25%); the overall mean time from symptom onset to treatment was 20 days (range, 0-78 days). A majority of patients (77.5%; 31 of 40 patients) presented with impending aortic rupture (indicated by periaortic effusion/hematoma) or branch vessel malperfusion. Seven combinations of stent grafts and dissection stents were used, and all devices were successfully deployed and patent. The 30-day mortality rate was 5% (2 of 40); two deaths occurred after 30 days, leading to a 1-year survival rate of 90%. Two deaths, occurring at 11 and 81 days postprocedure, respectively, were secondary to aortic rupture. Morbidity occurring within 30 days included stroke (7.5%), transient ischemic attack (2.5%), paraplegia (2.5%), retrograde progression of dissection (5%), and renal failure (12.5%). Additional morbidity after 30 days included one case of retrograde progression of dissection and one case of renal failure. None of the patients with renal failure became dialysis-dependent. Four patients (10%) underwent secondary interventions within 1 year. Favorable aortic remodeling was observed during the course of follow-up, indicated by an increase in the true lumen size and a concomitant decrease in the false lumen size along the dissected aorta, with completely thrombosed thoracic false lumen observed in 31% of patients at 12 months as compared to 0% at baseline. Conclusions: Initial data with a composite TEVAR construct have demonstrated favorable clinical and anatomic results. Continued enrollment and long-term data are needed to assess the overall effectiveness of this treatment strategy. (J Vasc Surg 2012; 55: 629-40.) C1 [Lombardi, Joseph V.] Cooper Univ Hosp, Div Vasc & Endovasc Surg, Dept Surg, Camden, NJ 08103 USA. [Cambria, Richard P.] Massachusetts Gen Hosp, Div Vasc Surg, Boston, MA 02114 USA. [Nienaber, Christoph A.] Univ Hosp Rostock, Clin Internal Med, Rostock, Germany. [Chiesa, Roberto] Hosp San Raffaele, I-20132 Milan, Italy. [Teebken, Omke] Hannover Med Sch, Dept Cardiac Thorac Transplantat & Vasc Surg, D-3000 Hannover, Germany. [Lee, Anthony] Christine E Lynn Heart & Vasc Inst, Boca Raton, FL USA. [Mossop, Peter] St Vincents Hosp Melbourne, Dept Med Imaging, Fitzroy, Vic, Australia. [Bharadwaj, Priya] MED Inst, W Lafayette, IN USA. RP Lombardi, JV (reprint author), Cooper Univ Hosp, Div Vasc & Endovasc Surg, Dept Surg, 3 Cooper Plaza,Suite 411, Camden, NJ 08103 USA. EM lombardi-joseph@cooperhealth.edu NR 22 TC 63 Z9 69 U1 0 U2 5 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 MAR PY 2012 VL 55 IS 3 BP 629 EP U319 DI 10.1016/j.jvs.2011.10.022 PG 14 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 901DE UT WOS:000300941100001 PM 22169668 ER PT J AU Bechara, CF Barshes, NR Lin, PH Kougias, P AF Bechara, Carlos F. Barshes, Neal R. Lin, Peter H. Kougias, Panagiotis TI Recanalization of flush iliac occlusions with the assistance of a contralateral iliac occlusive balloon SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID RECONSTRUCTION; MANAGEMENT AB Treating flush iliac artery occlusion by endovascular means can be very challenging and is a cause of technical failure requiring open surgical intervention. We describe a simple endovascular technique that can be valuable in increasing technical success and avoiding the use of a re-entry device. The technique involves placing an occlusive contralateral iliac artery balloon to assist in recanalizing a flush iliac artery occlusion. (J Vasc Surg 2012;55:872-4.) C1 Baylor Coll Med, Div Vasc & Endovasc Therapy, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. Michael E DeBakey VA Med Ctr, Houston, TX USA. RP Bechara, CF (reprint author), DeBakey VA Med Ctr, 2002 Holcombe Blvd,112, Houston, TX 77030 USA. EM bechara@bcm.edu NR 9 TC 1 Z9 1 U1 0 U2 0 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 MAR PY 2012 VL 55 IS 3 BP 872 EP 874 DI 10.1016/j.jvs.2011.10.029 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 901DE UT WOS:000300941100038 PM 22169670 ER PT J AU Goodney, PP Fisher, ES Cambria, RP AF Goodney, Philip P. Fisher, Elliott S. Cambria, Richard P. TI Roles for specialty societies and vascular surgeons in accountable care organizations SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; PERIPHERAL ARTERIAL-DISEASE; ABDOMINAL AORTIC-ANEURYSM; CRITICAL LIMB ISCHEMIA; NORTHERN NEW-ENGLAND; MEDICARE-POPULATION; CAROTID-ENDARTERECTOMY; PRACTICE GUIDELINES; AMERICAN-COLLEGE; LOWER-EXTREMITY AB With the passage of the Affordable Care Act, accountable care organizations (ACOs) represent a new paradigm in healthcare payment reform. Designed to limit growth in spending while preserving quality, these organizations aim to incant physicians to lower costs by returning a portion of the savings realized by cost-effective, evidence-based care back to the ACO. In this review, first, we will explore the development of ACOs within the context of prior attempts to control Medicare spending, such as the sustainable growth rate and managed care organizations. Second, we describe the evolution of ACOs, the demonstration projects that established their feasibility, and their current organizational structure. Third, because quality metrics are central to the use and implementation of ACOs, we describe current efforts to design, collect, and interpret quality metrics in vascular surgery. And fourth, because a "seat at the table" will be an important key to success for vascular surgeons in these efforts, we discuss how vascular surgeons can participate and lead efforts within ACOs. (J Vasc Surg 2012;55:875-82.) C1 [Goodney, Philip P.] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Hanover, NH USA. [Goodney, Philip P.; Fisher, Elliott S.] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. [Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Goodney, PP (reprint author), Dartmouth Hitchcock Med Ctr, 1 Med Ctr Dr, Lebanon, NH 03766 USA. EM philip.goodney@hitchcock.org FU NHLBI [1K08HL05676-01]; AVA/ACS FX Dr Goodney was supported by a K08 Award (1K08HL05676-01) from the NHLBI, and a AVA/ACS Supplemental Award. NR 62 TC 10 Z9 10 U1 0 U2 5 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 MAR PY 2012 VL 55 IS 3 BP 875 EP 882 DI 10.1016/j.jvs.2011.10.116 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 901DE UT WOS:000300941100039 PM 22370029 ER PT J AU Sperling, R Salloway, S Brooks, DJ Tampieri, D Barakos, J Fox, NC Raskind, M Sabbagh, M Honig, LS Porsteinsson, AP Lieberburg, I Arrighi, HM Morris, KA Lu, Y Liu, E Gregg, KM Brashear, HR Kinney, GG Black, R Grundman, M AF Sperling, Reisa Salloway, Stephen Brooks, David J. Tampieri, Donatella Barakos, Jerome Fox, Nick C. Raskind, Murray Sabbagh, Marwan Honig, Lawrence S. Porsteinsson, Anton P. Lieberburg, Ivan Arrighi, H. Michael Morris, Kristen A. Lu, Yuan Liu, Enchi Gregg, Keith M. Brashear, H. Robert Kinney, Gene G. Black, Ronald Grundman, Michael TI Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis SO LANCET NEUROLOGY LA English DT Article ID CEREBRAL MICROBLEEDS; ANGIOPATHY; BETA; INFLAMMATION; PREVALENCE; EPSILON-4; PROTEIN; TRIALS; BRAIN; MODEL AB Background Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid beta. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. Methods Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient's treatment, APOE epsilon 4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. Findings 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2.24 per 1 mg/kg increase in dose, 95% CI 1.40-3.62; p=0.0008) and presence of APOE epsilon 4 alleles (HR 2.55 per allele, 95% CI 1.57-4.12; p=0.0001). Interpretation ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE e4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. C1 [Sperling, Reisa] Harvard Univ, Sch Med, Brigham & Womens Hosp,Ctr Alzheimer Res & Treatme, Memory Disorders Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Salloway, Stephen] Butler Hosp, Providence, RI 02906 USA. [Brooks, David J.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Ctr Neurosci, London, England. [Tampieri, Donatella] McGill Univ, Montreal, PQ, Canada. [Barakos, Jerome] Calif Pacific Med Ctr, Francisco, CA USA. [Fox, Nick C.] UCL, Inst Neurol, London, England. [Raskind, Murray] VA Med Ctr, Seattle, WA USA. [Sabbagh, Marwan] Cleo Roberts Ctr Clin Res, Sun Hlth Res Inst, Sun City, AZ USA. [Honig, Lawrence S.] Columbia Univ, New York, NY USA. [Porsteinsson, Anton P.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Lieberburg, Ivan] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. [Arrighi, H. Michael; Morris, Kristen A.; Lu, Yuan; Liu, Enchi; Gregg, Keith M.; Brashear, H. Robert; Kinney, Gene G.; Grundman, Michael] Janssen Alzheimer Immunotherapy Res & Dev, San Francisco, CA USA. [Black, Ronald] Pifzer, Collegeville, PA USA. [Grundman, Michael] Global R&D Partners, San Diego, CA USA. RP Sperling, R (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Ctr Alzheimer Res & Treatme, Memory Disorders Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM reisa@rics.bwh.harvard.edu RI Fox, Nick/B-1319-2009; OI Fox, Nick/0000-0002-6660-657X; Brooks, David/0000-0003-2602-2518 FU Elan Corporation; Janssen Alzheimer Immunotherapy; Wyeth Pharmaceuticals; Pfizer; Celgene Corporation; Ceregene; Bayer AG; Baxter International; Bristol-Myers Squibb; Eli Lilly and Company; Janssen Alzheimer Immunotherapy Research and Development; Avid Radiopharmaceuticals; Genentech; Eisai; Hoffmann-La Roche; Medivation; Toyama Chemical Co; Elan Corporation (South San Francisco, CA, USA FX Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.; RS has served as a study investigator and a consultant for Janssen Alzheimer Immunotherapy Research and Development, and for Pfizer, and has received honoraria for participation in symposia. She has also served as a consultant or site investigator or both for Bristol-Myers Squibb, Roche, Elan, Biogen-IDEC, Avid, and Bayer. SS has served as a consultant and study investigator for Janssen Alzheimer Immunotherapy Research and Development, Pfizer, and Elan Corporation phase 2 and 3 studies of bapineuzumab. DT provides review of MRI images for Janssen Alzheimer Immunotherapy Research and Development. JB serves as a neuroradiological consultant to SYNARC, an imaging contract research organisation contracted by both sponsor companies; he also serves as a consultant to Janssen Alzheimer Immunotherapy Research and Development for non-clinical research activities. NCF has provided consulting or image analysis services or both to Elan Corporation, Janssen Alzheimer Immunotherapy Research and Development, Pfizer, Wyeth Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GE Healthcare, Lundbec.k A/S, and IXICO. MR serves as consultant to Janssen Alzheimer Immunotherapy Research and Development. MS participates in a consulting and advisory capacity for Eli Lilly and Company, Amerisciences, Takeda Pharmaceuticals, Eisai, Pfizer, and GlaxoSmithKline, and receives royalties from Wiley and AmeriSciences. He receives contracting fees and grants from Celgene Corporation, Ceregene, Bayer AG, Baxter International, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Janssen Alzheimer Immunotherapy Research and Development, Avid Radiopharmaceuticals, Genentech, and Eisai. LSH serves on the study steering committee and has acted as a consultant for Janssen Alzheimer Immunotherapy Research and Development, but receives less than US$10000 yearly for such consulting activities. APP has received grant and research support from Baxter International, Bristol-Myers Squibb, Eisai, Elan Corporation, Genentech, Hoffmann-La Roche, Janssen Alzheimer Immunotherapy Research and Development, Medivation, Pfizer, and Toyama Chemical Co. He has also served as a consultant and participated on advisory boards for Elan Corporation, Janssen Alzheimer Immunotherapy Research and Development, Medivation, Pfizer, Transition Therapeutics, and Toyama Chemical Co. He is also a member of the speakers' bureau for Forest Laboratories. RB is an employee of and receives stock and stock options from Pfizer. H MA, KAM, YL, EL, KMG, HRB, and GGK are employees of Janssen Alzheimer lmmunotherapy Research and Development. IL, H MA, ICAM, YL, EL, KMG, and GGK are stockholders in Elan Corporation. MG is a consultant to Janssen Alzheimer Immunotherapy Research and Development and is a stockholder in Elan Corporation. DJB declares no conflicts of interest.; This study was sponsored by Elan Corporation (South San Francisco, CA, USA; Janssen Alzheimer Immunotherapy acquired the Alzheimer Immunotherapy Program from Elan Corporation in September, 2009) and Wyeth Pharmaceuticals (Collegeville, PA, USA; which was acquired by Pfizer in October, 2009). We thank Lorna Fang for her contributions to the analytic programming, and Selena Scaglione and Mark McGovern for their contributions to study operation and management. Editorial support was provided by Elizabeth Yepez (Phase Five Communications; New York, NY, USA), and was funded by Janssen Alzheimer Immunotherapy Research and Development. Her involvement consisted of manuscript formatting only, and no contribution was made to content. NR 27 TC 149 Z9 152 U1 6 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2012 VL 11 IS 3 BP 241 EP 249 DI 10.1016/S1474-4422(12)70015-7 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 902BZ UT WOS:000301014900012 PM 22305802 ER PT J AU Smith, EE Schneider, JA Wardlaw, JM Greenberg, SM AF Smith, Eric E. Schneider, Julie A. Wardlaw, Joanna M. Greenberg, Steven M. TI Cerebral microinfarcts: the invisible lesions SO LANCET NEUROLOGY LA English DT Review ID SMALL VESSEL DISEASE; CORTICAL WATERSHED MICROINFARCTS; APPARENT DIFFUSION-COEFFICIENT; WHITE-MATTER LESIONS; AMYLOID ANGIOPATHY; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; ISCHEMIC-STROKE; BLOOD-PRESSURE; PATHOLOGICAL CORRELATION AB The association between small but still visible lacunar infarcts and cognitive decline has been established by population-based radiological and pathological studies. Microscopic examination of brain sections shows even smaller but substantially more numerous microinfarcts, the focus of this Review. These lesions often result from small vessel pathologies such as arteriolosclerosis or cerebral amyloid angiopathy. They typically go undetected in clinical radiological correlation studies that rely on conventional structural MRI, although the largest acute microinfarcts can be detected by diffusion-weighted imaging. In view of their high numbers and widespread distribution, microinfarcts could directly disrupt important cognitive networks and thus account for some of the neurological dysfunction associated with lesions visible on conventional MRI such as lacunar infarcts and white matter hyperintensities. Standardised neuropathological assessment criteria and the development of non-invasive means of detection during life would be major steps towards understanding the causes and consequences of otherwise macroscopically invisible microinfarcts. C1 [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Kistler Stroke Res Ctr, Boston, MA 02114 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, Calgary, AB, Canada. [Schneider, Julie A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Dept Pathol, Chicago, IL 60612 USA. [Schneider, Julie A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Wardlaw, Joanna M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol CCACE, Edinburgh, Midlothian, Scotland. [Wardlaw, Joanna M.] Scottish Imaging Network Platform Sci Excellence, Edinburgh, Midlothian, Scotland. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Kistler Stroke Res Ctr, 175 Cambridge St, Boston, MA 02114 USA. EM sgreenberg@partners.org OI Smith, Eric/0000-0003-3956-1668 FU Alberta Innovates Health Solutions; Alberta Heritage Fund for Medical Research; Canadian Institutes of Health Research; Scottish Funding Council; National Institutes of Health for the study of microinfarcts in cerebral amyloid angiopathy [2R01 AG26484-01] FX No external funding was obtained for this Review. EES receives salary support from Alberta Innovates Health Solutions (funded by the Alberta Heritage Fund for Medical Research) and the Canadian Institutes of Health Research. JMW receives partial funding support from the Scottish Funding Council. SMG receives salary support from the National Institutes of Health including for the study of microinfarcts in cerebral amyloid angiopathy (2R01 AG26484-01). SMG had full access to all the data and had the final responsibility for the decision to submit for publication. We thank Chunhui Yang for contributions to figure 1; Eric Jouvent and Hugues Chabriat for contributing figure 2; Dorothea Strozyk, Joe Verghese, and Richard O'Brien for contributing unpublished data used in table 1 and figure 4; and Chelsea Kidwell for providing details of her studies presented at the 2010 International Stroke Conference and published in abstract form. NR 95 TC 138 Z9 145 U1 7 U2 43 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2012 VL 11 IS 3 BP 272 EP 282 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 902BZ UT WOS:000301014900015 PM 22341035 ER PT J AU Reddy, MM Fernandes, MS Deshpande, A Weisberg, E Inguilizian, HV Abdel-Wahab, O Kung, AL Levine, RL Griffin, JD Sattler, M AF Reddy, M. M. Fernandes, M. S. Deshpande, A. Weisberg, E. Inguilizian, H. V. Abdel-Wahab, O. Kung, A. L. Levine, R. L. Griffin, J. D. Sattler, M. TI The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity SO LEUKEMIA LA English DT Article DE myeloid neoplasia; tyrosine kinase oncogene; signal transduction; PFKFB3; JAK2 ID FRUCTOSE 2,6-BISPHOSPHATE; CANCER-CELLS; TRANSCRIPTION FACTORS; 6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE; 6-PHOSPHOFRUCTO-2-KINASE; INHIBITION; MYC; PATHWAY; FAMILY; PFKFB3 AB Myeloproliferative neoplasms are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would, therefore, be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers. Leukemia (2012) 26, 481-489; doi:10.1038/leu.2011.225; published online 23 August 2011 C1 [Reddy, M. M.; Fernandes, M. S.; Deshpande, A.; Weisberg, E.; Griffin, J. D.; Sattler, M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Reddy, M. M.; Fernandes, M. S.; Deshpande, A.; Weisberg, E.; Griffin, J. D.; Sattler, M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Reddy, M. M.; Fernandes, M. S.; Deshpande, A.; Weisberg, E.; Griffin, J. D.; Sattler, M.] Harvard Univ, Sch Med, Boston, MA USA. [Inguilizian, H. V.; Kung, A. L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA. [Abdel-Wahab, O.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, O.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA. [Kung, A. L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. RP Sattler, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM martin_sattler@dfci.harvard.edu OI Abdel-Wahab, Omar/0000-0002-3907-6171; Kung, Andrew/0000-0002-9091-488X FU National Institutes of Health [CA134660-03] FX This study was supported in part by the National Institutes of Health grant (CA134660-03, MS). RLL is a Geoffrey Beene Junior Chair. NR 35 TC 12 Z9 12 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAR PY 2012 VL 26 IS 3 BP 481 EP 489 DI 10.1038/leu.2011.225 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 905RK UT WOS:000301290300014 PM 21860432 ER PT J AU Fan, AP Benner, T Bolar, DS Rosen, BR Adalsteinsson, E AF Fan, Audrey P. Benner, Thomas Bolar, Divya S. Rosen, Bruce R. Adalsteinsson, Elfar TI Phase-based regional oxygen metabolism (PROM) using MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cerebral metabolic rate of oxygen; cerebral venous oxygen saturation; cerebral blood flow; MR susceptometry ID CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; MAGNETIC-SUSCEPTIBILITY; HIGH-FIELD; OXIDATIVE-METABOLISM; RELAXATION-TIME; BRAIN; CORTEX; SUSCEPTOMETRY; VALIDATION AB Venous oxygen saturation (Yv) in cerebral veins and the cerebral metabolic rate of oxygen (CMRO2) are important indicators for brain function and disease. Although MRI has been used for global measurements of these parameters, currently there is no recognized technique to quantify regional Yv and CMRO2 using noninvasive imaging. This article proposes a technique to quantify CMRO2 from independent MRI estimates of Yv and cerebral blood flow. The approach uses standard gradient-echo and arterial spin labeling acquisitions to make these measurements. Using MR susceptometry on gradient-echo phase images, Yv was quantified for candidate vein segments in gray matter that approximate a long cylinder parallel to the main magnetic field. Local cerebral blood flow for the identified vessel was determined from a corresponding region in the arterial spin labeling perfusion map. Fick's principle of arteriovenous difference was then used to quantify CMRO2 locally around each vessel. Application of this method in young, healthy subjects provided gray matter averages of 59.6% +/- 2.3% for Yv, 51.7 +/- 6.4 mL/100 g/min for cerebral blood flow, and 158 +/- 18 mu ol/100 g/min for CMRO2 (mean +/- SD, n = 12), which is consistent with values previously reported by positron emission tomography and MRI. Magn Reson Med, 2012. (c) 2011 Wiley Periodicals, Inc. C1 [Fan, Audrey P.; Bolar, Divya S.; Adalsteinsson, Elfar] MIT, Elect Res Lab, Dept Elect Engn & Comp Sci, Magnet Resonance Imaging Grp, Cambridge, MA 02139 USA. [Benner, Thomas; Bolar, Divya S.; Rosen, Bruce R.; Adalsteinsson, Elfar] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Fan, Audrey P.; Bolar, Divya S.; Rosen, Bruce R.; Adalsteinsson, Elfar] Harvard MIT Hlth Sci & Technol, Cambridge, MA USA. RP Fan, AP (reprint author), MIT, Elect Res Lab, Dept Elect Engn & Comp Sci, Magnet Resonance Imaging Grp, 32 Vassar St,Room 36-792, Cambridge, MA 02139 USA. EM apfan@mit.edu FU NIH [T90-DA022759, T32-GM07753, R01-EB007942]; Siemens Healthcare; Siemens Healthcare, Siemens-MIT Alliance FX Grant sponsor: NIH; Grant numbers: T90-DA022759, T32-GM07753, R01-EB007942; Grant sponsor: Siemens Healthcare; Grant sponsor: Siemens Healthcare, Siemens-MIT Alliance. NR 45 TC 41 Z9 44 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD MAR PY 2012 VL 67 IS 3 BP 669 EP 678 DI 10.1002/mrm.23050 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 897UO UT WOS:000300683900011 PM 21713981 ER PT J AU Cummings, DE Bloom, SR Rubino, F AF Cummings, David E. Bloom, Stephen R. Rubino, Francesco TI At the heart of the benefits of bariatric surgery SO NATURE MEDICINE LA English DT Editorial Material ID MORTALITY; WEIGHT; OBESE AB Obesity is associated with an increased risk of cardiovascular events, thus weight loss would be expected to have a beneficial effect on cardiovascular disease. This view is supported by a recent paper that used participants from the ongoing Swedish Obese Subjects (SOS) study, a nonrandomized, prospective study to investigate the effects of bariatric surgery on cardiovascular disease(1). Individuals who underwent bariatric surgery had a significantly reduced number of total and fatal cardiovascular events compared with matched obese controls who did not undergo surgery. Surprisingly, the reduction in cardiovascular events was not related to the baseline body mass index (BMI) or the weight loss experienced by the treated patients. We asked three experts how this study affects understanding of the relationship between weight loss, metabolic and cardiovascular disease, as well as how bariatric surgery may mediate its effects on human health. C1 [Cummings, David E.] Univ Washington, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Cummings, David E.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Bloom, Stephen R.] Imperial Coll London Hammersmith, London, England. [Rubino, Francesco] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. RP Cummings, DE (reprint author), Univ Washington, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. NR 12 TC 1 Z9 1 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 MAR PY 2012 VL 18 IS 3 BP 358 EP 359 DI 10.1038/nm0312-358 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800034 PM 22395701 ER PT J AU Lipson, D Capelletti, M Yelensky, R Otto, G Parker, A Jarosz, M Curran, JA Balasubramanian, S Bloom, T Brennan, KW Donahue, A Downing, SR Frampton, GM Garcia, L Juhn, F Mitchell, KC White, E White, J Zwirko, Z Peretz, T Nechushtan, H Soussan-Gutman, L Kim, J Sasaki, H Kim, HR Park, SI Ercan, D Sheehan, CE Ross, JS Cronin, MT Janne, PA Stephens, PJ AF Lipson, Doron Capelletti, Marzia Yelensky, Roman Otto, Geoff Parker, Alex Jarosz, Mirna Curran, John A. Balasubramanian, Sohail Bloom, Troy Brennan, Kristina W. Donahue, Amy Downing, Sean R. Frampton, Garrett M. Garcia, Lazaro Juhn, Frank Mitchell, Kathy C. White, Emily White, Jared Zwirko, Zac Peretz, Tamar Nechushtan, Hovav Soussan-Gutman, Lior Kim, Jhingook Sasaki, Hidefumi Kim, Hyeong Ryul Park, Seung-il Ercan, Dalia Sheehan, Christine E. Ross, Jeffrey S. Cronin, Maureen T. Jaenne, Pasi A. Stephens, Philip J. TI Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies SO NATURE MEDICINE LA English DT Article ID MUTATIONS; SENSITIVITY; CARCINOMAS; ACTIVATION; INHIBITOR; GEFITINIB; ERLOTINIB; CETUXIMAB; PATHWAYS; TUMORS AB Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non-small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8-3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET. C1 [Lipson, Doron; Yelensky, Roman; Otto, Geoff; Parker, Alex; Jarosz, Mirna; Curran, John A.; Balasubramanian, Sohail; Bloom, Troy; Brennan, Kristina W.; Donahue, Amy; Downing, Sean R.; Frampton, Garrett M.; Garcia, Lazaro; Juhn, Frank; Mitchell, Kathy C.; White, Emily; White, Jared; Zwirko, Zac; Ross, Jeffrey S.; Cronin, Maureen T.; Stephens, Philip J.] Fdn Med, Cambridge, MA USA. [Capelletti, Marzia; Ercan, Dalia; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Peretz, Tamar; Nechushtan, Hovav] Hadassah Hebrew Univ Med Ctr, Sharett Inst Oncol, Jerusalem, Israel. [Soussan-Gutman, Lior] Oncotest Teva Pharmaceut Ind, Petah Tiqwa, Israel. [Kim, Jhingook] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Thorac Surg, Seoul, South Korea. [Sasaki, Hidefumi] Nagoya City Univ, Dept Oncol Immunol & Surg 2, Grad Sch Med Sci, Nagoya, Aichi, Japan. [Kim, Hyeong Ryul; Park, Seung-il] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Thorac Surg, Seoul, South Korea. [Sheehan, Christine E.; Ross, Jeffrey S.] Albany Med Ctr, Dept Pathol, Albany, NY USA. RP Stephens, PJ (reprint author), Fdn Med, Cambridge, MA USA. EM mcronin@foundationmedicine.com; pjanne@partners.org; pstephens@foundationmedicine.com FU Dana Farber/Harvard Cancer Center Lung Cancer SPORE [P50 CA090578]; Cammarata Family Foundation; Dana-Farber Cancer Institute; Japan Society for the Promotion of Science (JSPS) [23659674, 21390394, 21591820] FX We would like to thank M. Hawryluk for his help in preparing this manuscript. This work is supported by the Dana Farber/Harvard Cancer Center Lung Cancer SPORE P50 CA090578 (P.A.J.), the Cammarata Family Foundation Research Fund (M. C. and P.A.J.), the Nirenberg Fellowship at the Dana-Farber Cancer Institute (M. C. and P.A.J.) and the Japan Society for the Promotion of Science (JSPS), grant references 23659674, 21390394 and 21591820 (H.S.). NR 20 TC 366 Z9 383 U1 10 U2 59 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 MAR PY 2012 VL 18 IS 3 BP 382 EP 384 DI 10.1038/nm.2673 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800038 PM 22327622 ER PT J AU Lu, MJ Wan, M Leavens, KF Chu, QW Monks, BR Fernandez, S Ahima, RS Ueki, K Kahn, CR Birnbaum, MJ AF Lu, Mingjian Wan, Min Leavens, Karla F. Chu, Qingwei Monks, Bobby R. Fernandez, Sully Ahima, Rexford S. Ueki, Kohjiro Kahn, C. Ronald Birnbaum, Morris J. TI Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1 SO NATURE MEDICINE LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; PROTEIN-KINASE-B; MTOR COMPLEX 1; GLUCOSE-PRODUCTION; GENE-EXPRESSION; LIPID-METABOLISM; MICE LACKING; FACTOR FKHR; GROWTH; PHOSPHORYLATION AB Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin-and nutrient-mediated hepatic metabolic regulation in vivo. C1 [Lu, Mingjian; Wan, Min; Leavens, Karla F.; Chu, Qingwei; Monks, Bobby R.; Fernandez, Sully; Ahima, Rexford S.; Birnbaum, Morris J.] Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ueki, Kohjiro] Univ Tokyo, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo, Japan. [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. RP Birnbaum, MJ (reprint author), Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA. EM birnbaum@mail.med.upenn.edu OI Birnbaum, Morris/0000-0001-9972-8680 FU NIH [P30 DK19525]; US National Institutes of Health [RO1 DK56886]; diabetes training grant [T32 DK007314] FX The authors would like to thank M. Magnuson (Vanderbilt University) for providing the antibody to Gck and D. Accili (Columbia University) for sharing the Foxo1loxP/loxP mice. We are grateful to J. Schug, who helped with the microarray data analysis and generated the heat map and the density plot. The Functional Genomics Core and the Transgenic, Knockout, Mouse Phenotyping and Biomarker Cores of the University of Pennsylvania Diabetes and Endocrinology Research Center (NIH grant P30 DK19525) were instrumental in this work. This work was supported by the US National Institutes of Health grant RO1 DK56886 (M. J. B.) and the diabetes training grant T32 DK007314 (M.L.). NR 59 TC 100 Z9 104 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 MAR PY 2012 VL 18 IS 3 BP 388 EP U254 DI 10.1038/nm.2686 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800040 PM 22344295 ER PT J AU Sugimoto, H LeBleu, VS Bosukonda, D Keck, P Taduri, G Bechtel, W Okada, H William, C Bey, P Rusckowski, M Tampe, B Tampe, D Kanasaki, K Zeisberg, M Kalluri, R AF Sugimoto, Hikaru LeBleu, Valerie S. Bosukonda, Dattatreyamurty Keck, Peter Taduri, Gangadhar Bechtel, Wibke Okada, Hirokazu Carlson, William, Jr. Bey, Philippe Rusckowski, Mary Tampe, Bjoern Tampe, Desiree Kanasaki, Keizo Zeisberg, Michael Kalluri, Raghu TI Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis SO NATURE MEDICINE LA English DT Article ID BONE MORPHOGENETIC PROTEIN-7; TO-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; DIABETIC-NEPHROPATHY; RENAL FIBROSIS; TRANSFORMING GROWTH-FACTOR-BETA-2; CRYSTAL-STRUCTURE; TISSUE FIBROSIS; EXPRESSION; PROGRESSION AB Molecules associated with the transforming growth factor beta (TGF-beta) superfamily, such as bone morphogenic proteins (BMPs) and TGF-beta, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-beta 1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis. C1 [Sugimoto, Hikaru; LeBleu, Valerie S.; Taduri, Gangadhar; Bechtel, Wibke; Okada, Hirokazu; Kanasaki, Keizo; Zeisberg, Michael; Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA. [Bosukonda, Dattatreyamurty; Keck, Peter; Carlson, William, Jr.] Thrasos Innovat Inc, Montreal, PQ, Canada. [Carlson, William, Jr.; Bey, Philippe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Rusckowski, Mary] Univ Massachusetts, Div Nucl Med, Dept Radiol, Coll Med, Worcester, MA 01605 USA. [Tampe, Bjoern; Tampe, Desiree; Zeisberg, Michael; Kalluri, Raghu] Univ Gottingen, Goettingen Univ Med Ctr, Dept Nephrol & Rheumatol, D-3400 Gottingen, Germany. [Kalluri, Raghu] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Boston, MA USA. [Kalluri, Raghu] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Kalluri, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA. EM rkalluri@bidmc.harvard.edu RI LeBleu, Valerie /E-2991-2015; Kalluri, Raghu/E-2677-2015 OI Kalluri, Raghu/0000-0002-2190-547X FU US National Institutes of Health [DK55001, DK061688, DK081576, DK074558, CA155370 CA163191, CA125550, CA151925]; Else Kroner-Memorial-Stipend [P58/05//EKMS 05/59]; Research Training Grant in Gastroenterology [2T32DK007760-11]; Research Training Grant in Cardiovascular Biology [5T32HL007374-30] FX This study was supported by US National Institutes of Health grants DK55001, DK061688, DK081576, DK074558, CA155370 CA163191, CA125550, CA151925 and the Else Kroner-Memorial-Stipend P58/05//EKMS 05/59 (M.Z.). V. S. L. is funded from the Research Training Grant in Gastroenterology (2T32DK007760-11). H. S. is funded by the Research Training Grant in Cardiovascular Biology (5T32HL007374-30). Mice with the Alk3flox/flox allele (Alk3f/f) were kindly provided by Y. Mishina, US National Institutes of Health under a material transfer agreement. gamma GT-Cre mice, NP-1 cells and the polyclonal antibody to FSP1 were provided by E. Neilson, Vanderbilt University Medical Center. We thank S. McGoohan for his technical assistance. NR 40 TC 83 Z9 88 U1 3 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 EI 1546-170X J9 NAT MED JI Nat. Med. PD MAR PY 2012 VL 18 IS 3 BP 396 EP U264 DI 10.1038/nm.2629 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800041 PM 22306733 ER PT J AU White, YAR Woods, DC Takai, Y Ishihara, O Seki, H Tilly, JL AF White, Yvonne A. R. Woods, Dori C. Takai, Yasushi Ishihara, Osamu Seki, Hiroyuki Tilly, Jonathan L. TI Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women SO NATURE MEDICINE LA English DT Article ID EMBRYONIC STEM-CELLS; ADULT MAMMALIAN OVARIES; FEMALE INFERTILITY; GENE-EXPRESSION; BONE-MARROW; TRANSPLANTATION; MOUSE; MICE; OOGENESIS; PROTEIN AB Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in vivo have been identified in and isolated from adult mouse ovaries. Here we describe and validate a fluorescence-activated cell sorting-based protocol that can be used with adult mouse ovaries and human ovarian cortical tissue to purify rare mitotically active cells that have a gene expression profile that is consistent with primitive germ cells. Once established in vitro, these cells can be expanded for months and can spontaneously generate 35- to 50-mu m oocytes, as determined by morphology, gene expression and haploid (1n) status. Injection of the human germline cells, engineered to stably express GFP, into human ovarian cortical biopsies leads to formation of follicles containing GFP-positive oocytes 1-2 weeks after xenotransplantation into immunodeficient female mice. Thus, ovaries of reproductive-age women, similar to adult mice, possess rare mitotically active germ cells that can be propagated in vitro as well as generate oocytes in vitro and in vivo. C1 [White, Yvonne A. R.; Woods, Dori C.; Tilly, Jonathan L.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [White, Yvonne A. R.; Woods, Dori C.; Tilly, Jonathan L.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki] Saitama Med Univ, Saitama Med Ctr, Dept Obstet & Gynecol, Saitama, Japan. RP Tilly, JL (reprint author), Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. EM jtilly@partners.org FU US National Institute on Aging [NIH R37-AG012279]; Henry and Vivian Rosenberg Philanthropic Fund; Sea Breeze Foundation; Vincent Memorial Hospital; NIH [F32-AG034809] FX The authors thank L. Prickett-Rice and K. Folz-Donahue of the Harvard Stem Cell Institute Flow Cytometry Core Facility and J. Groeneweg for expert technical assistance. We also thank J. R. Mann and K. J. MacLaughlin for the provision of TgOG2 transgenic mice. This work was supported by a Method to Extend Research in Time (MERIT) Award from the US National Institute on Aging (NIH R37-AG012279), the Henry and Vivian Rosenberg Philanthropic Fund, the Sea Breeze Foundation and Vincent Memorial Hospital Research Funds. This work was conducted while D. C. W. was supported in part by a Ruth L. Kirschstein National Research Service Award (NIH F32-AG034809). NR 50 TC 219 Z9 234 U1 12 U2 102 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 MAR PY 2012 VL 18 IS 3 BP 413 EP U176 DI 10.1038/nm.2669 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800043 PM 22366948 ER PT J AU Eichhorn, PJA Rodon, L Gonzalez-Junca, A Dirac, A Gili, M Martinez-Saez, E Aura, C Barba, I Peg, V Prat, A Cuartas, I Jimenez, J Garcia-Dorado, D Sahuquillo, J Bernards, R Baselga, J Seoane, J AF Eichhorn, Pieter J. A. Rodon, Laura Gonzalez-Junca, Alba Dirac, Annette Gili, Maguei Martinez-Saez, Elena Aura, Claudia Barba, Ignasi Peg, Vicente Prat, Aleix Cuartas, Isabel Jimenez, Jose Garcia-Dorado, David Sahuquillo, Juan Bernards, Rene Baselga, Jose Seoane, Joan TI USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma SO NATURE MEDICINE LA English DT Article ID E3 UBIQUITIN LIGASE; GROWTH-FACTOR-BETA; GLIOMA; SMURF2; DEGRADATION; PATHWAY; SMAD7; GENETICS; TARGETS; BIOLOGY AB In advanced cancer, including glioblastoma, the transforming growth factor beta (TGF-beta) pathway acts as an oncogenic factor and is considered to be a therapeutic target. Using a functional RNAi screen, we identified the deubiquitinating enzyme ubiquitin-specific peptidase 15 (USP15) as a key component of the TGF-beta signaling pathway. USP15 binds to the SMAD7-SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) complex and deubiquitinates and stabilizes type I TGF-beta receptor (T beta R-I), leading to an enhanced TGF-beta signal. High expression of USP15 correlates with high TGF-beta activity, and the USP15 gene is found amplified in glioblastoma, breast and ovarian cancer. USP15 amplification confers poor prognosis in individuals with glioblastoma. Downregulation or inhibition of USP15 in a patient-derived orthotopic mouse model of glioblastoma decreases TGF-beta activity. Moreover, depletion of USP15 decreases the oncogenic capacity of patient-derived glioma-initiating cells due to the repression of TGF-beta signaling. Our results show that USP15 regulates the TGF-beta pathway and is a key factor in glioblastoma pathogenesis. C1 [Seoane, Joan] Vall dHebron Univ Hosp, VHIO, Barcelona, Spain. [Dirac, Annette; Bernards, Rene] Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands. [Dirac, Annette; Bernards, Rene] Netherlands Canc Inst, Ctr Biomed Genet, Amsterdam, Netherlands. [Martinez-Saez, Elena; Barba, Ignasi; Peg, Vicente; Garcia-Dorado, David; Sahuquillo, Juan] Vall dHebron Univ Hosp, VHIR, Barcelona, Spain. [Prat, Aleix] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Baselga, Jose; Seoane, Joan] Univ Autonoma Barcelona, Cerdanyola Del Valless, Spain. [Baselga, Jose] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Seoane, Joan] ICREA, Barcelona, Spain. RP Seoane, J (reprint author), Vall dHebron Univ Hosp, VHIO, Barcelona, Spain. EM jseoane@vhio.net RI Barba, Ignasi/H-5104-2013; Prat, Aleix/P-8561-2014; Sahuquillo, Juan/B-3577-2008; OI Prat, Aleix/0000-0003-2377-540X; Sahuquillo, Juan/0000-0003-0713-5875; Peg, Vicente/0000-0002-5203-6166; Martinez-Saez, Elena/0000-0001-6004-5364 FU Medical Oncology department; Neurosurgery department; Pathology department of the Vall d'Hebron Hospital; Instituto Carlos III [CM09/143, FIS (PI070648)]; Red Tematica de Investigacion Cooperativa en Enfermedades Cardiovasculares (RECAVA, ISCIII); European Research Council [ERC 205819]; Ministry of Science and Innovation [CSD2009-00080]; Asociacion Espanola Contra el Cancer (AECC) FX We thank A. Saez-Border as and A. Arias for technical support. We also thank the Medical Oncology department, the Neurosurgery department and the Pathology department of the Vall d'Hebron Hospital for support. E. M. S. is supported by the Instituto Carlos III (CM09/143). I. B. and D.G.-D. were supported by the Red Tematica de Investigacion Cooperativa en Enfermedades Cardiovasculares (RECAVA, ISCIII). This work was supported by the European Research Council grant (ERC 205819), Instituto Carlos III grant FIS (PI070648), Ministry of Science and Innovation grant Consolider Ingenio 2010 program (CSD2009-00080) and the Asociacion Espanola Contra el Cancer (AECC) grant. NR 37 TC 112 Z9 117 U1 2 U2 26 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 MAR PY 2012 VL 18 IS 3 BP 429 EP U192 DI 10.1038/nm.2619 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905IF UT WOS:000301264800045 PM 22344298 ER PT J AU Rugge, M Fassan, M Graham, DY AF Rugge, Massimo Fassan, Matteo Graham, David Y. TI Secondary prevention of gastric cancer SO NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY LA English DT Editorial Material ID STOMACH; DIAGNOSIS AB The natural history of 'epidemic' intestinal-type gastric cancer provides consistent data that enable clinicians to design multidisciplinary strategies for secondary prevention. A recent paper by Dinis-Ribeiro et al. reports guidelines for the management of patients with precancerous stomach lesions. C1 [Rugge, Massimo; Fassan, Matteo] Univ Padua, Dept Med, Surg Pathol & Cytopathol Unit, I-35121 Padua, PD, Italy. [Graham, David Y.] Baylor Coll Med, Div Digest Dis, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Rugge, M (reprint author), Univ Padua, Dept Med, Surg Pathol & Cytopathol Unit, Via Aristide Gabelli 61, I-35121 Padua, PD, Italy. EM massimo.rugge@unipd.it RI Fassan, Matteo/F-5152-2012; Rugge, Massimo/K-7525-2016 OI Fassan, Matteo/0000-0001-6515-5482; NR 10 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5045 J9 NAT REV GASTRO HEPAT JI Nat. Rev. Gastroenterol. Hepatol. PD MAR PY 2012 VL 9 IS 3 BP 128 EP 129 DI 10.1038/nrgastro.2012.19 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 905PM UT WOS:000301284700002 PM 22330815 ER PT J AU Li, HM Pink, MD Murphy, JG Stein, A Dell'Acqua, ML Hogan, PG AF Li, Huiming Pink, Matthew D. Murphy, Jonathan G. Stein, Alexander Dell'Acqua, Mark L. Hogan, Patrick G. TI Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID NMDA RECEPTOR ACTIVATION; PROTEIN-KINASE-A; ANCHORING PROTEIN; SELECTIVE-INHIBITION; CARDIAC-HYPERTROPHY; LIVING CELLS; COMPLEX; NFAT; PEPTIDE; AFFINITY AB In hippocampal neurons, the scaffold protein AKAP79 recruits the phosphatase calcineurin to L-type Ca2+ channels and couples Ca2+ influx to activation of calcineurin and of its substrate, the transcription factor NFAT. Here we show that an IAIIIT anchoring site in human AKAP79 binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT, albeit more strongly. A modest decrease in calcineurin-AKAP affinity due to an altered anchoring sequence is compatible with NFAT activation, whereas a further decrease impairs activation. Counterintuitively, increasing calcineurin-AKAP affinity increases recruitment of calcineurin to the scaffold but impairs NFAT activation; this is probably due to both slower release of active calcineurin from the scaffold and sequestration of active calcineurin by 'decoy' AKAP sites. We propose that calcineurin-AKAP79 scaffolding promotes NFAT signaling by balancing strong recruitment of calcineurin with its efficient release to communicate with NFAT. C1 [Li, Huiming; Hogan, Patrick G.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Li, Huiming; Hogan, Patrick G.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Li, Huiming] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Pink, Matthew D.; Murphy, Jonathan G.; Dell'Acqua, Mark L.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO USA. [Pink, Matthew D.; Murphy, Jonathan G.; Dell'Acqua, Mark L.] Univ Colorado, Sch Med, Program Neurosci, Aurora, CO USA. [Stein, Alexander] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Stein, Alexander] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Hogan, Patrick G.] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. RP Hogan, PG (reprint author), Childrens Hosp, Immune Dis Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM Mark.DellAcqua@ucdenver.edu; phogan@liai.org RI Stein, Alexander/I-4950-2012; OI Stein, Alexander/0000-0002-2696-0611; Dell'Acqua, Mark/0000-0003-3798-3461 FU National Center for Research Resources at the US National Institutes of Health [RR15-301]; US DOE [DE-AC02-06CH11357]; US National Institutes of Health [AI40127, MH080291, AI090428]; Pacific Mountain Affiliate; [T32NS007083]; [T32HD041697] FX We are grateful to the Department of Neurobiology, Harvard Medical School, for use of its spectrofluorometer, and to S. Lehrer, Boston Biomedical Research Institute, for access to the stopped-flow instrument. Diffraction data were collected at the Advanced Photon Source on Northeastern Collaborative Access Team beamline 24-ID-C, which is supported by award RR15-301 from the National Center for Research Resources at the US National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under Contract No. DE-AC02-06CH11357. We thank A. Sorkin, University of Pittsburgh, for providing the tandem YFP-CFP construct. The work was supported by US National Institutes of Health grants AI40127 (to A. Rao and P.G.H.), MH080291 (to M.L.D.) and AI090428 (to H.L.). M.D.P. was supported in part by T32NS007083 and by an American Heart Association Predoctoral Fellowship from the Pacific Mountain Affiliate. J.G.M. was supported in part by T32HD041697. NR 48 TC 54 Z9 56 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 EI 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2012 VL 19 IS 3 BP 337 EP U100 DI 10.1038/nsmb.2238 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 904GI UT WOS:000301181900011 PM 22343722 ER PT J AU Dolga, A Perocchi, F Doti, N Meissner, L Tobaben, S Grohm, J Zischka, H Plesnila, N Culmsee, C AF Dolga, A. Perocchi, F. Doti, N. Meissner, L. Tobaben, S. Grohm, J. Zischka, H. Plesnila, N. Culmsee, C. TI Mitochondrial SK2/K(Ca)2.2 channels mediate neuroprotective effects SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Dolga, A.; Tobaben, S.; Grohm, J.; Culmsee, C.] Univ Marburg, Inst Pharmakol & Klin Pharm, D-35043 Marburg, Germany. [Perocchi, F.] Harvard Univ, Sch Med, Boston, MA USA. [Perocchi, F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Doti, N.] CNR, Inst Biostruct & Bioimaging, I-80125 Naples, Italy. [Meissner, L.; Plesnila, N.] Univ Munich, Sch Med, Inst Stroke & Dementia Res, Munich, Germany. [Zischka, H.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Munich, Germany. NR 1 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 091 BP 22 EP 22 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500092 ER PT J AU Hamann, M Kuschka, J Gioioso, V Sharma, N Richter, A AF Hamann, M. Kuschka, J. Gioioso, V Sharma, N. Richter, A. TI Investigations of the cholinergic neurotransmitter system in DYT1 mice SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Meeting Abstract CT 78th Annual Congress of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) CY MAR 19-22, 2012 CL Dresden, GERMANY SP German Soc Expt & Clin Pharmacol & Toxicol (DGPT) C1 [Hamann, M.; Kuschka, J.; Richter, A.] Free Univ Berlin, Dept Vet Med, Inst Pharmacol & Toxicol, D-14195 Berlin, Germany. [Gioioso, V; Sharma, N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2012 VL 385 SU 1 MA 140 BP 33 EP 33 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898YY UT WOS:000300779500141 ER PT J AU Shin, JH Hoh, DJ Kalfas, IH AF Shin, John H. Hoh, Daniel J. Kalfas, Iain H. TI Iliac Screw Fixation Using Computer-Assisted Computer Tomographic Image Guidance: Technical Note SO NEUROSURGERY LA English DT Article DE Iliac screw; Image guidance; Navigation AB BACKGROUND: Iliac screw fixation is a powerful tool used by spine surgeons to achieve fusion across the lumbosacral junction for a number of indications, including deformity, tumor, and pseudarthrosis. Complications associated with screw placement are related to blind trajectory selection and excessive soft tissue dissection. OBJECTIVE: To describe the technique of iliac screw fixation using computed tomographic (CT)-based image guidance. METHODS: Intraoperative registration and verification of anatomic landmarks are performed with the use of a preoperatively acquired CT of the lumbosacral spine. With the navigation probe, the ideal starting point for screw placement is selected while visualizing the intended trajectory and target on a computer screen. Once the starting point is selected and marked with a burr, a drill guide is docked within this point and the navigation probe re-inserted, confirming the trajectory. The probe is then removed and the high-speed drill reinserted within the drill guide. Drilling is performed to a depth measured on the computer screen and a screw is placed. RESULTS: Confirmation of accurate placement of iliac screws can be performed with standard radiographs. CONCLUSION: CT-guided navigation allows for 3-dimensional visualization of the pelvis and minimizes complications associated with soft-tissue dissection and breach of the ilium during screw placement. C1 [Shin, John H.] Harvard Univ, Dept Neurosurg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Hoh, Daniel J.] Univ Florida, Dept Neurosurg, Gainesville, FL USA. [Kalfas, Iain H.] Cleveland Clin, Ctr Spine Hlth, Dept Neurosurg, Cleveland, OH 44106 USA. RP Shin, JH (reprint author), Harvard Univ, Dept Neurosurg, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,WAC 745, Boston, MA 02114 USA. EM shin.john@mgh.harvard.edu NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 2012 VL 70 SU 1 AR ons16 DI 10.1227/NEU.0b013e318230517a PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 904VY UT WOS:000301228100003 ER PT J AU Heffernan-Stroud, LA Helke, KL Jenkins, RW De Costa, AM Hannun, YA Obeid, LM AF Heffernan-Stroud, L. A. Helke, K. L. Jenkins, R. W. De Costa, A-M Hannun, Y. A. Obeid, L. M. TI Defining a role for sphingosine kinase 1 in p53-dependent tumors SO ONCOGENE LA English DT Article DE ceramide; sphingosine-1-phosphate; p53; sphingosine kinase; cancer; senescence ID PROGRAMMED CELL-DEATH; CERAMIDE-INDUCED APOPTOSIS; TANDEM MASS-SPECTROMETRY; BIOACTIVE SPHINGOLIPIDS; QUANTITATIVE-ANALYSIS; GENOTOXIC STRESS; HIGH EXPRESSION; DOWN-REGULATION; MICE DEFICIENT; CYCLE ARREST AB p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers. Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function. Bioactive sphingolipids have recently emerged as important regulators of proliferative, apoptotic and senescent cellular processes. In this study, we demonstrate that the enzyme sphingosine kinase 1 (SK1), a critical enzyme in the regulation of the key bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), serves as a key downstream target for p53 action. Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased. Importantly, deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by similar to 30%. Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice. The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence. Thus, targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer. Oncogene (2012) 31, 1166-1175; doi:10.1038/onc.2011.302; published online 18 July 2011 C1 [Obeid, L. M.] Med Univ S Carolina, Dept Med, Charleston, SC 29403 USA. [Heffernan-Stroud, L. A.; Obeid, L. M.] Med Univ S Carolina, Dept Mol & Cellular Biol & Pathobiol, Charleston, SC 29403 USA. [Helke, K. L.] Med Univ S Carolina, Dept Comparat Med Lab Anim Resources, Charleston, SC 29403 USA. [Jenkins, R. W.; Hannun, Y. A.; Obeid, L. M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29403 USA. [De Costa, A-M] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29403 USA. [Obeid, L. M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Dept Med, 114 Doughty St, Charleston, SC 29403 USA. EM obeidl@musc.edu OI obeid, lina/0000-0002-0734-0847; Helke, Kris/0000-0001-9746-0764 FU Biomedical Laboratory Research and Development Service of the VA Office of Research and Development [I01BX000156]; NIH/NIGMS [R01 GM062887]; NIH/NCI [P01 CA097132-project 3, P01 CA097132-project 1]; American Heart Association [AHA 081509E]; NIH MSTP [GM08716]; MUSC Hollings Cancer Center Abney Foundation; NIH/NIEHS [T32 ES012878, F30ES017379]; NCI [IPO1CA097132, P30 CA 138313]; NIH/NCRR SC COBRE [P20 RR017677]; NIH [C06 RR018823]; National Center for Research Resources FX This work was supported, in part, by Award Number I01BX000156 from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development, NIH/NIGMS R01 GM062887, NIH/NCI P01 CA097132-project 3 (to LMO). NIH/NCI P01 CA097132-project 1 (to YAH). American Heart Association Pre-Doctoral Fellowship AHA 081509E (to RWJ), NIH MSTP Training Grant GM08716 (to RWJ, AMDC, LAHS), MUSC Hollings Cancer Center Abney Foundation Scholarship (to RWJ, LAHS), NIH/NIEHS TG T32 ES012878, and NIH/NIEHS National Research Service Award Individual Predoctoral Fellowship F30ES017379 (to LAHS). Liquid chromatography-mass spectrometry analysis of sphingolipids was performed by Lipidomics Shared Resource, MUSC (Methods 2006, 39: 82-91) supported by NCI Grants: IPO1CA097132 and P30 CA 138313 and NIH/NCRR SC COBRE Grant P20 RR017677 as specified in Supplementary Information. Laboratory space in the CRI building of MUSC was supported by the NIH, Grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Refer to Supplementary Information for individual acknowledgements and the VA disclaimer. NR 72 TC 20 Z9 21 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD MAR PY 2012 VL 31 IS 9 BP 1166 EP 1175 DI 10.1038/onc.2011.302 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 901EW UT WOS:000300945900009 PM 21765468 ER PT J AU Helman, E Naxerova, K Kohane, IS AF Helman, E. Naxerova, K. Kohane, I. S. TI DNA hypermethylation in lung cancer is targeted at differentiation-associated genes SO ONCOGENE LA English DT Article DE Hypermethylation; development; non-small cell lung cancer; gene expression ID TUMOR-SUPPRESSOR GENE; CPG-ISLAND METHYLATION; EMBRYONIC STEM-CELLS; EARLY EVENT; GENOME; MARKERS; GERM; HYPOMETHYLATION; CARDIOMYOCYTES; RETINOBLASTOMA AB Aberrant DNA hypermethylation of tumor suppressor genes is thought to be an early event in tumorigenesis. Many studies have reported the methylation status of individual genes with known involvement in cancer, but an unbiased assessment of the biological function of the collective of hypermethylated genes has not been conducted so far. Based on the observation that a variety of human cancers recapitulate developmental gene expression patterns ( that is activate genes normally expressed in early development and suppress late developmental genes), we hypothesized that the silencing of differentiation-associated genes in cancer could be attributed in part to DNA hypermethylation. To this end, we investigated the developmental expression patterns of genes with hypermethylated CpG islands in primary human lung carcinomas and lung cancer cell lines. We found that DNA hypermethylation primarily affects genes that are expressed in late stages of murine lung development. Gene ontology characterization of these genes shows that they are almost exclusively involved in morphogenetic differentiation processes. Our results indicate that DNA hypermethylation in cancer functions as a selective silencing mechanism of genes that are required for the maintenance of a differentiated state. The process of cellular de-differentiation that is evident on both the microscopic and transcriptional level in cancer might at least partly be mediated by these epigenetic events. Our observations provide a mechanistic explanation for induction of differentiation upon treatment with DNA methyltransferase inhibitors. Oncogene (2012) 31, 1181-1188; doi:10.1038/onc.2011.307; published online 1 August 2011 C1 [Kohane, I. S.] Childrens Hosp, Informat Program, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. [Naxerova, K.] Harvard Univ, Sch Med, Boston, MA USA. [Naxerova, K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. RP Kohane, IS (reprint author), Childrens Hosp, Informat Program, Harvard Mit Div Hlth Sci & Technol, 300 Longwood Ave,Enders 6L, Boston, MA 02115 USA. EM Isaac_Kohane@hms.harvard.edu RI Kohane, Isaac Kohane/K-3716-2012; OI Kohane, Isaac Kohane/0000-0003-2192-5160; Naxerova, Kamila/0000-0001-7744-5110 NR 49 TC 12 Z9 12 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR PY 2012 VL 31 IS 9 BP 1181 EP 1188 DI 10.1038/onc.2011.307 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 901EW UT WOS:000300945900011 PM 21804601 ER PT J AU Singh, JP Ellenbogen, KA Desai, NR Mcalister, FA AF Singh, Jagmeet P. Ellenbogen, Kenneth A. Desai, Nihar R. Mcalister, Finlay A. TI ICDs, Guidelines, and National Registries: Opportunities to Enhance Quality of Patient Care SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Editorial Material ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; HEART-FAILURE; COST-EFFECTIVENESS; AMIODARONE; THERAPY C1 [Singh, Jagmeet P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv,Heart Ctr, Boston, MA 02114 USA. [Ellenbogen, Kenneth A.] VCU Sch Med, Div Cardiol, Richmond, VA USA. [Desai, Nihar R.] Brigham & Womens Hosp, Div Cardiol, Div Cardiovasc Med, Boston, MA 02115 USA. [Mcalister, Finlay A.] Univ Alberta Hosp, Div Internal Med, Edmonton, AB T6G 2B7, Canada. RP Singh, JP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac Arrhythmia Serv,Heart Ctr, Boston, MA 02114 USA. EM jsingh@partners.org RI McAlister, Finlay/C-4151-2013 NR 17 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD MAR PY 2012 VL 35 IS 3 BP 253 EP 258 DI 10.1111/j.1540-8159.2011.03300.x PG 6 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 902PB UT WOS:000301049300010 PM 22268567 ER PT J AU Shalaby, A Brumberg, G El-Saed, A Saba, S AF Shalaby, Alaa Brumberg, Genevieve El-Saed, Aiman Saba, Samir TI Mood Disorders and Outcome in Patients Receiving Cardiac Resynchronization Therapy SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE depression; anxiety; cardiac resynchronization therapy; mortality; heart failure ID CHRONIC HEART-FAILURE; DEPRESSIVE SYMPTOMS; CARDIOVERTER-DEFIBRILLATORS; MYOCARDIAL-INFARCTION; RISK; MORTALITY; ANXIETY; PREVALENCE; PREDICTORS; ARRHYTHMIAS AB Background: Mood disorders (MD) have been demonstrated to influence outcome in cardiac disease in general and specifically in chronic heart failure (HF). Little is known about their possible effect on response to cardiac resynchronization therapy (CRT). Objective: To evaluate the influence of MD on CRT response. Methods: We conducted a retrospective chart review of all cardiac CRT-D (CRT defibrillator) recipients (N = 153) at the Veterans Affairs Pittsburgh Healthcare System from beginning of 2004 through end of 2006. All-cause death and HF-related hospitalizations (HFH), individually and combined, were sought through 2009. Results: During a mean follow-up time of 31.4 +/- 14.7 months, there were 48 (31.4%) deaths and 55 (35.9%) HFHs in HF patients having New York Heart Association class of 2.9 +/- 0.3, left ventricular ejection fraction (LVEF) of 25.8 +/- 9.1%, left ventricular end-diastolic diameter (LVEDD) of 61.6 +/- 11.6 mm, and QRS of 152 +/- 30.5 ms. A total of 65 (42.5%) patients had MD (depression, anxiety, or posttraumatic stress disorder). Compared to others, patients in the MD group were at a significantly higher risk of HFH alone (47.7% vs 27.3%, P = 0.009) or when combined with death (58.5% vs 39.8%, P = 0.022) but not death alone (35.4% vs 28.4%, P = 0.36). The significant predictive effect of MD on HFH alone and when combined with death shown in univariate analysis was not attenuated after adjustment for age, ejection fraction, etiology of cardiomyopathy, cumulative number of any shocks, smoking, and evidence of postimplantation echocardiographic improvement. Conclusions: MD in patients with advanced but stable HF receiving CRT-D therapy was a predictor of HFH alone or when combined with death but not mortality alone. (PACE 2012; 35: 294-301) C1 [Shalaby, Alaa; Brumberg, Genevieve; El-Saed, Aiman; Saba, Samir] Univ Pittsburgh, Med Ctr, Vet Affairs Pittsburgh Hlth Syst, Div Cardiol,Cardiovasc Inst, Pittsburgh, PA 15240 USA. RP Shalaby, A (reprint author), Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Div Cardiol, 111C Univ Dr, Pittsburgh, PA 15240 USA. EM Alaa.Shalaby@va.gov NR 39 TC 6 Z9 6 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0147-8389 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD MAR PY 2012 VL 35 IS 3 BP 294 EP 301 DI 10.1111/j.1540-8159.2011.03304.x PG 8 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA 902PB UT WOS:000301049300015 PM 22229659 ER PT J AU Hermanrud, CE Pathiraja, V Matar, A Duran-Struuck, R Crepeau, RL Srinivasan, S Sachs, DH Huang, CA Wang, ZR AF Hermanrud, Christina E. Pathiraja, Vimukthi Matar, Abraham Duran-Struuck, Raimon Crepeau, Rebecca L. Srinivasan, Srimathi Sachs, David H. Huang, Christene A. Wang, Zhirui TI Expression and purification of non-N-glycosylated porcine interleukin 3 in yeast Pichia pastoris SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Porcine IL3; Pichia pastoris expression; Purification; Glycosylation; Mobilization ID HEMATOPOIETIC-CELL TRANSPLANTATION; LARGE-ANIMAL-MODEL; PROGENITOR CELLS; MIXED CHIMERISM; MINIATURE SWINE; GLYCOPROTEINS; MOBILIZATION; IMMUNOTOXIN; ENGRAFTMENT; TOLERANCE AB Yeast Pichia pastoris has been widely utilized to express heterologous recombinant proteins. P. pastoris expressed recombinant porcine interleukin 3 (IL3) has been used for porcine stem cell mobilization in allo-hematopoietic cell transplantation models and pig-to-primate xeno-hematopoietic cell transplantation models in our lab for many years. Since the yeast glycosylation mechanism is not exactly the same as those of other mammalian cells, P. pastoris expressed high-mannose glycoprotein porcine IL3 has been shown to result in a decreased serum half-life. Previously this was avoided by separation of the non-glycosylated porcine IL3 from the mixture of expressed glycosylated and non-glycosylated porcine IL3. However, this process was very inefficient and lead to a poor yield following purification. To overcome this problem, we engineered a non-N-glycosylated version of porcine IL3 by replacing the four potential N-glycosylation sites with four alanines. The codon-optimized non-N-glycosylated porcine IL3 gene was synthesized and expressed in P. pastoris. The expressed non-N-glycosylated porcine IL3 was captured using Ni-Sepharose 6 fast flow resin and further purified using strong anion exchange resin Poros 50 HQ. In vivo mobilization studies performed in our research facility demonstrated that the non-N-glycosylated porcine IL3 still keeps the original stem cell mobilization function. (C) 2011 Elsevier Inc. All rights reserved. C1 [Hermanrud, Christina E.; Pathiraja, Vimukthi; Matar, Abraham; Duran-Struuck, Raimon; Crepeau, Rebecca L.; Srinivasan, Srimathi; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Hermanrud, Christina E.; Pathiraja, Vimukthi; Matar, Abraham; Duran-Struuck, Raimon; Crepeau, Rebecca L.; Srinivasan, Srimathi; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Hermanrud, Christina E.; Sachs, David H.; Huang, Christene A.; Wang, Zhirui] MGH DF HCC Recombinant Prot Express & Purificat C, Boston, MA USA. RP Wang, ZR (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, MGH E,Bldg 149-6113,13th St, Boston, MA 02129 USA. EM zhirui.wang@tbrc.mgh.harvard.edu FU National Institutes of Health [R01A1084657-02]; Dana Farber/Harvard Cancer Center FX This work was supported by National Institutes of Health (R01A1084657-02 to CAH); and Dana Farber/Harvard Cancer Center Core development grant. NR 16 TC 1 Z9 1 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2012 VL 82 IS 1 BP 70 EP 74 DI 10.1016/j.pep.2011.11.011 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 900WZ UT WOS:000300923700011 PM 22154875 ER PT J AU Berry, RB Kushida, CA Kryger, MH Soto-Calderon, H Staley, B Kuna, ST AF Berry, Richard B. Kushida, Clete A. Kryger, Meir H. Soto-Calderon, Haideliza Staley, Bethany Kuna, Samuel T. TI Respiratory Event Detection by a Positive Airway Pressure Device SO SLEEP LA English DT Article DE CPAP; autoCPAP; APAP ID OBSTRUCTIVE SLEEP-APNEA; TREATING ADULT PATIENTS; PRACTICE PARAMETERS; TITRATING PRESSURES; HYPOPNEA SYNDROME; POLYSOMNOGRAPHY; CPAP; DIAGNOSIS; EFFICACY; UPDATE AB Study Objectives: Compare automatic event detection (AED) of respiratory events using a positive airway pressure (PAP) device with manual scoring of polysomnography (PSG) during PAP treatment of obstructive sleep apnea (OSA). Design: Prospective PSGs of patients using a PAP device. Setting: Six academic and private sleep disorders centers. Patients: A total of 148 PSGs from 115 participants with OSA (apnea-hypopnea index [AH I] >= 15 events/hr) were analyzed. Interventions: A signal generated by the PAP device identifying the AED of respiratory events based on airflow was recorded during PSG. Measurements and Results: The PSGs were manually scored without visualization of the AED signal and scoring of a hypopnea required a >= 4% oxygen desaturation. The apnea index (AI), hypopnea index (HI), and AH I by manual score and PAP AED were compared. A customized computer program compared individual events by manual scoring and AED to determine the true positive, false positive, false negative, or true negative events and found a sensitivity of 0.58 and a specificity of 0.98. The AH I, AI, and HI by the two methods were highly correlated. Bland-Altman analysis showed better agreement for AI than HI. Using a manually scored AH I of >= 10 events/hr to denote inadequate treatment, an AED AHI >= 10 events/hr had a sensitivity of 0.58 and a specificity of 0.94. Conclusions: An AHI < 10 events/hr by PAP AED is usually associated with good treatment efficacy. Differences between manually scored and AED events were primarily due to different criteria for hypopnea detection. C1 [Berry, Richard B.] Univ Florida, Dept Med, Gainesville, FL 32610 USA. [Kushida, Clete A.] Stanford Univ, Redwood City, CA USA. [Kryger, Meir H.] Gaylord Sleep Med, Wallingford, CT USA. [Soto-Calderon, Haideliza; Staley, Bethany; Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Soto-Calderon, Haideliza; Staley, Bethany; Kuna, Samuel T.] Univ Penn, Philadelphia, PA 19104 USA. RP Berry, RB (reprint author), Univ Florida, Dept Med, Box 100225 HSC, Gainesville, FL 32610 USA. EM sleep_doc@msn.com FU Philips-Respironics; Ventus Medical; ResMed; Dymedix; Ventus to Gaylord Hospital FX This study was sponsored by Philips-Respironics. Dr. Berry has received research support from Philips-Respironics and Ventus Medical via grant to the University of Florida and ResMed via grant to North Florida Foundation for Research and Education (Gainesville VAMC). Dr. Kushida has received research support from Philips-Respironics and ResMed via grants to Stanford and royalties from patent licensed to Philips-Respironics. Dr. Kryger has received research support from Philips-Respironics, ResMed, Dymedix, and Ventus to Gaylord Hospital. Dr. Kuna has received research support from Philips-Respironics. The other authors have indicated no financial conflicts of interest. NR 14 TC 17 Z9 20 U1 0 U2 2 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD MAR 1 PY 2012 VL 35 IS 3 BP 361 EP 367 DI 10.5665/sleep.1696 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 901GG UT WOS:000300950400010 PM 22379242 ER PT J AU Grandner, MA Martin, JL Patel, NP Jackson, NJ Gehrman, PR Pien, G Perlis, ML Xie, DW Sha, DH Weaver, T Gooneratne, NS AF Grandner, Michael A. Martin, Jennifer L. Patel, Nirav P. Jackson, Nicholas J. Gehrman, Philip R. Pien, Grace Perlis, Michael L. Xie, Dawei Sha, Daohang Weaver, Terri Gooneratne, Nalaka S. TI Age and Sleep Disturbances Among American Men And Women: Data From the US Behavioral Risk Factor Surveillance System SO SLEEP LA English DT Article DE Aging; sleep quality; fatigue; epidemiology; depression ID WORK HOURS RECOMMENDATIONS; OLDER-ADULTS; DAYTIME SLEEPINESS; PROSPECTIVE COHORT; HEALTH; INSOMNIA; ADOLESCENT; COMPLAINTS; DISORDERS; POPULATION AB Study Objective: Explore the prevalence of sleep-related complaints across age groups, examining effects of sex, general health, and depressed mood. Design: Cross-sectional analysis of data from the 2006 Behavioral Risk Factor Surveillance System (BRFSS). Setting: Epidemiologic. Participants: Complete-case analysis included 155,877 participants who responded to questions related to Self-Reported Sleep Disturbance (SLEEPDIST) and Self-Reported Tiredness/Lack of Energy (TIREDNESS). Interventions: None. Measurements and Results: Outcomes were self-reported complaints in response to survey questions assessing SLEEPDIST and TIREDNESS, dichotomized as reporting a complaint < 6 versus >= 6 nights or days, respectively, in a 2-wk period. Predictors were age, general health, and depressed mood. All analyses were adjusted for race/ethnicity, income, education, and time since last medical checkup. Across all age groups, women reported more SLEEPDIST and TIREDNESS. Poor general health, mild depressed mood, and moderate/severe depressed mood were associated with SLEEPDIST and TIREDNESS. Both SLEEPDIST and TIREDNESS generally declined across the life span, with fewest endorsements in respondents older than 80 yr. For SLEEPDIST, odds ratios (ORs, reference = 80+) declined from age 18-54 yr, rose slightly, and then declined again after age 59 yr in men. The pattern was similar for women, except a more marked rise was noted from age 40-59 yr. The pattern was similar for TIREDNESS. Conclusions: Advancing age was not associated with increased Self-Reported Sleep Disturbance or Self-Reported Tiredness/Lack of Energy. These results suggest that the often-reported increase in sleep problems with age is a nonlinear phenomenon, mediated by factors other than physiologic aging. C1 [Grandner, Michael A.; Jackson, Nicholas J.; Pien, Grace] Univ Penn, Ctr Sleep & Circadian Neurobiol, Dept Med, Div Sleep Med, Philadelphia, PA 19104 USA. [Martin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Martin, Jennifer L.] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Ctr, Los Angeles, CA USA. [Gehrman, Philip R.; Perlis, Michael L.] Univ Penn, Div Pulm & Crit Care Med, Dept Med, Philadelphia, PA 19104 USA. [Pien, Grace] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Xie, Dawei; Sha, Daohang] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Weaver, Terri] Univ Illinois, Chicago Coll Nursing, Biobehav & Hlth Sci Dept, Chicago, IL USA. [Gooneratne, Nalaka S.] Univ Penn, Div Geriatr Med, Dept Med, Philadelphia, PA 19104 USA. RP Grandner, MA (reprint author), Univ Penn, Ctr Sleep & Circadian Neurobiol, Dept Med, Div Sleep Med, 3624 Market St,Suite 205, Philadelphia, PA 19104 USA. EM Grand-ner@upenn.edu FU University of Pennsylvania Center for Sleep and Circadian Neurobiology [T32HL007713, K23AG028452, R21AG31390]; Boehringer Ingelheim; Sanofi-Aventis; Pharma; Actelion; Takeda; Gerson Lehman; Clinical Advisors; LEK; MedaCorp; Respironics Respiratory and Sleep Research Foundation; Cephalon, Inc. FX This work was supported by T32HL007713, K23AG028452 (to Dr. Martin), R21AG31390 (to Dr. Gooneratne) as well as funding for Biostatistical Support from the University of Pennsylvania Center for Sleep and Circadian Neurobiology. The authors thank Allan Pack, MB, ChB, PhD for guidance and other support. Also, the authors thank the BRFSS participants and the Centers for Disease Control and Prevention for collecting these data and making them available.; This was not an industry supported study. Dr. Patel has received research support from Boehringer Ingelheim unrelated to this study. Dr. Pien has the use of equipment on loan from Respironics unrelated to this study. Dr. Perlis has consulted for Gerson Lehrman Group, Clinical Advisors, Meda Corp/Leerink Swann, Actelion, SleepEasily, Sanofi-Aventis, L.E.K. Consulting LLC. He has received research support from Sanofi-Aventis, Pharma, and Cephalon and had speaking honoraria from Sanofi-Aventis, AASM, UR, and Internet Didactic Services. He has received salary and distributions from Actelion, Takeda, Gerson Lehman, Clinical Advisors, LEK, and MedaCorp. Dr. Weaver has received research equipment from Respironics, Inc. and Protech; grant support from Respironics Respiratory and Sleep Research Foundation, Cephalon, Inc. She has consulted for Apnex Medical, Inc., and Cephalon, Inc. and has FOSQ license Agreements with Sanofi-Aventis Pharmaceutical, Merck 7 Co., Inc., Sleep Solutions, N.V. Organon, Apnex Medical, Inc., Ventus medical, GlaxoSmithKline, and Respironics. The other authors have indicated no financial conflicts of interest. NR 54 TC 45 Z9 45 U1 2 U2 17 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 MAR 1 PY 2012 VL 35 IS 3 BP 395 EP 406 DI 10.5665/sleep.1704 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 901GG UT WOS:000300950400014 PM 22379246 ER PT J AU Turvey, CL Zulman, DM Nazi, KM Wakefield, BJ Woods, SS Hogan, TP Weaver, FM McInnes, K AF Turvey, Carolyn L. Zulman, Donna M. Nazi, Kim M. Wakefield, Bonnie J. Woods, Susan S. Hogan, Timothy P. Weaver, Frances M. McInnes, Keith TI Transfer of Information from Personal Health Records: A Survey of Veterans Using My HealtheVet SO TELEMEDICINE AND E-HEALTH LA English DT Article DE e-health; medical records; telehealth ID RANDOMIZED-TRIAL; MEDICAL-RECORD; SATISFACTION; SERVICES AB Objective: Personal health records provide patients with ownership of their health information and allow them to share information with multiple healthcare providers. However, the usefulness of these records relies on patients understanding and using their records appropriately. My HealtheVet is a Web-based patient portal containing a personal health record administered by the Veterans Health Administration. The goal of this study was to explore veterans' interest and use of My HealtheVet to transfer and share information as well as to identify opportunities to increase veteran use of the My HealtheVet functions. Materials and Methods: Two waves of data were collected in 2010 through an American Customer Satisfaction Index Web-based survey. A random sample of veterans usingMy HealtheVet was invited to participate in the survey conducted on the My HealtheVet portal through a Web-based pop-up browser window. Results: Wave One results (n = 25,898) found that 41% of veterans reported printing information, 21% reported saving information electronically, and only 4% ever sent information from My HealtheVet to another person. In Wave Two (n = 18,471), 30% reported self-entering medication information, with 18% sharing this information with their Veterans Affairs (VA) provider and 9.6% sharing with their non-VA provider. Conclusion: Although veterans are transferring important medical information from their personal health records, increased education and awareness are needed to increase use. Personal health records have the potential to improve continuity of care. However, more research is needed on both the barriers to adoption as well as the actual impact on patient health outcomes and well-being. C1 [Turvey, Carolyn L.; Wakefield, Bonnie J.] Iowa City VA Hlth Care Syst, Ctr Comprehens Access & Delivery Res & Evaluat CA, Iowa City, IA 52246 USA. [Turvey, Carolyn L.] Iowa City VA Hlth Care Syst, VA Off Rural Hlth, Vet Rural Hlth Resource Ctr Cent Reg, Iowa City, IA 52246 USA. [Turvey, Carolyn L.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Zulman, Donna M.] Univ Michigan, Robert Wood Johnson Fdn Clin Scholars Program, Ann Arbor, MI 48109 USA. [Zulman, Donna M.] VA Ann Arbor Hlth Care Syst, Ann Arbor, MI USA. [Nazi, Kim M.] US Dept Vet Affairs, Vet & Consumers Hlth Informat Off, Washington, DC USA. [Wakefield, Bonnie J.] Univ Missouri, Sinclair Sch Nursing, Columbia, MO USA. [Woods, Susan S.] Portland VA Med Ctr, Portland, OR USA. [Hogan, Timothy P.] Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL USA. [Hogan, Timothy P.] Edward Hines Jr VA Hosp, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL USA. [Hogan, Timothy P.] Edward Hines Jr VA Hosp, eHlth Qual Enhancement Res Initiat, Hines, IL USA. [Hogan, Timothy P.] Loyola Univ Chicago, Stritch Sch Med, Program Hlth Serv Res, Maywood, IL USA. [Weaver, Frances M.] Loyola Univ, Stritch Sch Med, Dept Med, Chicago, IL 60611 USA. [McInnes, Keith] ENRM Vet Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [McInnes, Keith] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. RP Turvey, CL (reprint author), Iowa City VA Hlth Care Syst, Ctr Comprehens Access & Delivery Res & Evaluat CA, 601 Highway 6 W 152,Suite 40, Iowa City, IA 52246 USA. EM carolyn-turvey@va.gov FU Department of Veteran Affairs, Health Services Research and Development Service through the eHealth QUERI; CADRE Center; Veterans Rural Health Resource Center-Central Region, VA Office of Rural Health FX Dr. Turvey is a Research Health Science Specialist in the Comprehensive Access & Delivery Research and Evaluation (CADRE) Center, Iowa City VA Health Care System. The work reported here was supported by the Department of Veteran Affairs, Health Services Research and Development Service through the eHealth QUERI, the CADRE Center, and the Veterans Rural Health Resource Center-Central Region, VA Office of Rural Health. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 13 TC 9 Z9 9 U1 1 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 J9 TELEMED E-HEALTH JI Telemed. e-Health PD MAR PY 2012 VL 18 IS 2 BP 109 EP 114 DI 10.1089/tmj.2011.0109 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 902MB UT WOS:000301041200006 PM 22304439 ER PT J AU Nambudiri, VE Landrum, MB Lamont, EB McNeil, BJ Bozeman, SR Freedland, SJ Keating, NL AF Nambudiri, Vinod E. Landrum, Mary Beth Lamont, Elizabeth B. McNeil, Barbara J. Bozeman, Samuel R. Freedland, Stephen J. Keating, Nancy L. TI Understanding Variation in Primary Prostate Cancer Treatment Within the Veterans Health Administration SO UROLOGY LA English DT Article ID AFFAIRS MEDICAL-CENTERS; RADICAL PROSTATECTOMY; GEOGRAPHIC-VARIATION; OF-LIFE; MEN; OUTCOMES; TRENDS; CARE; SERVICES; THERAPY AB OBJECTIVE To examine the variation in prostate cancer treatment in the Veterans Health Administration (VHA)-a national, integrated delivery system. We also compared the care for older men in the VHA with that in fee-for-service Medicare. METHODS We used data from the Veterans Affairs Central Cancer Registry linked with administrative data and Surveillance, Epidemiology, and End Results-Medicare data to identify men with local or regional prostate cancer diagnosed during 2001 to 2004. We used multinomial logistic and hierarchical regression models to examine the patient, tumor, and facility characteristics associated with treatment in the VHA and, among older patients, used propensity score methods to compare primary therapy between the VHA and fee-for-service Medicare. RESULTS The rates of radical prostatectomy and radiotherapy varied substantially across VHA facilities. Among the VHA patients, older age, black race/ethnicity, and greater comorbidity were associated with receiving neither radical prostatectomy nor radiotherapy. Facilities with more black patients with prostate cancer had lower rates of radical prostatectomy, and those with less availability of external beam radiotherapy had lower radiotherapy rates. The adjusted rates of radiotherapy (39.7% vs 52.0%) and radical prostatectomy (12.1% vs 15.8%) were lower and the rates of receiving neither treatment greater (48.2% vs 32.2%) in the VHA versus fee-for-service Medicare (P < .001). CONCLUSIONS In the VHA, the treatment rates varied substantially across facilities, and black men received less aggressive prostate cancer treatment than white men, suggesting factors other than patient preferences influence the treatment decisions. Also, primary prostate cancer therapy for older men is less aggressive in the VHA than in fee-for-service Medicare. UROLOGY 79: 537-545, 2012. (C) 2012 Elsevier Inc. C1 [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Adult Oncol, Boston, MA 02114 USA. ABT Associates Inc, Cambridge, MA 02138 USA. Durham Vet Affairs Med Ctr, Durham, NC USA. Duke Univ, Duke Prostate Ctr, Dept Surg, Div Urol, Durham, NC USA. Duke Univ, Dept Pathol, Durham, NC 27706 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU Department of Veterans Affairs through the Office of Policy and Planning; Prostate Cancer Foundation FX This work was funded by the Department of Veterans Affairs through the Office of Policy and Planning. The efforts of Drs. Freedland and Keating were also funded, in part, by the Prostate Cancer Foundation. NR 30 TC 17 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 0090-4295 J9 UROLOGY JI Urology PD MAR PY 2012 VL 79 IS 3 BP 537 EP 545 DI 10.1016/j.urology.2011.11.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 903XB UT WOS:000301154400019 PM 22245306 ER PT J AU Prisciandaro, JJ DeSantis, SM Chiuzan, C Brown, DG Brady, KT Tolliver, BK AF Prisciandaro, James J. DeSantis, Stacia M. Chiuzan, Cody Brown, Delisa G. Brady, Kathleen T. Tolliver, Bryan K. TI Impact of Depressive Symptoms on Future Alcohol Use in Patients with Co-Occurring Bipolar Disorder and Alcohol Dependence: A Prospective Analysis in an 8-Week Randomized Controlled Trial of Acamprosate SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Bipolar Disorder; Alcohol; Alcoholism; Comorbidity; Craving; Dependence; Depression; Drinking; Mania; Relapse ID SUBSTANCE USE DISORDERS; TREATMENT ENHANCEMENT PROGRAM; HIDDEN MARKOV-MODELS; ACUTE MANIA; STEP-BD; ABUSE; SCALE; HOSPITALIZATION; PARTICIPANTS; DISTINCTION AB Background: Bipolar disorders and alcohol use disorders commonly co-occur, yet little is known about the proximal impact of bipolar symptoms on alcohol use in patients with this comorbidity. The present study examined the impact of depressive symptoms and alcohol craving on proximal alcohol use in patients with co-occurring bipolar disorder and alcohol dependence. Methods: Data were collected during an 8-week randomized controlled trial of acamprosate for individuals with co-occurring bipolar disorder and alcohol dependence (n = 30). Depressive symptoms and alcohol craving were assessed biweekly using the Montgomery Asberg Depression Rating Scale (MADRS) and the Obsessive Compulsive Drinking Scale (OCDS), respectively. Daily alcohol use data were available via administration of the Time-line Follow-back interview at baseline and at subsequent weekly study visits. Correlational analyses and hidden Markov modeling were used to examine the prospective relationships between depressive symptoms, alcohol craving, and alcohol use. Results: Depressive symptoms and alcohol craving were significantly correlated with proximal (i. e., 1 week later) alcohol use across a variety of alcohol consumption summary measures. In hidden Markov models, depressive symptoms (OR = 1.3, 95% credible interval = [1.1, 1.5]) and alcohol craving (OR = 1.6, 95% credible interval = [1.4, 1.9]) significantly predicted transitioning from a light to a heavy drinking state, or remaining in a heavy drinking state. Conclusions: The results from the present study suggest that depressive symptoms and alcohol craving increase proximal risk for alcohol use in individuals with co-occurring bipolar and alcohol use disorders. C1 [Prisciandaro, James J.; Brown, Delisa G.; Brady, Kathleen T.; Tolliver, Bryan K.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Clin Neurosci Div, Charleston, SC 29425 USA. [DeSantis, Stacia M.; Chiuzan, Cody] Med Univ S Carolina, Dept Med, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Brady, Kathleen T.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Prisciandaro, JJ (reprint author), Med Univ S Carolina, Dept Psychiat & Behav Sci, Clin Neurosci Div, 67 President St,MSC861, Charleston, SC 29425 USA. EM priscian@musc.edu FU Forest Laboratories, Inc.; NIDA [T32 DA007288] FX This study was funded by an investigator-initiated research grant to BKT from Forest Laboratories, Inc.; Forest Laboratories had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the study for publication. JJP was supported by NIDA T32 DA007288. NR 40 TC 14 Z9 14 U1 3 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2012 VL 36 IS 3 BP 490 EP 496 DI 10.1111/j.1530-0277.2011.01645.x PG 7 WC Substance Abuse SC Substance Abuse GA 897PC UT WOS:000300663900012 PM 21933201 ER PT J AU Agrawal, A Freedman, ND Cheng, YC Lin, P Shaffer, JR Sun, Q Taylor, K Yaspan, B Cole, JW Cornelis, MC DeSensi, RS Fitzpatrick, A Heiss, G Kang, JH O'Connell, J Bennett, S Bookman, E Bucholz, KK Caporaso, N Crout, R Dick, DM Edenberg, HJ Goate, A Hesselbrock, V Kittner, S Kramer, J Nurnberger, JI Qi, L Rice, JP Schuckit, M van Dam, RM Boerwinkle, E Hu, F Levy, S Marazita, M Mitchell, BD Pasquale, LR Bierut, LJ AF Agrawal, Arpana Freedman, Neal D. Cheng, Yu-Ching Lin, Peng Shaffer, John R. Sun, Qi Taylor, Kira Yaspan, Brian Cole, John W. Cornelis, Marilyn C. DeSensi, Rebecca S. Fitzpatrick, Annette Heiss, Gerardo Kang, Jae H. O'Connell, Jeffrey Bennett, Siiri Bookman, Ebony Bucholz, Kathleen K. Caporaso, Neil Crout, Richard Dick, Danielle M. Edenberg, Howard J. Goate, Alison Hesselbrock, Victor Kittner, Steven Kramer, John Nurnberger, John I., Jr. Qi, Lu Rice, John P. Schuckit, Marc van Dam, Rob M. Boerwinkle, Eric Hu, Frank Levy, Steven Marazita, Mary Mitchell, Braxton D. Pasquale, Louis R. Bierut, Laura J. CA GENEVA Consortium TI Measuring alcohol consumption for genomic meta-analyses of alcohol intake: opportunities and challenges SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID U-SHAPED CURVE; WIDE ASSOCIATION; GENETIC INFLUENCES; ENVIRONMENTAL-INFLUENCES; GENOMEWIDE ASSOCIATION; DIETARY PATTERNS; SMOKING-BEHAVIOR; CANCER RISK; DEPENDENCE; MORTALITY AB Whereas moderate drinking may have health benefits, excessive alcohol consumption causes many important acute and chronic diseases and is the third leading contributor to preventable death in the United States. Twin studies suggest that alcohol-consumption patterns are heritable (50%); however, multiple genetic variants of modest effect size are likely to contribute to this heritable variation. Genome-wide association studies provide a tool for discovering genetic loci that contribute to variations in alcohol consumption. Opportunities exist to identify susceptibility loci with modest effect by meta-analyzing together multiple studies. However, existing studies assessed many different aspects of alcohol use, such as typical compared with heavy drinking, and these different assessments can be difficult to reconcile. In addition, many studies lack the ability to distinguish between lifetime and recent abstention or to assess the pattern of drinking during the week, and a variety of such concerns surround the appropriateness of developing a common summary measure of alcohol intake. Combining such measures of alcohol intake can cause heterogeneity and exposure misclassification, cause a reduction in power, and affect the magnitude of genetic association signals. In this review, we discuss the challenges associated with harmonizing alcohol-consumption data from studies with widely different assessment instruments, with a particular focus on large-scale genetic studies. Am J Clin Nutr 2012; 95: 539-47. C1 [Agrawal, Arpana] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Freedman, Neal D.; Caporaso, Neil] NCI, Bethesda, MD 20892 USA. [Cheng, Yu-Ching; Cole, John W.; O'Connell, Jeffrey; Kittner, Steven; Mitchell, Braxton D.] Univ Maryland, Bethesda, MD USA. [Shaffer, John R.; DeSensi, Rebecca S.; Marazita, Mary] Univ Pittsburgh, Pittsburgh, PA USA. [Sun, Qi; Cornelis, Marilyn C.; Qi, Lu; van Dam, Rob M.; Hu, Frank] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kang, Jae H.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Taylor, Kira] Univ Louisville, Louisville, KY 40292 USA. [Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Yaspan, Brian] Vanderbilt Univ, Nashville, TN USA. [Fitzpatrick, Annette; Bennett, Siiri] Univ Washington, GENEVA Coordinating Ctr, Seattle, WA 98195 USA. [Fitzpatrick, Annette; Bennett, Siiri; Bookman, Ebony] NHGRI, Morrisville, NC USA. [Crout, Richard] W Virginia Univ, Morgantown, WV 26506 USA. [Dick, Danielle M.] Virginia Commonwealth Univ, Richmond, VA USA. [Edenberg, Howard J.; Nurnberger, John I., Jr.] Indiana Univ, Indianapolis, IN 46204 USA. [Hesselbrock, Victor] Univ Connecticut, Farmington, CT USA. [Kramer, John; Levy, Steven] Univ Iowa, Iowa City, IA USA. [Schuckit, Marc] Univ Calif San Diego, San Diego, CA 92103 USA. [Boerwinkle, Eric] Univ Texas Houston, Houston, TX USA. [Pasquale, Louis R.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Agrawal, A (reprint author), Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid,CB 8134, St Louis, MO 63110 USA. EM arpana@wustl.edu RI van Dam, Rob/F-9674-2010; Lin, P/G-7702-2014; Freedman, Neal/B-9741-2015; OI van Dam, Rob/0000-0002-7354-8734; Freedman, Neal/0000-0003-0074-1098; Nurnberger, John/0000-0002-7674-1767; Edenberg, Howard/0000-0003-0344-9690; Mitchell, Braxton/0000-0003-4920-4744 FU NIH Genes, Environment and Health Initiative (GEI) [U01 HG004422]; Gene, Environment Association Studies (GENEVA) under GEI; Johns Hopkins University Center for Inherited Disease Research by NIH GEI [U01HG004438]; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH [HHSN268200782096C]; ABMRF/Foundation for Alcohol Research; Boston Obesity Nutrition Research Center [DK46200, U01HG004399, NIH R01 HL71981, K99HL098459]; American Heart Association Scientist Development Award; Canadian Institutes of Health Research (MCC); National Institutes of Dental and Craniofacial Research (NIDCR) as part of the trans-NIH GEI [U01-DE018903]; NIDCR [R01-DE 014899, R01-DE09551, R01-DE12101]; Iowa Fluoride Study; Iowa Bone Development Study; NIDCR through CIDR's NIH; NHLBI; National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; Office of Research and Development; Medical Research Service and the Baltimore Geriatrics Research, Education and Clinical Center of the Department of Veterans Affairs; National Institute of Neurological Disorders and Stroke; NIH Office of Research on Women's Health [R01 NS45012, U01 NS069208-01]; National Human Genome Research Institute [U01 HG004436]; NHGRI [U01HG004728, NEI R01EY015473]; NIH GEI [U01HG04424]; [K02DA21237]; [DA23668]; [T32 AG000262] FX The Study of Addiction: Genetics and Environment (SAGE): supported by the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene, Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning and with the general study coordination was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for the collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392), and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). LJB was supported by K02DA21237. AA receives support from the DA23668 and ABMRF/Foundation for Alcohol Research. NHS and HPFS: the Pilot and Feasibility program were sponsored by the Boston Obesity Nutrition Research Center (DK46200; QS), U01HG004399 (FH), NIH R01 HL71981 and K99HL098459 (QS), American Heart Association Scientist Development Award (LQ), and the Canadian Institutes of Health Research (MCC). Dental Caries: Study: "Dental Caries: Whole Genome Association and Gene Environment Studies" 1-U01-DE018903, PI Marazita. (Included in the alcohol cross-study were the Levy (IOWA) and Marazita (PITT) study populations so the acknowledgements below reflect only those studies.) Funding support for the GWAS was provided by the National Institutes of Dental and Craniofacial Research (NIDCR) as part of the trans-NIH GEI (U01-DE018903). Data and samples were provided by the Center for Oral Health Research in Appalachia (a collaboration of the University of Pittsburgh and West Virginia University funded by NIDCR R01-DE 014899) and the Iowa Fluoride Study and the Iowa Bone Development Study, funded by NIDCR R01-DE09551 and R01-DE12101, respectively. Genotyping was done by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to The Johns Hopkins University (contract number HHSN268200782096C). Funds for this project's genotyping were provided by the NIDCR through CIDR's NIH contract. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01-HG004446). Atherosclerosis Risk in Communities Study: supported by NHLBI Cardiovascular Epidemiology Training Grant (UNC) (National Research Service Award) to KT; carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C.; GEOS: supported in part by the Office of Research and Development, Medical Research Service and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs (SK and JWC); the National Institute of Neurological Disorders and Stroke and the NIH Office of Research on Women's Health (R01 NS4512 and U01 NS069208-01) (SK); the National Human Genome Research Institute (U01 HG004436) (BDM, SK, and JO); and grant T32 AG000262 (Y-CC). GLAUGEN: supported by grants NHGRI U01HG004728 and NEI R01EY015473 to LRP (Research to Prevent Blindness Physician Scientist Award). Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424). The GENEVA Coordinating Center (U01HG004446) provided assistance with genotype cleaning. NR 74 TC 16 Z9 16 U1 2 U2 14 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2012 VL 95 IS 3 BP 539 EP 547 DI 10.3945/ajcn.111.015545 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 897HK UT WOS:000300638700003 PM 22301922 ER PT J AU Dalrymple, LS Katz, R Kestenbaum, B de Boer, IH Fried, L Sarnak, MJ Shlipak, MG AF Dalrymple, Lorien S. Katz, Ronit Kestenbaum, Bryan de Boer, Ian H. Fried, Linda Sarnak, Mark J. Shlipak, Michael G. TI The Risk of Infection-Related Hospitalization With Decreased Kidney Function SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Renal disease; chronic kidney disease; infection; clinical epidemiology ID GLOMERULAR-FILTRATION-RATE; SERUM CYSTATIN-C; STAGE RENAL-DISEASE; CARDIOVASCULAR EVENTS; DEATH; CREATININE; MORBIDITY; DIALYSIS; DEFECTS; ADULTS AB Background: Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, estimated by serum cystatin C level, was associated with the risk of infection-related hospitalization in older individuals. Study Design: Cohort study. Setting & Participants: 5,142 Cardiovascular Health Study (CHS) participants with measured serum creatinine and cystatin C and without estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m(2) at enrollment. Predictor: The primary exposure of interest was eGFR using serum cystatin C level (eGFR(SCysC)). Outcome: Infection-related hospitalizations during a median follow-up of 11.5 years. Results: In adjusted analyses, eGFR(SCysC) categories of 60-89, 45-59, and 15-44 mL/min/1.73 m(2) were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with eGFRSCysC >= 90 mL/min/1.73 m2. When cause-specific infection was examined, eGFR(SCysC) of 15-44 mL/min/1.73 m2 was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with eGFR(SCysC) >= 90 mL/min/1.73 m(2). Limitations: No measures of urinary protein, study limited to principal discharge diagnosis. Conclusions: Lower kidney function, estimated using cystatin C level, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of decreased kidney function are associated with clinically significant higher risks of serious infection in older individuals. Am J Kidney Dis. 59(3): 356-363. (C) 2012 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Dalrymple, Lorien S.] Univ Calif Davis, Dept Med, Davis, CA 95616 USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kestenbaum, Bryan; de Boer, Ian H.] Univ Washington, Dept Med, Seattle, WA USA. [Fried, Linda] VA Pittsburgh Hlth Care Syst, Renal Sect, Pittsburgh, PA USA. [Fried, Linda] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Fried, Linda] Univ Pittsburgh, Dept Epidemiol, Sch Med, Pittsburgh, PA 15261 USA. [Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Boston, MA USA. [Shlipak, Michael G.] Vet Affairs Med Ctr, Med Serv, Gen Internal Med Sect, San Francisco, CA 94121 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Dalrymple, LS (reprint author), Div Nephrol, 4150 V St,Ste 3500, Sacramento, CA 95817 USA. EM lorien.dalrymple@ucdmc.ucdavis.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HL080295]; National Institute of Neurological Disorders and Stroke; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058, AG-027002]; National Center for Research [UL1 RR024146]; NHLBI; [N01-HC-85239]; [N01-HC-85079]; [N01-HC-85080]; [N01-HC-85081]; [N01-HC-85082]; [N01-HC-85083]; [N01-HC-85084]; [N01-HC-85085]; [N01-HC-85086]; [N01-HC-35129]; [N01 HC-15103]; [N01 HC-55222]; [N01-HC-75150]; [N01-HC-45133] FX This research was supported by contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, AG-027058, and AG-027002 from the National Institute on Aging and UL1 RR024146 from the National Center for Research. The CHS was funded through contracts with NHLBI and included substantial NHLBI involvement in the design and conduct of the study and the collection and management of the data. The funding source was not involved in data analysis, interpretation of the data, preparation, review, or approval of the manuscript. The contents are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. A full list of principal CHS investigators and institutions can be found at www.chs-nhlbi.org/pi.htm. NR 25 TC 20 Z9 20 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2012 VL 59 IS 3 BP 356 EP 363 DI 10.1053/j.ajkd.2011.07.012 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 898WE UT WOS:000300772300009 PM 21906862 ER PT J AU Greenblatt, MB Sargent, JL Farina, G Tsang, K Lafyatis, R Glimcher, LH Whitfield, ML Aliprantis, AO AF Greenblatt, Matthew B. Sargent, Jennifer L. Farina, Giuseppina Tsang, Kelly Lafyatis, Robert Glimcher, Laurie H. Whitfield, Michael L. Aliprantis, Antonios O. TI Interspecies Comparison of Human and Murine Scleroderma Reveals IL-13 and CCL2 as Disease Subset-Specific Targets SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; GENE-EXPRESSION ANALYSIS; SYSTEMIC-SCLEROSIS; RHEUMATOID-ARTHRITIS; PULMONARY-FIBROSIS; SKIN FIBROSIS; HOST DISEASE; SERUM-LEVELS; T-CELLS; INTERLEUKIN-13 AB Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both scIGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4R alpha, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13 treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets. (Am J Pathol 2012, 180:1080-1094; DOI: 10.1016/j.ajpath.2011.11.024) C1 [Greenblatt, Matthew B.; Tsang, Kelly; Glimcher, Laurie H.; Aliprantis, Antonios O.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Sargent, Jennifer L.; Whitfield, Michael L.] Dartmouth Med Sch, Dept Genet, Hanover, NH 03755 USA. [Farina, Giuseppina; Lafyatis, Robert] Boston Univ, Sch Med, Dept Med, Div Rheumatol, Boston, MA 02118 USA. [Glimcher, Laurie H.; Aliprantis, Antonios O.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Glimcher, Laurie H.; Aliprantis, Antonios O.] Harvard Univ, Sch Med, Boston, MA USA. [Glimcher, Laurie H.] Harvard Univ, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Glimcher, Laurie H.] MIT, Boston, MA USA. RP Aliprantis, AO (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 651 Huntington Ave,FXB 205, Boston, MA 02115 USA. EM michael.L.whitfield@dartmouth.edu; aaliprantis@partners.org OI Farina, Giuseppina Alessandra/0000-0002-3948-6920 FU Scleroderma Research Foundation; Arthritis Foundation; Burroughs Wellcome Fund; NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [K08AR054859]; NIAMS [U01AR055063, R01AR051089]; Scleroderma Foundation FX Supported by grants from the Scleroderma Research Foundation (M.L.W., A.O.A. and L.H.G.), a Hulda Irene Duggan Arthritis Investigator Award from the Arthritis Foundation (M.L.W.), a Career Award for Medical Scientists from the Burroughs Wellcome Fund (A.O.A.), by an NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases grant K08AR054859 (A.O.A), NIAMS grants U01AR055063 (R.L.) and R01AR051089 (R.L.), and by Scleroderma Foundation support (G.F.). NR 57 TC 35 Z9 35 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD MAR PY 2012 VL 180 IS 3 BP 1080 EP 1094 DI 10.1016/j.ajpath.2011.11.024 PG 15 WC Pathology SC Pathology GA 902EU UT WOS:000301022200021 PM 22245215 ER PT J AU Anderson, S Oyama, TT Lindsley, JN Schutzer, WE Beard, DR Gattone, VH Komers, R AF Anderson, Sharon Oyama, Terry T. Lindsley, Jessie N. Schutzer, William E. Beard, Douglas R. Gattone, Vincent H., II Komers, Radko TI 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE gender; estrogen; mammalian target of rapamycin 2; hydroxyestradiol p21; hypoxia-inducible factor-1 alpha ID HAN-SPRD RATS; ACTIVATED PROTEIN-KINASE; EPITHELIAL-CELL PROLIFERATION; RENAL-DISEASE; SIGNALING PATHWAY; INHIBITION SLOWS; CYSTIC-DISEASE; MTOR PATHWAY; CANCER CELLS; GROWTH AB Anderson S, Oyama TT, Lindsley JN, Schutzer WE, Beard DR, Gattone VH 2nd, Komers R. 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease. Am J Physiol Renal Physiol 302: F636-F645, 2012. First published December 7, 2011; doi: 10.1152/ajprenal.00265.2011.-Male gender is a risk factor for progression of polycystic kidney disease (PKD). 17 beta-Estradiol (E2) protects experimentally, but clinical use is limited by adverse effects. Novel E2 metabolites provide many benefits of E2 without stimulating the estrogen receptor, and thus may be safer. We hypothesized that E2 metabolites are protective in a model of PKD. Studies were performed in male control Han:SPRD rats, and in cystic males treated with orchiectomy, 2-methoxyestradiol, 2-hydroxyestradiol (2-OHE), or vehicle, from age 3 to 12 wk. Cystic rats exhibited renal functional impairment (similar to 50% decrease in glomerular filtration and renal plasma flow rates, P < 0.05) and substantial cyst development (20.5 +/- 2.0% of cortex area). 2-OHE was the most effective in limiting cysts (6.0 +/- 0.7% of cortex area, P < 0.05 vs. vehicle-treated cystic rats) and preserving function, in association with suppression of proliferation, apoptosis, and angiogenesis markers. Downregulation of p21 expression and increased expression of Akt, the mammalian target of rapamycin (mTOR), and some of its downstream effectors were significantly reversed by 2-OHE. Thus, 2-OHE limits disease progression in a cystic rodent model. Mechanisms include reduced renal cell proliferation, apoptosis, and angiogenesis. These effects may be mediated, at least in part, by preservation of p21 and suppression of Akt and mTOR. Estradiol metabolites may represent a novel, safe intervention to slow progression of PKD. C1 [Anderson, Sharon; Oyama, Terry T.; Lindsley, Jessie N.; Schutzer, William E.; Komers, Radko] Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97239 USA. [Anderson, Sharon] Portland VA Med Ctr, Med Serv, Portland, OR USA. [Schutzer, William E.; Beard, Douglas R.] Portland VA Med Ctr, Res Serv, Portland, OR USA. [Gattone, Vincent H., II] Indiana Univ Sch Med, Dept Anat & Cell Biol, Indianapolis, IN USA. RP Anderson, S (reprint author), Oregon Hlth & Sci Univ, Div Nephrol, CH12R,3303 SW Bond St, Portland, OR 97239 USA. EM anderssh@ohsu.edu FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [DK 078807]; Polycystic Kidney Research Foundation FX These studies were supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (DK 078807) and the Polycystic Kidney Research Foundation. NR 76 TC 5 Z9 5 U1 0 U2 4 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 MAR PY 2012 VL 302 IS 5 BP F636 EP F645 DI 10.1152/ajprenal.00265.2011 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 901BG UT WOS:000300936100014 PM 22160773 ER PT J AU Martin, TR Snapp, DL Tomita, DM AF Martin, Thomas R. Snapp, Deborah L. Tomita, Diane M. TI The Parker B. Francis Fellowship Program Analysis of 31 Years of Career Development Support SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE research training; fellowship support; survey; career development ID ORGANIZATIONAL-CLIMATE; MEDICAL-SCHOOL; RESPONSE RATES; WOMEN FACULTY AB Rationale: The Parker B. Francis (PBF) Fellowship Program has supported more than 750 M.D., M.D./Ph.D., and Ph.D. fellows since 1976, but there is little information about the effectiveness of the program in fostering successful careers and producing important research. Objectives: To survey all past PBF Fellows to obtain information about their productivity and career pathways. Methods: We obtained e-mail addresses for 526 (74%) of the 712 PBF awardees from 1976 to 2006, then sent an e-mail survey to the 526 past fellows and received 365 replies (69% response rate, 49% overall). Survey questions addressed time in research, areas of research, current position and responsibilities, and research funding. Measurements and Main Results: Seventy percent of the 365 respondents spend 25% or greater effort in research and 56% report 50% or more effort in research. Respondents have published an average of 2.7 peer-reviewed publications per year, totaling more than 15,678 peer-reviewed publications, of which 1,875 appeared in high-impact journals. Respondents have received more than $1.8 billion in direct research funding since their PBF Fellowships began. Ph.D. awardees spend more time in research than M.D. awardees, and current research effort did not differ by gender. PBF awardees have become prominent leaders in universities, the National Institutes of Health, health care, and industry. Conclusions: The PBF Program has been highly successful in producing a large number of scientific and clinical leaders in pulmonary and critical care medicine. The results provide comprehensive data about the success of this career development program and provide a model for programs designed to build the workforce in pulmonary and critical care medicine. C1 [Martin, Thomas R.] Univ Washington, Sch Med, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Martin, Thomas R.] VA Puget Sound Hlth Care Syst, Med Res Serv, Seattle, WA USA. RP Martin, TR (reprint author), Univ Washington, Sch Med, Dept Med, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. EM trmartin@u.washington.edu FU Francis Family Foundation, Kansas City, MO; Francis Family Foundation FX Supported by the Francis Family Foundation, Kansas City, MO.; The authors thank the Francis Family members and the Francis Family Foundation Board of Directors for their steadfast support of the Parker B. Francis Fellowship Program and the Parker B. Francis Council of Scientific Advisors for advice during the preparation of this report. The data in this report reflect the leadership of the past Scientific Directors of the PBF Program, S. Marsh Tenney, M.D., Donald F. Tierney, M.D. and Joseph D. Brain, Sc.D. NR 10 TC 2 Z9 2 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 1 PY 2012 VL 185 IS 5 BP 479 EP 485 DI 10.1164/rccm.201108-1390PP PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 900AG UT WOS:000300858400008 PM 22095548 ER PT J AU Kraft, S Faquin, WC Krane, JF AF Kraft, Stefan Faquin, William C. Krane, Jeffrey F. TI HPV-associated Neuroendocrine Carcinoma of the Oropharynx: A Rare New Entity With Potentially Aggressive Clinical Behavior SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE human papillomavirus; head and neck cancer; squamous cell carcinoma; neuroendocrine carcinoma; oropharynx ID SQUAMOUS-CELL-CARCINOMA; HUMAN-PAPILLOMAVIRUS DNA; TRANSCRIPTION FACTOR-I; NECK-CANCER; UTERINE CERVIX; IMMUNOHISTOCHEMICAL ANALYSIS; ADENOSQUAMOUS CARCINOMA; UNDIFFERENTIATED CARCINOMA; FAVORABLE PROGNOSIS; TONSILLAR CARCINOMA AB High-grade neuroendocrine carcinoma of the head and neck is an aggressive neoplasm which rarely arises in the oropharynx. Here we report a series of 8 oropharyngeal neuroendocrine carcinomas associated with both human papillomavirus (HPV) infection and tobacco exposure. The tumor occurred predominantly in male patients (6 of 8) at a mean age of 59 years. Histologically, these cases were all classified as poorly differentiated neuroendocrine carcinoma (small cell carcinoma) with high mitotic activity [mean 53.3 mitoses per 10 HPF], necrosis, high nuclear-to-cytoplasmic ratio, and nuclear molding. One case also exhibited a moderately differentiated component, and one other case had a component of squamous cell carcinoma with basaloid features. Neuroendocrine differentiation was confirmed by immunoreactivity for synaptophysin and/or chromogranin A in all cases. P63 staining was negative, except in 1 case. Seven of the 8 cases showed strong and diffuse p16 expression, a surrogate marker for high-risk HPV infection. HPV infection was confirmed in 6 of these 7 cases by HPV in situ hybridization and/or polymerase chain reaction analysis. HPV subtypes 16, 18, and 33 were identified in 1 case each by polymerase chain reaction testing. Six of the 7 patients for whom clinical history was available presented with advanced disease (4 with regional lymph node metastases, 1 with distant metastases, and 1 with distant and locoregional metastases). Disease recurred in 5 of the 6 patients with available clinical follow-up, with 3 developing distant metastases to brain, bones, lung, pleura, adrenal glands, and pancreas. These 3 cases were all from the HPV-positive group. In summary, neuroendocrine carcinoma of the oropharynx represents a rare novel HPV-associated entity with high-grade histologic features and aggressive clinical behavior. C1 [Kraft, Stefan; Krane, Jeffrey F.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kraft, Stefan; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Krane, JF (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM jkrane@partners.org NR 74 TC 28 Z9 29 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2012 VL 36 IS 3 BP 321 EP 330 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 902KY UT WOS:000301038200001 PM 22301491 ER PT J AU Khor, TS Alfaro, EE Ooi, EMM Li, Y Srivastava, A Fujita, H Do, YP Kumarasinghe, MP Lawyers, GY AF Khor, Tze Sheng Alfaro, Eduardo E. Ooi, Esther M. M. Li, Yuan Srivastava, Amitabh Fujita, Hiroshi Do, Youn Park Kumarasinghe, Marian Priyanthi Lawyers, Gregory Yves TI Divergent Expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2 in Dysplasia and Intramucosal Adenocarcinomas With Intestinal and Foveolar Morphology: Is This Evidence of Distinct Gastric and Intestinal Pathways to Carcinogenesis in Barrett Esophagus? SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Barrett esophagus; foveolar dysplasia; adenomatous dysplasia; hybrid dysplasia; intramucosal adenocarcinoma; immunophenotype; mucin core peptide expression; CDX-2 ID COLUMNAR-LINED ESOPHAGUS; IMMUNOHISTOCHEMICAL-DEMONSTRATION; GOBLET CELLS; METAPLASIA; DIAGNOSIS; EPITHELIUM; CANCER; DIFFERENTIATION; SURVEILLANCE; HISTOGENESIS AB Dysplasia in Barrett esophagus has been recognized to be morphologically heterogenous, featuring adenomatous, foveolar, and hybrid phenotypes. Recent studies have suggested a tumor suppressor role for CDX-2 in the metaplasia-dysplasia-carcinoma sequence. The phenotypic stability and role of CDX-2 in the neoplastic progression of different types of dysplasias have not been evaluated. Thirty-eight endoscopic mucosal resections with dysplasia and/or intramucosal carcinoma (IMC) arising in Barrett esophagus were evaluated for the expression of MUC5AC, MUC6, MUC2, CD 10, and CDX-2. The background mucosa was also evaluated. The results were correlated with morphologic classification and clinicopathologic parameters. Of 38 endoscopic mucosal resections, 23 had IMC and dysplasia, 8 had IMC only, and 7 had dysplasia only. Among dysplastic lesions, 73% were foveolar, 17% were adenomatous, and 10% were hybrid. Twenty of 23 cases with dysplasia and adjacent IMC showed an identical immunophenotype of dysplasia and IMC comprising 16 gastric, 3 intestinal, and I mixed immunophenotype. Three cases showed discordance of dysplasia and IMC immunophenotype. These findings suggest that most Barrett-related IMC cases are either gastric or intestinal, with phenotypic stability during progression supporting separate gastric and intestinal pathways of carcinogenesis. CDX-2 showed gradual downregulation of expression during progression in adenomatous dysplasia but not in foveolar or hybrid dysplasia, supporting a tumor suppressor role, at least in the intestinal pathway. CDX-2 was also found to be expressed to a greater degree in intestinal metaplasia compared with non-intestinalized columnar metaplasia. Consistent with CDX-2 as a tumor suppressor, this suggests that non-intestinalized columnar metaplasia may be an unstable intermediate state at risk for neoplastic progression. C1 [Khor, Tze Sheng; Alfaro, Eduardo E.; Ooi, Esther M. M.; Li, Yuan; Fujita, Hiroshi; Lawyers, Gregory Yves] Massachusetts Gen Hosp, Dept Pathol, Gastrointestinal Pathol Serv, Boston, MA 02114 USA. [Srivastava, Amitabh] Brigham & Womens Hosp, Boston, MA 02115 USA. [Srivastava, Amitabh; Lawyers, Gregory Yves] Harvard Univ, Sch Med, Boston, MA USA. [Khor, Tze Sheng; Kumarasinghe, Marian Priyanthi] Univ Western Australia, PathW Lab Med, Perth, WA 6009, Australia. [Ooi, Esther M. M.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Alfaro, Eduardo E.] Univ Costa Rica, Hosp Mexico, Dept Pathol, San Jose, Costa Rica. [Li, Yuan] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Pathol, Beijing 100730, Peoples R China. [Li, Yuan] Peking Union Med Coll, Beijing 100730, Peoples R China. [Fujita, Hiroshi] Kagoshima Univ, Grad Sch Med & Dent Sci, Kagoshima Univ Hosp, Dept Gastroenterol, Kagoshima 890, Japan. [Do, Youn Park] Pusan Natl Univ, Pusan Natl Univ Hosp, Med Res Inst, Sch Med,Dept Pathol, Pusan, South Korea. RP Lawyers, GY (reprint author), Massachusetts Gen Hosp, Dept Pathol, Gastrointestinal Pathol Serv, 55 Fruit St, Boston, MA 02114 USA. EM glauwers@partners.org RI Ooi, Esther/B-3257-2011 OI Ooi, Esther/0000-0002-2097-633X FU National Research and Development Program for Cancer Control [0920050]; Ministry for Health, Welfare and Family affairs, Republic of Korea; A&A Saw Medical Research Fellowship; National Health and Medical Research Council of Australia FX Funding for immunohistochemistry for this study was supported by a Grant (0920050) from the National Research and Development Program for Cancer Control, Ministry for Health, Welfare and Family affairs, Republic of Korea. T.S.K. is supported by an A&A Saw Medical Research Fellowship. E.M.M.O. is supported by a National Health and Medical Research Council of Australia Postdoctoral Research Fellowship. For the remaining authors none were declared. NR 39 TC 28 Z9 31 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2012 VL 36 IS 3 BP 331 EP 342 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA 902KY UT WOS:000301038200002 PM 22261707 ER PT J AU Kao, CS Idrees, MT Young, RH Ulbright, TM AF Kao, Chia-Sui Idrees, Muhammad T. Young, Robert H. Ulbright, Thomas M. TI Solid Pattern Yolk Sac Tumor: A Morphologic and lmmunohistochemical Study of 52 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE testis; mediastinum; yolk sac tumor; solid pattern ID GERM-CELL TUMORS; ENDODERMAL SINUS TUMOR; EMBRYONAL CARCINOMA; DIFFERENTIAL-DIAGNOSIS; ALPHA-FETOPROTEIN; SEMINOMA; OVARY; CHILDREN; IMMUNOHISTOCHEMISTRY; MARKER AB Yolk sac tumors may exhibit numerous patterns. One that has received little attention overall, yet is not uncommon, is a solid pattern, which is especially prone to misinterpretation, usually as seminoma, in biopsy specimens from metastatic or mediastinal sites. This distinction is of critical importance as the 2 tumors are treated differently. To determine features useful in the diagnosis of solid yolk sac tumor we reviewed 52 germ cell tumors (28 testicular primaries, 21 metastases from the testis, and 3 mediastinal primaries) that had a yolk sac tumor component with foci of solid growth, defined as a sheet-like arrangement of tumor cells occupying > 2 mm(2) and with no or only rare microcysts. Solid yolk sac tumor was almost always associated with other patterns, most commonly microcystic/reticular (75%), glandular (35%) myxoid (25%). The solid foci consisted of sheets of cells with usually abundant cytoplasm that was mostly (85%) pale to clear and frequently had intercellular basement membrane deposits (75%), rare microcysts (67%), significant nuclear pleomorphism (65%), and hyaline globules (65%). In 2 cases (4%), the cells were small with scant cytoplasm (blastema-like variant). A myxoid background (39%), lymphocytic infiltrate (17%), and an applique pattern (8%) were sometimes observed. On immunostaining, AE1/AE3 cytokeratin and glypican 3 provided the most intense and diffuse reactivity for solid yolk sac tumor, whereas a-fetoprotein was negative in 38%. CD117 stained 59%, whereas only rare cells in I case (3%) were weakly reactive for podoplanin; OCT3/4 was uniformly negative. We conclude that solid yolk sac tumor can generally be recognized by careful morphologic evaluation, especially its association with other yolk sac tumor patterns, the presence of intercellular band-like deposits of basement membrane, occasional microcysts, nuclear pleomorphism, intracellular hyaline globules, and usual absence of lymphocytes. In difficult cases a concise immunohistochemical panel consisting of AE1/AE3, glypican 3, and OCT3/4 distinguishes solid yolk sac tumor from other neoplasms. alpha-fetoprotein stains are commonly negative or weak and focal in solid yolk sac tumor and cannot be solely relied on for diagnosis. Common CD117 positivity in solid pattern yolk sac tumors makes it an unreliable discriminator between yolk sac tumor and seminoma. C1 [Kao, Chia-Sui; Idrees, Muhammad T.; Ulbright, Thomas M.] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Lab, Boston, MA USA. RP Ulbright, TM (reprint author), Indiana Univ, Hlth Pathol Lab, Room 4014,350 W 11th St, Indianapolis, IN 46202 USA. EM tulbrigh@iupui.edu NR 50 TC 21 Z9 28 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2012 VL 36 IS 3 BP 360 EP 367 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 902KY UT WOS:000301038200005 PM 22261704 ER PT J AU Baron, DM Yu, BL Lei, C Bagchi, A Beloiartsev, A Stowell, CP Steinbicker, AU Malhotra, R Bloch, KD Zapol, WM AF Baron, David M. Yu, Binglan Lei, Chong Bagchi, Aranya Beloiartsev, Arkadi Stowell, Christopher P. Steinbicker, Andrea U. Malhotra, Rajeev Bloch, Kenneth D. Zapol, Warren M. TI Pulmonary Hypertension in Lambs Transfused with Stored Blood Is Prevented by Breathing Nitric Oxide SO ANESTHESIOLOGY LA English DT Article ID SICKLE-CELL-DISEASE; ENDOTHELIAL DYSFUNCTION; STORAGE LESION; S-NITROSOHEMOGLOBIN; FREE HEMOGLOBIN; BANKED BLOOD; AWAKE LAMBS; HEMOLYSIS; SHEEP; VASOCONSTRICTION AB Background: During extended storage, erythrocytes undergo functional changes. These changes reduce the viability of erythrocytes leading to release of oxyhemoglobin, a potent scavenger of nitric oxide. We hypothesized that transfusion of ovine packed erythrocytes (PRBC) stored for prolonged periods would induce pulmonary vasoconstriction in lambs, and that reduced vascular nitric oxide concentrations would increase this vasoconstrictor effect. Methods: We developed a model of autologous stored blood transfusion in lambs (n = 36). Leukoreduced blood was stored for either 2 days (fresh PRBC) or 40 days (stored PRBC). Fresh or stored PRBC were transfused into donors instrumented for awake hemodynamic measurements. Hemodynamic effects of PRBC transfusion were also studied after infusion of N-G-nitro-L-arginine methyl-ester (25 mg/kg) or during inhalation of nitric oxide (80 ppm). Results: Cell-free hemoglobin levels were higher in the supernatant of stored PRBC than in supernatant of fresh PRBC (Mean +/- SD, 148 +/- 20 vs. 41 +/- 13 mg/dl, respectively, P < 0.001). Pulmonary artery pressure during transfusion of stored PRBC transiently increased from 13 +/- 1 to 18 +/- 1 mmHg (P < 0.001) and was associated with increased plasma hemoglobin concentrations. N-G-intro-L-arginine methyl-ester potentiated the increase in pulmonary arterial pressure induced by transfusing stored PRBC, whereas inhalation of nitric oxide prevented the vasoconstrictor response. Conclusions: Our results suggest that patients with reduced vascular nitric oxide levels because of endothelial dysfunction may be more susceptible to adverse effects of transfusing blood stored for prolonged periods. These patients might benefit from transfusion of fresh PRBC, when available, or inhaled nitric oxide supplementation to prevent the pulmonary hypertension associated with transfusion of stored PRBC. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Zapol, WM (reprint author), Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM wzapol@partners.org OI Malhotra, Rajeev/0000-0003-0120-4630 FU Eleanor and Miles Shore 50th Anniversary Fellowship (Boston, Massachusetts); German Research Foundation (Bonn, Germany) [SW 119/3-1]; National Institutes of Health (Bethesda, Maryland) [T32, HL074352]; American Heart Association (Dallas, Texas); Ikaria FX Received from Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Submitted for publication August 2, 2011. Accepted for publication November 21, 2011. Supported by funds of the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. Dr. Yu was supported by the Eleanor and Miles Shore 50th Anniversary Fellowship (Boston, Massachusetts). Dr. Steinbicker was supported by grant No. SW 119/3-1 from the German Research Foundation (Bonn, Germany). Dr. Malhotra was supported by a National Institutes of Health T32 grant (Bethesda, Maryland) and a Fellow-to-Faculty Transition Award from the American Heart Association (Dallas, Texas). Dr. Bloch was supported by a National Institutes of Health R01 grant No. HL074352 (Bethesda, Maryland). Dr. Zapol receives royalties from patents on inhaled nitric oxide licensed by Massachusetts General Hospital to Linde Corporation, Munich, Germany, and Ikaria Corporation, Clinton, New Jersey. Dr. Bloch has received grants from Ikaria to study inhaled nitric oxide. Drs. Zapol and Yu have applied for a U.S. patent entitled "Attenuation of artificial oxygen carrier-induced vasoconstriction," Provisional Patent Application 60/864,734. The remaining authors report no conflicts of interest. NR 47 TC 28 Z9 32 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD MAR PY 2012 VL 116 IS 3 BP 637 EP 647 DI 10.1097/ALN.0b013e318246ef77 PG 11 WC Anesthesiology SC Anesthesiology GA 898UE UT WOS:000300766700019 PM 22293717 ER PT J AU Wong, VM Wenk, JF Zhang, ZH Cheng, GM Acevedo-Bolton, G Burger, M Saloner, DA Wallace, AW Guccione, JM Ratcliffe, MB Ge, L AF Wong, Vincent M. Wenk, Jonathan F. Zhang, Zhihong Cheng, Guangming Acevedo-Bolton, Gabriel Burger, Mike Saloner, David A. Wallace, Arthur W. Guccione, Julius M. Ratcliffe, Mark B. Ge, Liang TI The Effect of Mitral Annuloplasty Shape in Ischemic Mitral Regurgitation: A Finite Element Simulation SO ANNALS OF THORACIC SURGERY LA English DT Article ID DILATED CARDIOMYOPATHY; LEFT-VENTRICLE; WALL STRESS; VALVE; REPAIR; MODEL; RECONSTRUCTION; PATHOGENESIS; HYPERTROPHY; DIMENSIONS AB Background. Undersized mitral annuloplasty (MA) is the preferred surgical treatment for chronic ischemic mitral regurgitation. However, the preferred shape of undersized MA is unclear. Methods. A previously described finite element model of the left ventricle with mitral valve based on magnetic resonance images of a sheep with chronic ischemic mitral regurgitation after posterolateral myocardial infarction was used. Saddle-shape (Edwards Physio II) and asymmetric (IMR ETlogix) MA rings were digitized and meshed. Virtual annuloplasty was performed using virtual sutures to attach the MA ring. Left ventricular diastole and systole were performed before and after virtual MA of each type. Results. Both types of MA reduced the septolateral dimension of the mitral annulus and abolished mitral regurgitation. The asymmetric MA was associated with lower virtual suture force in the P2 region but higher force in P1 and P3 regions. Although both types of MA reduced fiber stress at the left ventricular base, fiber stress reduction after asymmetric MA was slightly greater. Neither type of MA affected fiber stress at the left ventricular equator or apex. Although both types of MA increased leaflet curvature and reduced leaflet stress, stress reduction with saddle-shape MA was slightly greater. Both MA types reduced stress on the mitral chordae. Conclusions. The effects of saddle-shape and asymmetric MA rings are similar. Finite element simulations are a powerful tool that may reduce the need for animal and clinical trials. (Ann Thorac Surg 2012; 93: 776-82) (C) 2012 by The Society of Thoracic Surgeons C1 Univ Calif San Francisco, Dept Surg, San Francisco, CA USA. Univ Calif San Francisco, Dept Bioengn, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Livermore Software Technol Corp, Livermore, CA USA. Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. RP Ratcliffe, MB (reprint author), San Francisco VA Med Ctr, Surg Serv 112, 4150 Clement St, San Francisco, CA 94121 USA. EM mark.ratcliffe@va.gov FU NIH [R01-HL-084431, R01-HL-077921, 86400] FX We thank Edwards Lifesciences for providing samples of the annuloplasty rings used in this work. This study was supported by NIH grants R01-HL-084431 (M.B.R.) and R01-HL-077921 and 86400 (J.M.G.). NR 39 TC 22 Z9 23 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD MAR PY 2012 VL 93 IS 3 BP 776 EP 782 DI 10.1016/j.athoracsur.2011.08.080 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 899RB UT WOS:000300832700028 PM 22245588 ER PT J AU Lanuti, M Sharma, A Willers, H Digumarthy, SR Mathisen, DJ Shepard, JAO AF Lanuti, Michael Sharma, Amita Willers, Henning Digumarthy, Subba R. Mathisen, Douglas J. Shepard, Jo-Anne O. TI Radiofrequency Ablation for Stage I Non-Small Cell Lung Cancer: Management of Locoregional Recurrence SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 47th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 31-FEB 02, 2011 CL San Diego, CA SP Soc Thorac Surg ID BODY RADIATION-THERAPY; THERMAL ABLATION; RISK PATIENTS; TUMORS; RADIOTHERAPY; OUTCOMES; SAFETY AB Background. This study characterizes the management of locoregional recurrence (LRR) in patients with highrisk stage I non- small cell lung cancer (NSCLC) treated with lung radiofrequency ablation (RFA). Methods. Consecutive patients with biopsy-proven stage I NSCLC underwent computed tomography-guided lung RFA from December 2003 to 2010. All patients were deemed medically inoperable or refused an operation. RFA was performed with curative intent. Results. Fifty-five ablations were performed in 45 patients (age, 51 to 89 years) with stage I NSCLC. At a median follow-up of 32 months, LRR occurred in 21 (38%) within a mean of 12 +/- 10 (range, 1-44) months from RFA. Recurrence was observed locally in the tumor bed in 18 (33%), in regional nodes in 4 (7%), and distant in 2 (4%). The mean maximal tumor diameter was 2.3 +/- 1.3 (range, 0.7 to 4.5) cm. In tumors exceeding 3 cm, 10 (80%) were associated with LRR. Recurrent lesions were treated with repeat RFA (5), radiotherapy (8), chemoradiotherapy (5), and chemotherapy (2). Local control was achieved by repeat RFA in 2 of 5 (40%) or by radiotherapy in 8 lesions (100%), with 2 regional nodal failures (median follow-up, 40 +/- 13 months). Overall survival among patients who did or did not experience LRR was similar (32% to 35%). Repeat RFA was not associated with any significant complications or procedure-related 30-day mortality. Conclusions. Lung RFA is associated with increased rates of local failure in tumors exceeding 3 cm and in contact with larger segmental vessels. Patients with local failure can be promptly salvaged with SBRT or repeat RFA, without detriment to overall survival. (Ann Thorac Surg 2012;93:921-8) (C) 2012 by The Society of Thoracic Surgeons C1 [Lanuti, Michael] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Thorac Surg,Div Thorac Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Lanuti, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Thorac Surg,Div Thorac Radiol, 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM mlanuti@partners.org NR 22 TC 31 Z9 36 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD MAR PY 2012 VL 93 IS 3 BP 921 EP 928 DI 10.1016/j.athoracsur.2011.11.043 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 899RB UT WOS:000300832700059 PM 22296982 ER PT J AU Wivagg, CN Hung, DT AF Wivagg, Carl N. Hung, Deborah T. TI Resuscitation-Promoting Factors Are Required for beta-Lactam Tolerance and the Permeability Barrier in Mycobacterium tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID ESCHERICHIA-COLI; HYDROLASES AB Mycobacterial resuscitation-promoting factors (RPFs) have been of great interest since the discovery that they promote the growth of nonculturable Mycobacterium tuberculosis cells. Yet, their precise role in mycobacterial survival and infection has remained elusive. We performed a chemical screen to identify molecules that show preferential killing of a Mycobacterium tuberculosis mutant lacking RPFs over wild-type bacilli and found that the mutant has enhanced sensitivity to the beta-lactam class of antibiotics. By monitoring beta-lactam diffusion across the mycobacterial outer membrane, we found that the RPFs are required to maintain the outer membrane integrity, as their deletion results in an increase in outer membrane permeability. C1 [Wivagg, Carl N.; Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [Hung, Deborah T.] Broad Inst, Infect Dis Initiat, Cambridge, MA USA. [Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Hung, Deborah T.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Hung, DT (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. EM hung@molbio.mgh.harvard.edu NR 9 TC 4 Z9 4 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2012 VL 56 IS 3 BP 1591 EP 1594 DI 10.1128/AAC.06027-11 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 897DN UT WOS:000300623300059 PM 22155826 ER PT J AU Ballen, KK Koreth, J Chen, YB Dey, BR Spitzer, TR AF Ballen, Karen K. Koreth, John Chen, Yi-Bin Dey, Bimalangshu R. Spitzer, Thomas R. TI Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant SO BLOOD LA English DT Review ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; ACUTE-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; ALLOGENEIC TRANSPLANTATION; ANTITHYMOCYTE GLOBULIN; PERIPHERAL-BLOOD; POSTTRANSPLANTATION CYCLOPHOSPHAMIDE; LYMPHOPROLIFERATIVE DISEASE AB Only 30% of patients who require an allogeneic hematopoietic cell transplant will have an HLA-matched sibling donor. A search for an unrelated donor will be undertaken for patients without a matched family donor. However, many patients, particularly patients of diverse racial and ethnic backgrounds, may not be able to rapidly identify a suitably matched unrelated donor. Three alternative graft sources, umbilical cord blood (UCB), haploidentical (haplo)-related donor, and mis-matched unrelated donor (MMUD) are available. UCB is associated with decreased GVHD, but hematologic recovery and immune reconstitution are slow. Haplo-HCT is characterized by donor availability for transplantation and after transplantation adoptive cellular immunotherapy but may be complicated by a high risk of graft failure and relapse. A MMUD transplant may also be an option, but GVHD may be of greater concern. Phase 2 studies have documented advances in HLAtyping, GVHD prophylaxis, and infection prevention, which have improved survival. The same patient evaluated in different transplant centers may be offered MMUD, UCB, or haplo-HCT depending on center preference. In this review, we discuss the rationale for donor choice and the need of phase 3 studies to help answer this important question. (Blood. 2012; 119(9): 1972-1980) C1 [Ballen, Karen K.; Chen, Yi-Bin; Dey, Bimalangshu R.; Spitzer, Thomas R.] Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, Boston, MA 02114 USA. [Koreth, John] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Dept Med, 0 Emerson,Suite 118, Boston, MA 02114 USA. EM kballen@partners.org FU Advisory Board of Millennium FX Conflict-of-interest disclosure: J.K. acquired research funding and is on the Advisory Board of Millennium. The remaining authors declare no competing financial interests. NR 93 TC 70 Z9 75 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2012 VL 119 IS 9 BP 1972 EP 1980 DI 10.1182/blood-2011-11-354563 PG 9 WC Hematology SC Hematology GA 901GA UT WOS:000300949500006 PM 22210876 ER PT J AU Tai, YT Horton, HM Kong, SY Pong, E Chen, H Cemerski, S Bernett, MJ Nguyen, DHT Karki, S Chu, SY Lazar, GA Munshi, NC Desjarlais, JR Anderson, KC Muchhal, US AF Tai, Yu-Tzu Horton, Holly M. Kong, Sun-Young Pong, Erik Chen, Hsing Cemerski, Saso Bernett, Matthew J. Nguyen, Duc-Hanh T. Karki, Sher Chu, Seung Y. Lazar, Greg A. Munshi, Nikhil C. Desjarlais, John R. Anderson, Kenneth C. Muchhal, Umesh S. TI Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function SO BLOOD LA English DT Article ID DEPENDENT CELLULAR CYTOTOXICITY; C-RECEPTOR POLYMORPHISMS; METASTATIC BREAST-CANCER; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; XENOGRAFT MODELS; LUNG-CANCER; TUMOR-CELLS; IMMUNOTHERAPY; ANTIGEN AB HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance Fc gamma R binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti-HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B-dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via Fc gamma R-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM. (Blood. 2012; 119(9): 2074-2082) C1 [Horton, Holly M.; Pong, Erik; Chen, Hsing; Cemerski, Saso; Bernett, Matthew J.; Nguyen, Duc-Hanh T.; Karki, Sher; Chu, Seung Y.; Lazar, Greg A.; Desjarlais, John R.; Muchhal, Umesh S.] Xencor Inc, Monrovia, CA 91016 USA. [Tai, Yu-Tzu; Kong, Sun-Young; Munshi, Nikhil C.; Anderson, Kenneth C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Tai, Yu-Tzu; Kong, Sun-Young; Munshi, Nikhil C.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA 02115 USA. [Kong, Sun-Young] Natl Canc Ctr, Res Inst & Hosp, Goyang, South Korea. [Munshi, Nikhil C.] Boston Vet Adm Healthcare Syst, W Roxbury, MA USA. RP Muchhal, US (reprint author), Xencor Inc, 111 W Lemon Ave, Monrovia, CA 91016 USA. EM umuchhal@xencor.com FU NCI NIH HHS [P01 CA078378, P01 CA155258, R01 CA050947, P50 CA100707] NR 50 TC 28 Z9 28 U1 3 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 1 PY 2012 VL 119 IS 9 BP 2074 EP 2082 DI 10.1182/blood-2011-06-364521 PG 9 WC Hematology SC Hematology GA 901GA UT WOS:000300949500017 PM 22246035 ER PT J AU LaCasce, AS Vandergrift, JL Rodriguez, MA Abel, GA Crosby, AL Czuczman, MS Nademanee, AP Blayney, DW Gordon, LI Millenson, M Vanderplas, A Lepisto, EM Zelenetz, AD Niland, J Friedberg, JW AF LaCasce, Ann S. Vandergrift, Jonathan L. Rodriguez, Maria A. Abel, Gregory A. Crosby, Allison L. Czuczman, Myron S. Nademanee, Auayporn P. Blayney, Douglas W. Gordon, Leo I. Millenson, Michael Vanderplas, Ann Lepisto, Eva M. Zelenetz, Andrew D. Niland, Joyce Friedberg, Jonathan W. TI Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database SO BLOOD LA English DT Article ID PROGRESSION-FREE SURVIVAL; INTERNATIONAL PROGNOSTIC INDEX; PROSPECTIVE RANDOMIZED-TRIAL; EUROPEAN MCL NETWORK; IMMUNOCHEMOTHERAPY; TRANSPLANTATION; RITUXIMAB; MULTICENTER; SUPERIOR; MIPI AB Few randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role of aggressive induction is unclear. The National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Database, a prospective cohort study collecting clinical, treatment, and outcome data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial therapies in MCL. Patients younger than 65 diagnosed between 2000 and 2008 were included if they received RHCVAD (rituximab fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone), RCHOP+HDT/ASCR (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone + high-dose therapy/autologous stem cell rescue), RHCVAD+HDT/ASCR, or RCHOP. Clinical parameters were similar for patients treated with RHCVAD (n = 83, 50%), RCHOP+HDT/ASCR (n = 34, 20%), RCHOP (n = 29, 17%), or RHCVAD+HDT/ASCR (n = 21, 13%). Overall, 70 (42%) of the 167 patients progressed and 25 (15%) expired with a median follow-up of 33 months. There was no difference in progression-free survival (PFS) between aggressive regimens (P > .57), which all demonstrated superior PFS compared with RCHOP (P < .004). There was no difference in overall survival (OS) between the RHCVAD and RCHOP+HDT/ASCR (P = .98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR, which had similar PFS and OS. Despite aggressive regimens, the median PFS was 3 to 4 years. Future trials should focus on novel agents rather than comparing current approaches. (Blood. 2012; 119(9): 2093-2099) C1 [LaCasce, Ann S.; Abel, Gregory A.; Crosby, Allison L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vandergrift, Jonathan L.; Lepisto, Eva M.] Natl Comprehens Canc Network, Ft Washington, MD USA. [Rodriguez, Maria A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Czuczman, Myron S.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Nademanee, Auayporn P.; Vanderplas, Ann; Niland, Joyce] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Blayney, Douglas W.] Stanford Canc Ctr, Stanford, CA USA. [Gordon, Leo I.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Millenson, Michael] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Friedberg, Jonathan W.] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. RP LaCasce, AS (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM ann_lacasce@dfci.harvard.edu OI Zelenetz, Andrew/0000-0003-1403-6883; Gordon, Leo/0000-0003-1666-7064 NR 23 TC 45 Z9 47 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 1 PY 2012 VL 119 IS 9 BP 2093 EP 2099 DI 10.1182/blood-2011-07-369629 PG 7 WC Hematology SC Hematology GA 901GA UT WOS:000300949500019 PM 22234679 ER PT J AU Tsao, S Yao, M Tsao, H Henry, FP Zhao, Y Kochevar, JJ Redmond, RW Kochevar, IE AF Tsao, S. Yao, M. Tsao, H. Henry, F. P. Zhao, Y. Kochevar, J. J. Redmond, R. W. Kochevar, I. E. TI Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID PROSPECTIVE RANDOMIZED-TRIAL; CELL CARCINOMA; PORCINE SKIN; INCISIONS; GUIDELINES; ADHESIVE; CARE; SURGERY; REPAIR; SCARS AB Background Apposition of wound edges by sutures provides a temporary scaffold and tension support for healing. We have developed a novel tissue-sealing technology, photoactivated tissue bonding (PTB), which immediately crosslinks proteins between tissue planes, thereby sealing on a molecular scale. Objectives To determine the effectiveness of PTB for superficial closure of skin excisions and to compare the results with standard epidermal suturing. Methods A split-lesion, paired comparison study of 31 skin excisions was performed. Following deep closure with absorbable sutures, one-half of each wound was superficially closed with nonabsorbable nylon sutures while the other half was stained with Rose Bengal dye and treated with green light. Overall appearance and scar characteristics were rated at 2 weeks and 6 months in a blinded manner by three dermatologists viewing photographs, by two onsite physicians and by patients. Results At 2 weeks, neither sutured nor PTB-treated segments showed dehiscence; however, PTB-sealed segments showed less erythema than sutured segments as determined by photographic (P = 0.001) and onsite evaluations (P = 0.005). Overall appearance after PTB was judged better than after sutures (P = 0.002). At 6 months, scars produced by PTB were deemed superior to scars resulting from sutures in terms of appearance (P < 0.001), width (P = 0.002) and healing (P = 0.003). Patients were more satisfied with the appearance of the PTB-sealed wound half after 2 weeks and 6 months (P = 0.013 and P = 0.003, respectively). Conclusions A novel molecular suturing technique produces effective wound sealing and less scarring than closure with nylon interrupted epidermal sutures. Comparisons with better suturing techniques are warranted. C1 [Tsao, S.; Yao, M.; Tsao, H.; Redmond, R. W.; Kochevar, I. E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Yao, M.; Tsao, H.; Henry, F. P.; Redmond, R. W.; Kochevar, I. E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Zhao, Y.; Kochevar, J. J.] Kochevar Res Associates, Boston, MA USA. RP Kochevar, IE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. EM kochevar@helix.mgh.harvard.edu OI Henry, Francis P./0000-0003-4170-7806 FU Dermatology Foundation; U.S. Department of Defense [FA9550-04-1-0079] FX This study was supported by grants from the Dermatology Foundation and the U.S. Department of Defense Medical Free Electron Program (FA9550-04-1-0079). The laser was initially on loan from IRIDEX Corporation and was purchased during the study. NR 25 TC 15 Z9 17 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD MAR PY 2012 VL 166 IS 3 BP 555 EP 563 DI 10.1111/j.1365-2133.2011.10710.x PG 9 WC Dermatology SC Dermatology GA 897ZG UT WOS:000300701900032 PM 22032650 ER PT J AU Shu, XO Long, JR Lu, W Li, C Chen, WY Delahanty, R Cheng, J Cai, H Zheng, Y Shi, JJ Gu, K Wang, WJ Kraft, P Gao, YT Cai, QY Zheng, W AF Shu, Xiao Ou Long, Jirong Lu, Wei Li, Chun Chen, Wendy Y. Delahanty, Ryan Cheng, Jiarong Cai, Hui Zheng, Ying Shi, Jiajun Gu, Kai Wang, Wen-Jing Kraft, Peter Gao, Yu-Tang Cai, Qiuyin Zheng, Wei TI Novel Genetic Markers of Breast Cancer Survival Identified by a Genome-Wide Association Study SO CANCER RESEARCH LA English DT Article ID ESTROGEN-RECEPTOR; SUSCEPTIBILITY LOCI; MUTATION CARRIERS; SYNUCLEIN-GAMMA; RISK; POLYMORPHISMS; CHEMOTHERAPY; EXPRESSION; PROTEIN; POPULATION AB Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 x 10(-8)) and replication stage (P = 0.06; P-combined 1.17 x 10(-7)). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18-1.68] for the AG genotype and 2.64 (95% CI, 1.74-4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 x 10(-6)). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses' Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 x 10(-7)). Similar associations were observed for these two SNPs with breast cancer-specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis. Cancer Res; 72(5); 1182-9. (C) 2012 AACR. C1 [Shu, Xiao Ou; Long, Jirong; Delahanty, Ryan; Cai, Hui; Shi, Jiajun; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN 37203 USA. [Shu, Xiao Ou; Long, Jirong; Delahanty, Ryan; Cai, Hui; Shi, Jiajun; Cai, Qiuyin; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37203 USA. [Li, Chun] Vanderbilt Univ, Sch Med, Dept Biostat, Nashville, TN 37203 USA. [Lu, Wei; Zheng, Ying; Gu, Kai; Wang, Wen-Jing] Shanghai Municipal Ctr Dis Control & Prevent, Shanghai, Peoples R China. [Cheng, Jiarong; Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Chen, Wendy Y.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Chen, Wendy Y.] Harvard Univ, Sch Med, Boston, MA USA. [Chen, Wendy Y.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, 2525 W End Ave,Suite 600,IMPH, Nashville, TN 37203 USA. EM xiao-ou.shu@vanderbilt.edu RI Li, Chun/B-8388-2012 FU U.S. NIH/National Cancer Institute [R01CA118229, R01CA124558, R01CA064277, R01CA090899]; U.S. Department of Defense (DOD) [BC011118, BC050791]; Vanderbilt-Ingram Cancer Center [P30 CA68485] FX This work was supported by the U.S. NIH/National Cancer Institute (grant numbers: R01CA118229 to X.O. Shu and R01CA124558, R01CA064277, and R01CA090899 to W. Zheng), as well as the U.S. Department of Defense (DOD) Breast Cancer Research Program (Idea Awards BC011118 to X.O. Shu and BC050791 to Q. Cai). Sample preparation and discovery stage genotyping were conducted at the Survey and Biospecimen and Microarray Shared Resources, which are supported, in part, by the Vanderbilt-Ingram Cancer Center (P30 CA68485). NR 39 TC 33 Z9 34 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2012 VL 72 IS 5 BP 1182 EP 1189 DI 10.1158/0008-5472.CAN-11-2561 PG 8 WC Oncology SC Oncology GA 901TG UT WOS:000300989100017 PM 22232737 ER PT J AU Hirata, H Hinoda, Y Ueno, K Nakajima, K Ishii, N Dahiya, R AF Hirata, Hiroshi Hinoda, Yuji Ueno, Koji Nakajima, Koichi Ishii, Nobuhisa Dahiya, Rajvir TI MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer SO CARCINOGENESIS LA English DT Article ID CELL CARCINOMA; KIDNEY CANCER; IN-VIVO; THERAPY; EXPRESSION; THERAPEUTICS; INHIBITOR; PATHWAY; GROWTH AB The aim of this project is to identify new therapeutic microRNAs (miRNAs) for von Hippel-Lindau (VHL)-inactivated renal cancer cells. We initially identified several potential miRNAs targeting CTNNB1 and MEK1 using several targets scan algorithms. Only miR-1826 was found to target CTNNB1 and MEK1. Therefore, we focused on miRNA-1826 and performed 3' untranslated region (UTR) luciferase assay, functional analyses and association study between miR-1826 expression and renal cancer patient outcomes. miR-1826 expression was significantly lower in renal cancer tissues compared with non-neoplastic areas and lower expression was significantly associated with overall shorter survival and earlier recurrence after radical nephrectomy. Following miR-1826 transfection, 3' UTR luciferase activity and protein expression of beta-catenin and MEK1 were significantly downregulated in renal cancer cells. Introduction of miR-1826 also inhibited renal cancer cell proliferation, invasion and migration. Additionally, miR-1826 promoted apoptosis and G(1) arrest in VHL-inactivated renal cancer cells. Knockdowns of CTNNB1 and MEK1 by small interfering RNAs reproduced the tumor-suppressive effect of miR-1826. Our data suggest that the miR-1826 plays an important role as a tumor suppressor by downregulating beta-catenin and MEK1 in VHL-inactivated renal cancers. C1 [Hirata, Hiroshi; Ueno, Koji; Dahiya, Rajvir] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA 94121 USA. [Hirata, Hiroshi; Ueno, Koji; Dahiya, Rajvir] Univ Calif San Francisco, San Francisco, CA 94121 USA. [Hinoda, Yuji] Yamaguchi Univ, Grad Sch Med, Dept Oncol & Lab Med, Yamaguchi 7558505, Japan. [Nakajima, Koichi; Ishii, Nobuhisa] Toho Univ, Dept Urol, Fac Med, Tokyo 1438540, Japan. RP Dahiya, R (reprint author), Vet Affairs Med Ctr, Dept Urol, Urol Res Ctr 112F, 4150 Clement St, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu FU National Institutes of Health [RO1CA130860, RO1CA160079, RO1CA138642, T32-DK07790, 1I01BX001123]; VA Research Enhancement Award Program (REAP); Merit Review grants; Yamada Science Foundation FX This study was supported by grants (RO1CA130860, RO1CA160079, RO1CA138642, T32-DK07790, 1I01BX001123) from the National Institutes of Health, VA Research Enhancement Award Program (REAP), Merit Review grants and Yamada Science Foundation. NR 29 TC 29 Z9 33 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2012 VL 33 IS 3 BP 501 EP 508 DI 10.1093/carcin/bgr302 PG 8 WC Oncology SC Oncology GA 901SW UT WOS:000300988100004 PM 22180573 ER PT J AU Becker, JR Robinson, TY Sachidanandan, C Kelly, AE Coy, S Peterson, RT MacRae, CA AF Becker, Jason R. Robinson, Tamara Y. Sachidanandan, Chetana Kelly, Amy E. Coy, Shannon Peterson, Randall T. MacRae, Calum A. TI In vivo natriuretic peptide reporter assay identifies chemical modifiers of hypertrophic cardiomyopathy signalling SO CARDIOVASCULAR RESEARCH LA English DT Article DE Natriuretic peptides; Hypertrophy; Heart development; Heart failure; Hypertrophic cardiomyopathy ID CHRONIC HEART-FAILURE; MUSCLE-CELL-LINE; EXPRESSION; ZEBRAFISH; PATHWAYS; GENE; ANF AB Despite increased understanding of the fundamental biology regulating cardiomyocyte hypertrophy and heart failure, it has been challenging to find novel chemical or genetic modifiers of these pathways. Traditional cell-based methods do not model the complexity of an intact cardiovascular system and mammalian models are not readily adaptable to chemical or genetic screens. Our objective was to create an in vivo model suitable for chemical and genetic screens for hypertrophy and heart failure modifiers Using the developing zebrafish, we established that the cardiac natriuretic peptide genes (nppa and nppb), known markers of cardiomyocyte hypertrophy and heart failure, were induced in the embryonic heart by pathological cardiac stimuli. This pathological induction was distinct from the developmental regulation of these genes. We created a luciferase-based transgenic reporter line that accurately modelled the pathological induction patterns of the zebrafish nppb gene. Utilizing this reporter line, we were able to show remarkable conservation of pharmacological responses between the larval zebrafish heart and adult mammalian models. By performing a focused screen of chemical agents, we were able to show a distinct response of a genetic model of hypertrophic cardiomyopathy to the histone deacetylase inhibitor, Trichostatin A, and the mitogen-activated protein kinase kinase 1/2 inhibitor, U0126. We believe this in vivo reporter line will offer a unique approach to the identification of novel chemical or genetic regulators of myocardial hypertrophy and heart failure. C1 [Becker, Jason R.; Robinson, Tamara Y.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN 37232 USA. [Sachidanandan, Chetana; Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Kelly, Amy E.; Coy, Shannon; MacRae, Calum A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. RP Becker, JR (reprint author), Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, 2220 Pierce Ave,340 PRB, Nashville, TN 37232 USA. EM jason.becker@vanderbilt.edu FU NIH [T32HL007208]; Massachusetts General Hospital Hypertrophic Cardiomyopathy Center; British Heart Foundation FX This work was supported by NIH T32HL007208 and Vanderbilt Physician Scientist Development Program award to J.R.B. Massachusetts General Hospital Hypertrophic Cardiomyopathy Center and British Heart Foundation grants to C.A.M. NR 22 TC 15 Z9 16 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2012 VL 93 IS 3 BP 463 EP 470 DI 10.1093/cvr/cvr350 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 899BZ UT WOS:000300789300013 PM 22198505 ER PT J AU Verma, A Matsunaga, J Artiushin, S Pinne, M Houwers, DJ Haake, DA Stevenson, B Timoney, JF AF Verma, Ashutosh Matsunaga, James Artiushin, Sergey Pinne, Marija Houwers, Dirk J. Haake, David A. Stevenson, Brian Timoney, John F. TI Antibodies to a Novel Leptospiral Protein, LruC, in the Eye Fluids and Sera of Horses with Leptospira-Associated Uveitis SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID EQUINE RECURRENT UVEITIS; SURFACE-EXPOSED LIPOPROTEIN; OUTER-MEMBRANE; SIGNAL PEPTIDES; INTERROGANS; PATHOGENESIS; PREDICTION; IDENTIFICATION; INFECTION; FAMILY AB Screening of an expression library of Leptospira interrogans with eye fluids from uveitic horses resulted in identification of a novel protein, LruC. LruC is located in the inner leaflet of the leptospiral outer membrane, and an lruC gene was detected in all tested pathogenic L. interrogans strains. LruC-specific antibody levels were significantly higher in eye fluids and sera of uveitic horses than healthy horses. These findings suggest that LruC may play a role in equine leptospiral uveitis. C1 [Verma, Ashutosh; Artiushin, Sergey; Timoney, John F.] Univ Kentucky, Dept Vet Sci, MH Gluck Equine Res Ctr, Lexington, KY 40546 USA. [Matsunaga, James; Pinne, Marija] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Matsunaga, James; Pinne, Marija; Haake, David A.] UCLA Sch Med, Dept Med, Los Angeles, CA USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Verma, Ashutosh; Stevenson, Brian] Univ Kentucky, Coll Med, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40506 USA. [Houwers, Dirk J.] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Vet Microbiol Diagnost Ctr, Utrecht, Netherlands. RP Verma, A (reprint author), Univ Kentucky, Coll Med, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40506 USA. FU Keeneland Endowment; Paul Mellon Fellowship; Public Health Service from National Institute of Allergy and Infectious Diseases [AI-34431]; VA FX This work was supported by the Keeneland Endowment. A. Verma was funded by a Paul Mellon Fellowship in Equine Studies. The support of Public Health Service grant AI-34431 (to D. A. H.) from the National Institute of Allergy and Infectious Diseases and VA Medical Research Funds (to D. A. H. and J. M.) is also acknowledged. NR 39 TC 9 Z9 9 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAR PY 2012 VL 19 IS 3 BP 452 EP 456 DI 10.1128/CVI.05524-11 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 899UF UT WOS:000300841200026 PM 22237897 ER PT J AU Nardi, V Song, Y Santamaria-Barria, JA Cosper, AK Lam, Q Faber, AC Boland, GM Yeap, BY Bergethon, K Scialabba, VL Tsao, H Settleman, J Ryan, DP Borger, DR Bhan, AK Hoang, MP Iafrate, AJ Cusack, JC Engelman, JA Dias-Santagata, D AF Nardi, Valentina Song, Youngchul Santamaria-Barria, Juan A. Cosper, Arjola K. Lam, Quynh Faber, Anthony C. Boland, Genevieve M. Yeap, Beow Y. Bergethon, Kristin Scialabba, Vanessa L. Tsao, Hensin Settleman, Jeffrey Ryan, David P. Borger, Darrell R. Bhan, Atul K. Hoang, Mai P. Iafrate, Anthony J. Cusack, James C. Engelman, Jeffrey A. Dias-Santagata, Dora TI Activation of PI3K Signaling in Merkel Cell Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; LARGE T-ANTIGEN; POLYOMAVIRUS INFECTION; RAPAMYCIN INHIBITOR; ANTITUMOR-ACTIVITY; CANCER; SKIN; MUTATIONS; NVP-BEZ235; TUMORS AB Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor, often metastatic at presentation, for which current chemotherapeutic regimens are largely ineffective. As its pathogenesis is still unknown, we hypothesized that deregulation of signaling pathways commonly activated in cancer may contribute to MCC tumorigenesis and may provide insights into targeted therapy approaches for this malignancy. Experimental Design: We retrospectively profiled 60 primary MCC samples using a SNaPshot-based tumor genotyping assay to screen for common mutations in 13 cancer genes. Results: We identified mutations in 9 (15%) MCC primary tumors, including mutations in TP53 (3 of 60) and activating mutations in the PIK3CA gene (6 of 60). Sanger sequencing of the primary MCC tumors detected one additional PIK3CA mutation (R19K) that had not been previously described in cancer. Merkel cell polyoma virus (MCPyV) was detected in 38 (66%) MCC cases and patients with MCPyV-positive cancers showed a trend toward better survival. With one exception, the presence of MCPyV and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling through the PI3K/pAKT pathway was active in one MCPyV-positive and in all MCPyV-negative MCC cell lines, as evidenced by AKT phosphorylation. Importantly, the presence of a PIK3CA-activating mutation was associated with sensitivity to treatment with ZST474, a specific phosphoinositide 3-kinase (PI3K) inhibitor, and to NVP-BEZ235, a dual PI3K/mTOR inhibitor, targeted agents under active clinical development. Conclusions: PI3K pathway activation may drive tumorigenesis in a subset of MCC and screening these tumors for PIK3CA mutations could help identify patients who may respond to treatment with PI3K pathway inhibitors. Clin Cancer Res; 18(5); 1227-36. (C)2012 AACR. C1 [Nardi, Valentina; Lam, Quynh; Bergethon, Kristin; Scialabba, Vanessa L.; Bhan, Atul K.; Hoang, Mai P.; Iafrate, Anthony J.; Dias-Santagata, Dora] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Santamaria-Barria, Juan A.; Boland, Genevieve M.; Cusack, James C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Song, Youngchul; Cosper, Arjola K.; Faber, Anthony C.; Yeap, Beow Y.; Settleman, Jeffrey; Ryan, David P.; Borger, Darrell R.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Yeap, Beow Y.; Tsao, Hensin; Settleman, Jeffrey; Ryan, David P.; Borger, Darrell R.; Bhan, Atul K.; Hoang, Mai P.; Iafrate, Anthony J.; Cusack, James C.; Engelman, Jeffrey A.; Dias-Santagata, Dora] Harvard Univ, Sch Med, Boston, MA USA. RP Dias-Santagata, D (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,GRJ-1028A, Boston, MA 02114 USA. EM ddiassantagata@partners.org FU [P30 CA06516] FX This study was supported by grant no. P30 CA06516 (B.Y. Yeap). 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 56 TC 32 Z9 32 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2012 VL 18 IS 5 BP 1227 EP 1236 DI 10.1158/1078-0432.CCR-11-2308 PG 10 WC Oncology SC Oncology GA 902LW UT WOS:000301040700007 PM 22261808 ER PT J AU Riester, M Taylor, JM Feifer, A Koppie, T Rosenberg, JE Downey, RJ Bochner, BH Michor, F AF Riester, Markus Taylor, Jennifer M. Feifer, Andrew Koppie, Theresa Rosenberg, Jonathan E. Downey, Robert J. Bochner, Bernard H. Michor, Franziska TI Combination of a Novel Gene Expression Signature with a Clinical Nomogram Improves the Prediction of Survival in High-Risk Bladder Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID RADICAL CYSTECTOMY; CARCINOMA; ASSOCIATION; PERFORMANCE; MICROARRAYS; CLASSIFIER; GENERATION; THERAPY; STAGE AB Purpose: We aimed to validate and improve prognostic signatures for high-risk urothelial carcinoma of the bladder. Experimental Design: We evaluated microarray data from 93 patients with bladder cancer managed by radical cystectomy to determine gene expression patterns associated with clinical and prognostic variables. We compared our results with published bladder cancer microarray data sets comprising 578 additional patients and with 49 published gene signatures from multiple cancer types. Hierarchical clustering was utilized to identify subtypes associated with differences in survival. We then investigated whether the addition of survival-associated gene expression information to a validated postcystectomy nomogram utilizing clinical and pathologic variables improves prediction of recurrence. Results: Multiple markers for muscle invasive disease with highly significant expression differences in multiple data sets were identified, such as fibronectin 1 (FN1), NNMT, POSTN, and SMAD6. We identified signatures associated with pathologic stage and the likelihood of developing metastasis and death from bladder cancer, as well as with two distinct clustering subtypes of bladder cancer. Our novel signature correlated with overall survival in multiple independent data sets, significantly improving the prediction concordance of standard staging in all data sets [mean Delta C-statistic: 0.14; 95% confidence interval (CI), 0.01-0.27; P < 0.001]. Tested in our patient cohort, it significantly enhanced the performance of a postoperative survival nomogram (Delta C-statistic: 0.08, 95% CI, -0.04-0.20; P < 0.005). Conclusions: Prognostic information obtained from gene expression data can aid in posttreatment prediction of bladder cancer recurrence. Our findings require further validation in external cohorts and prospectively in a clinical trial setting. Clin Cancer Res; 18(5); 1323-33. (C)2012 AACR. C1 [Riester, Markus; Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Riester, Markus; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Dana Farber Canc Inst, Bladder Canc Ctr, Boston, MA 02215 USA. [Taylor, Jennifer M.; Feifer, Andrew; Bochner, Bernard H.] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, New York, NY 10021 USA. [Downey, Robert J.] Mem Sloan Kettering Canc Ctr, Dept Surg, Thorac Serv, New York, NY 10021 USA. [Koppie, Theresa] Univ Calif Davis, Dept Urol, Sacramento, CA 95817 USA. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM michor@jimmy.harvard.edu OI Rosenberg, Jonathan/0000-0003-2637-4249; Riester, Markus/0000-0002-4759-8332 FU NCI initiative [U54CA143798]; NIH [T32 CA82088] FX This work was supported from the NCI initiative to found Physical Science Oncology Centers (U54CA143798; M. Riester, F. Michor) and an NRSA training grant T32 CA82088 from the NIH (J.M. Taylor). NR 39 TC 52 Z9 53 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2012 VL 18 IS 5 BP 1323 EP 1333 DI 10.1158/1078-0432.CCR-11-2271 PG 11 WC Oncology SC Oncology GA 902LW UT WOS:000301040700016 PM 22228636 ER PT J AU Azim, HA Michiels, S Bedard, PL Singhal, SK Criscitiello, C Ignatiadis, M Haibe-Kains, B Piccart, MJ Sotiriou, C Loi, S AF Azim, Hatem A., Jr. Michiels, Stefan Bedard, Philippe L. Singhal, Sandeep K. Criscitiello, Carmen Ignatiadis, Michail Haibe-Kains, Benjamin Piccart, Martine J. Sotiriou, Christos Loi, Sherene TI Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling SO CLINICAL CANCER RESEARCH LA English DT Article ID MOLECULAR PORTRAITS; SIGNATURE; SUBTYPES; SURVIVAL; STROMA; POPULATION; AGE; CLASSIFICATION; METASTASIS; PREDICTOR AB Purpose: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age. Experimental Design: Patients were assigned to molecular subtypes [estrogen receptor (ER)(+)/HER2(-); HER2(+), ER-/HER2(-))] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model. Results: A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER-/HER2(-) tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR = 1.34, 95% CI 1.10-1.63, P = 0.004). The proliferation gene signatures showed no significant interaction with age in ER+/HER2(-) tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n = 1,188 and 2,334). Conclusions: Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed. Clin Cancer Res; 18(5); 1341-51. (C)2012 AACR. C1 [Azim, Hatem A., Jr.; Michiels, Stefan; Singhal, Sandeep K.; Criscitiello, Carmen; Ignatiadis, Michail; Sotiriou, Christos; Loi, Sherene] Univ Libre Brussels, Breast Canc Translat Res Lab BCTL JC Heuson, Inst Jules Bordet, B-1000 Brussels, Belgium. [Piccart, Martine J.] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. [Bedard, Philippe L.] Univ Toronto, Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON, Canada. [Haibe-Kains, Benjamin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Computat Biol & Funct Genom Lab, Boston, MA 02115 USA. RP Loi, S (reprint author), Univ Libre Brussels, Breast Canc Translat Res Lab BCTL JC Heuson, Inst Jules Bordet, Blvd Waterloo 125, B-1000 Brussels, Belgium. EM sherene.loi@bordet.be RI Haibe-Kains, Benjamin/D-3702-2011; Michiels, Stefan/L-1516-2013; Loi, Sherene/H-1979-2016; OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Michiels, Stefan/0000-0002-6963-2968; Loi, Sherene/0000-0001-6137-9171 FU ESMO FX H.A. Azim Jr is supported by an ESMO translational research grant. NR 49 TC 87 Z9 88 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2012 VL 18 IS 5 BP 1341 EP 1351 DI 10.1158/1078-0432.CCR-11-2599 PG 11 WC Oncology SC Oncology GA 902LW UT WOS:000301040700018 PM 22261811 ER PT J AU Rosenberg, JE Chen, MH Nguyen, PL Braccioforte, MH Moran, BJ D'Amico, AV AF Rosenberg, Jonathan E. Chen, Ming-Hui Nguyen, Paul L. Braccioforte, Michelle H. Moran, Brian J. D'Amico, Anthony V. TI Hormonal Therapy or External-Beam Radiation With Brachytherapy and the Risk of Death From Prostate Cancer in Men With Intermediate Risk Prostate Cancer SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Androgen deprivation therapy; Brachytherapy; External-beam radiotherapy; Hormonal therapy; Prostate cancer ID RANDOMIZED CONTROLLED-TRIAL; ANDROGEN SUPPRESSION; DOSE-ESCALATION; ADENOCARCINOMA; RADIOTHERAPY AB Supplemental androgen suppression therapy may lower the risk of prostate-cancer-specific mortality in men with intermediate-risk prostate cancer who are undergoing brachytherapy. Prospective validation in a randomized controlled trial is needed. Purpose: To determine whether external-beam radiotherapy (EBRT) improves disease control compared with supplemental androgen suppression therapy (AST) in men with intermediate-risk prostate cancer who are being treated with brachytherapy. Patients and Methods: A total of 807 men with intermediate-risk prostate cancer (T2bNXM0, Gleason <= 7, prostate-specific antigen [PSA] <20 ng/mL; or cT1c-T2bNXM0, Gleason 7) were consecutively treated with either AST and brachytherapy or EBRT and brachytherapy, between 1997 and 2007, and were followed up until September 21, 2007. A Fine and Gray competing risks multivariable regression model was used to assess whether AST or radiotherapy dose escalation reduced the risk of prostate-cancer specific mortality (PCSM) when adjusting for age, PSA, Gleason score, and tumor category. Results: Treatment with brachytherapy and with EBRT was associated with a significant increase in the risk of PCSM compared with brachytherapy and AST (adjusted hazard ratio [HR] 4.027 [95% CI, 1.168-13.89]; P = .027) after adjusting for age and prostate cancer prognostic factors. A Gleason score of 4+3 and increasing PSA were associated with worse PCSM (adjusted HR 8.882 [95% CI, 1.095-72.04]; P = .041; and adjusted HR 8.029 [95% CI, 2.38-28.8]; P = .0014, respectively). Conclusion: Supplemental AST use compared with EBRT is associated with a lower risk of PCSM in men with intermediate-risk PC undergoing brachytherapy. Prospective validation in a randomized controlled trial is needed. (C) 2012 Elsevier Inc. All rights reserved. C1 [Rosenberg, Jonathan E.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Nguyen, Paul L.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Braccioforte, Michelle H.; Moran, Brian J.] Prostate Canc Fdn Chicago, Westmont, IL USA. RP Rosenberg, JE (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 44 Binney Sr,D1230, Boston, MA 02115 USA. EM jonathan_rosenberg@dfci.harvard.edu NR 14 TC 1 Z9 1 U1 0 U2 0 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 MAR PY 2012 VL 10 IS 1 BP 21 EP 25 DI 10.1016/j.clgc.2011.10.003 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 902KG UT WOS:000301036400004 PM 22130293 ER PT J AU McGlone, SM Bailey, RR Zimmer, SM Popovich, MJ Tian, Y Ufberg, P Muder, RR Lee, BY AF McGlone, S. M. Bailey, R. R. Zimmer, S. M. Popovich, M. J. Tian, Y. Ufberg, P. Muder, R. R. Lee, B. Y. TI The economic burden of Clostridium difficile SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Article DE Burden; Clostridium difficile; cost; economics; stochastic model ID INTENSIVE-CARE-UNIT; HYPERVIRULENT STRAIN; COST-EFFECTIVENESS; RISK-FACTORS; DISEASE; INFECTION; COLECTOMY; DIARRHEA; COLITIS; MORTALITY AB lthough Clostridium difficile (C. difficile) is the leading cause of infectious diarrhoea in hospitalized patients, the economic burden of this major nosocomial pathogen for hospitals, third-party payers and society remains unclear. We developed an economic computer simulation model to determine the costs attributable to healthcare-acquired C. difficile infection (CDI) from the hospital, third-party payer and societal perspectives. Sensitivity analyses explored the effects of varying the cost of hospitalization, C. difficile-attributable length of stay, and the probability of initial and secondary recurrences. The median cost of a case ranged from $9179 to $11 456 from the hospital perspective, $8932 to $11 679 from the third-party payor perspective, and $13 310 to $16 464 from the societal perspective. Most of the costs incurred were accrued during a patients primary CDI episode. Hospitals with an incidence of 4.1 CDI cases per 100 000 discharges would incur costs =$3.2 million (hospital perspective); an incidence of 10.5 would lead to costs =$30.6 million. Our model suggests that the annual US economic burden of CDI would be =$496 million (hospital perspective), =$547 million (third-party payer perspective) and =$796 million (societal perspective). Our results show that C. difficile infection is indeed costly, not only to third-party payers and the hospital, but to society as well. These results are consistent with current literature citing C. difficile as a costly disease. C1 [McGlone, S. M.; Bailey, R. R.; Popovich, M. J.; Tian, Y.; Ufberg, P.; Lee, B. Y.] Univ Pittsburgh, Sch Med, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [McGlone, S. M.; Bailey, R. R.; Popovich, M. J.; Tian, Y.; Ufberg, P.; Lee, B. Y.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Zimmer, S. M.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Muder, R. R.] VA Pittsburgh Hlth Syst, Div Infect Dis, Pittsburgh, PA USA. RP McGlone, SM (reprint author), Univ Pittsburgh, Sch Med, Dept Biomed Informat, 3520 Forbes Ave,1st Floor, Pittsburgh, PA 15213 USA. EM smm168@pitt.edu OI Slayton, Rachel/0000-0003-4699-8040 FU National Institute General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) [5U54GM088491-02]; Pennsylvania Department of Health (DOH) FX This study was supported by the National Institute General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) (grant number 5U54GM088491-02) and the Pennsylvania Department of Health (DOH). The funders had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, and preparation, review or approval of the manuscript. NR 45 TC 87 Z9 91 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1198-743X J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD MAR PY 2012 VL 18 IS 3 BP 282 EP 289 DI 10.1111/j.1469-0691.2011.03571.x PG 8 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 899SX UT WOS:000300837600019 PM 21668576 ER PT J AU David, CM AF David, Charlene M. TI Clinical Nurse Specialist Practice in Fall Prevention: Comparing, Sharing, and Improving SO CLINICAL NURSE SPECIALIST LA English DT Meeting Abstract C1 [David, Charlene M.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0887-6274 J9 CLIN NURSE SPEC JI Clin. Nurse Spec. PD MAR-APR PY 2012 VL 26 IS 2 BP E12 EP E12 PG 1 WC Nursing SC Nursing GA 897FS UT WOS:000300632600033 ER PT J AU Valdez, C Richardson, J Holmquist, J Tjoelker, R AF Valdez, Christine Richardson, Jenny Holmquist, Jennifer Tjoelker, Rita TI Back to the Future: Building a Clinical Nurse Specialist Residency Program SO CLINICAL NURSE SPECIALIST LA English DT Meeting Abstract C1 [Valdez, Christine; Richardson, Jenny; Holmquist, Jennifer; Tjoelker, Rita] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0887-6274 J9 CLIN NURSE SPEC JI Clin. Nurse Spec. PD MAR-APR PY 2012 VL 26 IS 2 BP E6 EP E6 PG 1 WC Nursing SC Nursing GA 897FS UT WOS:000300632600015 ER PT J AU Polyak, K AF Polyak, Kornelia TI On Chromatin Remodeling in Mammary Gland Differentiation and Breast Tumorigenesis SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Editorial Material ID MAPS; PLURIPOTENT; CELLS C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Polyak, K (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM kornelia_polyak@dfci.harvard.edu NR 11 TC 1 Z9 1 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD MAR PY 2012 VL 4 IS 3 AR a013417 DI 10.1101/cshperspect.a013417 PG 2 WC Cell Biology SC Cell Biology GA 901EJ UT WOS:000300944200013 ER PT J AU Bromley, E AF Bromley, Elizabeth TI The Texture of the Real: Experimentation and Experience in Schizophrenia SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE Cognition; Reductionism; Stigma; Schizophrenia; Neuroscience ID MENTAL-ILLNESS; SOCIOLOGY; COGNITION; MATRICS; PSYCHOLOGY; SCIENCE; BRAIN; SELF; NEUROCOGNITION; CONSTRUCTION AB The dominance of the neurosciences in psychiatric research raises questions about the relationship between research practices and the lived experience of mental illness. Here, I use data from a group of researchers focusing on neurocognition in schizophrenia to explore the problem of representation in psychiatric research and the forms that neuroscientific evidence assumes for those who produce it. These researchers grappled with the complexity of schizophrenia not by narrowing disease concepts to biological facts but by referencing measurement techniques to generate new versions of schizophrenia. By linking experimental findings to inchoate concepts of personhood and social experience, I found that they reframed and reinforced cultural values, including that those with schizophrenia are destined to a debased and deficient existence. I argue that cognition has emerged as an essential feature of schizophrenia not only because of its representational utility but also because of the ontological work the concept performs. In closing, I present some implications for the neurobiological and social sciences. C1 [Bromley, Elizabeth] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Ctr Hlth Serv & Soc, Los Angeles, CA 90024 USA. [Bromley, Elizabeth] Desert Pacific Mental Illness Res Educ & Clin Ctr, W Los Angeles VA Healthcare Ctr, 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@mednet.ucla.edu NR 93 TC 1 Z9 1 U1 6 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD MAR PY 2012 VL 36 IS 1 BP 154 EP 174 DI 10.1007/s11013-011-9241-z PG 21 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 899WQ UT WOS:000300847700011 PM 22183201 ER PT J AU Galanopoulou, AS Buckmaster, PS Staley, KJ Moshe, SL Perucca, E Engel, J Loscher, W Noebels, JL Pitkanen, A Stables, J White, HS O'Brien, TJ Simonato, M AF Galanopoulou, Aristea S. Buckmaster, Paul S. Staley, Kevin J. Moshe, Solomon L. Perucca, Emilio Engel, Jerome, Jr. Loescher, Wolfgang Noebels, Jeffrey L. Pitkanen, Asla Stables, James White, H. Steve O'Brien, Terence J. Simonato, Michele CA Amer Epilepsy Soc Basic Sci Comm Int League Epilepsy Working Grp TI Identification of new epilepsy treatments: Issues in preclinical methodology SO EPILEPSIA LA English DT Article DE Antiseizure drug; Antiepileptogenesis; Disease modification; Comorbidities; Biomarkers ID TEMPORAL-LOBE EPILEPSY; INFANTILE SPASMS; ANTIEPILEPTIC DRUGS; PERSISTENT SEIZURES; FUTURE-DIRECTIONS; FEBRILE SEIZURES; ANIMAL-MODEL; RODENT MODEL; MOUSE MODEL; EPILEPTOGENESIS AB Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, that is, age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome, or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. C1 [Galanopoulou, Aristea S.; Moshe, Solomon L.] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Saul R Korey Dept Neurol, Lab Dev Epilepsy,Montefiore Einstein Epilepsy Man, Bronx, NY 10461 USA. [Buckmaster, Paul S.] Stanford Univ, Dept Comparat Med & Neurol, Stanford, CA 94305 USA. [Buckmaster, Paul S.] Stanford Univ, Dept Neurol Sci, Stanford, CA 94305 USA. [Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA USA. [Moshe, Solomon L.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. [Perucca, Emilio] Univ Pavia, Dept Internal Med & Therapeut, Clin Pharmacol Unit, I-27100 Pavia, Italy. [Perucca, Emilio] IRCCS C Mondino Fdn, Natl Neurol Inst, Pavia, Italy. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Engel, Jerome, Jr.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Loescher, Wolfgang] Univ Vet Med, Dept Pharmacol Toxicol & Pharm, Hannover, Germany. [Noebels, Jeffrey L.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Pitkanen, Asla] Univ Eastern Finland, AI Virtanen Inst Mol Sci, Epilepsy Res Lab, Kuopio, Finland. [Pitkanen, Asla] Kuopio Univ Hosp, Dept Neurol, SF-70210 Kuopio, Finland. [Stables, James] NINDS, ASP, NIH, Bethesda, MD 20892 USA. [White, H. Steve] Univ Utah, Dept Pharmacol & Toxicol, Salt Lake City, UT 84112 USA. [O'Brien, Terence J.] Univ Melbourne, Dept Med, Royal Melbourne Hosp, Parkville, Vic 3052, Australia. [O'Brien, Terence J.] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Parkville, Vic, Australia. [Simonato, Michele] Univ Ferrara, Dept Clin & Expt Med, Pharmacol Sect, I-44100 Ferrara, Italy. [Simonato, Michele] Univ Ferrara, Ctr Neurosci, I-44100 Ferrara, Italy. [Simonato, Michele] Natl Inst Neurosci, Palermo, Italy. RP Galanopoulou, AS (reprint author), Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Saul R Korey Dept Neurol, Lab Dev Epilepsy,Montefiore Einstein Epilepsy Man, 1410 Pelham Pkwy S,Kennedy Ctr Rm 306, Bronx, NY 10461 USA. EM aristea.galanopoulou@einstein.yu.edu RI French, Jacqueline/G-6795-2013; O'Brien, Terence/L-8102-2013; OI Noebels, Jeffrey /0000-0002-2887-0839; French, Jacqueline/0000-0003-2242-8027; O'Brien, Terence/0000-0002-7198-8621 FU NIH NINDS/NICHD [NS62947]; Johnson Johnson; Novartis; NIH [R01 NS20253, R01-NS43209, 2UO1-NS45911, P01 NS02808, R01 NS33310, U01 NS42372]; Heffer Family Foundation; Eisai; GlaxoSmithKline; Bial; Pfizer; UCB Pharma; Upsher-Smith; Vertex; Italian Ministry of Health; Italian Ministry for University and Research; Italian Medicines Agency; European Commission of the EU; NeuroAdjuvants, Inc.; Janssen-Cilag; Sanofi-Synthelabo; Chiesi Pharmaceuticals (Italy); Schering-Plough FX ASG has received research support from NIH NINDS/NICHD grant NS62947 (PI) and recent research grant by Johnson & Johnson. ASG has also received consultancy fees from Novartis and royalties from Morgan and Claypool Life Sciences. PSB has nothing to disclose. KJS has nothing to disclose. SLM has received research support from NIH: R01 NS20253 (PI), R01-NS43209 (Investigator), 2UO1-NS45911 (Investigator), and the Heffer Family Foundation. SLM is serving on the Editorial Board of Neurobiology of Disease, Epileptic Disorders, Brain and Development, and Physiological Research and has received a consultancy fee from Eisai and speaker's fee and travel from GlaxoSmithKline. EP received speaker's or consultancy fees and/or research grants from Bial, Eisai, GlaxoSmithKline, Johnson & Johnson, Novartis, Pfizer, Pfizer, UCB Pharma, Upsher-Smith, and Vertex. EP receives research support from the Italian Ministry of Health, the Italian Ministry for University and Research, the Italian Medicines Agency, and the European Commission of the EU. EP also serves on the editorial boards of Acta Neurologica Scandinavica, CNS Drugs, Epileptic Disorders, Epilepsy Research, Seizure, Lancet Neurology, Expert Reviews in Neurotherapeutics, Clinical Pharmacokinetics, Therapeutic Advances in Drug Safety, Frontiers in Clinical Trials and Pharmacotherapy, and Clinical Drug Investigation. JEJr has received research funding from NIH grants P01 NS02808, R01 NS33310, U01 NS42372, honoraria from Medtronic, Eisai, Johnson & Johnson, Lippincottand royalties from Medlink, Wolters-Kluwer, Blackwell, and Elsevier. WL has nothing to disclose. JLN has nothing to disclose. AP has nothing to disclose. JS has nothing to disclose. HSW has served as a paid consultant to Johnson & Johnson Pharmaceutical Research and Development, GlaxoSmithKline, Valeant Pharmaceuticals, Eli Lilly & Co., and Upsher-Smith Laboratories, Inc., is a member of the UCB Pharma Speakers Bureau, the NeuroTherapeutics Scientific Advisory Board, has received research funding from NeuroAdjuvants, Inc., and is one of two scientific cofounders of NeuroAdjuvants, Inc., Salt Lake City, UT. TJO'B has received unrestricted research grants from UCB Pharma Janssen-Cilag, Sanofi-Synthelabo, and Novartis. TJO'B has received speaking honorarium from UCB Pharma Janssen-Cilag, Sanofi-Synthelabo, and SciGen. MS has received research funding from GlaxoSmithKline, Chiesi Pharmaceuticals (Italy), Sanofi-Synthelabo, and Schering-Plough. We confirm that we have read the Journal's position on issues relating to ethical publication. This statement is consistent with these guidelines NR 61 TC 85 Z9 87 U1 1 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD MAR PY 2012 VL 53 IS 3 BP 571 EP 582 DI 10.1111/j.1528-1167.2011.03391.x PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 899TF UT WOS:000300838400023 PM 22292566 ER PT J AU Beinart, R Danik, S Palacios, I Barrett, C Inglessis, I Agnihotri, A Passeri, J AF Beinart, Roy Danik, Stephan Palacios, Igor Barrett, Conor Inglessis, Ignacio Agnihotri, Arvind Passeri, Jonathan TI Ventricular tachycardia following trans-apical aortic valve replacement SO EUROPACE LA English DT Article AB Transcatheter aortic valve replacement (TAVR) is a relatively new procedure for high-risk patients with severe aortic stenosis. We report a case of a new left ventricular outflow tract ventricular tachycardia following TAVR. C1 [Beinart, Roy; Danik, Stephan; Palacios, Igor; Barrett, Conor; Inglessis, Ignacio; Agnihotri, Arvind; Passeri, Jonathan] Massachusetts Gen Hosp, Ctr Heart, Boston, MA 02114 USA. RP Passeri, J (reprint author), Massachusetts Gen Hosp, Ctr Heart, YAW 5D,55 Fruit St, Boston, MA 02114 USA. EM jpasseri@partners.org NR 3 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1099-5129 J9 EUROPACE JI Europace PD MAR PY 2012 VL 14 IS 3 BP 450 EP 452 DI 10.1093/europace/eur324 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 898EC UT WOS:000300717700028 PM 22016303 ER PT J AU Zuniga, J Buendia-Roldan, I Zhao, Y Jimenez, L Torres, D Romo, J Ramirez, G Cruz, A Vargas-Alarcon, G Sheu, CC Chen, F Su, L Tager, AM Pardo, A Selman, M Christiani, DC AF Zuniga, J. Buendia-Roldan, I. Zhao, Y. Jimenez, L. Torres, D. Romo, J. Ramirez, G. Cruz, A. Vargas-Alarcon, G. Sheu, C-C. Chen, F. Su, L. Tager, A. M. Pardo, A. Selman, M. Christiani, D. C. TI Genetic variants associated with severe pneumonia in A/H1N1 influenza infection SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE A/H1N1; genetic susceptibility; influenza; Mexicans; single-nucleotide polymorphisms; viral pneumonia ID GENOME-WIDE ASSOCIATION; H1N1 VIRUS-INFECTION; A H1N1; COMPLEMENT; RECEPTOR; SUSCEPTIBILITY; DISEASE; C1Q AB The A/H1N1 influenza strain isolated in Mexico in 2009 caused severe pulmonary illness in a small number of exposed individuals. Our objective was to determine the influence of genetic factors on their susceptibility. We carried out a case-control association study genotyping 91 patients with confirmed severe pneumonia from A/H1N1 infection and 98 exposed but asymptomatic household contacts, using the HumanCVD BeadChip (Illumina, San Diego, CA, USA). Four risk single-nucleotide polymorphisms were significantly (p < 0.0001) associated with severe pneumonia: rs1801274 (Fc fragment of immunoglobulin G, low-affinity IIA, receptor (FCGR2A) gene, chromosome 1; OR 2.68, 95% CI 1.69-4.25); rs9856661 (gene unknown, chromosome 3; OR 2.62, 95% CI 1.64-4.18); rs8070740 (RPA interacting protein (RPAIN) gene, chromosome 17; OR 2.67, 95% CI 1.63-4.39); and rs3786054 (complement component 1, q subcomponent binding protein (C1QBP) gene, chromosome 17; OR 3.13, 95% CI 1.89-5.17). All SNP associations remained significant after adjustment for sex and comorbidities. The SNPs on chromosome 17 were in linkage disequilibrium. These findings revealed that gene polymorphisms located in chromosomes 1 and 17 might influence susceptibility to development of severe pneumonia in A/H1N1 infection. Two of these SNPs are mapped within genes (FCGR2A, C1QBP) involved in the handling of immune complexes and complement activation, respectively, suggesting that these genes may confer risk due to increased activation of host immunity. C1 [Zhao, Y.; Sheu, C-C.; Chen, F.; Su, L.; Christiani, D. C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Zuniga, J.; Buendia-Roldan, I.; Jimenez, L.; Torres, D.; Romo, J.; Ramirez, G.; Cruz, A.; Selman, M.] Univ Nacl Autonoma Mexico, Inst Nacl Enfermedades Resp Ismael Cosio Villegas, Mexico City 04510, DF, Mexico. [Vargas-Alarcon, G.] Univ Nacl Autonoma Mexico, Inst Nacl Cardiol, Mexico City 04510, DF, Mexico. [Pardo, A.] Univ Nacl Autonoma Mexico, Fac Ciencias, Mexico City 04510, DF, Mexico. [Tager, A. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02115 USA. [Tager, A. M.; Christiani, D. C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Pulm & Crit Care Unit, Boston, MA 02115 USA. [Sheu, C-C.] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Div Pulm & Crit Care Med, Kaohsiung, Taiwan. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU National Council of Science and Technology of Mexico (Mexico City, Mexico) (CONACYT) [127002]; National Institutes of Health (Bethesda, MD, USA) [ES00002, HL060710, HL095732] FX This study was supported by grants from the National Council of Science and Technology of Mexico (Mexico City, Mexico) (CONACYT grant number 127002), and National Institutes of Health (Bethesda, MD, USA) (grant numbers ES00002, HL060710 and HL095732). NR 30 TC 33 Z9 34 U1 1 U2 8 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD MAR PY 2012 VL 39 IS 3 BP 604 EP 610 DI 10.1183/09031936.00020611 PG 7 WC Respiratory System SC Respiratory System GA 900JS UT WOS:000300883800015 PM 21737555 ER PT J AU Taylor, AM Humphries, JM White, RM Murphey, RD Burns, CE Zon, LI AF Taylor, Alison M. Humphries, Jessica M. White, Richard M. Murphey, Ryan D. Burns, Caroline E. Zon, Leonard I. TI Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; RIBOSOMAL-PROTEIN S19; ERYTHROPOIESIS; DEFICIENCY; GENE; IDENTIFICATION; ABNORMALITIES; DISRUPTION; MUTATIONS; REVEALS AB Disruption of ribosomal proteins is associated with hematopoietic phenotypes in cell culture and animal models. Mutations in ribosomal proteins are seen in patients with Diamond Blackfan anemia, a rare congenital disease characterized by red cell aplasia and distinctive craniofacial anomalies. A zebrafish screen uncovered decreased hematopoietic stem cells in embryos with mutations in ribosomal protein rps29. Here, we determined that rps29(-/-) embryos also have red blood cell defects and increased apoptosis in the head. As the p53 pathway has been shown to play a role in other ribosomal protein mutants, we studied the genetic relationship of rps29 and p53. Transcriptional profiling revealed that genes upregulated in the rps29 mutant are enriched for genes upregulated by p53 after irradiation. p53 mutation near completely rescues the rps29 morphological and hematopoietic phenotypes, demonstrating that p53 mediates the effects of rps29 knockdown. We also identified neuronal gene orthopedia protein a (otpa) as one whose expression correlates with rps29 expression, suggesting that levels of expression of some genes are dependent on rps29 levels. Together, our studies demonstrate a role of p53 in mediating the cellular defects associated with rps29 and establish a role for rps29 and p53 in hematopoietic stem cells and red blood cell development. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Zon, Leonard I.] Harvard Univ, Sch Med, Childrens Hosp Boston, Stem Cell Program, Boston, MA 02115 USA. [Taylor, Alison M.; Humphries, Jessica M.; White, Richard M.; Murphey, Ryan D.; Zon, Leonard I.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Taylor, Alison M.; Humphries, Jessica M.; White, Richard M.; Murphey, Ryan D.; Zon, Leonard I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Taylor, Alison M.; Humphries, Jessica M.; White, Richard M.; Murphey, Ryan D.; Burns, Caroline E.; Zon, Leonard I.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Burns, Caroline E.] Massachusetts Gen Hosp, Charlestown, MA USA. RP Zon, LI (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Stem Cell Program, 1 Blackfan St,Karp Bldg,7th Floor, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health Cell and Developmental Biology Training [GM07226]; Howard Hughes Medical Institute (Chevy Chase, MD, USA); National Heart, Lung, and Blood Institute (Bethesda, MD, USA) [5U01 HL10001-02] FX A.M.T. was supported in part by National Institutes of Health Cell and Developmental Biology Training Grant GM07226. L.I.Z. is supported by the Howard Hughes Medical Institute (Chevy Chase, MD, USA), and this work was funded by National Heart, Lung, and Blood Institute (Bethesda, MD, USA) grant 5U01 HL10001-02. NR 36 TC 27 Z9 27 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD MAR PY 2012 VL 40 IS 3 BP 228 EP 237 DI 10.1016/j.exphem.2011.11.007 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 899GY UT WOS:000300805600006 PM 22120640 ER PT J AU Keating, A Pineda, R AF Keating, Anne Pineda, Roberto, II TI Trichosporon asahii Keratitis in a Patient With a Type I Boston Keratoprosthesis and Contact Lens SO EYE & CONTACT LENS-SCIENCE AND CLINICAL PRACTICE LA English DT Article DE Fungal keratitis; Trichosporon; Boston keratoprosthesis; Contact lens ID FUNGAL KERATITIS AB Purpose: The aim of the study was to report a case of Trichosporon asahii in a patient with a type I Boston keratoprosthesis and contact lens with review of the literature. Methods: A case report and literature review are provided. Results: A 70-year-old monocular South Asian man with light perception vision and dense corneal scarring from previously failed amniotic membrane grafting and one failed corneal transplant was evaluated for a keratoprosthesis for visual rehabilitation. Three months after undergoing uneventful implantation of a type I Boston keratoprosthesis and placement of a therapeutic contact lens, he was found on routine follow-up to have a corneal infiltrate that was culture positive for T. asahii. The fungal keratitis was successfully treated with topical amphotericin B and oral ketoconazole. Conclusions: Contact lens wear is a known risk factor for fungal keratitis. Trichosporon is an uncommon agent of fungal keratitis. We report the first known case of fungal keratitis caused by T. asahii in a patient with a keratoprosthesis and contact lens. C1 [Keating, Anne; Pineda, Roberto, II] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Keating, A (reprint author), 7th Floor,243 Charles St, Boston, MA 02114 USA. EM keat0026@gmail.com NR 6 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1542-2321 J9 EYE CONTACT LENS JI Eye Contact Lens-Sci. Clin. Pra. PD MAR PY 2012 VL 38 IS 2 BP 130 EP 132 DI 10.1097/ICL.0b013e31822c3703 PG 3 WC Ophthalmology SC Ophthalmology GA 898YB UT WOS:000300777200010 PM 21876439 ER PT J AU Provenzale, D AF Provenzale, Dawn TI A Guide for Success as a Clinical Investigator SO GASTROENTEROLOGY LA English DT Editorial Material C1 [Provenzale, Dawn] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Provenzale, Dawn] US Dept Vet Affairs, Durham, NC USA. RP Provenzale, D (reprint author), Duke Univ, Med Ctr, 508 Fulton St 152, Durham, NC 27705 USA. EM dawn.provenzale@dm.duke.edu NR 5 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2012 VL 142 IS 3 BP 418 EP 421 DI 10.1053/j.gastro.2012.01.009 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898XC UT WOS:000300774700013 PM 22266151 ER PT J AU Ananthakrishnan, AN Khalili, H Higuchi, LM Bao, Y Korzenik, JR Giovannucci, EL Richter, JM Fuchs, CS Chan, AT AF Ananthakrishnan, Ashwin N. Khalili, Hamed Higuchi, Leslie M. Bao, Ying Korzenik, Joshua R. Giovannucci, Edward L. Richter, James M. Fuchs, Charles S. Chan, Andrew T. TI Higher Predicted Vitamin D Status Is Associated With Reduced Risk of Crohn's Disease SO GASTROENTEROLOGY LA English DT Article DE Ultraviolet Exposure; Nutrition; Inflammatory Bowel Disease; IBD ID INFLAMMATORY-BOWEL-DISEASE; FOOD FREQUENCY QUESTIONNAIRE; RECEPTOR GENE POLYMORPHISM; COLORECTAL-CANCER; 25-HYDROXYVITAMIN-D LEVELS; 1,25-DIHYDROXYVITAMIN D-3; ULCERATIVE-COLITIS; ALPHA-TOCOPHEROL; UNITED-STATES; D DEFICIENCY AB BACKGROUND & AIMS: Vitamin D influences innate immunity, which is believed to be involved in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, data examining vitamin D status in relation to risk of CD and UC are lacking. METHODS: We conducted a prospective cohort study of 72,719 women (age, 40-73 y) enrolled in the Nurses' Health Study. In 1986, women completed an assessment of diet and lifestyle, from which a 25-hydroxy vitamin D [25(OH) D] prediction score was developed and validated against directly measured levels of plasma 25(OH) D. Through 2008, we confirmed reported diagnoses of incident CD or UC through medical record review. We used Cox proportional hazards modeling to examine the hazard ratio (HR) for incident CD or UC after adjusting for potential confounders. RESULTS: During 1,492,811 person-years of follow-up evaluation, we documented 122 incident cases of CD and 123 cases of UC. The median predicted 25(OH) D level was 22.3 ng/mL in the lowest and 32.2 ng/mL in the highest quartiles. Compared with the lowest quartile, the multivariate-adjusted HR associated with the highest quartile of vitamin D was 0.54 (95% confidence interval [CI], 0.30-.99) for CD (P-trend = .02) and 0.65 (95% CI, 0.34-1.25) for UC (P-trend = .17). Compared with women with a predicted 25(OH) D level less than 20 ng/mL, the multivariate-adjusted HR was 0.38 (95% CI, 0.15-0.97) for CD and 0.57 (95% CI, 0.19-1.70) for UC for women with a predicted 25(OH) D level greater than 30 ng/mL. There was a significant inverse association between dietary and supplemental vitamin D and UC, and a nonsignificant reduction in CD risk. CONCLUSIONS: Higher predicted plasma levels of 25(OH) D significantly reduce the risk for incident CD and nonsignificantly reduce the risk for UC in women. C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Khalili, Hamed; Higuchi, Leslie M.; Bao, Ying; Korzenik, Joshua R.; Richter, James M.; Fuchs, Charles S.; Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Higuchi, Leslie M.] Childrens Hosp Boston, Div Gastroenterol & Nutr, Boston, MA USA. [Bao, Ying; Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Div Gastroenterol, 55 Fruit St,GRJ 722, Boston, MA 02114 USA. EM achan@partners.org FU American Gastroenterological Association; IBD Working Group; Broad Foundation; National Institutes of Health [R01 CA137178, P01 CA87969, P30 DK043351, K08 DK064256]; Procter and Gamble; Warner Chilcott FX This work was supported by a Research Scholars Award of the American Gastroenterological Association (A.N.A.), the IBD Working Group (H. K.), the Broad Medical Research Program of the Broad Foundation (A. T. C), and the National Institutes of Health (R01 CA137178, P01 CA87969, P30 DK043351, and K08 DK064256).; These authors disclose the following: Joshua Korzenik has been a consultant for Procter and Gamble, Shire Pharmaceuticals, CytokinePharma, and receives research support from Procter and Gamble and Warner Chilcott; James Richter is a consultant for Policy Analysis, Inc; and Andrew Chan has served as a consultant for Bayer HealthCare and Millennium Pharmaceuticals. The remaining authors disclose no conflicts. NR 49 TC 122 Z9 131 U1 3 U2 25 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2012 VL 142 IS 3 BP 482 EP 489 DI 10.1053/j.gastro.2011.11.040 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898XC UT WOS:000300774700026 PM 22155183 ER PT J AU Liao, GX Detre, C Berger, SB Engel, P Malefyt, RD Herzog, RW Bhan, AK Terhorst, C AF Liao, Gongxian Detre, Cynthia Berger, Scott B. Engel, Pablo Malefyt, Rene de Waal Herzog, Roland W. Bhan, Atul K. Terhorst, Cox TI Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family-Related Protein Regulates CD4(+)T Cell-Mediated Colitis in Mice SO GASTROENTEROLOGY LA English DT Article DE TNF; Immune Regulation; Inflammation; IBD ID (GITR)-GITR LIGAND PATHWAY; T-CELLS; DENDRITIC CELLS; INTESTINAL INFLAMMATION; MURINE MACROPHAGE; CUTTING EDGE; GITR; IMMUNITY; EXPRESSION; MUCOSAL AB BACKGROUND & AIMS: The glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR; also called TNFRSF18 or CD357) regulates the T cell-mediated immune response and is present on surfaces of regulatory T (Treg) cells and activated CD4(+) T cells. We investigated the roles of GITR in the development of colitis in mice. METHODS: Chronic enterocolitis was induced by the transfer of wild-type or GITR(-/-) CD4(+) T cells to GITR(-/-) x Rag(-/-) or Rag(-/-) mice. We determined the severity of colitis by using the disease activity index; measured levels of inflammatory cytokines, T cells, and dendritic cells; and performed histologic analysis of colon samples. RESULTS: Transfer of nonfractionated CD4(+) cells from wild-type or GITR(-/-) donors induced colitis in GITR(-/-) x Rag(-/-) but not in Rag(-/-) mice. Among mice with transfer-induced colitis, the percentage of Treg and T-helper (Th) 17 cells was reduced but that of Th1 cells increased. Treg cells failed to prevent colitis in GITR(-/-) x Rag(-/-) recipients; this was not the result of aberrant function of GITR(-/-) Treg or T effector cells but resulted from an imbalance between the numbers of tolerogenic CD103(+) and PDCA1(+) plasmacytoid dendritic cells in GITR(-/-) mice. This imbalance impaired Treg cell development and expanded the Th1 population in GITR(-/-) x Rag(-/-) mice following transfer of nonfractionated CD4(+) cells. CONCLUSIONS: GITR is not required on the surface of Treg and T effector cells to induce colitis in mice; interactions between GITR and its ligand are not required for induction of colitis. GITR instead appears to control dendritic cell and monocyte development; in its absence, mice develop aggravated chronic enterocolitis via an imbalance of colitogenic Th1 cells and Treg cells. C1 [Liao, Gongxian; Detre, Cynthia; Berger, Scott B.; Terhorst, Cox] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Immunol, Boston, MA 02115 USA. [Bhan, Atul K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Engel, Pablo] Univ Barcelona, Sch Med, Dept Cell Biol Immunol & Neurosci, Immunol Unit, Barcelona, Spain. [Malefyt, Rene de Waal] Merck Res Labs, Palo Alto, CA USA. [Herzog, Roland W.] Univ Florida, Canc & Genet Res Ctr, Gainesville, FL USA. RP Liao, GX (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Immunol, Boston, MA 02115 USA. EM gliao@bidmc.harvard.edu FU National Institutes of Health [P01 HL078810, R01 DK-52510, PHS 5T32AI7512-24] FX Supported by the National Institutes of Health (P01 HL078810 and R01 DK-52510 to C. T. and PHS 5T32AI7512-24 to G.L.) NR 32 TC 10 Z9 10 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2012 VL 142 IS 3 BP 582 EP U256 DI 10.1053/j.gastro.2011.11.031 PG 18 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 898XC UT WOS:000300774700037 PM 22155173 ER PT J AU Jakobiec, FA Zakka, FR Townsend, DJ AF Jakobiec, Frederick A. Zakka, Fouad R. Townsend, Daniel J. TI Pleomorphic basal cell carcinoma of the eyelid with true ductular differentiation SO GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article C1 [Jakobiec, Frederick A.; Zakka, Fouad R.] David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Jakobiec, Frederick A.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jakobiec, Frederick A.; Zakka, Fouad R.; Townsend, Daniel J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu NR 10 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0721-832X J9 GRAEF ARCH CLIN EXP JI Graefes Arch. Clin. Exp. Ophthalmol. PD MAR PY 2012 VL 250 IS 3 BP 451 EP 454 DI 10.1007/s00417-011-1836-0 PG 4 WC Ophthalmology SC Ophthalmology GA 902LH UT WOS:000301039100018 PM 22037988 ER PT J AU Hoogeveen-Westerveld, M Ekong, R Povey, S Karbassi, I Batish, SD den Dunnen, JT van Eeghen, A Thiele, E Mayer, K Dies, K Wen, L Thompson, C Sparagana, SP Davies, P Aalfs, C van den Ouweland, A Halley, D Nellist, M AF Hoogeveen-Westerveld, Marianne Ekong, Rosemary Povey, Sue Karbassi, Izabela Batish, Sat Dev den Dunnen, Johan T. van Eeghen, Agnies Thiele, Elizabeth Mayer, Karin Dies, Kira Wen, Li Thompson, Catherine Sparagana, Steven P. Davies, Peter Aalfs, Cora van den Ouweland, Ans Halley, Dicky Nellist, Mark TI Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex SO HUMAN MUTATION LA English DT Article DE TSC1; TSC2; tuberous sclerosis complex; hamartin; tuberin ID CELL-GROWTH; GENE; MUTATIONS; HAMARTIN AB Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Previously, we demonstrated that pathogenic amino acid substitutions in the N-terminal domain of TSC1 (amino acids 50224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1-TSC2-dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N-terminal region of TSC1 is essential for TSC1 function. Hum Mutat 33:476479, 2012. (C) 2011 Wiley Periodicals, Inc. C1 [Hoogeveen-Westerveld, Marianne; van den Ouweland, Ans; Halley, Dicky; Nellist, Mark] Erasmus MC, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands. [Ekong, Rosemary; Povey, Sue] UCL, Res Dept Genet Evolut & Environm, London WC1E 6BT, England. [Karbassi, Izabela; Batish, Sat Dev] Athena Diagnost Inc, Worcester, MA USA. [den Dunnen, Johan T.] Leiden Univ Med Ctr, Dept Human & Clin Genet, NL-2333 ZC Leiden, Netherlands. [van Eeghen, Agnies; Thiele, Elizabeth] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mayer, Karin] Ctr Human Genet & Lab Med, D-82152 Martinsried, Germany. [Dies, Kira] Childrens Hosp Boston, Dept Neurol, Boston, MA USA. [Wen, Li] Cent S Univ, Inst Reprod & Stem Cell Engn, Changsha 410078, Hunan, Peoples R China. [Thompson, Catherine; Sparagana, Steven P.] Texas Scottish Rite Hosp Children, Dept Neurol, Dallas, TX 75219 USA. [Sparagana, Steven P.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Davies, Peter] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. [Aalfs, Cora] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. RP Nellist, M (reprint author), Erasmus MC, Dept Clin Genet, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM m.nellist@erasmusmc.nl FU U.S. Department of Defense Congressionally Directed Medical Research Program [TS060052]; Tuberous Sclerosis Alliance FX The U.S. Department of Defense Congressionally Directed Medical Research Program (TS060052); The Tuberous Sclerosis Alliance. NR 16 TC 17 Z9 17 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAR PY 2012 VL 33 IS 3 BP 476 EP 479 DI 10.1002/humu.22007 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 898AB UT WOS:000300706000006 PM 22161988 ER PT J AU Fuhlbrigge, A Peden, D Apter, AJ Boushey, HA Camargo, CA Gern, J Heymann, PW Martinez, FD Mauger, D Teague, WG Blaisdell, C AF Fuhlbrigge, Anne Peden, David Apter, Andrea J. Boushey, Homer A. Camargo, Carlos A., Jr. Gern, James Heymann, Peter W. Martinez, Fernando D. Mauger, David Teague, William G. Blaisdell, Carol TI Asthma outcomes: Exacerbations SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma exacerbations; severity of acute asthma; systemic steroids in asthma; urgent asthma care ID RANDOMIZED CONTROLLED-TRIAL; METERED-DOSE INHALER; MILD PERSISTENT ASTHMA; EXHALED NITRIC-OXIDE; INNER-CITY CHILDREN; BUDESONIDE/FORMOTEROL COMBINATION THERAPY; POORLY CONTROLLED ASTHMA; BROMIDE PLUS FENOTEROL; AMBIENT AIR-POLLUTION; DRY POWDER INHALER AB Background: The goals of asthma treatment include preventing recurrent exacerbations. Yet there is no consensus about the terminology for describing or defining "exacerbation" or about how to characterize an episode's severity. Objective: National Institutes of Health institutes and other federal agencies convened an expert group to propose how asthma exacerbation should be assessed as a standardized asthma outcome in future asthma clinical research studies. Methods: We used comprehensive literature reviews and expert opinion to compile a list of asthma exacerbation outcomes and classified them as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop in March 2010 and finalized in September 2011. Results: No dominant definition of "exacerbation" was found. The most widely used definitions included 3 components, all related to treatment, rather than symptoms: (1) systemic use of corticosteroids, (2) asthma-specific emergency department visits or hospitalizations, and (3) use of short-acting beta-agonists as quick-relief (sometimes referred to as "rescue" or "reliever") medications. Conclusions: The working group participants propose that the definition of "asthma exacerbation" be "a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome." As core outcomes, they propose inclusion and separate reporting of several essential variables of an exacerbation. Furthermore, they propose the development of a standardized, component-based definition of "exacerbation" with clear thresholds of severity for each component. (J Allergy Clin Immunol 2012; 129: S34-48.) C1 [Blaisdell, Carol] NHLBI, DLD, NIH, Bethesda, MD 20892 USA. [Fuhlbrigge, Anne] Brigham & Womens Hosp, Boston, MA 02115 USA. [Peden, David] Univ N Carolina, Chapel Hill, NC USA. [Apter, Andrea J.] Univ Penn, Philadelphia, PA 19104 USA. [Boushey, Homer A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gern, James] Univ Wisconsin, Madison, WI 53706 USA. [Heymann, Peter W.; Teague, William G.] Univ Virginia, Charlottesville, VA USA. [Martinez, Fernando D.] Univ Arizona, Tucson, AZ USA. [Mauger, David] Penn State Univ, Hershey, PA USA. RP Blaisdell, C (reprint author), NHLBI, DLD, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM blaisdellcj@nhlbi.nih.gov FU National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; Agency for Healthcare Research and Quality; Merck Childhood Asthma Network; Robert Wood Johnson Foundation; US Environmental Protection Agency; NIH/NIAID; MedImmune; Aquinox Pharmaceuticals; GlaxoSmithKline; Genentech; Sanofi-Aventis; Centocor; Boehringer Ingelheim; Biota; Theraclone; NIH; Novartis; NIH/NHLBI; American Lung Association FX The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.; Disclosure of potential conflict of interest: A. Fuhlbrigge is on the Merck Respiratory Advisory Board and is a consultant for the Lovelace Respiratory and Research Institute. D. Peden has received research support from the NIH/NIAID, MedImmune, the US Environmental Protection Agency, and Aquinox Pharmaceuticals. A. J. Apter has received research support from the NHLBI and is on the AAAAI Board of Directors. H. A. Boushey has provided ad-hoc consultation for Kalobics; is on the Pharmaxis advisory committee; is on the ad-hoc advisory committee for Merck and GlaxoSmithKline; has provided consultation for Genentech and Johnson & Johnson; and has received research support from GlaxoSmithKline and Genentech. C. A. Camargo, Jr, is a consultant for Dey, Genentech, Merck, Novartis, and Pfizer; and has received research support from GlaxoSmithKline and Sanofi-Aventis. J. Gern is on the Scientific Advisory Board and has stock options in 3V Biosciences, and has received consulting fees from Centocor, Boehringer Ingelheim, GlaxoSmithKline, Biota, MedImmune, and Theraclone. P. W. Heymann has received research support from the NIH and Novartis. F. D. Martinez has consulted for MedImmune and received lecture honorarium from Abbott. W. G. Teague is a speaker for Merck and Genentech, and has received research support from the NIH/NHLBI and the American Lung Association. C. Blaisdell is on the American Academy of Pediatrics Executive Board and is an abstract reviewer for the Pediatric Academic Society. The rest of the authors declare that they have no relevant conflicts of interest. NR 138 TC 66 Z9 67 U1 2 U2 14 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2012 VL 129 IS 3 SU S BP S34 EP S48 DI 10.1016/j.jaci.2011.12.983 PG 15 WC Allergy; Immunology SC Allergy; Immunology GA 901OL UT WOS:000300976600004 PM 22386508 ER PT J AU Raddi, G Morado, DR Yan, J Haake, DA Yang, XF Liu, J AF Raddi, Gianmarco Morado, Dustin R. Yan, Jie Haake, David A. Yang, X. Frank Liu, Jun TI Three-Dimensional Structures of Pathogenic and Saprophytic Leptospira Species Revealed by Cryo-Electron Tomography SO JOURNAL OF BACTERIOLOGY LA English DT Article ID BORRELIA-BURGDORFERI; ELECTRON TOMOGRAPHY; FLAGELLAR MOTOR; CELLULAR ARCHITECTURE; PERIPLASMIC FLAGELLA; TREPONEMA-PRIMITIA; FINE-STRUCTURE; MOTILITY; INTERROGANS; BACTERIA AB Leptospira interrogans is the primary causative agent of the most widespread zoonotic disease, leptospirosis. An in-depth structural characterization of L. interrogans is needed to understand its biology and pathogenesis. In this study, cryo-electron tomography (cryo-ET) was used to compare pathogenic and saprophytic species and examine the unique morphological features of this group of bacteria. Specifically, our study revealed a structural difference between the cell envelopes of L. interrogans and Leptospira biflexa involving variations in the lipopolysaccharide (LPS) layer. Through cryo-ET and subvolume averaging, we determined the first three-dimensional (3-D) structure of the flagellar motor of leptospira, with novel features in the flagellar C ring, export apparatus, and stator. Together with direct visualization of chemoreceptor arrays, DNA packing, periplasmic filaments, spherical cytoplasmic bodies, and a unique "cap" at the cell end, this report provides structural insights into these fascinating Leptospira species. C1 [Yang, X. Frank] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. [Raddi, Gianmarco; Morado, Dustin R.; Liu, Jun] Univ Texas Med Sch Houston, Dept Pathol & Lab Med, Houston, TX USA. [Yan, Jie] Zhejiang Univ, Coll Med, Dept Med Microbiol & Parasitol, Hangzhou 310003, Zhejiang, Peoples R China. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Haake, David A.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA USA. RP Yang, XF (reprint author), Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. EM xfyang@iupui.edu; jun.liu.1@uth.tmc.edu FU National Institute of Allergy and Infectious Diseases (NIAID) [R01AI087946, 5R01AI034431]; Welch Foundation [AU-1714]; VA FX This work was supported in part by grants R01AI087946 (to J. Liu) and 5R01AI034431 (to D. A. Haake) from the National Institute of Allergy and Infectious Diseases (NIAID), by grant AU-1714 from the Welch Foundation (to J. Liu), and by VA Medical Research funds (to D. A. Haake). NR 50 TC 22 Z9 23 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAR PY 2012 VL 194 IS 6 BP 1299 EP 1306 DI 10.1128/JB.06474-11 PG 8 WC Microbiology SC Microbiology GA 899WI UT WOS:000300846900003 PM 22228733 ER PT J AU Cole, LW Kesselheim, JC Kesselheim, AS AF Cole, Lindsay W. Kesselheim, Jennifer C. Kesselheim, Aaron S. TI Ethical Issues in New Drug Prescribing SO JOURNAL OF BIOETHICAL INQUIRY LA English DT Article DE Pharmaceutical marketing; Adverse event; Randomized controlled trial; Food and drug administration; Pharmaceutical industry ID OFF-LABEL; PHYSICIANS; INDUSTRY; PERSPECTIVE; BEHAVIOR; EVENTS AB We use the format of a hypothetical case study to review issues related to pharmaceutical product approval and physician prescribing practices. In this case, a new FDA-approved drug is recommended for a patient who subsequently experiences an adverse event that may or may not be related to the prescription. This case raises a number of ethical and legal considerations physicians routinely face when deciding whether to recommend such drugs for their patients. Despite the need for ongoing observation by the regulatory apparatus, physicians should be cognizant of the limitations of the drug approval system and the post-approval prescription drug surveillance system. We discuss physicians' ethical obligations when faced with a newly approved drug, including seeking out independent sources of learning, reporting adverse effects, and notifying patients about limitations in available knowledge about therapeutic recommendations. C1 [Kesselheim, Aaron S.] Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Cole, Lindsay W.] Harvard Univ, Sch Med, Boston, MA USA. [Kesselheim, Jennifer C.] Dana Farber Canc Inst, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Kesselheim, Aaron S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA USA. RP Kesselheim, AS (reprint author), Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. EM akesselheim@partners.org FU Agency for Healthcare Research and Quality [K08HS18465-01]; Robert Wood Johnson Foundation FX Dr. Aaron Kesselheim is supported by a career development award from the Agency for Healthcare Research and Quality (K08HS18465-01) and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. The authors report no potential conflicts of interest. NR 36 TC 2 Z9 2 U1 1 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1176-7529 J9 J BIOETHIC INQ JI J. Bioethical Inq. PD MAR PY 2012 VL 9 IS 1 BP 77 EP 83 DI 10.1007/s11673-011-9342-y PG 7 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 898WW UT WOS:000300774100010 PM 23180203 ER PT J AU Roche-Labarbe, N Fenoglio, A Aggarwal, A Dehaes, M Carp, SA Franceschini, MA Grant, PE AF Roche-Labarbe, Nadege Fenoglio, Angela Aggarwal, Alpna Dehaes, Mathieu Carp, Stefan A. Franceschini, Maria Angela Grant, Patricia Ellen TI Near-infrared spectroscopy assessment of cerebral oxygen metabolism in the developing premature brain SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE brain hemodynamic development; cerebral oxygen consumption; diffuse correlation spectroscopy; frequency-domain near-infrared spectroscopy; premature neonates ID DIFFUSE CORRELATION SPECTROSCOPY; BLOOD-FLOW; PRETERM INFANTS; OPTICAL-PROPERTIES; NEWBORN-INFANTS; VISUAL-CORTEX; QUANTIFICATION; HEMODYNAMICS; ABSORPTION; SCATTERING AB Little is known about cerebral blood flow, cerebral blood volume (CBV), oxygenation, and oxygen consumption in the premature newborn brain. We combined quantitative frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation (SO2) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BFix) to determine the relationship between these measures, gestational age at birth (GA), and chronological age. We followed 56 neonates of various GA once a week during their hospital stay. We provide absolute values of SO2 and CBV, relative values of BFix, and relative cerebral metabolic rate of oxygen (rCMRO(2)) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO2 correlates with chronological age (r = -0.54, P value <= 0.001) but not with PMA (r = -0.07), whereas BFix and rCMRO(2) correlate better with PMA (r = 0.37 and 0.43, respectively, P value <= 0.001). Relative CMRO2 during the first month of life is lower when GA is lower. Blood flow index and rCMRO(2) are more accurate biomarkers of the brain development than SO2 in the premature newborns. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 481-488; doi: 10.1038/jcbfm.2011.145; published online 26 October 2011 C1 [Roche-Labarbe, Nadege; Carp, Stefan A.; Franceschini, Maria Angela] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Fenoglio, Angela; Dehaes, Mathieu; Grant, Patricia Ellen] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Aggarwal, Alpna; Grant, Patricia Ellen] Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. RP Roche-Labarbe, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM nadege@nmr.mgh.harvard.edu RI Roche-Labarbe, Nadege/N-9101-2015 OI Roche-Labarbe, Nadege/0000-0002-5010-0400 FU NIH [R01 HD042908, P41-RR14075, R21-HD058725]; National Center for Research Resources [UL1RR025758] FX This work was supported by NIH Grant R01 HD042908, P41-RR14075, and R21-HD058725 and by Clinical Translational Science Award UL1RR025758 to Harvard University and Brigham and Women's Hospital from the National Center for Research Resources. NR 40 TC 27 Z9 28 U1 4 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2012 VL 32 IS 3 BP 481 EP 488 DI 10.1038/jcbfm.2011.145 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 901FN UT WOS:000300948200010 PM 22027937 ER PT J AU Mbye, LH Keles, E Tao, LY Zhang, J Chung, J Larvie, M Koppula, R Lo, EH Whalen, MJ AF Mbye, Lamin H. Keles, Eyup Tao, Luyang Zhang, Jimmy Chung, Joonyong Larvie, Mykol Koppula, Rajani Lo, Eng H. Whalen, Michael J. TI Kollidon VA64, a membrane-resealing agent, reduces histopathology and improves functional outcome after controlled cortical impact in mice SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE blood-brain barrier; edema; Kollidon VA64; mice; plasmalemma; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; SURFACTANT POLOXAMER-188; MECHANICAL TRAUMA; PRENATAL EXPOSURE; CELL-DEATH; PERMEABILITY; NEURONS; DAMAGE; EPILEPTOGENESIS; RECOVERY AB Loss of plasma membrane integrity is a feature of acute cellular injury/death in vitro and in vivo. Plasmalemma-resealing agents are protective in acute central nervous system injury models, but their ability to reseal cell membranes in vivo has not been reported. Using a mouse controlled cortical impact (CCI) model, we found that propidium iodide-positive (PI+) cells pulse labeled at 6, 24, or 48 hours maintained a degenerative phenotype and disappeared from the injured brain by 7 days, suggesting that plasmalemma permeability is a biomarker of fatal cellular injury after CCI. Intravenous or intracerebroventricular administration of Kollidon VA64, poloxamer P188, or polyethylene glycol 8000 resealed injured cell membranes in vivo (P < 0.05 versus vehicle or poloxamer P407). Kollidon VA64 (1 mmol/L, 500 mu L) administered intravenously to mice 1 hour after CCI significantly reduced acute cellular degeneration, chronic brain tissue damage, brain edema, blood-brain barrier damage, and postinjury motor deficits (all P < 0.05 versus vehicle). However, VA64 did not rescue pulse-labeled PI+ cells from eventual demise. We conclude that PI permeability within 48 hours of CCI is a biomarker of eventual cell death/loss. Kollidon VA64 reduces secondary damage after CCI by mechanisms other than or in addition to resealing permeable cells. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 515-524; doi: 10.1038/jcbfm.2011.158; published online 16 November 2011 C1 [Mbye, Lamin H.; Keles, Eyup; Zhang, Jimmy; Chung, Joonyong; Koppula, Rajani; Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat, Charlestown, MA 02129 USA. [Mbye, Lamin H.; Keles, Eyup; Zhang, Jimmy; Chung, Joonyong; Koppula, Rajani; Whalen, Michael J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Neurosci, Charlestown, MA 02129 USA. [Tao, Luyang] Soochow Univ, Inst Forens Sci, Suzhou, Peoples R China. [Larvie, Mykol; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Whalen, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Crit Care Med, Charlestown, MA 02129 USA. EM mwhalen@partners.org FU NINDS [5RO1NS061255]; Nature Science Foundation of China FX This study was supported by NINDS 5RO1NS061255 (MJW) and the Nature Science Foundation of China (LT). NR 36 TC 13 Z9 14 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAR PY 2012 VL 32 IS 3 BP 515 EP 524 DI 10.1038/jcbfm.2011.158 PG 10 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 901FN UT WOS:000300948200013 PM 22086196 ER PT J AU Klein, KP Hannum, WH Fields, HW Proffit, WR AF Klein, Katherine P. Hannum, Wallace H. Fields, Henry W. Proffit, William R. TI Interactive Distance Learning in Orthodontic Residency Programs: Problems and Potential Solutions SO JOURNAL OF DENTAL EDUCATION LA English DT Article DE dental education; distance education; orthodontic education; orthodontics ID EDUCATION AB Sharing resources through distance education has been proposed as one way to deal with a lack of full-time faculty members and maintain high-quality content in orthodontic residency programs. To keep distance education for orthodontic residents cost-effective while retaining interaction, a blended approach was developed that combines observation of web-based seminars with live post-seminar discussions. To evaluate this approach, a grant from the American Association of Orthodontists (AAO) opened free access during the 2009-10 academic year to twenty-five recorded seminars in four instructional sequences to all sixty-three orthodontic programs in the United States and Canada. The only requirement was to also participate in the evaluation. Just over half (52 percent) of the U.S. programs chose to participate; the primary reason for participating was because faculty members wanted their residents to have exposure to other faculty members and ideas. The non-participating programs cited technical and logistical problems and their own ability to teach these subjects satisfactorily as reasons. Although participating distant faculty members and residents were generally pleased with the experience, problems in both educational and technical aspects were observed. Educationally, the biggest problem was lack of distant resident preparation and expectation of a lecture rather than a seminar. Technically, the logistics of scheduling distant seminars and uneven quality of the audio and video recordings were the major concerns of both residents and faculty members. Proposed solutions to these educational and technical problems are discussed. C1 [Proffit, William R.] Univ N Carolina, Sch Dent, Dept Orthodont, Chapel Hill, NC 27599 USA. [Klein, Katherine P.] Massachusetts Gen Hosp, Div Dent, Boston, MA 02114 USA. [Hannum, Wallace H.] Univ N Carolina, Sch Educ, Chapel Hill, NC 27599 USA. [Fields, Henry W.] Ohio State Univ, Coll Dent, Div Orthodont, Columbus, OH 43210 USA. RP Proffit, WR (reprint author), Univ N Carolina, Sch Dent, Dept Orthodont, CB 7450, Chapel Hill, NC 27599 USA. EM william_proffit@dentistry.unc.edu NR 11 TC 1 Z9 2 U1 0 U2 2 PU AMER DENTAL EDUCATION ASSOC PI WASHINGTON PA 1400 K STREET, NW, STE 1100, WASHINGTON, DC 20005 USA SN 0022-0337 J9 J DENT EDUC JI J. Dent. Educ. PD MAR PY 2012 VL 76 IS 3 BP 322 EP 329 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 902KO UT WOS:000301037200007 PM 22383600 ER PT J AU Horton, E Wright, R Barbosa, FC Plummer, L Kaina, J Buck, C Jiang, N Quinton, R Crowley, WF Balasubramanian, R AF Horton, Edward Wright, Rohanna Barbosa, Flavia Costa Plummer, Lacey Kaina, Jennifer Buck, Cassandra Jiang, Ning Quinton, Richard Crowley, William F., Jr. Balasubramanian, Ravikumar TI LOW SPINAL BONE MINERAL DENSITY IN MEN WITH ISOLATED GNRH DEFICIENCY IS RELATED TO THE DEGREE OF PUBERTAL ACTIVATION OF HYPOTHALAMO-PITUITARY-GONADAL AXIS SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Horton, Edward; Barbosa, Flavia Costa; Plummer, Lacey; Kaina, Jennifer; Buck, Cassandra; Jiang, Ning; Crowley, William F., Jr.; Balasubramanian, Ravikumar] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Wright, Rohanna; Quinton, Richard] Royal Victoria Infirm, Dept Endocrinol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. 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 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 618 EP 618 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200014 ER PT J AU Buonanno, F Meng, R Feeney, K Cao, J Lo, EH Elia, M Thayer, M Ning, MM AF Buonanno, Ferdinando Meng, Ran Feeney, Kathleen Cao, Jing Lo, Eng H. Elia, Mikaela Thayer, Molly Ning, MingMing TI ANTIPHOSPHOLIPID ANTIBODY ELEVATION IS ASSOCIATED WITH "SILENT STROKES" IN PATIENTS WITH PATENT FORAMEN OVALE SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Ning, MingMing] Harvard Univ, Sch Med, Mass Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 619 EP 619 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200018 ER PT J AU Lewkowitz-Shpuntoff, H Balasubramanian, R Chavan, N Kaina, J Dwyer, A Seminara, S Plummer, L Hayes, F Crowley, WF Pitteloud, N AF Lewkowitz-Shpuntoff, Hilana Balasubramanian, Ravikumar Chavan, Niraj Kaina, Jennifer Dwyer, Andrew Seminara, Stephanie Plummer, Lacey Hayes, Francis Crowley, William F., Jr. Pitteloud, Nelly TI FUNCTIONAL GONADOTROPIN-RELEASING HORMONE DEFICIENCY IN MEN SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lewkowitz-Shpuntoff, Hilana] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Dwyer, Andrew; Pitteloud, Nelly] CHU Vaudois, CH-1011 Lausanne, Switzerland. RI Dwyer, Andrew/D-8099-2012; PITTELOUD, Nelly/K-2709-2014 OI Dwyer, Andrew/0000-0002-7023-6794; 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 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 619 EP 619 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200017 ER PT J AU Chou, SH Feske, SK Simmons, SL Orzell, S Du, R Marckmann, A Lo, EH Ning, MM AF Chou, Sherry H. Feske, Steven K. Simmons, Suzanne L. Orzell, Susannah Du, Rose Marckmann, Andrea Lo, Eng H. Ning, MingMing TI ELEVATED CEREBROSPINAL FLUID METALLOPROTEINASE-9 IS ASSOCIATED WITH POOR 6-MONTH OUTCOME FOLLOWING SUBARACHNOID HEMORRHAGE SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract C1 [Chou, Sherry H.; Feske, Steven K.; Simmons, Suzanne L.; Orzell, Susannah; Du, Rose; Ning, MingMing] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chou, Sherry H.; Marckmann, Andrea; Lo, Eng H.; Ning, MingMing] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chou, Sherry H.; Feske, Steven K.; Du, Rose; Lo, Eng H.; Ning, MingMing] Harvard Univ, Sch Med, Boston, MA USA. RI Du, Rose/I-5402-2012 OI Du, Rose/0000-0003-2641-6496 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 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD MAR PY 2012 VL 60 IS 3 BP 620 EP 620 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 898YL UT WOS:000300778200022 ER PT J AU Funkhouser, WK Lubin, IM Monzon, FA Zehnbauer, BA Evans, JP Ogino, S Nowak, JA AF Funkhouser, William K., Jr. Lubin, Ira M. Monzon, Federico A. Zehnbauer, Barbara A. Evans, James P. Ogino, Shuji Nowak, Jan A. TI Relevance, Pathogenesis, and Testing Algorithm for Mismatch Repair-Defective Colorectal Carcinomas A Report of the Association for Molecular Pathology SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; SPORADIC COLON-CANCER; REVISED BETHESDA GUIDELINES; POPULATION-BASED SAMPLE; TUMOR MICROSATELLITE-INSTABILITY; FRAMESHIFT-INDUCED NEOPEPTIDES; COST-EFFECTIVENESS ANALYSIS; MLH1 PROMOTER METHYLATION; HNPCC MUTATION CARRIERS; BRAF V600E MUTATION AB Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening,criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response arc: similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder. (J moL Diagn, 2012, 14:91-103; DOI:10.1016/j.jmoldx.2011.11.001) C1 [Funkhouser, William K., Jr.] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Funkhouser, William K., Jr.; Lubin, Ira M.; Monzon, Federico A.] Univ N Carolina, Mismatch Repair Defect CRC Working Grp, Assoc Mol Pathol Clin Practice Comm, Chapel Hill, NC 27599 USA. [Evans, James P.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Lubin, Ira M.; Zehnbauer, Barbara A.] Ctr Dis Control & Prevent, Div Lab Sci & Stand, Atlanta, GA USA. [Monzon, Federico A.] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Canc Epidemiol Pmgram, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Canc Ctr, Boston, MA USA. [Nowak, Jan A.] Northshore Univ HealthSyst, Evanston, IL USA. RP Funkhouser, WK (reprint author), Univ N Carolina, Sch Med, Dept Pathol & Lab Med, CB 7525,Brinkhous Bullitt Bldg, Chapel Hill, NC 27599 USA. EM bill_funkhouser@med.unc.edu NR 130 TC 57 Z9 57 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD MAR PY 2012 VL 14 IS 2 BP 91 EP 103 DI 10.1016/j.jmoldx.2011.11.001 PG 13 WC Pathology SC Pathology GA 901ZF UT WOS:000301007700001 PM 22260991 ER PT J AU Kolasinski, J Stagg, CJ Chance, S Esiri, M Chang, E Palace, JA McNab, JA Jenkinson, M Miller, K Johansen-Berg, H AF Kolasinski, J. Stagg, C. J. Chance, S. Esiri, M. Chang, E. Palace, J. A. McNab, J. A. Jenkinson, M. Miller, K. Johansen-Berg, H. TI COMPARISON OF HISTOLOGICAL AND DIFFUSION-WEIGHTED MRI TECHNIQUES IN THE ANALYSIS OF POST MORTEM MULTIPLE SCLEROSIS BRAINS SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the Association-of-British-Neurologists CY 2011 CL Gateshead, ENGLAND SP Assoc British Neurologists C1 Univ Oxford, Ctr Funct Magnet Resonance Imaging Brain, Oxford OX1 2JD, England. Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England. Massachusetts Gen Hosp, AA Martinos Ctr, Boston, MA 02114 USA. EM jkolasinski@me.com NR 0 TC 0 Z9 0 U1 2 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAR PY 2012 VL 83 IS 3 DI 10.1136/jnnp-2011-301993.181 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 897AE UT WOS:000300612200183 ER PT J AU Matilde, L Eichler, F Hornemann, T Murphy, SM Polke, J Bull, K Houlden, H Reilly, MM AF Matilde, L. Eichler, F. Hornemann, T. Murphy, S. M. Polke, J. Bull, K. Houlden, H. Reilly, M. M. TI HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1: CORRELATION OF SEVERITY AND PLASMA ATYPICAL DEOXY-SPHYNGOID BASES SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the Association-of-British-Neurologists CY 2011 CL Gateshead, ENGLAND SP Assoc British Neurologists C1 UCL Inst Neurol, MRC Ctr Neuromuscular Dis, London, England. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. Univ Zurich Hosp, Inst Clin Chem, Zurich, Switzerland. EM m.laura@ion.ucl.ac.uk RI Reilly, Mary/C-8482-2013; Houlden, Henry/C-1532-2008 OI Houlden, Henry/0000-0002-2866-7777 NR 0 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAR PY 2012 VL 83 IS 3 DI 10.1136/jnnp-2011-301993.16 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 897AE UT WOS:000300612200017 ER PT J AU Salgado, C Neff, T Frazier, L Vargas, SO VanderVeen, D AF Salgado, Cristian Neff, Tobias Frazier, Lindsay Vargas, Sara O. VanderVeen, Deborah TI An Unusual Case of Congenital Primitive Neuroectodermal Tumor With Ocular Metastasis SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE Ewing; PNET; medical oncology; tumors; brain ID EWING SARCOMA FAMILY; MULTIPLE METASTASES AB Primitive neuroectodermal tumor (PNET) is most common in the second decade of life. Congenital PNET is very rare. Ocular metastasis of PNET is likewise exceedingly rare; with only 5 previously published cases. We report an unusual congenital PNET of the face, which metastasized to subcutis, eyes, and brain. The primary tumor responded to chemotherapy (vincristine/doxorubicin/cyclophosphamide) with metachronous progression of ocular lesions. A therapeutic trial of intraocular bevacizumab showed no efficacy on intraocular lesions. Eventually the patient developed cerebral metastasis, and second line therapy with topotecan/cyclophosphamide was initiated. The tumor progressed and the patient died after acute herniation. C1 [Neff, Tobias; Frazier, Lindsay] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [Salgado, Cristian; VanderVeen, Deborah] Childrens Hosp Boston, Dept Ophthalmol, Boston, MA 02115 USA. [Vargas, Sara O.] Childrens Hosp Boston, Dept Pathol, Boston, MA 02115 USA. [Neff, Tobias; Frazier, Lindsay] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Salgado, Cristian] Pontificia Univ Catolica, Santiago, Chile. RP Neff, T (reprint author), Childrens Hosp Boston, Div Hematol Oncol, 300 Longwood Ave,Karp Res Bldg Rb08005E, Boston, MA 02115 USA. EM Tobias.Neff@tch.harvard.edu OI Neff, Tobias/0000-0002-0188-8393 NR 14 TC 2 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD MAR PY 2012 VL 34 IS 2 BP E69 EP E71 DI 10.1097/MPH.0b013e318221ca9b PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 898HH UT WOS:000300730900008 PM 22052164 ER PT J AU Robinson, A Kardos, M Kimball, AB AF Robinson, Amanda Kardos, Marisa Kimball, Alexandra B. TI Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): Why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article DE Physician Global Assessment; Psoriasis Area and Severity Index; psoriasis severity assessment tools ID PLACEBO-CONTROLLED TRIAL; INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY; OPEN-LABEL EXTENSION; TO-SEVERE PSORIASIS; PHASE-III TRIAL; DOUBLE-BLIND; INFLIXIMAB INDUCTION; EFALIZUMAB THERAPY; CLINICAL-RESPONSE; 50 MG AB Background: Although there are many psoriasis assessment tools currently published, one of the unmet needs in psoriasis research remains consensus about the single best validated and reproducible assessment tool. Objectives: In this systematic review we sought to determine the degree of correlation between two commonly used psoriasis assessment tools, the Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA). Methods: Randomized controlled systemic trials in moderate to severe psoriasis were reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. We recorded and compared the percent of patients achieving both 75% reduction in PASI score (PASI 75) and PGA 0 or 1 (clear or almost clear) at 8 to 16 weeks, 17 to 24 weeks, and greater than 24 weeks of treatment with the investigational drug. Results: Our literature review yielded 30 randomized controlled trials using biologic agents in moderate to severe psoriasis. We found that the two assessment tools correlate very tightly except at the lower bounds of therapeutic efficacy. The r(2) values for the correlation between PASI 75 and a score of clear or almost clear on the PGA were 0.9157 at 8 to 16 weeks and 0.892 at 17 to 24 weeks. Limitations: Limitations of our study include the small number of randomized controlled trials publishing the percent of patients achieving 75% reduction in PASI score and a score of clear or almost clear on the PGA after 24 weeks of therapy. In addition, our results are not generalizable beyond the patients with moderate to severe plaque psoriasis. Conclusion: The two assessment tools are substantially redundant and either alone is a sufficient tool for assessing psoriasis severity in patients with moderate to severe disease. Because the PASI is better validated and more detailed, it remains the score of choice for clinical trials, but the simpler PGA may be well suited for community-based outcomes projects. (J Am Acad Dermatol 2012;66:369-75.) C1 [Robinson, Amanda; Kardos, Marisa; Kimball, Alexandra B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Kardos, Marisa] Tufts Univ, Sch Med, Medford, MA 02155 USA. [Kimball, Alexandra B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Kimball, AB (reprint author), CURTIS, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU National Psoriasis Foundation/USA FX Funding sources: National Psoriasis Foundation/USA. NR 41 TC 64 Z9 65 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2012 VL 66 IS 3 BP 369 EP 375 DI 10.1016/j.jaad.2011.01.022 PG 7 WC Dermatology SC Dermatology GA 901CJ UT WOS:000300939000012 PM 22041254 ER PT J AU Murrell, DF Daniel, BS Joly, P Borradori, L Amagai, M Hashimoto, T Caux, F Marinovic, B Sinha, AA Hertl, M Bernard, P Sirois, D Cianchini, G Fairley, JA Jonkman, MF Pandya, AG Rubenstein, D Zillikens, D Payne, AS Woodley, D Zambruno, G Aoki, V Pincelli, C Diaz, L Hall, RP Meurer, M Mascaro, JM Schmidt, E Shimizu, H Zone, J Swerlick, R Mimouni, D Culton, D Lipozencic, J Bince, B Grando, SA Bystryn, JC Werth, VP AF Murrell, Dedee F. Daniel, Benjamin S. Joly, Pascal Borradori, Luca Amagai, Masayuki Hashimoto, Takashi Caux, Frederic Marinovic, Branka Sinha, Animesh A. Hertl, Michael Bernard, Philippe Sirois, David Cianchini, Giuseppe Fairley, Janet A. Jonkman, Marcel F. Pandya, Amit G. Rubenstein, David Zillikens, Detlef Payne, Aimee S. Woodley, David Zambruno, Giovanna Aoki, Valeria Pincelli, Carlo Diaz, Luis Hall, Russell P. Meurer, Michael Mascaro, Jose M., Jr. Schmidt, Enno Shimizu, Hiroshi Zone, John Swerlick, Robert Mimouni, Daniel Culton, Donna Lipozencic, Jasna Bince, Benjamin Grando, Sergei A. Bystryn, Jean-Claude Werth, Victoria P. TI Definitions and outcome measures for bullous pemphigoid: Recommendations by an international panel of experts SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Review DE bullous pemphigoid; consensus; definitions; outcome measures; severity score ID TOPICAL CORTICOSTEROIDS AB Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies. (J Am Acad Dermatol 2012;66:479-85.) C1 [Murrell, Dedee F.; Daniel, Benjamin S.] Univ New S Wales, St George Hosp, Dept Dermatol, Sydney, NSW, Australia. [Joly, Pascal] Univ Rouen, Rouen Univ Hosp, Dermatol Clin, Dept Dermatol,INSERM,U905, F-76821 Mont St Aignan, France. [Borradori, Luca] Univ Hosp Bern, Dept Dermatol, Bern, Switzerland. [Amagai, Masayuki] Keio Univ, Sch Med, Tokyo, Japan. [Hashimoto, Takashi] Kurume Univ, Sch Med, Kurume, Fukuoka, Japan. [Caux, Frederic] Univ Paris 08, Dept Dermatol, Bobigny, France. [Marinovic, Branka; Lipozencic, Jasna] Univ Zagreb, Hosp Ctr & Sch Med, Dept Dermatol & Venereol, Zagreb 41000, Croatia. [Sinha, Animesh A.] SUNY Buffalo, Dept Dermatol, Buffalo, NY 14260 USA. [Hertl, Michael] Univ Hosp, Dept Dermatol, Marburg, Germany. [Sirois, David] NYU, Coll Dent, Dept Oral Med, New York, NY 10003 USA. [Cianchini, Giuseppe] IRCCS, Inst Dermopat Immacolata, Immunodermatol Dept, Rome, Italy. [Zambruno, Giovanna] IRCCS, Inst Dermopat Immacolata, Lab Mol & Cell Biol, Rome, Italy. [Fairley, Janet A.] Univ Iowa, Dept Dermatol, Iowa City, IA USA. [Fairley, Janet A.] Dept Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Jonkman, Marcel F.] Univ Groningen, Univ Med Ctr Groningen, NL-9700 AB Groningen, Netherlands. [Rubenstein, David; Diaz, Luis; Culton, Donna] Univ N Carolina, Dept Dermatol, Chapel Hill, NC 27514 USA. [Pandya, Amit G.] Univ Texas SW Med Ctr Dallas, Dallas, TX USA. [Zillikens, Detlef; Schmidt, Enno] Univ Lubeck, Dept Dermatol, Lubeck, Germany. [Woodley, David] Univ So Calif, Dept Dermatol, Keck Sch Med, Los Angeles, CA 90089 USA. [Payne, Aimee S.; Werth, Victoria P.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Aoki, Valeria] Univ Sao Paulo, Dept Dermatol, BR-05508 Sao Paulo, Brazil. [Pincelli, Carlo] Univ Modena & Reggio Emilia, Inst Dermatol, Sch Biosci & Biotechnol, Modena, Italy. [Hall, Russell P.] Duke Med Ctr, Div Dermatol, Durham, NC USA. [Shimizu, Hiroshi] Hokkaido Univ, Grad Sch Med, Dept Dermatol, Sapporo, Hokkaido, Japan. [Meurer, Michael] Tech Univ Dresden, Carl Gustav Carus Med Sch, Dresden, Germany. [Mascaro, Jose M., Jr.] Univ Barcelona, Dept Dermatol, E-08007 Barcelona, Spain. [Zone, John] Univ Utah, Dept Dermatol, Salt Lake City, UT 84112 USA. [Bince, Benjamin] Jose R Reyes Mem Med Ctr, Dept Dermatol, Manila, Philippines. [Swerlick, Robert] Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. [Bystryn, Jean-Claude] NYU, Med Ctr, New York, NY 10003 USA. [Mimouni, Daniel] Rabin Med Ctr, Dept Dermatol, Petah Tiqwa, Israel. [Bernard, Philippe] Robert Debre Univ Hosp, Dept Dermatol, Reims, France. [Grando, Sergei A.] Univ Calif Irvine, Dept Biol Chem, Dept Dermatol, Ctr Canc, Irvine, CA 92717 USA. [Grando, Sergei A.] Univ Calif Irvine, Res Inst, Inst Immunol, Irvine, CA USA. [Werth, Victoria P.] Philadelphia Dept Vet Affairs Med Ctr, Philadelphia, PA USA. RP Murrell, DF (reprint author), Univ New S Wales, St George Hosp, Dept Dermatol, Sydney, NSW, Australia. EM d.murrell@unsw.edu.au RI Cianchini, Giuseppe/I-8877-2012; Amagai, Masayuki/K-5325-2013; Schmidt, Enno/C-4008-2009; Jonkman, Marcel/H-4647-2011; Pincelli, Carlo/A-7288-2012; Aoki, Valeria/H-1415-2012; OI Amagai, Masayuki/0000-0003-3314-7052; Schmidt, Enno/0000-0002-1206-8913; Pincelli, Carlo/0000-0003-4416-2637; Marinovic, Branka/0000-0001-8441-5016; Hashimoto, Takashi/0000-0002-0144-3255 FU International Pemphigus and Pemphigoid Foundation; National Institutes of Health [K24-AR 02207] FX The International Pemphigus and Pemphigoid Foundation generously supported renting rooms at the American Academy of Dermatology and audiovisual equipment; the European Society for Dermatological Research and European Academy of Dermatology provided meeting rooms. This report was supported in part by a grant from the National Institutes of Health (K24-AR 02207) to Dr Werth. NR 10 TC 59 Z9 62 U1 6 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2012 VL 66 IS 3 BP 479 EP 485 DI 10.1016/j.jaad.2011.06.032 PG 7 WC Dermatology SC Dermatology GA 901CJ UT WOS:000300939000026 PM 22056920 ER PT J AU Levy, C Hutt, E Pointer, L AF Levy, Cari Hutt, Evelyn Pointer, Lauren TI Site of Death Among Veterans Living in Veterans Affairs Nursing Homes SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Site of death; nursing home; veterans; hospice; end-of-life ID HOSPICE CARE; LIFE; END; MORTALITY; RESIDENTS; TURNOVER; SERVICES; QUALITY; BENEFIT; INDEX AB Objectives: To determine predictors of dying in VA nursing homes, community living centers (CLCs), compared with dying in a hospital. Design: Retrospective cohort study. Setting: VA CLCs. Participants: Included were 7408 CLC decedents from FY2005 to FY2007. Measurements: Outcome: Site of death obtained from VA Vital Statistics files. Predictors of Death Site: VA-MDS variables defining patient demographics, functional status, cognitive status, major diagnostic categories, and care planning documentation. Analysis: Logistic regression was used to estimate the odds ratio of death in the CLC relative to the hospital for patient and facility characteristics. Results: Among decedents, 87% died in the CLC and 13% in a hospital. More than half of all decedents were neither enrolled in hospice nor designated as having end-stage disease. The strongest predictor of site of death in a CLC relative to a hospital was being enrolled in hospice (OR = 20.94; 95% CI: 12.38, 35.44). A designation of end-stage disease increased the odds of death in a CLC by 3.9 times (95% CI: 2.78, 5.47) compared with death in a hospital. Advance directive rates in CLCs were high (73.4%); having any advance directive increased the odds of death in a CLC by 1.57 times (95% CI: 1.35, 1.82). Conclusion: Recognition of end-stage disease and documentation of advance directives are powerful determinants of site of death for CLC residents. Receipt of hospice care in a CLC is a strong predictor of site of death in a CLC even in the absence of collaboration with community-based hospice and financial incentives to avoid hospitalization. Copyright (C) 2012 - American Medical Directors Association, Inc. C1 [Levy, Cari; Hutt, Evelyn] Univ Colorado Denver, Div Hlth Care Policy & Res, Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Levy, C (reprint author), Univ Colorado Denver, Div Hlth Care Policy & Res, Denver Vet Affairs Med Ctr, 1055 Clermont,Mailstop 151, Denver, CO 80220 USA. EM cari.levy@va.gov FU Veterans Affairs Career Development Award FX This research was funded by a Veterans Affairs Career Development Award. NR 26 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD MAR PY 2012 VL 13 IS 3 BP 199 EP 201 DI 10.1016/j.jamda.2011.08.004 PG 3 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 898IE UT WOS:000300734700004 PM 21945536 ER PT J AU Akins, CW AF Akins, Cary W. TI The ethical dilemma of Thoracic Surgery recertification SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. RP Akins, CW (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Cardiac Surg, Cox 648,55 Fruit St, Boston, MA 02114 USA. EM cakins@partners.org NR 2 TC 4 Z9 4 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 MAR PY 2012 VL 143 IS 3 BP 521 EP 522 DI 10.1016/j.jtcvs.2011.12.015 PG 3 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 897BX UT WOS:000300617300003 PM 22244565 ER PT J AU Yarbrough, WM Mukherjee, R Ikonomidis, JS Zile, MR Spinale, FG AF Yarbrough, William M. Mukherjee, Rupak Ikonomidis, John S. Zile, Michael R. Spinale, Francis G. TI Myocardial remodeling with aortic stenosis and after aortic valve replacement: Mechanisms and future prognostic implications SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; HYPERTENSIVE HEART-DISEASE; OVERLOADED HUMAN HEART; C-REACTIVE PROTEIN; GROWTH-FACTOR-BETA; MATRIX METALLOPROTEINASES; PRESSURE-OVERLOAD; DIASTOLIC DYSFUNCTION; TISSUE INHIBITOR; NATRIURETIC PEPTIDE AB Aortic valve stenosis is a common cause of left ventricular pressure overload, a pathologic process that elicits myocyte hypertrophy and alterations in extracellular matrix composition, both of which contribute to increases in left ventricular stiffness. However, clinical and animal studies suggest that increased myocardial extracellular matrix fibrillar collagen content occurs later in the time course of left ventricular pressure overload at a time coincident with severe abnormalities in diastolic function followed by the development of symptomatic heart failure. Aortic valve replacement remains the most effective treatment for elimination of chronic pressure overload secondary to aortic stenosis but has traditionally been recommended only after the onset of clinical symptoms. Long-termfollow-up of patients with symptomatic aortic stenosis after aortic valve replacement suggests that valve replacement may not result in complete reversal of the maladaptive changes that occur within the myocardial extracellular matrix secondary to the pressure overload state. To the contrary, residual left ventricular extracellular matrix abnormalities such as these are likely responsible for persistent abnormalities in diastolic function and increased morbidity and mortality after aortic valve replacement. Defining the mechanisms and pathways responsible for regulating the myocardial extracellular matrix during the natural history of aortic stenosis may provide a means by which to detect crucial structural milestones and thereby permit more precise identification of the development of maladaptive left ventricular remodeling. (J Thorac Cardiovasc Surg 2012;143:656-64) C1 [Yarbrough, William M.; Mukherjee, Rupak; Ikonomidis, John S.; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Dept Med, Charleston, SC 29425 USA. [Zile, Michael R.] Med Univ S Carolina, Div Cardiol, Dept Med, Charleston, SC 29425 USA. [Zile, Michael R.; Spinale, Francis G.] Ralph H Johnson Vet Assoc Med Ctr, Charleston, SC USA. RP Spinale, FG (reprint author), Strom Thurmond Res Ctr, 114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU American Association for Thoracic Surgery; National Institutes of Health [HL 57952]; Veterans' Affairs Health Administration FX This work was supported by the Third Edward D. Churchill Research Scholarship (American Association for Thoracic Surgery), a National Institutes of Health Supplement award (HL 57952), and the Veterans' Affairs Health Administration. NR 58 TC 21 Z9 22 U1 1 U2 4 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 MAR PY 2012 VL 143 IS 3 BP 656 EP 664 DI 10.1016/j.jtcvs.2011.04.044 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 897BX UT WOS:000300617300024 PM 21762938 ER PT J AU Tolpin, DA Collard, CD Lee, VV Virani, SS Allison, PM Elayda, MA Pan, W AF Tolpin, Daniel A. Collard, Charles D. Lee, Vei-Vei Virani, Salim S. Allison, Paul M. Elayda, MacArthur A. Pan, Wei TI Subclinical changes in serum creatinine and mortality after coronary artery bypass grafting SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID ACUTE KIDNEY INJURY; ACUTE-RENAL-FAILURE; GELATINASE-ASSOCIATED LIPOCALIN; CARDIAC-SURGERY; CARDIOTHORACIC SURGERY; BIOMARKER; OUTCOMES; IMPACT; STRATIFICATION; SEVERITY AB Background: Changes in postoperative serum creatinine levels have been used to define acute renal injury in patients undergoing cardiac surgery with cardiopulmonary bypass. It remains unclear, however, whether subclinical increases in serum creatinine that do not meet current Acute Kidney Injury Network or RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria for acute renal injury are predictive of mortality after cardiac surgery. Methods: Multivariate logistic regression was performed in a retrospective cohort of 3914 consecutive patients undergoing primary, isolated coronary artery bypass grafting with cardiopulmonary bypass to determine whether postoperative serum creatinine change independently predicts 30-day all-cause mortality in patients with normal renal function and with varying levels of preoperative renal insufficiency. To control further for selection bias, multivariate logistic regression was performed on a propensity-matched cohort (n = 2042) to determine whether subclinical increases in serum creatinine predict mortality. Results: Negative change in serum creatinine was associated with reduced 30-day all-cause mortality. Even subclinical increases in serum creatinine were associated with increased mortality relative to patients with negative changes in serum creatinine (odds ratio, 3.93; 95% confidence interval, 1.68-9.22; P <.01). After propensity matching, subclinical increases in serum creatinine were still associated with increased mortality (odds ratio, 4.13; 95% confidence interval, 1.37-12.45; P = .01). Conclusions: Subclinical increases in serum creatinine that do not meet acute renal injury criteria are independently associated with 30-day all-cause mortality in patients with normal renal function or preoperative renal insufficiency undergoing coronary artery bypass grafting. (J Thorac Cardiovasc Surg 2012;143:682-8) C1 [Tolpin, Daniel A.; Collard, Charles D.; Pan, Wei] St Lukes Episcopal Hosp, Texas Heart Inst, Div Cardiovasc Anesthesiol, Houston, TX 77030 USA. [Lee, Vei-Vei; Elayda, MacArthur A.] St Lukes Episcopal Hosp, Texas Heart Inst, Div Biostat & Epidemiol, Houston, TX 77030 USA. [Tolpin, Daniel A.; Collard, Charles D.; Pan, Wei] Baylor Coll Med, Dept Anesthesiol, Houston, TX 77030 USA. [Virani, Salim S.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Hlth Serv Res & Dev Ctr Excellence, Houston, TX 77030 USA. [Allison, Paul M.] St Lukes Episcopal Hosp, Dept Pathol, Chem Coagulat & Blood Donor Ctr, Houston, TX 77030 USA. RP Pan, W (reprint author), St Lukes Episcopal Hosp, Texas Heart Inst, Div Cardiovasc Anesthesiol, 6720 Bertner Ave,Room 0520, Houston, TX 77030 USA. EM wpan@heart.thi.tmc.edu OI Virani, Salim/0000-0001-9541-6954 NR 23 TC 24 Z9 25 U1 0 U2 3 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 MAR PY 2012 VL 143 IS 3 BP 682 EP + DI 10.1016/j.jtcvs.2011.09.044 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 897BX UT WOS:000300617300027 PM 22054657 ER PT J AU Prigerson, HG AF Prigerson, Holly G. TI Mind over menopausal symptoms in women with breast cancer SO LANCET ONCOLOGY LA English DT Editorial Material ID PREVALENCE; THERAPY C1 Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. EM Holly_Prigerson@dfci.harvard.edu NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2012 VL 13 IS 3 BP 227 EP 229 DI 10.1016/S1470-2045(11)70381-3 PG 4 WC Oncology SC Oncology GA 900IO UT WOS:000300880600023 PM 22340964 ER PT J AU Cheung, AM Tile, L Cardew, S Pruthi, S Robbins, J Tomlinson, G Kapral, MK Khosla, S Majumdar, S Erlandson, M Scher, J Hu, HX Demaras, A Lickley, L Bordeleau, L Elser, C Ingle, J Richardson, H Goss, PE AF Cheung, Angela M. Tile, Lianne Cardew, Savannah Pruthi, Sandhya Robbins, John Tomlinson, George Kapral, Moira K. Khosla, Sundeep Majumdar, Sharmila Erlandson, Marta Scher, Judy Hu, Hanxian Demaras, Alice Lickley, Lavina Bordeleau, Louise Elser, Christine Ingle, James Richardson, Harriet Goss, Paul E. TI Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial SO LANCET ONCOLOGY LA English DT Article ID X-RAY ABSORPTIOMETRY; MINERAL DENSITY; ADJUVANT TREATMENT; DISTAL RADIUS; INTERGROUP EXEMESTANE; AROMATASE INHIBITORS; ATAC TRIAL; TAMOXIFEN; ANASTROZOLE; OSTEOPOROSIS AB Background Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. Methods In this nested safety substudy of the MAP. 3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP. 3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2.0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP. 3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. Findings 351 women (176 given exemestane, 175 given placebo; median age 61.3 years [IQR 59.2-64.9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6.1% (95% CI -7.0 to -5.2) in the exemestane group and -1.8% (-2.4 to -1.2) in the placebo group (difference -4.3%, 95% CI -5.3 to -3.2; p<0.0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0.70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5.0% (95% CI -5.5 to -4.4) in the exemestane group and -1.3% (-1.7 to -1.0) in the placebo group (difference -3.7%, 95% CI -4.3 to -3.0; p<0.0001). The mean percent change in cortical thickness was -7.9% (SD 7.3) in the exemestane group and -1.1% (5.7) in the placebo group at the distal radius (difference -6.8%, 95% CI -8.5 to -5.0; p<0.0001) and -7.6% (SD 5.9) in the exemestane group and -0.7% (4.9) in the placebo group at the distal tibia (difference -6.9%, -8.4 to -5.5; p<0.0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2.4% [95% CI -3.1 to -1.7] exemestane vs -0.5% [-1.1 to 0.2] placebo; difference -1.9%, 95% CI -2.9 to -1.0; p<0.0001), total hip (-1.8% [-2.3 to -1.2] exemestane vs -0.6% [-1.1 to -0.1] placebo; difference -1.2%, -1.9 to -0.4; p=0.004), and femoral neck (-2.4% [-3.2 to -1.7] exemestane vs -0.8% [-1.5 to 0.1] placebo; difference -1.6%, -2.7 to -0.6; p=0.002). Interpretation 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. C1 [Cheung, Angela M.; Tile, Lianne; Cardew, Savannah; Tomlinson, George; Kapral, Moira K.; Erlandson, Marta; Scher, Judy; Hu, Hanxian; Demaras, Alice] Univ Hlth Network, Toronto, ON M5G 2C4, Canada. [Elser, Christine] Univ Toronto, Mt Sinai Hosp, Marvelle Koffl er Breast Ctr, Toronto, ON M5G 1X5, Canada. [Lickley, Lavina] Univ Toronto, Womens Coll Hosp, Toronto, ON, Canada. [Khosla, Sundeep] Mayo Clin, Endocrine Res Unit, Rochester, MN USA. [Majumdar, Sharmila] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Robbins, John] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Bordeleau, Louise] McMaster Univ, Juravinski Canc Ctr, Hamilton, ON, Canada. [Richardson, Harriet] Queens Univ, Canc Res Inst, Kingston, ON, Canada. [Goss, Paul E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cheung, AM (reprint author), Univ Hlth Network, 200 Elizabeth St,7 Eaton N,Room 221, Toronto, ON M5G 2C4, Canada. EM angela.cheung@uhn.ca RI Tomlinson, George/L-5432-2016 OI Khosla, Sundeep/0000-0002-2936-4372; Tomlinson, George/0000-0002-9328-6399 FU Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society); Canadian Breast Cancer Research Alliance, Canadian Institutes of Health Research [018518]; Canadian Breast Cancer Research Alliance, Canadian Cancer Society [018518]; Canadian Cancer Society; Pfizer; Canadian Institutes of Health Research/Institute of Gender and Health; Lillian Love Chair in Women's Health at the University of Toronto/University Health Network; Avon Foundation FX Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).; We thank the women who volunteered their time to participate in this substudy; Cancer Care Ontario; David McCready and Ruth Heisey for their assistance in identifying potential participants; the clinical coordinators (Irene Ho, Suzanne Cohen, Alexandra Tse, Jean Jensen, Denise Macias, Olivera Jugovic, Ilda Carvalhana, Nicole Heffernan); those who contributed to data collection, cleaning, analysis, and quality control (Queenie Wong, Gail Jefferson, Farrah Ahmed, Diana Yau, and Karen Stratton); the central office staff of the NCIC CTG who contributed to the conduct of the MAP. 3 trial as well as this substudy; Jamieson Laboratories for their provision of calcium and vitamin D supplements; and Pfizer Pharmaceuticals for their provision of exemestane and placebo. This study (NCIC CTG MAP.3BSS) was supported by the Canadian Breast Cancer Research Alliance, a joint initiative between the Canadian Institutes of Health Research and the Canadian Cancer Society [grant number 018518], and is a substudy of the NCIC CTG MAP.3 study. The main study was supported the Canadian Cancer Society and Pfizer. AMC is supported in part by a Canadian Institutes of Health Research/Institute of Gender and Health Senior Investigator Award, and the Lillian Love Chair in Women's Health at the University of Toronto/University Health Network. PEG is supported in part by the Avon Foundation. NR 44 TC 43 Z9 43 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2012 VL 13 IS 3 BP 275 EP 284 DI 10.1016/S1470-2045(11)70389-8 PG 10 WC Oncology SC Oncology GA 900IO UT WOS:000300880600035 PM 22318095 ER PT J AU Lee, BL Liedke, PER Barrios, CH Simon, SD Finkelstein, DM Goss, PE AF Lee, Brittany L. Liedke, Pedro E. R. Barrios, Carlos H. Simon, Sergio D. Finkelstein, Dianne M. Goss, Paul E. TI Breast cancer in Brazil: present status and future goals SO LANCET ONCOLOGY LA English DT Review ID MIDDLE-INCOME COUNTRIES; GUIDELINE IMPLEMENTATION; COST-EFFECTIVENESS; CHRONIC DISEASES; LATIN-AMERICA; HEALTH-CARE; RADIOTHERAPY; MANAGEMENT; DIAGNOSIS; SURVIVAL AB Breast cancer is the most common cancer in women worldwide and 70% of breast cancer deaths occur in women from low-income and middle-income countries. Latin America has about 115 000 new cases of disease every year, with about 50 000 arising in Brazil. We examined the present status of breast cancer in Brazil as an example of the health effects of geographical, ethnic, and socioeconomic diversities on delivery of care. Our goal was to identify deficiencies that could be responsible for disparities in survival from breast cancer. We searched the English and Portuguese published work and reviewed national databases and Brazilian publications. Although the availability of publications specific to Brazil is low in general, we identified several factors that could account for disparities: delays in diagnosis due to low cancer awareness and implementation of mammography screening, unknown quality of surgery, and restricted access to radiotherapy and modern systemic therapies. C1 [Lee, Brittany L.; Liedke, Pedro E. R.; Finkelstein, Dianne M.; Goss, Paul E.] Massachusetts Gen Hosp, Ctr Canc, Int Breast Canc Res Program, Boston, MA 02114 USA. [Lee, Brittany L.; Liedke, Pedro E. R.; Finkelstein, Dianne M.; Goss, Paul E.] Harvard Univ, Sch Med, Boston, MA USA. [Barrios, Carlos H.] Pontificia Univ Rio Grande Sul PUCRS, Sch Med, Ctr Pesquisa Oncol, Porto Alegre, RS, Brazil. [Liedke, Pedro E. R.; Barrios, Carlos H.; Simon, Sergio D.] Grp Brasileiro Estudos Canc Mama GBECAM, Sao Paulo, Brazil. [Barrios, Carlos H.] Grp Latino Amer Invest Clin Oncol GLICO, Porto Alegre, RS, Brazil. [Simon, Sergio D.] Univ Fed Sao Paulo UNIFESP, Sao Paulo, Brazil. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Int Breast Canc Res Program, 55 Fruit St,Lawrence House,LRH 302, Boston, MA 02114 USA. EM pgoss@partners.org RI Barrios, Carlos/G-8525-2015 FU Avon Foundation New York, NY, USA FX PEG, DMF, and PERL are supported by The Avon Foundation New York, NY, USA, which had no role in the planning or writing of this manuscript. BLL would like to thank the Department of Medicine and Division of Global Health for supporting her clinical rotation in Brazil, and the Pontificia Universidade do Rio Grande do Sul. NR 76 TC 43 Z9 53 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD MAR PY 2012 VL 13 IS 3 BP E95 EP E102 PG 8 WC Oncology SC Oncology GA 900IO UT WOS:000300880600010 PM 22381937 ER PT J AU Lee, SH DeCandia, TR Ripke, S Yang, J Sullivan, PF Goddard, ME Keller, MC Visscher, PM Wray, NR AF Lee, S. Hong DeCandia, Teresa R. Ripke, Stephan Yang, Jian Sullivan, Patrick F. Goddard, Michael E. Keller, Matthew C. Visscher, Peter M. Wray, Naomi R. CA Schizophrenia Psychiat Genome-Wide Int Schizophrenia Consortium ISC Mol Genetics Schizophrenia TI Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs SO NATURE GENETICS LA English DT Article ID MULTIPLE RARE ALLELES; COMPLEX TRAIT; HUMAN HEIGHT; DISEASE; ASSOCIATION; VARIANTS; TWIN AB Schizophrenia is a complex disorder caused by both genetic and environmental factors. Using 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ), we estimate that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. We show that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to its length (r = 0.89, P = 2.6 x 10(-8)), that the genetic basis of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 x 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases. C1 [Lee, S. Hong; Visscher, Peter M.; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Lee, S. Hong; Yang, Jian; Visscher, Peter M.; Wray, Naomi R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [DeCandia, Teresa R.; Keller, Matthew C.] Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. [DeCandia, Teresa R.; Keller, Matthew C.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Ripke, Stephan] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02139 USA. [Ripke, Stephan] Harvard Univ, Cambridge, MA 02138 USA. [Yang, Jian; Visscher, Peter M.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld 4102, Australia. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Goddard, Michael E.] Univ Melbourne, Dept Agr & Food Syst, Melbourne, Vic, Australia. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Melbourne, Vic, Australia. RP Wray, NR (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. EM naomi.wray@uq.edu.au RI Lee, Sang Hong/A-2569-2011; Hansen, Thomas/O-5965-2014; Wray, Naomi/C-8639-2015; Yang, Jian/A-5852-2010; OI Lee, Sang Hong/0000-0001-9701-2718; Hansen, Thomas/0000-0001-6703-7762; Wray, Naomi/0000-0001-7421-3357; Yang, Jian/0000-0003-2001-2474; KELLER, MATTHEW/0000-0002-6075-9882; Goddard, Michael/0000-0001-9917-7946; Visscher, Peter/0000-0002-2143-8760 FU Australian National Health and Medical Research Council [389892, 442915, 496688, 613672, 613601]; Australian Research Council [DP0770096, DP1093502, FT0991360]; US National Institute of Mental Health [MH085812]; Netherlands Scientific Organization (NWO) [480-05-003] FX We thank S. D. Gordon for technical assistance. We acknowledge funding from the Australian National Health and Medical Research Council (389892, 442915, 496688, 613672 and 613601), the Australian Research Council (DP0770096, DP1093502 and FT0991360) and the US National Institute of Mental Health (MH085812). This research utilized the Cluster Computer, which is funded by the Netherlands Scientific Organization (NWO; 480-05-003). Acknowledgments for PGC-SCZ are listed in the Supplementary Note. NR 27 TC 253 Z9 255 U1 9 U2 59 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 247 EP U35 DI 10.1038/ng.1108 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600006 PM 22344220 ER PT J AU Ghoussaini, M Fletcher, O Michailidou, K Turnbull, C Schmidt, MK Dicks, E Dennis, J Wang, Q Humphreys, MK Luccarini, C Baynes, C Conroy, D Maranian, M Ahmed, S Driver, K Johnson, N Orr, N Silva, ID Waisfisz, Q Meijers-Heijboer, H Uitterlinden, AG Rivadeneira, F Hall, P Czene, K Irwanto, A Liu, JJ Nevanlinna, H Aittomaki, K Blomqvist, C Meindl, A Schmutzler, RK Muller-Myhsok, B Lichtner, P Chang-Claude, J Hein, R Nickels, S Flesch-Janys, D Tsimiklis, H Makalic, E Schmidt, D Bui, M Hopper, JL Apicella, C Park, DJ Southey, M Hunter, DJ Chanock, SJ Broeks, A Verhoef, S Hogervorst, FBL Fasching, PA Lux, MP Beckmann, MW Ekici, AB Sawyer, E Tomlinson, I Kerin, M Marme, F Schneeweiss, A Sohn, C Burwinkel, B Guenel, P Truong, T Cordina-Duverger, E Menegaux, F Bojesen, SE Nordestgaard, BG Nielsen, SF Flyger, H Milne, RL Alonso, MR Gonzalez-Neira, A Benitez, J Anton-Culver, H Ziogas, A Bernstein, L Dur, CC Brenner, H Muller, H Arndt, V Stegmaier, C Justenhoven, C Brauch, H Bruning, T Wang-Gohrke, S Eilber, U Dork, T Schurmann, P Bremer, M Hillemanns, P Bogdanova, NV Antonenkova, NN Rogov, YI Karstens, JH Bermisheva, M Prokofieva, D Khusnutdinova, E Lindblom, A Margolin, S Mannermaa, A Kataja, V Kosma, VM Hartikainen, JM Lambrechts, D Yesilyurt, BT Floris, G Leunen, K Manoukian, S Bonanni, B Fortuzzi, S Peterlongo, P Couch, FJ Wang, XS Stevens, K Lee, A Giles, GG Baglietto, L Severi, G McLean, C Alnaes, GG Kristensen, V Borrensen-Dale, AL John, EM Miron, A Winqvist, R Pylkas, K Jukkola-Vuorinen, A Kauppila, S Andrulis, IL Glendon, G Mulligan, AM Devilee, P van Asperen, CJ Tollenaar, RAEM Seynaeve, C Figueroa, JD Garcia-Closas, M Brinton, L Lissowska, J Hooning, MJ Hollestelle, A Oldenburg, RA van den Ouweland, AMW Cox, A Reed, MWR Shah, M Jakubowska, A Lubinski, J Jaworska, K Durda, K Jones, M Schoemaker, M Ashworth, A Swerdlow, A Beesley, J Chen, XQ Muir, KR Lophatananon, A Rattanamongkongul, S Chaiwerawattana, A Kang, D Yoo, KY Noh, DY Shen, CY Yu, JC Wu, PE Hsiung, CN Perkins, A Swann, R Velentzis, L Eccles, DM Tapper, WJ Gerty, SM Graham, NJ Ponder, BAJ Chenevix-Trench, G Pharoah, PDP Lathrop, M Dunning, AM Rahman, N Peto, J Easton, DF AF Ghoussaini, Maya Fletcher, Olivia Michailidou, Kyriaki Turnbull, Clare Schmidt, Marjanka K. Dicks, Ed Dennis, Joe Wang, Qin Humphreys, Manjeet K. Luccarini, Craig Baynes, Caroline Conroy, Don Maranian, Melanie Ahmed, Shahana Driver, Kristy Johnson, Nichola Orr, Nicholas Silva, Isabel dos Santos Waisfisz, Quinten Meijers-Heijboer, Hanne Uitterlinden, Andre G. Rivadeneira, Fernando Hall, Per Czene, Kamila Irwanto, Astrid Liu, Jianjun Nevanlinna, Heli Aittomaki, Kristiina Blomqvist, Carl Meindl, Alfons Schmutzler, Rita K. Mueller-Myhsok, Bertram Lichtner, Peter Chang-Claude, Jenny Hein, Rebecca Nickels, Stefan Flesch-Janys, Dieter Tsimiklis, Helen Makalic, Enes Schmidt, Daniel Bui, Minh Hopper, John L. Apicella, Carmel Park, Daniel J. Southey, Melissa Hunter, David J. Chanock, Stephen J. Broeks, Annegien Verhoef, Senno Hogervorst, Frans B. L. Fasching, Peter A. Lux, Michael P. Beckmann, Matthias W. Ekici, Arif B. Sawyer, Elinor Tomlinson, Ian Kerin, Michael Marme, Frederik Schneeweiss, Andreas Sohn, Christof Burwinkel, Barbara Guenel, Pascal Truong, Therese Cordina-Duverger, Emilie Menegaux, Florence Bojesen, Stig E. Nordestgaard, Borge G. Nielsen, Sune F. Flyger, Henrik Milne, Roger L. Rosario Alonso, M. Gonzalez-Neira, Anna Benitez, Javier Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Dur, Christina Clarke Brenner, Hermann Mueller, Heiko Arndt, Volker Stegmaier, Christa Justenhoven, Christina Brauch, Hiltrud Bruening, Thomas Wang-Gohrke, Shan Eilber, Ursula Doerk, Thilo Schuermann, Peter Bremer, Michael Hillemanns, Peter Bogdanova, Natalia V. Antonenkova, Natalia N. Rogov, Yuri I. Karstens, Johann H. Bermisheva, Marina Prokofieva, Darya Khusnutdinova, Elza Lindblom, Annika Margolin, Sara Mannermaa, Arto Kataja, Vesa Kosma, Veli-Matti Hartikainen, Jaana M. Lambrechts, Diether Yesilyurt, Betul T. Floris, Giuseppe Leunen, Karin Manoukian, Siranoush Bonanni, Bernardo Fortuzzi, Stefano Peterlongo, Paolo Couch, Fergus J. Wang, Xianshu Stevens, Kristen Lee, Adam Giles, Graham G. Baglietto, Laura Severi, Gianluca McLean, Catriona Alnaes, Grethe Grenaker Kristensen, Vessela Borrensen-Dale, Anne-Lise John, Esther M. Miron, Alexander Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Kauppila, Saila Andrulis, Irene L. Glendon, Gord Mulligan, Anna Marie Devilee, Peter van Asperen, Christie J. Tollenaar, Rob A. E. M. Seynaeve, Caroline Figueroa, Jonine D. Garcia-Closas, Montserrat Brinton, Louise Lissowska, Jolanta Hooning, Maartje J. Hollestelle, Antoinette Oldenburg, Rogier A. van den Ouweland, Ans M. W. Cox, Angela Reed, Malcolm W. R. Shah, Mitul Jakubowska, Ania Lubinski, Jan Jaworska, Katarzyna Durda, Katarzyna Jones, Michael Schoemaker, Minouk Ashworth, Alan Swerdlow, Anthony Beesley, Jonathan Chen, Xiaoqing Muir, Kenneth R. Lophatananon, Artitaya Rattanamongkongul, Suthee Chaiwerawattana, Arkom Kang, Daehee Yoo, Keun-Young Noh, Dong-Young Shen, Chen-Yang Yu, Jyh-Cherng Wu, Pei-Ei Hsiung, Chia-Ni Perkins, Annie Swann, Ruth Velentzis, Louiza Eccles, Diana M. Tapper, Will J. Gerty, Susan M. Graham, Nikki J. Ponder, Bruce A. J. Chenevix-Trench, Georgia Pharoah, Paul D. P. Lathrop, Mark Dunning, Alison M. Rahman, Nazneen Peto, Julian Easton, Douglas F. CA Netherlands Collaborative Grp Here FBCS Gene Environm Interaction Breast C kConFab Investigators Australian Ovarian Canc Study Grp TI Genome-wide association analysis identifies three new breast cancer susceptibility loci SO NATURE GENETICS LA English DT Article ID HORMONE-RELATED PROTEIN; DEVELOPMENTAL REGULATORY MOLECULE; ULNAR-MAMMARY SYNDROME; PARATHYROID-HORMONE; NEGATIVE-FEEDBACK; COMMON VARIANTS; CONFER SUSCEPTIBILITY; GENE-EXPRESSION; CELL CARCINOMA; RETINOIC ACID AB Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for similar to 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in similar to 70,000 cases and similar to 68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 x 10(-35)), 12q24 (rs1292011; P = 4.3 x 10(-19)) and 21q21 (rs2823093; P = 1.1 x 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth. C1 [Ghoussaini, Maya; Dicks, Ed; Luccarini, Craig; Baynes, Caroline; Conroy, Don; Maranian, Melanie; Ahmed, Shahana; Driver, Kristy; Shah, Mitul; Pharoah, Paul D. P.; Dunning, Alison M.; Easton, Douglas F.] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. [Fletcher, Olivia; Johnson, Nichola; Orr, Nicholas; Ashworth, Alan] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Humphreys, Manjeet K.; Pharoah, Paul D. P.; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England. 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[Shen, Chen-Yang; Wu, Pei-Ei; Hsiung, Chia-Ni] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Yu, Jyh-Cherng] Triserv Gen Hosp, Dept Surg, Taipei, Taiwan. [Perkins, Annie; Swann, Ruth; Velentzis, Louiza] Univ Westminster, Breast Canc Res Grp, Dept Mol & Appl Biosci, London W1R 8AL, England. [Eccles, Diana M.; Tapper, Will J.; Gerty, Susan M.; Graham, Nikki J.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Ponder, Bruce A. J.] Univ Cambridge, Dept Oncol, Cambridge, England. [Ponder, Bruce A. J.] Canc Res UK CRUK Cambridge Res Inst, Cambridge, England. [Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] CEPH, Fdn Jean Dausset, Paris, France. RP Easton, DF (reprint author), Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England. EM douglas@srl.cam.ac.uk RI Gonzalez-Neira, Anna/C-5791-2015; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; 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; Andrulis, Irene/E-7267-2013; Dzhemileva, Lilya/K-8636-2013; Dork, Thilo/J-8620-2012; Jakubowska, Anna/O-8050-2014; Shen, CY/F-6271-2010; Verdrengh, Evelien/H-4571-2012; Noh, Dong-Young/G-5531-2011; Kang, Dae Hee/E-8631-2012; Yoo, Keun-Young/J-5548-2012; truong, therese/A-2837-2013; Muller-Myhsok, Bertram/A-3289-2013; Kerin, Michael/D-6748-2013; Ekici, Arif/C-3971-2013; Rahman, Nazneen/D-2802-2013; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Bruning, Thomas/0000-0001-9560-5464; Brenner, Hermann/0000-0002-6129-1572; manoukian, siranoush/0000-0002-6034-7562; Fortuzzi, Stefano/0000-0002-5662-3800; Hollestelle, Antoinette/0000-0003-1166-1966; Dennis, Joe/0000-0003-4591-1214; Czene, Kamila/0000-0002-3233-5695; Dzhemileva, Lilya/0000-0003-3315-4746; Giles, Graham/0000-0003-4946-9099; Arndt, Volker/0000-0001-9320-8684; Rahman, Nazneen/0000-0003-4376-0440; Schoemaker, Minouk/0000-0001-8403-2234; Lux, Michael Patrick/0000-0002-2781-2178; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Rivadeneira, Fernando/0000-0001-9435-9441; Nevanlinna, Heli/0000-0002-0916-2976; dos Santos Silva, Isabel/0000-0002-6596-8798; Cox, Angela/0000-0002-5138-1099; Bui, Minh/0000-0002-9099-6870; Park, Daniel/0000-0002-6354-0931 FU Cancer Research UK [10118, 10124, A10710]; Medical Research Council [G0700491]; NCI NIH HHS [R25 CA092049]; Wellcome Trust [090532] NR 67 TC 135 Z9 139 U1 4 U2 65 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 312 EP U120 DI 10.1038/ng.1049 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600018 PM 22267197 ER PT J AU Bellenguez, C Bevan, S Gschwendtner, A Spencer, CCA Burgess, AI Pirinen, M Jackson, CA Traylor, M Strange, A Su, Z Band, G Syme, PD Malik, R Pera, J Norrving, B Lemmens, R Freeman, C Schanz, R James, T Poole, D Murphy, L Segal, H Cortellini, L Cheng, YC Woo, D Nalls, MA Muller-Myhsok, B Meisinger, C Seedorf, U Ross-Adams, H Boonen, S Wloch-Kopec, D Valant, V Slark, J Furie, K Delavaran, H Langford, C Deloukas, P Edkins, S Hunt, S Gray, E Dronov, S Peltonen, L Gretarsdottir, S Thorleifsson, G Thorsteinsdottir, U Stefansson, K Boncoraglio, GB Parati, EA Attia, J Holliday, E Levi, C Franzosi, MG Goel, A Helgadottir, A Blackwell, JM Bramon, E Brown, MA Casas, JP Corvin, A Duncanson, A Jankowski, J Mathew, CG Palmer, CNA Plomin, R Rautanen, A Sawcer, SJ Trembath, RC Viswanathan, AC Wood, NW Worrall, BB Kittner, SJ Mitchell, BD Kissela, B Meschia, JF Thijs, V Lindgren, A Macleod, MJ Slowik, A Walters, M Rosand, J Sharma, P Farrall, M Sudlow, CLM Rothwell, PM Dichgans, M Donnelly, P Markus, HS AF Bellenguez, Celine Bevan, Steve Gschwendtner, Andreas Spencer, Chris C. A. Burgess, Annette I. Pirinen, Matti Jackson, Caroline A. Traylor, Matthew Strange, Amy Su, Zhan Band, Gavin Syme, Paul D. Malik, Rainer Pera, Joanna Norrving, Bo Lemmens, Robin Freeman, Colin Schanz, Renata James, Tom Poole, Deborah Murphy, Lee Segal, Helen Cortellini, Lynelle Cheng, Yu-Ching Woo, Daniel Nalls, Michael A. Mueller-Myhsok, Bertram Meisinger, Christa Seedorf, Udo Ross-Adams, Helen Boonen, Steven Wloch-Kopec, Dorota Valant, Valerie Slark, Julia Furie, Karen Delavaran, Hossein Langford, Cordelia Deloukas, Panos Edkins, Sarah Hunt, Sarah Gray, Emma Dronov, Serge Peltonen, Leena Gretarsdottir, Solveig Thorleifsson, Gudmar Thorsteinsdottir, Unnur Stefansson, Kari Boncoraglio, Giorgio B. Parati, Eugenio A. Attia, John Holliday, Elizabeth Levi, Chris Franzosi, Maria-Grazia Goel, Anuj Helgadottir, Anna Blackwell, Jenefer M. Bramon, Elvira Brown, Matthew A. Casas, Juan P. Corvin, Aiden Duncanson, Audrey Jankowski, Janusz Mathew, Christopher G. Palmer, Colin N. A. Plomin, Robert Rautanen, Anna Sawcer, Stephen J. Trembath, Richard C. Viswanathan, Ananth C. Wood, Nicholas W. Worrall, Bradford B. Kittner, Steven J. Mitchell, Braxton D. Kissela, Brett Meschia, James F. Thijs, Vincent Lindgren, Arne Macleod, Mary Joan Slowik, Agnieszka Walters, Matthew Rosand, Jonathan Sharma, Pankaj Farrall, Martin Sudlow, Cathie L. M. Rothwell, Peter M. Dichgans, Martin Donnelly, Peter Markus, Hugh S. CA ISGC WTCCC2 TI Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke SO NATURE GENETICS LA English DT Article ID ATRIAL-FIBRILLATION; HISTONE DEACETYLASES; SUSCEPTIBILITY LOCI; ALGORITHM; GENETICS; DISEASE; SIGNALS; ROLES; RISK AB Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes. C1 [Bellenguez, Celine; Spencer, Chris C. A.; Pirinen, Matti; Strange, Amy; Su, Zhan; Band, Gavin; Freeman, Colin; Goel, Anuj; Helgadottir, Anna; Rautanen, Anna; Farrall, Martin; Donnelly, Peter] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Bevan, Steve; Traylor, Matthew; James, Tom; Markus, Hugh S.] St Georges Univ London, Stroke & Dementia Res Grp, London, England. [Gschwendtner, Andreas; Malik, Rainer; Dichgans, Martin] Univ Munich, Univ Munchen Klinikum, Inst Stroke & Dementia Res, Munich, Germany. [Burgess, Annette I.; Poole, Deborah; Segal, Helen; Rothwell, Peter M.] Univ Oxford, Nuffield Dept Clin Neurosci, Stroke Prevent Res Unit, Oxford, England. [Jackson, Caroline A.; Sudlow, Cathie L. M.] Univ Edinburgh, Div Clin Neurosci, Edinburgh, Midlothian, Scotland. [Syme, Paul D.; Macleod, Mary Joan] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland. [Pera, Joanna; Ross-Adams, Helen; Wloch-Kopec, Dorota; Slowik, Agnieszka] Jagiellonian Univ, Coll Med, Dept Neurol, Krakow, Poland. [Norrving, Bo; Delavaran, Hossein; Lindgren, Arne] Lund Univ, Dept Clin Sci, Lund, Sweden. [Norrving, Bo; Delavaran, Hossein; Lindgren, Arne] Skane Univ Hosp, Dept Neurol, Lund, Sweden. [Lemmens, Robin; Thijs, Vincent] Univ Hosp Leuven, Dept Neurol, Louvain, Belgium. [Lemmens, Robin; Thijs, Vincent] VIB, Vesalius Res Ctr, Louvain, Belgium. [Schanz, Renata; Slark, Julia; Sharma, Pankaj] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England. [Murphy, Lee] Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil Genet Core Lab, Edinburgh, Midlothian, Scotland. [Cortellini, Lynelle; Valant, Valerie; Furie, Karen; Rosand, Jonathan] Massachusetts Gen Hosp, Dept Neurol, Ctr Human Genet Res, Boston, MA 02114 USA. [Cortellini, Lynelle; Valant, Valerie; Rosand, Jonathan] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Cheng, Yu-Ching; Mitchell, Braxton D.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Woo, Daniel; Kissela, Brett] Univ Cincinnati, Coll Med, Dept Neurol, Cincinnati, OH USA. [Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Meisinger, Christa] German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Seedorf, Udo] Univ Munster, Leibniz Inst Arterioskleroseforsch, Munster, Germany. [Boonen, Steven] Univ Hosp Leuven, Div Geriatr Med, Louvain, Belgium. [Langford, Cordelia; Deloukas, Panos; Edkins, Sarah; Hunt, Sarah; Gray, Emma; Dronov, Serge; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Gretarsdottir, Solveig; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari; Helgadottir, Anna] deCODE Genet, Reykjavik, Iceland. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, Reykjavik, Iceland. [Boncoraglio, Giorgio B.; Parati, Eugenio A.] Fdn Ist Ricovero & Cura Carattere Sci IRCCS, Ist Neurol Carlo Besta, Milan, Italy. [Attia, John; Holliday, Elizabeth; Levi, Chris] Univ Newcastle, Hunter Med Res Inst, Ctr Brain & Mental Hlth Res, Newcastle, NSW 2300, Australia. [Franzosi, Maria-Grazia] Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Goel, Anuj; Helgadottir, Anna; Farrall, Martin] Univ Oxford, Dept Cardiovasc Med, Oxford, England. [Blackwell, Jenefer M.] Univ Western Australia, Ctr Child Hlth Res, Perth, WA, Australia. [Blackwell, Jenefer M.] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England. [Bramon, Elvira] Kings Coll London, Inst Psychiat, Biomed Res Ctr Mental Hlth, Div Psychol Med & Psychiat, London WC2R 2LS, England. [Brown, Matthew A.] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst, Brisbane, Qld, Australia. [Casas, Juan P.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Casas, Juan P.] UCL, Dept Epidemiol & Publ Hlth, London, England. [Corvin, Aiden] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Duncanson, Audrey] Wellcome Trust Res Labs, London, England. [Jankowski, Janusz] Barts & London Queen Marys Sch Med & Dent, Ctr Gastroenterol, London, England. [Jankowski, Janusz] Univ Oxford, Div Clin Pharmacol, Oxford, England. [Mathew, Christopher G.; Trembath, Richard C.] Kings Coll London, Guys Hosp, Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland. [Plomin, Robert] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Sawcer, Stephen J.] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Viswanathan, Ananth C.] Natl Hlth Serv NHS Fdn Trust, Moorfields Eye Hosp, Biomed Res Ctr Ophthalmol, Natl Inst Hlth Res NIHR, London, England. [Viswanathan, Ananth C.] UCL, Inst Ophthalmol, London, England. [Wood, Nicholas W.] UCL, Inst Neurol, Dept Mol Neuroscience, London, England. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA. [Worrall, Bradford B.] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Kittner, Steven J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Kittner, Steven J.] Baltimore Vet Affairs Med Ctr, Baltimore Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Walters, Matthew] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Donnelly, Peter] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. RP Donnelly, P (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM peter.donnelly@well.ox.ac.uk; hmarkus@sgul.ac.uk RI Jankowski, Janusz/H-2706-2012; Blackwell, Jenefer/H-3015-2015; Mathew, Christopher/G-3434-2015; Study, GoDARTS/K-9448-2016; Boncoraglio, Giorgio/B-8647-2011; Palmer, Colin/C-7053-2008; Thijs, Vincent/C-3647-2009; Muller-Myhsok, Bertram/A-3289-2013; Deloukas, Panos/B-2922-2013; Attia, John/F-5376-2013; Jackson, Caroline/B-5954-2012; Meisinger, Christine/B-5358-2014; Wood, Nicholas/C-2505-2009; OI Seedorf, Udo/0000-0003-4652-5358; Murphy, Lee/0000-0001-6467-7449; Corvin, Aiden/0000-0001-6717-4089; Norrving, Bo/0000-0002-8024-5096; Hunt, Sarah/0000-0002-8350-1235; Brown, Matthew A/0000-0003-0538-8211; Macleod, Mary Joan/0000-0003-2115-8184; Traylor, Matthew/0000-0001-6624-8621; Jankowski, Janusz/0000-0003-2130-9181; Mathew, Christopher/0000-0003-4178-1838; Palmer, Colin/0000-0002-6415-6560; Thijs, Vincent/0000-0002-6614-8417; Deloukas, Panos/0000-0001-9251-070X; Attia, John/0000-0001-9800-1308; Jackson, Caroline/0000-0002-2067-2811; Wood, Nicholas/0000-0002-9500-3348; Pirinen, Matti/0000-0002-1664-1350; Plomin, Robert/0000-0002-0756-3629; Bevan, Steve/0000-0003-0490-6830; Trembath, Richard/0000-0003-0550-3400; Meisinger, Christa/0000-0002-9026-6544; Mitchell, Braxton/0000-0003-4920-4744; Kissela, Brett/0000-0002-9773-4013 FU Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 085475/B/08/Z, 085475/Z/08/Z, WT084724MA, WTCCC2] FX We thank S. Bertrand, J. Bryant, S. L. Clark, J. S. Conquer, T. Dibling, J. C. Eldred, S. Gamble, C. Hind, M. L. Perez, C. R. Stribling, S. Taylor and A. Wilk of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We acknowledge use of the British 1958 Birth Cohort DNA collection, which is funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank the following individuals who contributed to collection, phenotyping, sample processing and data management for the different cohorts: A. Burgess, A. Syed and N. Paul (Oxford Vascular Study); M. Dennis, P. Sandercock, C. Warlow, S. Hart, S. Keir, J. Wardlaw, A. Farrall, G. Potter, A. Hutchison and M. McDowall (Edinburgh Stroke Study); A. Pasdar and H. Clinkscale (Aberdeen); P. Higgins (Glasgow); T. G. Brott, R. D. Brown, S. Silliman, M. Frankel, D. Case, S. Rich, J. Hardy, A. Singleton (ISGS); M. J. Sparks, K. Ryan, J. Cole, M. Wozniak, B. Stern, R. Wityk, C. Johnson and D. Buchholz (GEOS); and J. Maguire, S. Koblar, J. Golledge, J. Surm, G. Hankey, J. Jannes, M. Lewis, R. Scott, L. Lincz; P. Moscato and R. Baker (Australian Stroke Genetics Collaborative membership). The principal funding for this study was provided by the Wellcome Trust as part of the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z and WT084724MA). For details of other funding support, see the Supplementary Note. NR 30 TC 153 Z9 155 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2012 VL 44 IS 3 BP 328 EP U141 DI 10.1038/ng.1081 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 899VC UT WOS:000300843600021 ER PT J AU Manning, AL Dyson, NJ AF Manning, Amity L. Dyson, Nicholas J. TI GENOMIC INSTABILITY IN CANCER - OPINION RB: mitotic implications of a tumour suppressor SO NATURE REVIEWS CANCER LA English DT Review ID MEROTELIC KINETOCHORE ORIENTATION; CELL-CYCLE PROGRESSION; CHROMOSOMAL INSTABILITY; DNA-DAMAGE; RETINOBLASTOMA PROTEIN; HISTONE DEACETYLASE; CLONAL EVOLUTION; REPRESS TRANSCRIPTION; PROMOTES ANEUPLOIDY; MICROARRAY ANALYSIS AB RB, a well known tumour suppressor that functions in the control of cell cycle progression and proliferation, has recently been shown to have additional functions in the maintenance of genomic stability, such that inactivation of RB family proteins promotes chromosome instability (CIN) and aneuploidy. Several studies have provided potential explanations for these phenomena that occur following RB loss, and they suggest that this new function of RB may contribute to its role in tumour suppression. C1 [Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU American Cancer Society; Massachusetts General Hospital Cancer Center Saltonstall Foundation; AstraZeneca; NIH [GM81607, CA64402] FX We thank D. Compton and L. Kabeche for sharing their unpublished data, N. Ganem for critical reading and suggestions on the manuscript, and the reviewers for their helpful comments. This work was supported by an American Cancer Society Fellowship to A. L. M., the Massachusetts General Hospital Cancer Center Saltonstall Foundation Scholarship to N.J.D., and funding from AstraZeneca and NIH grants GM81607 and CA64402 to N.J.D. NR 70 TC 55 Z9 57 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAR PY 2012 VL 12 IS 3 BP 220 EP 226 DI 10.1038/nrc3216 PG 7 WC Oncology SC Oncology GA 899RK UT WOS:000300833600014 PM 22318235 ER PT J AU Mahindra, A Laubach, J Raje, N Munshi, N Richardson, PG Anderson, K AF Mahindra, Anuj Laubach, Jacob Raje, Noopur Munshi, Nikhil Richardson, Paul G. Anderson, Kenneth TI Latest advances and current challenges in the treatment of multiple myeloma SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Review ID LENALIDOMIDE PLUS DEXAMETHASONE; RANDOMIZED CONTROLLED-TRIAL; STEM-CELL TRANSPLANTATION; IN-VIVO CYTOTOXICITY; INHIBITS OSTEOCLASTOGENESIS; EXTRAMEDULLARY DISEASE; COMBINATION THERAPY; ANTITUMOR-ACTIVITY; CLONAL EVOLUTION; HEDGEHOG PATHWAY AB Effectively treating patients with multiple myeloma is challenging. The development of therapeutic regimens over the past decade that incorporate the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has been the cornerstone of improving the outcome of patients with myeloma. Although these treatment regimens have improved patient survival, nearly all patients eventually relapse. Our improved understanding of the biology of the disease and the importance of the microenvironment has translated into ongoing work to help overcome the challenge of relapse. Several classes of agents including next-generation proteasome inhibitors, immunomodulatory agents, selective histone-deacetylase inhibitors, antibody and antitumor immunotherapy approaches are currently undergoing preclinical and clinical evaluation. This Review provides an update on the latest advances in the treatment of multiple myeloma. In particular, we focus on novel therapies including modulating protein homeostasis, kinases inhibitors, targeting accessory cells and cytokines, and immunomodulatory agents. A discussion of the challenges associated with these therapeutic approaches is also presented. C1 [Mahindra, Anuj; Raje, Noopur] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Laubach, Jacob; Munshi, Nikhil; Richardson, Paul G.; Anderson, Kenneth] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mahindra, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Hematol & Oncol, 55 Fruit St, Boston, MA 02114 USA. EM amahindra@gmail.com NR 102 TC 108 Z9 116 U1 5 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2012 VL 9 IS 3 BP 135 EP 143 DI 10.1038/nrclinonc.2012.15 PG 9 WC Oncology SC Oncology GA 901DX UT WOS:000300943000004 PM 22349016 ER PT J AU Bogdanova, Y Verfaellie, M AF Bogdanova, Yelena Verfaellie, Mieke TI Cognitive Sequelae of Blast-Induced Traumatic Brain Injury: Recovery and Rehabilitation SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE Neurorehabilitation; Executive function; Memory; OEF/OIF; TBI; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; OF-THE-LITERATURE; MILD HEAD-INJURY; RANDOMIZED CONTROLLED-TRIAL; SYMPTOM VALIDITY TEST; NEUROPSYCHOLOGICAL OUTCOMES; POSTCONCUSSIVE SYMPTOMS; RECURRENT CONCUSSION; ABSTINENT ALCOHOLICS AB Blast-related traumatic brain injury (bTBI) poses a significant concern for military personnel engaged in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). Given the highly stressful context in which such injury occurs, psychiatric comorbidities are common. This paper provides an overview of mild bTBI and discusses the cognitive sequelae and course of recovery typical of mild TBI (mTBI). Complicating factors that arise in the context of co-morbid posttraumatic stress disorder (PTSD) are considered with regard to diagnosis and treatment. Relatively few studies have evaluated the efficacy of cognitive rehabilitation in civilian mTBI, but we discuss cognitive training approaches that hold promise for addressing mild impairments in executive function and memory, akin to those seen in OEF/OIF veterans with bTBI and PTSD. Further research is needed to address the patient and environmental characteristics associated with optimal treatment outcome. C1 [Verfaellie, Mieke] VA Boston Healthcare Syst, Psychol Res 151 A, Boston, MA 02130 USA. [Bogdanova, Yelena; Verfaellie, Mieke] Boston Univ, Sch Med, Memory Disorders Res Ctr, VA Boston Healthcare Syst, Boston, MA 02118 USA. RP Bogdanova, Y (reprint author), VA Boston Healthcare Syst, Psychol Res 151 A, 150 S Huntington Ave, Boston, MA 02130 USA. EM bogdanov@bu.edu RI Schueter, nicos/A-3625-2014; OI Verfaellie, Mieke/0000-0001-5535-4584 FU Clinical Science Research and Development; Rehabilitation Research and Development Services of the Department of Veterans Affairs; National Institutes of Health; Boston University Clinical and Translational Science Institute FX This research was supported by the Clinical Science Research and Development and the Rehabilitation Research and Development Services of the Department of Veterans Affairs; the National Institutes of Health and Boston University Clinical and Translational Science Institute. We thank Dr. Jennifer J. Vasterling for her expert advice and helpful discussion, and Sarah M. Kark, B.S., for assistance with manuscript preparation. The authors have no conflicts of interest to disclose. NR 188 TC 47 Z9 48 U1 7 U2 35 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 EI 1573-6660 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD MAR PY 2012 VL 22 IS 1 BP 4 EP 20 DI 10.1007/s11065-012-9192-3 PG 17 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 900MU UT WOS:000300892100003 PM 22350691 ER PT J AU Dolan, S Martindale, S Robinson, J Kimbrel, NA Meyer, EC Kruse, MI Morissette, SB Young, KA Gulliver, SB AF Dolan, Sara Martindale, Sarah Robinson, Jennifer Kimbrel, Nathan A. Meyer, Eric C. Kruse, Marc I. Morissette, Sandra B. Young, Keith A. Gulliver, Suzy Bird TI Neuropsychological Sequelae of PTSD and TBI Following War Deployment among OEF/OIF Veterans SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE PTSD; TBI; Veterans ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMATIC BRAIN-INJURY; MEDIAL PREFRONTAL CORTEX; VIETNAM COMBAT VETERANS; SYMPTOM VALIDITY TEST; HIPPOCAMPAL VOLUME; IRAQ-WAR; TEST-PERFORMANCE; INTELLECTUAL RESOURCES; COGNITIVE-ABILITY AB Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) are highly prevalent among Veterans of the conflicts in Iraq and Afghanistan. These conditions are associated with common and unique neuropsychological and neuroanatomical changes. This review synthesizes neuropsychological and neuroimaging studies for both of these disorders and studies examining their co-occurrence. Recommendations for future research, including use of combined neuropsychological and advanced neuroimaging techniques to study these disorders alone and in concert, are presented. It is clear from the dearth of literature that addiitonal studies are required to examine and understand the impact of specific factors on neurocognitive outcome. Of particular relevance are temporal relationships between PTSD and mTBI, risk and resilience factors associated with both disorders and their co-occurrence, and mTBI-specific factors such as time since injury and severity of injury, utilizing comprehensive, yet targeted cognitive tasks. C1 [Dolan, Sara; Martindale, Sarah] Baylor Univ, Dept Psychol & Neurosci, Waco, TX 76798 USA. [Dolan, Sara; Robinson, Jennifer; Kimbrel, Nathan A.; Meyer, Eric C.; Kruse, Marc I.; Morissette, Sandra B.; Young, Keith A.; Gulliver, Suzy Bird] US Dept Vet Affairs, Ctr Excellence Res Returning War Vet, Waco, TX USA. [Dolan, Sara; Kimbrel, Nathan A.; Meyer, Eric C.; Kruse, Marc I.; Morissette, Sandra B.; Young, Keith A.; Gulliver, Suzy Bird] Texas A&M Hlth Sci Ctr, Coll Med, Dept Psychiat & Behav Sci, Temple, TX USA. [Robinson, Jennifer] Scott & White Healthcare, Neurosci Inst, Temple, TX USA. [Kruse, Marc I.] City Austin Travis Cty Emergency Med Serv Dept, Austin, TX USA. [Kruse, Marc I.] Austin Fire Dept, Austin, TX USA. RP Dolan, S (reprint author), Baylor Univ, Dept Psychol & Neurosci, Waco, TX 76798 USA. EM sara_dolan@baylor.edu RI Schueter, nicos/A-3625-2014; Kimbrel, Nathan/P-3109-2016; OI Kimbrel, Nathan/0000-0001-7218-1005; Dolan, Sara/0000-0002-0156-8226; Martindale, Sarah/0000-0002-0059-3454 FU Department of Veterans Affairs (VA) [I01RX000304]; Rehabilitation Research and Development Service of the VA Office of Research and Development FX This research was supported by the Department of Veterans Affairs (VA) VISN 17 Center of Excellence for Research on Returning War Veterans, a Merit Award (I01RX000304) to Sandra B. Morissette, Ph.D. from the Rehabilitation Research and Development Service of the VA Office of Research and Development entitled, "Functional Outcomes in OEF/OIF Veterans with PTSD and Alcohol Misuse," a DVA VISN 17 New Investigator Award to Nathan A. Kimbrel, Ph.D. entitled, "Genetic and Environmental Effects on PTSD, Depression, and Alcohol Misuse," and a DVA VISN 17 New Investigator Award to Eric C. Meyer, Ph.D. entitled, "Experiential Avoidance, Neurocognition, and Functional Outcomes in PTSD." NR 116 TC 31 Z9 32 U1 4 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD MAR PY 2012 VL 22 IS 1 BP 21 EP 34 DI 10.1007/s11065-012-9190-5 PG 14 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 900MU UT WOS:000300892100004 PM 22350690 ER PT J AU Betthauser, LM Bahraini, N Krengel, MH Brenner, LA AF Betthauser, Lisa M. Bahraini, Nazanin Krengel, Maxine H. Brenner, Lisa A. TI Self-Report Measures to Identify Post Traumatic Stress Disorder and/or Mild Traumatic Brain Injury and Associated Symptoms in Military Veterans of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE Operation Enduring Freedom; Operation Iraqi Freedom; Traumatic Brain Injury; Post Traumatic Stress Disorder; Assessment; Self-report measures ID AFGHANISTAN WAR VETERANS; VA HEALTH-CARE; POSTTRAUMATIC-STRESS; POSTCONCUSSIVE SYMPTOMS; PSYCHOMETRIC PROPERTIES; OEF/OIF VETERANS; PTSD CHECKLIST; MENTAL-HEALTH; BLAST INJURY; US VETERANS AB Individuals serving in Iraq and Afghanistan sustain injuries associated with physical and psychological trauma. Among such injuries, mild traumatic brain injury (mTBI) and post traumatic stress disorder (PTSD) are common. Self-report measures are frequently used to identify mTBI and/or PTSD and symptoms associated with these conditions. In addition to providing information regarding mTBI and PTSD, the goal of this literature review was to identify and present information on the psychometric properties of measures used to obtain information regarding these common conditions among Veterans who have returned from Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF). A comprehensive review of studies in which self-report measures were used to evaluate mTBI, PTSD, and associated symptoms among OEF/OIF Veterans is presented. Findings suggest that additional work is needed to identify psychometrically sound and clinically useful self-report measures that assess mTBI and PTSD and associated symptoms among OEF/OIF Veterans. C1 [Betthauser, Lisa M.; Bahraini, Nazanin; Brenner, Lisa A.] Mental Illness Res Educ & Clin Ctr, Vet Integrated Serv Network 19, Denver, CO 80220 USA. [Betthauser, Lisa M.] Univ Colorado, Dept Psychol, Denver, CO 80202 USA. [Bahraini, Nazanin; Brenner, Lisa A.] Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. [Krengel, Maxine H.] VA Boston Healthcare Syst, Boston, MA USA. [Krengel, Maxine H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Brenner, Lisa A.] Univ Colorado Denver, Dept Neurol, Sch Med, Aurora, CO USA. [Brenner, Lisa A.] Univ Colorado Denver, Sch Med, Dept Phys Med & Rehabil, Aurora, CO USA. RP Betthauser, LM (reprint author), Mental Illness Res Educ & Clin Ctr, Vet Integrated Serv Network 19, 1055 Clermont St, Denver, CO 80220 USA. EM Lisa.Betthauser@va.gov RI Schueter, nicos/A-3625-2014; OI Krengel, Maxine/0000-0001-7632-590X NR 80 TC 12 Z9 13 U1 4 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 EI 1573-6660 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD MAR PY 2012 VL 22 IS 1 BP 35 EP 53 DI 10.1007/s11065-012-9191-4 PG 19 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 900MU UT WOS:000300892100005 PM 22350740 ER PT J AU Passias, PG Kozanek, M Wood, KB AF Passias, Peter G. Kozanek, Michal Wood, Kirkham B. TI Surgical Treatment of Low-Grade Isthmic Spondylolisthesis With Transsacral Fibular Strut Grafts SO NEUROSURGERY LA English DT Article DE Fibular allograft; Interbody; Isthmic spondylolisthesis; Low-grade; Lumbar spine; Posterior arthrodesis ID LUMBAR INTERBODY FUSION; POSTERIOR; DECOMPRESSION; FIXATION; SURGERY; SPINE AB BACKGROUND: The ideal surgical treatment for adult low-grade isthmic spondylolisthesis (ALIS) remains unknown. Isolated anterior and posterior procedures are popular but have resulted in equivocal outcomes, whereas combined anterior and posterior procedures are associated with higher complication rates despite improved outcome. OBJECTIVE: To evaluate the clinical and radiographic outcomes following the treatment of ALIS using a 1-stage posterior approach with posterior decompression and posterolateral arthrodesis combined with an interbody fibular allograft strut. METHODS: Fifteen patients underwent fusion by a single surgeon using our modified technique. Seven patients were female and 8 were male, with a mean age of 48 years. All patients were classified as Meyerding grade II slips and underwent a posterior approach only, a decompressive laminectomy, and a circumferential fusion with the use of a transsacral fibular allograft and a posterolateral instrumented fusion. Postoperative clinical and radiographic evaluations were performed at 3, 6, and 12 months, and then on an annual basis. RESULTS: The average follow-up interval was 61 months. Three complications were seen: a single dural tear, an L5 radiculopathy secondary to a malpositioned pedicle screw, and one patient with urinary retention. The spines of all patients were determined to be fused by the 6-month postoperative visit. All patients returned to their normal activities of daily living. Significant improvements in the visual analog score were seen at all follow-up intervals. CONCLUSION: Transsacral interbody fibular allograft can be used successfully to supplement a posterolateral instrumented fusion in selected patients with low-grade ALIS. C1 [Passias, Peter G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Spine Surg,Dept Orthopaed Surg, Boston, MA 02114 USA. RP Passias, PG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Spine Surg,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM panagmd@gmail.com NR 18 TC 3 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 2012 VL 70 IS 3 BP 758 EP 763 DI 10.1227/NEU.0b013e3182338b2b PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 898ZU UT WOS:000300781700034 PM 21866066 ER PT J AU Simon, MV Chiappa, KH Borges, LF AF Simon, Mirela V. Chiappa, Keith H. Borges, Lawrence F. TI Phase Reversal of Somatosensory Evoked Potentials Triggered by Gracilis Tract Stimulation: Case Report of a New Technique for Neurophysiologic Dorsal Column Mapping SO NEUROSURGERY LA English DT Article DE Dorsal column mapping; Phase reversal; Somatosensory evoked potentials ID SURGERY; ADJUNCT AB BACKGROUND AND IMPORTANCE: Reliable visual identification of the median raphae, essential for the preservation of function of the posterior dorsal columns during intramedullary spinal cord tumor resection, is not possible in many cases, because of distorted local anatomy. In such cases, intraoperative neurophysiologic mapping of the dorsal columns offers invaluable information to the surgeon, and guides the myelotomy. We hereby describe such a new technique. CLINICAL PRESENTATION: A 41-year-old man with a C3-C4 intramedullary spinal cord tumor underwent successful myelotomy and tumor resection. Dorsal column mapping was performed by use of an 8-contact minielectrode strip placed on the dorsal spinal cord. Direct electrical stimulation was applied via 2 adjacent contacts of the strip at a time, in an attempt to stimulate in succession the left and right dorsal columns. Somatosensory evoked potentials (SSEPs) were recorded after each stimulation, via scalp electrodes. A sharp change in polarity of the recorded scalp SSEPs (phase reversal) indicated when the stimulation of the opposite dorsal column occurred. Myelotomy was performed in between the minielectrode contacts identified as being situated closest to the raphe. The posterior tibial SSEPs were continuously monitored during and after myelotomy and until the dura closure. No changes from premyelotomy SSEPs were present. Postoperatively, the patient had preservation of the posterior column function. CONCLUSION: SSEP phase-reversal technique is a promising new method to identify the neurophysiologic midline in intramedullary tumor resection. Fast and easy to perform, its final role in neurophysiologic dorsal column mapping awaits confirmation in future applications. C1 [Simon, Mirela V.; Chiappa, Keith H.] Massachusetts Gen Hosp, Neurophysiol Div, Dept Neurol, Boston, MA 02114 USA. [Simon, Mirela V.; Chiappa, Keith H.; Borges, Lawrence F.] Harvard Univ, Sch Med, Boston, MA USA. [Borges, Lawrence F.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Simon, MV (reprint author), Massachusetts Gen Hosp, Neurophysiol Div, Dept Neurol, WACC 739-G,55 Fruit St, Boston, MA 02114 USA. EM mvsimon@partners.org NR 16 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 2012 VL 70 IS 3 BP E783 EP E788 DI 10.1227/NEU.0b013e31822e0a76 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 898ZU UT WOS:000300781700001 PM 21778916 ER PT J AU Tanna, AP Budenz, DL Bandi, J Feuer, WJ Feldman, RM Herndon, LW Rhee, DJ Whiteside-de Vos, J Huang, J Anderson, DR AF Tanna, Angelo P. Budenz, Donald L. Bandi, Jagadeesh Feuer, William J. Feldman, Robert M. Herndon, Leon W. Rhee, Douglas J. Whiteside-de Vos, Julia Huang, Joyce Anderson, Douglas R. TI Glaucoma Progression Analysis Software Compared with Expert Consensus Opinion in the Detection of Visual Field Progression in Glaucoma SO OPHTHALMOLOGY LA English DT Article ID AUTOMATED PERIMETRY; CATARACT-EXTRACTION; TRIAL; VARIABILITY AB Purpose: To compare the results of Glaucoma Progression Analysis (GPA, Carl Zeiss Meditec, Dublin, CA) to subjective expert consensus in the detection of glaucomatous visual field progression. Design: Retrospective, observational case series. Participants: We included 100 eyes of 83 glaucoma patients. Methods: Five serial Humphrey visual fields from 100 eyes of 83 glaucoma patients were evaluated by 5 masked glaucoma subspecialists for determination of progression. Four months later, with a randomly reordered patient sequence, the same visual field series were reevaluated by the same graders, at which time they had access to the Glaucoma Progression Analysis (GPA) printout. Main Outcome Measures: The level of agreement between majority expert consensus and GPA, both before and after access to GPA data, was assessed using kappa statistics. Results: On initial review and on reevaluation with access to the GPA printout, the level of agreement between majority expert consensus and GPA was fair (kappa = 0.52, 95% confidence interval [CI], 0.35-0.69 and kappa = 0.62; 95% CI, 0.46-0.78, respectively). Expert consensus was more likely to classify a series of fields as showing progression than was GPA (P <= 0.002). There was good agreement between expert consensus on initial review and reevaluation 4 months later (kappa = 0.77; 95% CI, 0.65-0.90). Conclusions: The level of agreement between majority expert consensus of subjective determination of visual field progression and GPA is fair. In cases of disagreement with GPA, the expert consensus classification was usually progression. Access to the results of GPA did not significantly change the level of agreement between expert consensus and the GPA result; however, expert consensus did change in 11 of 100 cases. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2012;119:468-473 (C) 2012 by the American Academy of Ophthalmology. C1 [Tanna, Angelo P.; Huang, Joyce] Northwestern Univ, Feinberg Sch Med, Dept Ophthalmol, Chicago, IL 60611 USA. [Budenz, Donald L.; Bandi, Jagadeesh; Feuer, William J.; Anderson, Douglas R.] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Miami, FL 33136 USA. [Budenz, Donald L.; Bandi, Jagadeesh] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. [Feldman, Robert M.] Univ Texas Med Sch Houston, Dept Ophthalmol & Visual Sci, Houston, TX USA. [Herndon, Leon W.] Duke Univ, Ctr Eye, Durham, NC USA. [Rhee, Douglas J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Whiteside-de Vos, Julia] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Budenz, DL (reprint author), Univ N Carolina, Dept Ophthalmol, 5151 Bioinformat CB 7040, Chapel Hill, NC 27599 USA. EM dbudenz@med.unc.edu FU Research to Prevent Blindness; NEI [P30 EY-014801]; Carl Zeiss Meditec, Inc; National Institutes of Health, National Eye Institute [EY 07127] FX Supported by an unrestricted grant from Research to Prevent Blindness (A.P.T., D.L.B., J.B., W.J.F., D.R.A.); NEI grant P30 EY-014801 (D.L.B., J.B., W.J.F., D.R.A.); an unrestricted grant from Carl Zeiss Meditec, Inc; and National Institutes of Health, National Eye Institute Training Grant EY 07127 Clinical Trials Training Program in Vision Research (Dr. Whiteside). NR 28 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2012 VL 119 IS 3 BP 468 EP 473 DI 10.1016/j.ophtha.2011.08.041 PG 6 WC Ophthalmology SC Ophthalmology GA 901ID UT WOS:000300957200006 PM 22137043 ER PT J AU Inamoto, Y Chai, XY Kurland, BF Cutler, C Flowers, MED Palmer, JM Carpenter, PA Heffernan, MJ Jacobsohn, D Jagasia, MH Pidala, J Khera, N Vogelsang, GB Weisdorf, D Martin, PJ Pavletic, SZ Lee, SJ AF Inamoto, Yoshihiro Chai, Xiaoyu Kurland, Brenda F. Cutler, Corey Flowers, Mary E. D. Palmer, Jeanne M. Carpenter, Paul A. Heffernan, Mary J. Jacobsohn, David Jagasia, Madan H. Pidala, Joseph Khera, Nandita Vogelsang, Georgia B. Weisdorf, Daniel Martin, Paul J. Pavletic, Steven Z. Lee, Stephanie J. CA Chronic GVHD Consortium TI Validation of Measurement Scales in Ocular Graft-versus-Host Disease SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT BMT Tandem Meeting CY FEB, 2011 CL Honolulu, HI ID QUALITY-OF-LIFE; CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; STEM-CELL TRANSPLANTATION; DRY EYE SYNDROME; TERM-FOLLOW-UP; CLINICAL-TRIALS; THERAPEUTIC RESPONSE; HEALTH-STATUS AB Purpose: To validate measurement scales for rating ocular chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. Candidate scales were recommended for use in clinical trials by the National Institutes of Health (NIH) Chronic GVHD Consensus Conference or have been previously validated in dry eye syndromes. Design: Prospective follow-up study. Participants: Between August 2007 and June 2010, the study enrolled 387 patients with chronic GVHD in a multicenter, prospective, observational cohort. Methods: Using anchor-based methods, we compared clinician or patient-reported changes in eye symptoms (8-point scale) with calculated changes in 5 candidate scales: The NIH eye score, patient-reported global rating of eye symptoms, Lee eye subscale, Ocular Surface Disease Index, and Schirmer test. Change was examined for 333 follow-up visits where both clinician and patient reported eye involvement at the previous visit. Linear mixed models were used to account for within-patient correlation. Main Outcome Measures: An 8-point scale of clinician or patient-reported symptom change was used as an anchor to measure symptom changes at the follow-up visits. Results: In serial evaluations, agreement regarding improvement, stability, or worsening between the clinician and patient was fair (weighted kappa = 0.34). Despite only fair agreement between evaluators, all scales except the Schirmer test correlated with both clinician-reported and patient-reported changes in ocular GVHD activity. Among all scales, changes in the NIH eye scores showed the greatest sensitivity to symptom change reported by clinicians or patients. Conclusions: Our results support the use of the NIH eye score as a sensitive measure of eye symptom changes in clinical trials assessing treatment of chronic GVHD. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:487-493 (C) 2012 by the American Academy of Ophthalmology. C1 [Inamoto, Yoshihiro; Chai, Xiaoyu; Kurland, Brenda F.; Flowers, Mary E. D.; Carpenter, Paul A.; Heffernan, Mary J.; Khera, Nandita; Martin, Paul J.; Lee, Stephanie J.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Cutler, Corey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Palmer, Jeanne M.] Med Coll Wisconsin, Div Hematol Oncol, Milwaukee, WI 53226 USA. [Jacobsohn, David] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. [Jagasia, Madan H.] Vanderbilt Univ, Med Ctr, Hematol & Stem Cell Transplant Program, Nashville, TN USA. [Pidala, Joseph] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Vogelsang, Georgia B.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Weisdorf, Daniel] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN USA. [Pavletic, Steven Z.] NCI, Bethesda, MD 20892 USA. RP Lee, SJ (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-290, Seattle, WA 98109 USA. EM sjlee@fhcrc.org OI Kurland, Brenda/0000-0002-5669-0595 FU NCI NIH HHS [P01 CA018029, CA118953, CA18029, P30 CA015704, R01 CA118953, U01 CA118953, U01 CA118953-05, U54 CA163438] NR 37 TC 30 Z9 30 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2012 VL 119 IS 3 BP 487 EP 493 DI 10.1016/j.ophtha.2011.08.040 PG 7 WC Ophthalmology SC Ophthalmology GA 901ID UT WOS:000300957200009 PM 22153706 ER PT J AU Yonker, LM Mark, EJ Canapari, CA AF Yonker, Lael M. Mark, Eugene J. Canapari, Craig A. TI Aspergilloma in a Patient With an Occult Congenital Pulmonary Airway Malformation SO PEDIATRIC PULMONOLOGY LA English DT Article ID BRONCHOGENIC CYST; HEMOPTYSIS; LUNG AB We describe the case of a 14-year-old male who presented with a right upper lobe aspergilloma forming in a previously occult congenital pulmonary airway malformation. This is the first case describing an aspergilloma forming within a CPAM. Pediatr Pulmonol. 2012; 47:308-310. (c) 2011 Wiley Periodicals, Inc. C1 [Yonker, Lael M.; Mark, Eugene J.; Canapari, Craig A.] Harvard Univ, Sch Med, Boston, MA USA. [Yonker, Lael M.; Mark, Eugene J.; Canapari, Craig A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yonker, LM (reprint author), 275 Cambridge St,5th Floor, Boston, MA 02114 USA. EM lyonker@partners.org NR 20 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 8755-6863 J9 PEDIATR PULM JI Pediatr. Pulmonol. PD MAR PY 2012 VL 47 IS 3 BP 308 EP 310 DI 10.1002/ppul.21538 PG 3 WC Pediatrics; Respiratory System SC Pediatrics; Respiratory System GA 897ZJ UT WOS:000300702300013 PM 21905264 ER PT J AU Lee, ACW Harada, N AF Lee, Alan Chong W. Harada, Nancy TI Telehealth as a Means of Health Care Delivery for Physical Therapist Practice SO PHYSICAL THERAPY LA English DT Editorial Material ID TELEREHABILITATION; OUTCOMES; REHABILITATION C1 [Lee, Alan Chong W.] Mt St Marys Coll, Doctor Phys Therapy Program, Los Angeles, CA 90007 USA. [Lee, Alan Chong W.] Scripps Mercy Hosp, San Diego, CA USA. [Lee, Alan Chong W.] Univ Calif San Diego, Med Ctr, San Diego, CA 92103 USA. [Harada, Nancy] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Harada, Nancy] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Lee, ACW (reprint author), Mt St Marys Coll, Doctor Phys Therapy Program, 10 Chester Pl, Los Angeles, CA 90007 USA. EM allee@msmc.la.edu NR 33 TC 4 Z9 5 U1 1 U2 3 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD MAR PY 2012 VL 92 IS 3 BP 463 EP 468 DI 10.2522/ptj.20110100 PG 6 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 901CY UT WOS:000300940500011 PM 22135703 ER PT J AU Reisman, JS Weinberg, A Ponte, C Kradin, R AF Reisman, Jonathan S. Weinberg, Arnold Ponte, Carlos Kradin, Richard TI Monomicrobial Pseudomonas necrotizing fasciitis: A case of infection by two strains and a review of 37 cases in the literature SO SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Review DE Pseudomonas infection; necrotizing fasciitis; immunocompromise ID AERUGINOSA INFECTIONS; CLINICAL PRESENTATION; EYELID NECROSIS; OCULAR ADNEXA; GANGRENE; MICROBIOLOGY; CHILDREN; BITE; SKIN AB Necrotizing fasciitis due to Pseudomonas aeruginosa is rare. We report a case of monomicrobial Pseudomonas necrotizing fasciitis and review 37 cases in the literature. The mortality rate was 30%, and most infections occurred in the immunocompromised. Clinicians should consider empiric pseudomonal antibiotic coverage in the severely immunocompromised with potentially necrotizing infections. C1 [Reisman, Jonathan S.] Massachusetts Gen Hosp, Harvard Internal Med Pediat Program, Boston, MA 02114 USA. [Weinberg, Arnold] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ponte, Carlos; Kradin, Richard] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kradin, Richard] Massachusetts Gen Hosp, Pulm Crit Care Unit, Boston, MA 02114 USA. RP Reisman, JS (reprint author), Harvard Massachusetts Gen Hosp, Med Pediat Program, 275 Cambridge St,5th Floor, Boston, MA 02114 USA. EM Reisman.jonathan@gmail.com NR 41 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0036-5548 J9 SCAND J INFECT DIS JI Scand. J. Infect. Dis. PD MAR PY 2012 VL 44 IS 3 BP 216 EP 221 DI 10.3109/00365548.2011.626441 PG 6 WC Infectious Diseases SC Infectious Diseases GA 898UT UT WOS:000300768500009 PM 22126406 ER PT J AU Horan, WP Foti, D Hajcak, G Wynn, JK Green, MF AF Horan, William P. Foti, Dan Hajcak, Greg Wynn, Jonathan K. Green, Michael F. TI Intact motivated attention in schizophrenia: Evidence from event-related potentials SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia Event-Related Potentials (ERP); Late Positive Potential; P300; Emotion ID EMOTION AB Emotionally significant stimuli typically capture attention (called motivated attention) even when they are irrelevant to tasks where attention is directed. Previous studies indicate that several components of emotional processing are intact in schizophrenia when subjects are instructed to attend to emotionally-evocative stimuli. However, few studies have examined whether emotional stimuli capture attention to a normal degree in people with schizophrenia when attention is directed elsewhere. The current event-related potential study examined motivated attention to task-irrelevant emotional stimuli in 35 stabilized outpatients and 26 healthy controls with a modified visual P300 oddball detection task. Participants viewed images of rare target and commonly occurring standard letter stimuli, as well as intermixed emotional (unpleasant, pleasant, neutral) pictures. Subjects were instructed to count the number of rare targets; the emotional valence of the picture stimuli was, therefore, task-irrelevant. We separately evaluated the Early Posterior Negativity (EPN) and Late Positive Potential (LPP) to emotional pictures and the P300 to target stimuli. Patients and controls showed similar patterns of EPN and LPP amplitude to the emotional stimuli, such that the EPN and LPP were larger for both pleasant and unpleasant versus neutral pictures. Although patients performed worse than controls on the target counting task, both groups showed comparable P300 differentiation between target versus non-target stimuli. Emotional stimuli captured attentional resources in people with schizophrenia even when the emotional stimuli were task-irrelevant, suggesting intact motivated attention at the level of early electrophysiological responding. (C) 2011 Elsevier B.V. All rights reserved. C1 [Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, Los Angeles, CA 90073 USA. [Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Foti, Dan; Hajcak, Greg] SUNY Stony Brook, Stony Brook, NY USA. RP Horan, WP (reprint author), Univ Calif Los Angeles, MIRECC 210A,Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM horan@ucla.edu RI Wynn, Jonathan/H-3749-2014 OI Wynn, Jonathan/0000-0002-1763-8540 FU NARSAD; National Institute of Mental Health [MH082782, MH065707, MH43292] FX This work was supported by a NARSAD Young Investigator Award (to WPH) and the National Institute of Mental Health (MH082782 to WPH; MH065707, MH43292 to MFG). Funding sources had no role in study design or in the collection, analysis and interpretation of data; or in the writing of this report. NR 20 TC 22 Z9 22 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2012 VL 135 IS 1-3 BP 95 EP 99 DI 10.1016/j.schres.2011.11.005 PG 5 WC Psychiatry SC Psychiatry GA 901CT UT WOS:000300940000017 PM 22126898 ER PT J AU Tucker, JD Yang, LG Yang, B Young, D Henderson, GE Huang, SJ Lu, HK Chen, XS Cohen, MS AF Tucker, Joseph D. Yang, Li-Gang Yang, Bin Young, Darwin Henderson, Gail E. Huang, Shu-Jie Lu, He-Kun Chen, Xiang-Sheng Cohen, Myron S. TI Prior HIV Testing Among STD Patients in Guangdong Province, China: Opportunities for Expanding Detection of Sexually Transmitted HIV Infection SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SERVICE PROVIDERS; RURAL CHINA; ATTITUDES; STIGMA; WILLINGNESS; PHYSICIANS; KNOWLEDGE; SYPHILIS; HEALTH AB Background: Expanding HIV testing is important among individuals at increased risk for sexual HIV transmission in China, but little is known about prior HIV testing experiences among sexually transmitted disease (STD) patients. Methods: This cross-sectional study of 1792 outpatients from 6 public STD clinics in Guangdong Province recorded detailed information about ever having been tested for HIV infection in addition to sociodemographic variables, health seeking, clinical STD history, and HIV stigma using a validated survey instrument. Results: A total of 456 (25.4%) of the STD patients in this sample had ever been tested for HIV infection. STD patients who were male, had higher income, more education, were at City A and City C, received STD services at public facilities, had used intravenous drugs, and had a history of an STD were more likely to ever receive an HIV test in multivariate analysis. Low perceived HIV risk was the most common reason for not receiving an HIV test. Only 7.7% of the sample reported fear of discrimination or loss of face as influencing their lack of HIV testing. Conclusion: Incomplete prior HIV screening among STD patients in China suggests the need for broadening HIV testing opportunities at STD clinics and similar clinical settings attended by those with increased sexual risk. C1 [Tucker, Joseph D.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. [Tucker, Joseph D.; Yang, Li-Gang; Yang, Bin] Guangdong Prov Ctr Skin Dis & STD Control, STD Control Dept, Guangzhou, Guangdong, Peoples R China. [Tucker, Joseph D.; Young, Darwin; Henderson, Gail E.; Cohen, Myron S.] Univ N Carolina, Dept Med, Chapel Hill Sch Med, Chapel Hill, NC USA. [Huang, Shu-Jie; Lu, He-Kun] Jiangmen Municipal Skin Hosp, STD Control Dept, Jiangmen, Peoples R China. [Chen, Xiang-Sheng] Chinese Acad Med Sci, Natl Ctr STD Control, Nanjing, Jiangsu, Peoples R China. [Chen, Xiang-Sheng] Peking Union Med Coll, Inst Dermatol, Nanjing, Jiangsu, Peoples R China. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Dept Med, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jtucker4@partners.org FU NIH (US NIH) [1K01TW008200-01A1]; UNC [NIH FIC D43 TW01039]; UNC Social Science Research on HIV/AIDS in China [NIH NICHD R24 HD056670-01]; UNC Center for AIDS Research; China-Australia Health and HIV/AIDS Facility Project [HIV 04]; WHO [A70577]; Harvard Institute for Global Health; American Society of Tropical Medicine and Hygiene FX Supported by funds from an NIH Fogarty K01 Award (US NIH 1K01TW008200-01A1), the UNC Fogarty AIDS International Research and Training Program (NIH FIC D43 TW01039), the UNC Social Science Research on HIV/AIDS in China (NIH NICHD R24 HD056670-01), the UNC Center for AIDS Research, the China-Australia Health and HIV/AIDS Facility Project (HIV 04), the WHO Rapid Syphilis Test Project (UNICEF/UNDP/World Bank/ WHO A70577), the Harvard Institute for Global Health, and Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene Wellcome Postdoctoral Fellowship in Tropical Infectious Diseases. NR 33 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAR PY 2012 VL 39 IS 3 BP 182 EP 187 DI 10.1097/OLQ.0b013e318237b3b4 PG 6 WC Infectious Diseases SC Infectious Diseases GA 900VS UT WOS:000300920400004 PM 22337103 ER PT J AU Schnelldorfer, T AF Schnelldorfer, Thomas TI Image-enhanced laparoscopy: A promising technology for detection of peritoneal micrometastases SO SURGERY LA English DT Article ID GREEN FLUORESCENT PROTEIN; ACID-INDUCED FLUORESCENCE; 5-AMINOLEVULINIC ACID; PHOTODYNAMIC DIAGNOSIS; ENDOMETRIOTIC LESIONS; CANCER METASTASES; SERUM ALBUMIN; FLUOROPHORE; ANTIBODY; SURGERY C1 [Schnelldorfer, Thomas] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Schnelldorfer, Thomas] Philadelphia Vet Affairs Med Ctr, Sect Gen Surg, Philadelphia, PA USA. RP Schnelldorfer, T (reprint author), Univ Penn, Sch Med, Dept Surg, 3400 Spruce St, Philadelphia, PA 19104 USA. EM thomas.schnelldorfer@va.gov NR 38 TC 5 Z9 5 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD MAR PY 2012 VL 151 IS 3 BP 345 EP 350 DI 10.1016/j.surg.2011.12.012 PG 6 WC Surgery SC Surgery GA 902CP UT WOS:000301016500001 PM 22329962 ER PT J AU Wang, LH Lin, F Wang, J Wu, JC Han, R Zhu, LJ Zhang, GX DiFiglia, M Qin, ZH AF Wang, Linhui Lin, Fang Wang, Jin Wu, Junchao Han, Rong Zhu, Lujia Zhang, Guoxing DiFiglia, Marian Qin, Zhenghong TI Truncated N-terminal huntingtin fragment with expanded-polyglutamine (htt552-100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA LA English DT Article DE Huntingtons disease; astrocytes; brain-derived neurotrophic factor; huntingtin; transcription ID MUTANT HUNTINGTIN; CELLULAR TOXICITY; CASPASE CLEAVAGE; MEDIATED TRANSCRIPTION; ALZHEIMERS-DISEASE; REDUCES TOXICITY; BDNF-GENE; IN-VIVO; EXPRESSION; PROTEIN AB Although huntingtin (htt) can be cleaved at many sites by caspases, calpains, and aspartyl proteases, amino acid (aa) 552 was defined as a preferred site for cleavage in human Huntington disease (HD) brains in vivo. To date, the normal function of wild-type N-terminal htt fragment 1-552 aa (htt552) and its pathological roles of mutant htt552 are still unknown. Although mutant htt (mhtt) is also expressed in astrocytes, whether and how mhtt contributes to the neurodegeneration through astrocytes in HD remains largely unknown. In this study, a glia HD model, using an adenoviral vector to express wild-type htt552 (htt552-18Q) and its mutation (htt552-100Q) in rat primary cortical astrocytes, was generated to investigate the influence of htt552 on the transcription of brain-derived neurotrophic factor (BDNF). Results from enzyme linked immunosorbent assay showed that the level of BDNF in astrocyte-conditioned medium was decreased in the astrocytes expressing htt552-100Q. Quantitative real-time polymerase chain reaction demonstrated that htt552-100Q reduced the transcripts of the BDNF III and IV, hence, repressed the transcription of BDNF. Furthermore, immunofluorescence showed that aggregates formed by htt552-100Q entrapped transcription factors cAMP-response element-binding protein and stimulatory protein 1, which might account for the reduction of BDNF transcription. These findings suggest that mhtt552 reduces BDNF transcription in astrocytes, which might contribute to the neuronal dysfunction in HD. C1 [Lin, Fang; Wang, Jin; Wu, Junchao; Han, Rong; Zhu, Lujia; Qin, Zhenghong] Soochow Univ, Sch Pharm, Dept Pharmacol, Suzhou 215123, Peoples R China. [Lin, Fang; Wang, Jin; Wu, Junchao; Han, Rong; Zhu, Lujia; Qin, Zhenghong] Soochow Univ, Sch Pharm, Lab Aging & Nervous Dis, Suzhou 215123, Peoples R China. [Wang, Linhui; Zhang, Guoxing] Soochow Univ, Sch Biol & Basic Med Sci, Dept Physiol, Suzhou 215123, Peoples R China. [DiFiglia, Marian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurobiol Lab, Boston, MA 02129 USA. RP Qin, ZH (reprint author), Soochow Univ, Sch Pharm, Dept Pharmacol, Suzhou 215123, Peoples R China. EM qinzhenhong@suda.edu.cn FU National Natural Science Foundation of China [30900464]; Jiangsu Higher Education Institutions FX This work was supported by grants from the National Natural Science Foundation of China (No. 30900464) and PAPD (the Priority Academic Program Development of Jiangsu Higher Education Institutions). NR 52 TC 3 Z9 4 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1672-9145 J9 ACTA BIOCH BIOPH SIN JI Acta Biochim. Biophys. Sin. PD MAR PY 2012 VL 44 IS 3 BP 249 EP 258 DI 10.1093/abbs/gmr125 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 898GM UT WOS:000300727400008 PM 22234237 ER PT J AU Melendez, RI McGinty, JF Kalivas, PW Becker, HC AF Melendez, Roberto I. McGinty, Jacqueline F. Kalivas, Peter W. Becker, Howard C. TI Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice SO ADDICTION BIOLOGY LA English DT Article DE Alcohol dependence; alcohol withdrawal; brain regional adaptations; chronic intermittent alcohol exposure; gene expression profiling; microarray analysis ID FRONTAL-CORTEX; MICROARRAY ANALYSIS; ALCOHOL-DRINKING; SYNAPTIC PLASTICITY; NEUROTROPHIC FACTOR; NONPREFERRING RATS; NUCLEUS-ACCUMBENS; DENDRITIC SPINES; DRUG-ADDICTION; DEFICIENT MICE AB Neuroadaptations that participate in the ontogeny of alcohol dependence are likely a result of altered gene expression in various brain regions. The present study investigated brain region-specific changes in the pattern and magnitude of gene expression immediately following chronic intermittent ethanol (CIE) exposure and 8 hours following final ethanol exposure [i.e. early withdrawal (EWD)]. High-density oligonucleotide microarrays (Affymetrix 430A 2.0, Affymetrix, Santa Clara, CA, USA) and bioinformatics analysis were used to characterize gene expression and function in the prefrontal cortex (PFC), hippocampus (HPC) and nucleus accumbens (NAc) of C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME, USA). Gene expression levels were determined using gene chip robust multi-array average followed by statistical analysis of microarrays and validated by quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. Results indicated that immediately following CIE exposure, changes in gene expression were strikingly greater in the PFC (284 genes) compared with the HPC (16 genes) and NAc (32 genes). Bioinformatics analysis revealed that most of the transcriptionally responsive genes in the PFC were involved in Ras/MAPK signaling, notch signaling or ubiquitination. In contrast, during EWD, changes in gene expression were greatest in the HPC (139 genes) compared with the PFC (four genes) and NAc (eight genes). The most transcriptionally responsive genes in the HPC were involved in mRNA processing or actin dynamics. Of the few genes detected in the NAc, the most representatives were involved in circadian rhythms. Overall, these findings indicate that brain region-specific and time-dependent neuroadaptive alterations in gene expression play an integral role in the development of alcohol dependence and withdrawal. C1 [Becker, Howard C.] Med Univ S Carolina, Charleston Alcohol Res Ctr, Ctr Drug & Alcohol Programs, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Becker, Howard C.] Ralph H Johnson Dept Vet Affairs, Charleston, SC USA. [Melendez, Roberto I.; McGinty, Jacqueline F.; Kalivas, Peter W.; Becker, Howard C.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. RP Becker, HC (reprint author), Med Univ S Carolina, Charleston Alcohol Res Ctr, Ctr Drug & Alcohol Programs, Dept Psychiat & Behav Sci, 67 President St,MSC-861, Charleston, SC 29425 USA. EM beckerh@musc.edu FU [R01 AA013885]; [P50 AA010761]; [P50 DA015369] FX This study was supported by grants R01 AA013885 (H.C.B.), P50 AA010761 (H.C.B.) and P50 DA015369 (P.W.K.). The authors thank Rolf Fritz and Kay Fernandez for excellent technical assistance and Saurin Jani for assistance with bioinformatics analysis. NR 83 TC 30 Z9 31 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2012 VL 17 IS 2 BP 351 EP 364 DI 10.1111/j.1369-1600.2011.00357.x PG 14 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 896LT UT WOS:000300568500012 PM 21812870 ER PT J AU Wray, LO Mavandadi, S Klaus, JR Tew, JD Oslin, DW Sweet, RA AF Wray, Laura O. Mavandadi, Shahrzad Klaus, Johanna R. Tew, James D., Jr. Oslin, David W. Sweet, Robert A. TI The Association Between Mental Health and Cognitive Screening Scores in Older Veterans SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Cognitive impairment; mental health screening; older adults; primary care ID PRIMARY-CARE SETTINGS; LATE-LIFE DEPRESSION; ALZHEIMERS-DISEASE; COMMUNITY POPULATION; RISK-FACTOR; DEMENTIA; IMPAIRMENT; METAANALYSIS; RELIABILITY; VALIDATION AB Objectives: To examine overall cognitive screening results and the relationship between cognitive screen score and sociodemographic characteristics, reason for referral, and clinical outcomes of older veterans referred by primary care for a behavioral health assessment. Design: Cross-sectional, naturalistic study. Setting: Primary care clinics affiliated with two VA Medical Centers. Participants: The sample included 4,325 older veterans referred to the Behavioral Health Laboratory who completed an initial mental health/substance abuse assessment. Veterans were categorized into the following three groups on the basis of cognitive status: within normal limits, possible cognitive impairment, and possible dementia. Measurements: Sociodemographic and clinical data on reason for referral, cognitive functioning (i.e., Blessed Orientation-Memory-Concentration test), and behavioral health assessment outcomes were extracted from patients' medical records. Data were analyzed using multiple linear and logistic regressions. Results: Results of cognitive screenings indicated that the majority of the sample was within normal limits (62.5%), with 25.8%, 8.1%, and 3.6% of patients evidencing possible cognitive impairment, possible dementia, and Blessed Orientation-Memory-Concentration scores of 17 or more, respectively. With regard to reason for referral, patients with greater cognitive impairment were more likely to be identified by the antidepressant case finder than patients with less impairment. Increased age, non-white ethnicity, self-perceived inadequate finances, major depressive disorder, and symptoms of psychosis were associated with greater cognitive impairment. Conclusions: Findings highlight the importance of evaluating cognitive status in older adults who are referred for a behavioral health assessment and/or receive a new mental health/substance abuse diagnosis. Doing so has the potential to improve recognition and treatment of cognitive impairment and dementia, thereby improving quality of care for many older adults. (Am J Geriatr Psychiatry 2012; 20:215-227) C1 [Wray, Laura O.] Ctr Integrated Healthcare, Dept Vet Affairs, Buffalo, NY 14215 USA. [Wray, Laura O.] SUNY Buffalo, Sch Med & Biomed Sci, Div Geriatr, Buffalo, NY 14260 USA. [Mavandadi, Shahrzad; Klaus, Johanna R.; Oslin, David W.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Mavandadi, Shahrzad; Klaus, Johanna R.; Oslin, David W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Tew, James D., Jr.; Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. [Tew, James D., Jr.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Western Psychiat Inst & Clin, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. RP Wray, LO (reprint author), Ctr Integrated Healthcare, Dept Vet Affairs, VAWNYHS 116N,3495 Bailey Ave, Buffalo, NY 14215 USA. EM laura.wray@va.gov FU USPHS [AG027224] FX This study was supported in part by USPHS grant AG027224. NR 51 TC 3 Z9 3 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 BP 215 EP 227 DI 10.1097/JGP.0b013e3182410cdb PG 13 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 897IH UT WOS:000300642300004 PM 22251868 ER PT J AU Shah, A Fried, LF Chen, SC Qiu, Y Li, SY Cavanaugh, KL Norris, KC Whaley-Connell, AT McCullough, PA Mehrotra, R AF Shah, Anuja Fried, Linda F. Chen, Shu-Cheng Qiu, Yang Li, Suying Cavanaugh, Kerri L. Norris, Keith C. Whaley-Connell, Adam T. McCullough, Peter A. Mehrotra, Rajnish CA KEEP Investigators TI Associations Between Access to Care and Awareness of CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Access to care; awareness; chronic kidney disease; health insurance ID CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; HEALTH-CARE; US ADULTS; POPULATION; PREVALENCE; PATIENT; TRENDS AB Background: Most individuals with chronic kidney disease (CKD) in the United States are unaware of their condition, creating challenges in implementing early interventions to delay disease progression. Whether characteristics expected to enhance health care access are associated with greater CKD awareness has not been studied adequately. Method: Data from volunteer participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP), 2000-2010, with presumed CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2) or albumin-creatinine ratio >30 mg/g) were analyzed. Given that the diagnosis of CKD was based on a single measurement of kidney function, the diagnosis is presumed, but not confirmed. Associations of CKD awareness with measures of access to care (health insurance coverage, type of health insurance, prescription drug coverage, and self-reported level of difficulty obtaining care) were examined using logistic regression. Results: Of 29,144 participants with CKD, 6,751 (23%) reported CKD awareness. No significant association was found between availability of health insurance or prescription drug coverage and CKD awareness; results did not vary by diabetic status or in analyses restricted to participants with eGFR <60 mL/min/1.73 m(2). Participants reporting extreme or some difficulty obtaining medical care were more likely than those reporting no difficulty to be aware of CKD (adjusted OR, 1.25; 95% CI, 1.05-1.50). Conclusions: Most KEEP participants with CKD are unaware of the condition, results that are not modified by the availability of health insurance or prescription drug coverage. The mechanisms underlying the association of perceived difficulty in access to care with greater CKD awareness require further study. Am J Kidney Dis. 59(3)(S2):S16-S23. 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 [Shah, Anuja; Mehrotra, Rajnish] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Fried, Linda F.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Chen, Shu-Cheng; Qiu, Yang; Li, Suying] Minneapolis Med Res Fdn Inc, Chron Kidney Dis Res Grp, Minneapolis, MN USA. [Cavanaugh, Kerri L.] Vanderbilt Univ, Nashville, TN USA. [Norris, Keith C.] Charles R Drew Univ Med & Sci, Los Angeles, CA 90059 USA. [Whaley-Connell, Adam T.] Univ Missouri, Columbia Sch Med, Harry S Truman VA Med Ctr, Columbia, MO USA. [Whaley-Connell, Adam T.] Univ Missouri, Columbia Sch Med, Dept Internal Med, Div Nephrol & Hypertens, Columbia, MO USA. [McCullough, Peter A.] St John Providence Hlth Syst, Providence Pk Heart Inst, Novi, MI USA. RP Mehrotra, R (reprint author), Harbor UCLA, Los Angeles Biomed Res Inst, 1124 W Carson St, Torrance, CA 90502 USA. EM rmehrotra@labiomed.org OI Whaley-Connell, Adam/0000-0001-8955-5560 FU Amgen; Abbott; Siemens; Astellas; Fresenius Medical Care; Genzyme; LifeScan; Nephroceuticals; Pfizer; National Kidney Foundation of Southern California; National Institutes of Health (NIH) [R21 DK077341, RR026138, MD000182, R03AG040638-01]; DaVita Inc.; Department of Veteran's Affairs [CDA-2]; American Society of Nephrology-Association of Specialty Professors-National Institute on Aging; [DK K23080952] FX The KEEP is a program of the National Kidney Foundation Inc and is supported by Amgen, Abbott, Siemens, Astellas, Fresenius Medical Care, Genzyme, LifeScan, Nephroceuticals, and Pfizer. Dr Shah is supported by a research grant from the National Kidney Foundation of Southern California and a Genzyme Fellowship Grant. Dr Mehrotra is supported by National Institutes of Health (NIH) grant R21 DK077341 and a research grant from DaVita Inc. Dr Cavanaugh is supported by DK K23080952. Dr Norris receives support from NIH grants RR026138 and MD000182. Dr Whaley-Connell is supported by the Department of Veteran's Affairs CDA-2, the NIH grant R03AG040638-01, and the American Society of Nephrology-Association of Specialty Professors-National Institute on Aging Development Grant in Geriatric Nephrology. NR 17 TC 10 Z9 10 U1 2 U2 5 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 MAR PY 2012 VL 59 IS 3 SU 2 BP S16 EP S23 DI 10.1053/j.ajkd.2011.10.042 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 896ZA UT WOS:000300608900003 PM 22339898 ER PT J AU Viron, M Baggett, T Hill, M Freudenreich, O AF Viron, Mark Baggett, Travis Hill, Michele Freudenreich, Oliver TI Schizophrenia for Primary Care Providers: How to Contribute to the Care of a Vulnerable Patient Population SO AMERICAN JOURNAL OF MEDICINE LA English DT Review DE Cardiovascular disease; Management; Medical morbidity; Primary care; Schizophrenia; Treatment ID SERIOUS MENTAL-ILLNESS; HEALTH-CARE; 1ST-EPISODE PSYCHOSIS; GENERAL-PRACTITIONERS; ANTIPSYCHOTIC-DRUGS; BIPOLAR DISORDER; MEDICAL-CARE; LIFE-STYLE; MORTALITY; PEOPLE AB Patients with schizophrenia represent a vulnerable population with high medical needs that are often missed or undertreated. Primary care providers have the potential to reduce health disparities experienced by this population and make a substantial difference in the overall health of these patients. This review provides primary care providers with a general understanding of the psychiatric and medical issues specific to patients with schizophrenia and a clinically practical framework for engaging and assessing this vulnerable patient population and assisting them in achieving optimal health. Initial steps in this framework include conducting a focused medical evaluation of psychosis and connecting patients with untreated psychosis to psychiatric care as promptly as possible. Given the significant contribution of cardiovascular disease to morbidity and mortality in schizophrenia, a top priority of primary care for patients with schizophrenia should be cardiovascular disease prevention and treatment through regular risk factor screening, appropriate lifestyle interventions, and other indicated therapies. (C) 2012 Elsevier Inc. All rights reserved. . The American Journal of Medicine (2012) 125, 223-230 C1 [Viron, Mark; Hill, Michele; Freudenreich, Oliver] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Baggett, Travis] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Viron, M (reprint author), Massachusetts Gen Hosp, Schizophrenia Program, 25 Staniford St, Boston, MA 02114 USA. EM mviron@partners.org FU Pfizer FX Dr Freudenreich has received research grant support from Pfizer and honoraria from Reed Medical Education for Continuing Medical Education lectures, and has served as a consultant for Transcept and Beacon Health Strategies. The remaining authors have no conflicts of interests to disclose. NR 59 TC 7 Z9 7 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD MAR PY 2012 VL 125 IS 3 BP 223 EP 230 DI 10.1016/j.amjmed.2011.05.002 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 897BI UT WOS:000300615400010 PM 22340915 ER PT J AU O'Seaghdha, CM Lyass, A Massaro, JM Meigs, JB Coresh, J D'Agostino, RB Astor, BC Fox, CS AF O'Seaghdha, Conall M. Lyass, Asya Massaro, Joseph M. Meigs, James B. Coresh, Josef D'Agostino, Ralph B., Sr. Astor, Brad C. Fox, Caroline S. TI A Risk Score for Chronic Kidney Disease in the General Population SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Chronic kidney disease; CKD; Risk score ID GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; IMPROVING GLOBAL OUTCOMES; ATHEROSCLEROSIS RISK; POSITION STATEMENT; SERUM CREATININE; RENAL-DISEASE; PREDICTION; COMMUNITIES; PROGRESSION AB BACKGROUND: Stratification of individuals at risk for chronic kidney disease may allow optimization of preventive measures to reduce disease incidence and complications. We sought to develop a risk score that estimates an individual's absolute risk of incident chronic kidney disease. METHODS: Framingham Heart Study participants free of baseline chronic kidney disease, who attended a baseline examination in 1995-1998 and follow-up in 2005-2008, were included in the analysis (n = 2490). Chronic kidney disease was defined as an estimated glomerular filtration rate <60 mL/min/1.73m(2) using the Modification of Diet in Renal Disease equation. Participants were assessed for the development of chronic kidney disease at 10 years follow-up. Stepwise logistic regression was used to identify chronic kidney disease risk factors, and these were used to construct a risk score predicting 10-year chronic kidney disease risk. Performance characteristics were assessed using calibration and discrimination measures. The final model was externally validated in the bi-ethnic Atherosclerosis Risk in Communities Study (n = 1777). RESULTS: There were 1171 men and 1319 women at baseline, and the mean age was 57.1 years. At follow-up, 9.2% (n = 229) had developed chronic kidney disease. Age, diabetes, hypertension, baseline estimated glomerular filtration rate, and albuminuria were independently associated with incident chronic kidney disease (P < .05), and these covariates were incorporated into a risk function (c-statistic 0.813). In external validation in the ARIC study, the c-statistic was 0.74 in whites (n = 1353) and 0.75 in blacks (n = 424). CONCLUSION: Risk stratification for chronic kidney disease is achievable using a risk score derived from clinical factors that are readily accessible in primary care. The utility of this score in identifying individuals in the community at high risk of chronic kidney disease warrants further investigation. Published by Elsevier Inc. . The American Journal of Medicine (2012) 125, 270-277 C1 [O'Seaghdha, Conall M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [O'Seaghdha, Conall M.] Massachusetts Gen Hosp, Div Renal, Brigham & Womens Hosp, Boston, MA 02114 USA. [O'Seaghdha, Conall M.; Meigs, James B.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Lyass, Asya; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Massaro, Joseph M.] Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Coresh, Josef; Astor, Brad C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute [N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; National Institute of Diabetes and Digestive and Kidney Diseases [1 R01 DK076770-01]; [U01HL075572-01] FX The Framingham Heart Study is supported by the National Heart, Lung, and Blood Institute (N01-HC-25195); urinary albumin excretion assay reagents were donated by Roche Diagnostics Inc. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, with the ARIC Carotid MRI Study funded by U01HL075572-01. Drs Astor and Coresh are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK076770-01). NR 39 TC 16 Z9 16 U1 0 U2 11 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 MAR PY 2012 VL 125 IS 3 BP 270 EP 277 DI 10.1016/j.amjmed.2011.09.009 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 897BI UT WOS:000300615400020 PM 22340925 ER PT J AU Miranda, A Figoni, SF Cha, T Flanagan, T Mandal, O Silva, M Scremin, AME Scremin, OU AF Miranda, Alberto Figoni, Stephen F. Cha, Tha Flanagan, Terrance Mandal, Oanh Silva, Mariana Scremin, A. M. Erika Scremin, Oscar U. TI Calf Tissue Oxygenation During Exercise in Men with and Without Risk Factors for Developing Peripheral Arterial Disease SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Rehabilitation; Exercise Test; Spectroscopy; Near-Infrared; Peripheral Vascular Diseases ID NEAR-INFRARED SPECTROSCOPY; INTERMITTENT CLAUDICATION; SHORT-TERM; VASCULAR-DISEASE; LOWER-EXTREMITY; SMOKING; POPULATION; SATURATION; REHABILITATION; DYSFUNCTION AB Miranda A, Figoni SF, Cha T, Flanagan T, Mandal O, Silva M, Scremin AME, Scremin OU: Calf tissue oxygenation during exercise in men with and without risk factors for developing peripheral arterial disease. Am J Phys Med Rehabil 2012;91:200Y210. Objective: This study aimed to compare calf tissue oxygenation responses to calf exercise in men without diagnosed peripheral arterial disease but with selected risk factors for peripheral arterial disease with those without risk factors. Design: A cross-sectional quasi-experimental design was used. The no-risk group (n = 20) had none of the risk factors (diabetes, hypertension, hyperlipidemia, obesity, current or 10 pack-yr smoking history, or age >= 65 yrs). The at-risk group (n = 45) had one to six risk factors. Medial calf tissue oxygenation (percentage saturation) was determined using near-infrared spectroscopy during seven consecutive 5-min test stages: rest, O-W active plantar/dorsiflexion, rest, 4-W resistive plantar flexion, rest, 8-W resistive plantar flexion, and rest. Resistive exercise was performed on the Stresst'er calf ergometer. Results: Compared with the no-risk group, decrements in calf tissue oxygenation induced by light-to-moderate resistive calf exercise in the at-risk group was significantly greater (by 9% saturation) (4-W: P < 0.001; 8-W: P = 0.002). Conclusions: Men with risk factors for developing peripheral arterial disease but without such diagnosis demonstrated greater decrements in calf tissue oxygenation during calf exercise compared with men without risk factors. Further development of this test may lead to early diagnosis and intervention to modify risk factors and prevent co-morbidities. C1 [Scremin, A. M. Erika] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst,Phys Med &, Los Angeles, CA 90095 USA. [Miranda, Alberto; Figoni, Stephen F.; Cha, Tha; Flanagan, Terrance; Mandal, Oanh; Silva, Mariana; Scremin, A. M. Erika] VA Greater Los Angeles Healthcare Syst, Rehabil Serv, Los Angeles, CA USA. [Scremin, Oscar U.] VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Scremin, Oscar U.] Univ Calif Los Angeles, Dept Physiol, Geffen Sch Med, VA Greater Los Angeles Healthcare Syst,Phys Med &, Los Angeles, CA 90024 USA. RP Miranda, A (reprint author), VA W Los Angeles Healthcare Ctr, PM&RS 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 35 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD MAR PY 2012 VL 91 IS 3 BP 200 EP 210 DI 10.1097/PHM.0b013e3182411df9 PG 11 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 898BA UT WOS:000300708900003 PM 22257970 ER PT J AU Saladin, ME Santa Ana, EJ LaRowe, SD Simpson, AN Tolliver, BK Price, KL McRae-Clark, AL Brady, KT AF Saladin, Michael E. Santa Ana, Elizabeth J. LaRowe, Steven D. Simpson, Annie N. Tolliver, Bryan K. Price, Kimber L. McRae-Clark, Aimee L. Brady, Kathleen T. TI Does Alexithymia Explain Variation in Cue-Elicited Craving Reported by Methamphetamine-Dependent Individuals? SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID PSYCHOACTIVE SUBSTANCE DEPENDENCE; MAINTAINING ABSTINENCE; SCALE; ALCOHOL; ABUSERS; VALIDATION; DEPRESSION; REACTIVITY; DISORDERS; WOMEN AB Drug craving is an important motivational phenomenon among addicted individuals, and successful management of craving is essential to both the initiation and maintenance of abstinence. Although craving in response to drug cues is common in drug-dependent individuals, it is not universal. At the present time, it is not known why approximately 2030% of all addicted persons fail to report appreciable craving in laboratory-based cue reactivity studies. This study examined the possibility that alexithymia, a personality attribute characterized by a difficulty identifying and describing emotions, may contribute to the impoverished cue-elicited craving experienced by some addicts. Specifically, we tested the hypothesis that alexithymia, as measured by the Toronto Alexithymia Scale (TAS), would be inversely related to the magnitude of cue-elicited craving obtained in a cue reactivity protocol. Forty methamphetamine-dependent individuals completed the TAS and provided craving ratings for methamphetamine after presentation of methamphetamine-associated cues. Thirteen participants (32%) reported no methamphetamine cue-elicited craving. Contrary to expectation, TAS factor 1 (a measure of difficulty identifying feelings) scores were positively associated with cue-elicited craving. Thus, the results suggest that increasing difficulty-identifying feelings may be associated with higher cue-elicited craving. Clinical implications for this finding are discussed. (Am J Addict 2012:21:130135) C1 [Saladin, Michael E.] Med Univ S Carolina, Coll Hlth Profess, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Saladin, Michael E.; Santa Ana, Elizabeth J.; Simpson, Annie N.; Tolliver, Bryan K.; Price, Kimber L.; McRae-Clark, Aimee L.; Brady, Kathleen T.] Med Univ S Carolina, Clin Neurosci Div, Charleston, SC 29425 USA. [Santa Ana, Elizabeth J.; LaRowe, Steven D.] Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv, Subst Abuse Treatment Ctr, Charleston, SC USA. [LaRowe, Steven D.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Simpson, Annie N.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. RP Saladin, ME (reprint author), Med Univ S Carolina, Coll Hlth Profess, Dept Hlth Sci & Res, 77 President St,Room 222,MSC700, Charleston, SC 29425 USA. EM saladinm@musc.edu RI McRae-Clark, Aimee/I-3341-2013 OI McRae-Clark, Aimee/0000-0002-9774-318X FU NCRR NIH HHS [KL2 RR029880, KL2 RR029880-01, KL2 RR029880-02, KL2 RR029880-03, TL1 RR029881, TL1 RR029881-01, TL1 RR029881-02, TL1 RR029881-03, UL1 RR029882, UL1 RR029882-01, UL1 RR029882-02, UL1 RR029882-03]; NIDA NIH HHS [R25 DA020537, P20 DA022658, P20 DA022658-01, P20 DA022658-02, P20 DA022658-02S1, P20 DA022658-03, P20 DA022658-04, U10 DA013727, U10 DA013727-10, U10 DA013727-10S1, U10 DA013727-10S2, U10 DA013727-10S3, U10 DA013727-11, U10 DA013727-11S1, U10 DA013727-12] NR 47 TC 7 Z9 8 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAR-APR PY 2012 VL 21 IS 2 BP 130 EP 135 DI 10.1111/j.1521-0391.2011.00214.x PG 6 WC Substance Abuse SC Substance Abuse GA 894SO UT WOS:000300447300006 PM 22332856 ER PT J AU Cooper, ZR Powers, CL Cobb, JP AF Cooper, Zara R. Powers, Carol L. Cobb, J. Perren TI Putting the Patient First Honoring Advance Directives Prior to Surgery SO ANNALS OF SURGERY LA English DT Editorial Material ID QUALITY-OF-LIFE; CARE; END; DECISIONS; CANCER; ILL C1 [Cooper, Zara R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Powers, Carol L.] Harvard Univ, Community Eth Comm, Boston, MA 02115 USA. [Cobb, J. Perren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Crit Care Ctr,Dept Anaesthesia, Boston, MA 02115 USA. [Cobb, J. Perren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Crit Care Ctr,Dept Surg, Boston, MA 02115 USA. RP Cooper, ZR (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM ZCOOPER@partners.org NR 23 TC 9 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2012 VL 255 IS 3 BP 424 EP 426 DI 10.1097/SLA.0b013e318246c1ad PG 3 WC Surgery SC Surgery GA 897FI UT WOS:000300631300004 PM 22281702 ER PT J AU Wang, JP Dang, P Raut, CP Pandalai, PK Maduekwe, UN Rattner, DW Lauwers, GY Yoon, SS AF Wang, Jiping Dang, Ping Raut, Chandrajit P. Pandalai, Prakash K. Maduekwe, Ugwuji N. Rattner, David W. Lauwers, Gregory Y. Yoon, Sam S. TI Comparison of a Lymph Node Ratio-Based Staging System With the 7th AJCC System for Gastric Cancer Analysis of 18,043 Patients From the SEER Database SO ANNALS OF SURGERY LA English DT Article ID INDEPENDENT PROGNOSTIC-FACTOR; N-RATIO; UNITED-STATES; SURVIVAL; ADENOCARCINOMA; CARCINOMA; IMPACT; CHEMORADIOTHERAPY; LYMPHADENECTOMY; GASTRECTOMY AB Objectives: The American Joint Committee on Cancer (AJCC) staging system for gastric cancer bases N status on absolute number of metastatic nodes, regardless of the number of examined nodes. We examined a modified staging system utilizing node ratio (Nr), the ratio of metastatic to examined nodes. Methods: A total of 18,043 gastric cancer patients who underwent gastrectomy were identified from the US Surveillance, Epidemiology, and End Results (SEER) database. A training set was divided into 5 Nr groups, and a TNrM staging system was constructed. Median survival and overall survival, based on 7th edition AJCC and TNrM staging systems, were compared, and the analysis was repeated in a validation set. Results: Median examined nodes were 10 to 11. For the training set, overall survival for all 5 AJCC N categories was significantly different when sub-grouped into 15 or fewer versus more than 15 examined nodes, but overall survival was similar regardless of the number of examined nodes in 4 of 5 Nr categories. Seven AJCC stages had statistically different overall survival between subgroups, whereas only 1 TNrM stage had statistically different overall survival between subgroups. When misclassification was defined as any subgroup in which median survival fell outside the 95% confidence interval of the group's overall median survival, AJCC staging misclassified 57% of patients and TNrM staging misclassified only 12%. Similar results were found in the validation set. Conclusions: The AJCC system classifies SEER gastric cancer patients into stages in which subgroups often have wide variations in survival. For patients undergoing limited lymph node analysis, the proposed TNrM system may predict survival more accurately. C1 [Wang, Jiping; Raut, Chandrajit P.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Wang, Jiping; Raut, Chandrajit P.] Harvard Univ, Sch Med, Boston, MA USA. [Dang, Ping; Pandalai, Prakash K.; Maduekwe, Ugwuji N.; Rattner, David W.; Yoon, Sam S.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Wang, JP (reprint author), Brigham & Womens Hosp, Dept Surg, 353 Carrie Hall,75 Francis St, Boston, MA 02115 USA. EM jwang39@partners.org; syoon@partners.org NR 32 TC 69 Z9 78 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2012 VL 255 IS 3 BP 478 EP 485 DI 10.1097/SLA.0b013e31824857e2 PG 8 WC Surgery SC Surgery GA 897FI UT WOS:000300631300013 PM 22330040 ER PT J AU Derwall, M Malhotra, R Lai, CS Beppu, Y Aikawa, E Seehra, JS Zapol, WM Bloch, KD Yu, PB AF Derwall, Matthias Malhotra, Rajeev Lai, Carol S. Beppu, Yuko Aikawa, Elena Seehra, Jasbir S. Zapol, Warren M. Bloch, Kenneth D. Yu, Paul B. TI Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE atherosclerosis; calcification; lipids; reactive oxygen species; signal transduction ID LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; MATRIX GLA PROTEIN; FATTY LIVER-DISEASE; OXIDATIVE STRESS; ENDOTHELIAL-CELLS; REGULATORY MECHANISMS; MURINE MODELS; NADPH OXIDASE; IN-VIVO AB Objective-The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain-and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes. Methods and Results-We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR-/- mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis. Conclusion-These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification. (Arterioscler Thromb Vasc Biol. 2012;32:613-622.) C1 [Derwall, Matthias] Rhein Westfal TH Aachen, Uniklin Aachen, Dept Anesthesia, D-52074 Aachen, Germany. [Derwall, Matthias; Beppu, Yuko; Zapol, Warren M.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Malhotra, Rajeev; Lai, Carol S.; Bloch, Kenneth D.; Yu, Paul B.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Malhotra, Rajeev; Lai, Carol S.; Bloch, Kenneth D.; Yu, Paul B.] Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Aikawa, Elena] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Derwall, Matthias] Rhein Westfal TH Aachen, D-52074 Aachen, Germany. [Seehra, Jasbir S.] Acceleron Pharma Inc, Cambridge, MA USA. RP Derwall, M (reprint author), Rhein Westfal TH Aachen, Uniklin Aachen, Dept Anesthesia, Pauwelsstr 30, D-52074 Aachen, Germany. EM mderwall@ukaachen.de; pbyu@partners.org OI Yu, Paul/0000-0003-2145-4944; Malhotra, Rajeev/0000-0003-0120-4630 FU German Research Foundation (Deutsche Forschungsgemeinschaft) [DE-1685-1/1]; US National Institutes of Health [T32HL007208, AR057374]; Leducq Foundation; Massachusetts Technology Transfer Center, Boston MA; Howard Hughes Medical Institute; American Heart Association [11FTF7290032] FX This work was supported by a research fellowship award of the German Research Foundation (Deutsche Forschungsgemeinschaft, DE-1685-1/1, M.D.), the US National Institutes of Health (T32HL007208, R.M.; AR057374, P.B.Y.), the Leducq Foundation (Multidisciplinary Program to Elucidate the Role of Bone Morphogenetic Protein Signaling in the Pathogenesis of Pulmonary and Systemic Vascular Diseases, K.D.B. and P.B.Y.), the Massachusetts Technology Transfer Center, Boston MA (P.B.Y.), the Howard Hughes Medical Institute (P.B.Y.), and the American Heart Association (11FTF7290032, R.M.). NR 53 TC 68 Z9 77 U1 0 U2 8 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 MAR PY 2012 VL 32 IS 3 BP 613 EP U168 DI 10.1161/ATVBAHA.111.242594 PG 23 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 897HP UT WOS:000300639300016 PM 22223731 ER PT J AU Noto, D Cefalu, AB Valenti, V Fayer, F Pinotti, E Ditta, M Spina, R Vigna, G Yue, P Kathiresan, S Tarugi, P Averna, MR AF Noto, Davide Cefalu, Angelo B. Valenti, Vincenza Fayer, Francesca Pinotti, Elisa Ditta, Mariangela Spina, Rossella Vigna, Giovanni Yue, Pin Kathiresan, Sekar Tarugi, Patrizia Averna, Maurizio R. TI Prevalence of ANGPTL3 and APOB Gene Mutations in Subjects With Combined Hypolipidemia SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE epidemiology; lipoproteins; genetics; hypobetalipoproteinemia ID FAMILIAL HYPOBETALIPOPROTEINEMIA; LIPOPROTEIN-LIPASE; TRIGLYCERIDE; CHOLESTEROL; METABOLISM AB Objective-Mutations of the ANGPTL3 gene have been associated with a novel form of primary hypobetalipoproteinemia, the combined hypolipidemia (cHLP), characterized by low total cholesterol and low HDL-cholesterol levels. The aim of this work is to define the role of ANGPTL3 gene as determinant of the combined hypolipidemia phenotype in 2 large cohorts of 913 among American and Italian subjects with primary hypobetalipoproteinemia (total cholesterol <5th percentile). Methods and Results-The combined hypolipidemia cut-offs were chosen according to total cholesterol and HDL-cholesterol levels reported in the ANGPTL3 kindred described to date: total cholesterol levels, <2nd percentile and HDL-cholesterol, levels <2nd decile. Seventy-eight subjects with combined hypolipidemia were analyzed for ANGPTL3 and APOB genes. We identified nonsense and/or missense mutations in ANGPTL3 gene in 8 subjects; no mutations of the APOB gene were found. Mutated ANGPTL3 homozygous/compound heterozygous subjects showed a more severe biochemical phenotype compared to heterozygous or ANGPTL3 negative subjects, although ANGPTL3 heterozygotes did not differ from ANGPTL3 negative subjects. Conclusion-These results demonstrated that in a cohort of subjects with severe primary hypobetalipoproteinemia the prevalence of ANGPTL3 gene mutations responsible for a combined hypolipidemia phenotype is about 10%, whereas mutations of APOB gene are absent. (Arterioscler Thromb Vasc Biol. 2012; 32:805-809.) C1 [Noto, Davide; Cefalu, Angelo B.; Valenti, Vincenza; Fayer, Francesca; Ditta, Mariangela; Spina, Rossella; Averna, Maurizio R.] Univ Palermo, Dept Internal Med & Med Specialties, I-90127 Palermo, Italy. [Pinotti, Elisa; Tarugi, Patrizia] Univ Modena & Reggio Emilia, Dept Biomed Sci, I-41100 Modena, Italy. [Vigna, Giovanni] Univ Ferrara, Dept Clin & Expt Med, I-44100 Ferrara, Italy. [Yue, Pin] Washington Univ, Sch Med, St Louis, MO USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Averna, MR (reprint author), Univ Palermo, Dept Internal Med & Med Specialties, Via Vespro 141, I-90127 Palermo, Italy. EM tarugi@unimore.it; maurizio.averna@unipa.it RI Tarugi, Patrizia/D-2179-2015; Vigna, Giovanni/H-2826-2015; OI Tarugi, Patrizia/0000-0001-6864-7853; Vigna, Giovanni/0000-0001-8640-7052; Noto, Davide/0000-0002-5346-2829; Cefalu', Angelo Baldassare/0000-0003-1259-8284; Averna, Maurizio/0000-0003-3558-9209 FU University of Palermo; Italian Ministry of Education, University and Research [2009-RLKXPF]; Fondazione Cassa di Risparmio di Modena FX This work was supported by contract grants from the University of Palermo (60% to M.R.A. and A.B.C.), Grant 2009-RLKXPF "PRIN 2009" from the Italian Ministry of Education, University and Research (to M.R.A.), and the "Fondazione Cassa di Risparmio di Modena" (to P.T.). NR 18 TC 25 Z9 25 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAR PY 2012 VL 32 IS 3 BP 805 EP U591 DI 10.1161/ATVBAHA.111.238766 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 897HP UT WOS:000300639300037 PM 22247256 ER PT J AU Tian, L Luo, NL Zhu, XL Chung, BH Garvey, WT Fu, YC AF Tian, Ling Luo, Nanlan Zhu, Xiaolin Chung, Byung-Hong Garvey, W. Timothy Fu, Yuchang TI Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: Differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses SO ATHEROSCLEROSIS LA English DT Article DE Adiponectin; Adiponectin receptor; APPL1; Macrophages; Foam cells; Atherosclerosis; Inflammation ID MONOCYTE-DERIVED MACROPHAGES; PLASMA-PROTEIN ADIPONECTIN; LIPID-ACCUMULATION; METABOLIC SYNDROME; RECEPTORS; ATHEROSCLEROSIS; DISEASE; OBESITY; PERSPECTIVE; ACTIVATION AB Objective: Adiponectin is an adipokine that exerts anti-inflammatory and anti-atherogenic effects during macrophage transformation into foam cells. To further understand the signaling pathways of adiponectin involved in macrophage foam cell transformation, we investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in mediating adiponectin action on foam cell transformation. Methods and Results: Transfections were performed to overexpress or knockdown AdipoR1 or AdipoR2 genes in human THP-1 monocytes. Lentiviral-shRNAs were also used to knockdown APPL1 gene in these cells. Foam cell transformation was induced via exposure to oxidized low-density lipoprotein (oxLDL). Our results showed that both AdipoR1 and AdipoR2 were critical for transducing the adiponectin signal that suppresses lipid accumulation and inhibits transformation from macrophage to foam cell. However, AdipoR1 and AdipoR2 were found to have differential effects in diminishing proinflammatory responses. While AdipoR1 was required by adiponectin to suppress tumor necrosis factor alpha (TNF alpha) and monocyte chemotactic protein 1 (MCP-1) gene expression, AdipoR2 served as the dominant receptor for adiponectin suppression of scavenger receptor A type 1 (SR-AI) and upregulation of interleukin-1 receptor antagonist (IL-1Ra). Knockdown of APPL1 significantly abrogated the ability of adiponectin to inhibit lipid accumulation, SR-AI and nuclear factor-kappa B (NF-kappa B) gene expression, and Akt phosphorylation in macrophage foam cells. Conclusions: In current studies, we have demonstrated that adiponectin's abilty to suppress macrophage lipid accumulation and foam cell formation is mediated through AdipoR1 and AdipoR2 and the APPL1 docking protein. However, AdipoR1 and AdipoR2 exhibited a differential ability to regulate inflammatory cytokines and SR-A1. These novel data support the idea that the adiponectin-AdipoR1/ 2-APPL1 axis may serve as a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Tian, Ling; Luo, Nanlan; Chung, Byung-Hong; Garvey, W. Timothy; Fu, Yuchang] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Zhu, Xiaolin] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. [Garvey, W. Timothy] Birmingham Vet Affairs Med Ctr, Birmingham, AL 35233 USA. RP Fu, YC (reprint author), Univ Alabama, Dept Nutr Sci, 1675 Univ Blvd, Birmingham, AL 35294 USA. EM yfu@uab.edu RI 王, 强/F-4212-2011 FU UAB Diabetes Research and Training Center [P60-DK079626]; American Diabetes Association [1-07-RA-49]; National Institutes of Health [DK-083562, DK-038764]; Department of Veterans Affairs; research core facilities of the UAB Diabetes Research and Training Center [P60-DK079626] FX We are grateful to Dr. Feng Liu, and Dr. Lily Q. Dong (University of Texas Health Science Center at San Antonio) for their generous provision of reagents. We thank Drs. Stacey Cofield, Katherine Ingram, Nianjun Liu, Guodong Wu and Rongbing Xie (University of Alabama at Birmingham) for their help on statistical analysis. This work was supported by a pilot & feasibility grant from the UAB Diabetes Research and Training Center (P60-DK079626), a grant from American Diabetes Association (1-07-RA-49) to YF, grants from the National Institutes of Health (DK-083562 and DK-038764) to WTG, and a Merit Review grant from the Department of Veterans Affairs to WTG. We also gratefully acknowledge the support of the research core facilities of the UAB Diabetes Research and Training Center (P60-DK079626). NR 30 TC 33 Z9 36 U1 0 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2012 VL 221 IS 1 BP 66 EP 75 DI 10.1016/j.atherosclerosis.2011.12.014 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 897EV UT WOS:000300629500010 PM 22227293 ER PT J AU Huang, G Wang, D Zeb, I Budoff, MJ Harman, SM Miller, V Brinton, EA El Khoudary, SR Manson, JE Sowers, MR Hodis, HN Merriam, GR Cedars, MI Taylor, HS Naftolin, F Lobo, RA Santoro, N Wildman, RP AF Huang, Gary Wang, Dan Zeb, Irfan Budoff, Matthew J. Harman, S. Mitchell Miller, Virginia Brinton, Eliot A. El Khoudary, Samar R. Manson, JoAnn E. Sowers, MaryFran R. Hodis, Howard N. Merriam, George R. Cedars, Marcelle I. Taylor, Hugh S. Naftolin, Frederick Lobo, Rogerio A. Santoro, Nanette Wildman, Rachel P. TI Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS) SO ATHEROSCLEROSIS LA English DT Article DE Coronary calcification; Ectopic fat; Cardiac fat; Hepatic fat; Risk factors; Women ID EPICARDIAL ADIPOSE-TISSUE; CORONARY-ARTERY-DISEASE; VISCERAL ABDOMINAL FAT; INTIMA-MEDIA THICKNESS; PERICARDIAL FAT; LIVER-DISEASE; METABOLIC SYNDROME; INSULIN-RESISTANCE; ASSOCIATION; OBESITY AB Objective: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women. Methods: Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n = 650). Results: Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r = 0.21 and 0.19, respectively; P < 0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides = -0.16, 0.11, and 0.11, respectively, P < 0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4-1.6], 1.5 [0.8-2.9], and 1.8 [1.0-3.4]; p for linear trend = 0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat. Conclusion: While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Huang, Gary; Wang, Dan; Wildman, Rachel P.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. [Zeb, Irfan; Budoff, Matthew J.] Harbor UCLA, Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA USA. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ USA. [Miller, Virginia] Mayo Clin, Dept Surg, Rochester, MN USA. [Miller, Virginia] Mayo Clin, Dept Physiol, Rochester, MN USA. [Brinton, Eliot A.] Univ Utah, Sch Med, Dept Cardiovasc Genet, Salt Lake City, UT USA. [El Khoudary, Samar R.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Manson, JoAnn E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Sowers, MaryFran R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Hodis, Howard N.] Univ So Calif, Keck Sch Med, Atherosclerosis Res Unit, Los Angeles, CA 90033 USA. [Merriam, George R.] Univ Washing, Sch Med, Dept Med, Seattle, WA USA. [Cedars, Marcelle I.] Univ Washing, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Cedars, Marcelle I.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Taylor, Hugh S.] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. [Naftolin, Frederick] NYU, Dept Obstet & Gynecol, Sch Med, New York, NY 10016 USA. [Lobo, Rogerio A.] Columbia Univ, Coll Med, Dept Obstet & Gynecol, New York, NY USA. [Santoro, Nanette] Univ Colorado, Denver Sch Med, Dept Obstet & Gynecol & Womens Hlth, Aurora, CO USA. RP Wildman, RP (reprint author), Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, 1300 Morris Pk Ave,Belfer Bldg,Room 1309, Bronx, NY 10461 USA. EM rachel.wildman@einstein.yu.edu OI El Khoudary Abushaban, Samar/0000-0003-2913-0821 FU Aurora Foundation; National Institutes of Health (NIH) [HL90639]; Mayo CTSA [1 UL1 RR024150]; Mayo Foundation; National Center for Research Resources (NCRR), a component of at NIH [CTSA UL1 RR024139, UL1 RR024131]; NIH Roadmap for Medical Research FX KEEPS is funded by grants from the Aurora Foundation to the Kronos Longevity Research Institute, National Institutes of Health (NIH) HL90639 to VMM, 1 UL1 RR024150, Mayo CTSA 1 UL1 RR024150, the Mayo Foundation, CTSA UL1 RR024139 and UL1 RR024131 from the National Center for Research Resources (NCRR), a component of at NIH and NIH Roadmap for Medical Research. The manuscript's contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov. Study medications were supplied in part by Bayer Health Care and by Abbott Pharmaceuticals. NR 30 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD MAR PY 2012 VL 221 IS 1 BP 198 EP 205 DI 10.1016/j.atherosclerosis.2011.12.004 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 897EV UT WOS:000300629500029 PM 22209479 ER PT J AU Doss, BD Rowe, LS Morrison, KR Libet, J Birchler, GR Madsen, JW McQuaid, JR AF Doss, Brian D. Rowe, Lorelei Simpson Morrison, Kristen R. Libet, Julian Birchler, Gary R. Madsen, Joshua W. McQuaid, John R. TI Couple Therapy for Military Veterans: Overall Effectiveness and Predictors of Response SO BEHAVIOR THERAPY LA English DT Article DE couple therapy; marital therapy; effectiveness; veterans; military ID RANDOMIZED CLINICAL-TRIAL; MARITAL-THERAPY; OUTCOME RESEARCH; COMMUNITY SAMPLE; MARRIED-COUPLES; COMBAT VETERANS; CLIENT FEEDBACK; PSYCHOTHERAPY; METAANALYSIS; DISSATISFACTION AB Despite the numerous challenges facing U.S. veterans and their relationships, there have been no examinations of the effectiveness of couple therapy for relationship distress provided to veterans. In the present study, 177 couples presenting for couple therapy at two Veteran Administration Medical Centers completed assessments of relationship satisfaction prior to therapy and weekly during therapy. Results revealed that the average couple showed significant gains in relationship satisfaction during treatment (d=0.44 for men; d=0.47 for women); gains were larger for couples beginning therapy in the distressed range (d=0.61 for men; d=0.58 for women) than for couples in the nondistressed range (d=0.19 for men; d=0.22 for women). Rates of premature termination were high, with 19% of couples completing fewer than three sessions and 62% rated as not completing a "full course" of therapy. Benchmarking analyses demonstrated that the average gains were larger than would be expected from natural remission and similar to previous effectiveness trials; however, average gains were smaller than those observed in couple therapy efficacy trials. Relationship, psychological, and demographic characteristics were generally unrelated to the amount of change in therapy after controlling for initial satisfaction. However, African American couples showed significantly larger gains than Caucasian, non-Hispanic couples. Thus, though yielding smaller effects than those shown in efficacy trials, the impact of couple therapy for veterans' relationship problems appears to generalize across various demographic, psychological, and relationship characteristics. C1 [Doss, Brian D.] Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. [Rowe, Lorelei Simpson] So Methodist Univ, Dallas, TX 75275 USA. [Birchler, Gary R.; Madsen, Joshua W.] VA San Diego Healthcare Syst, San Diego, CA USA. [Madsen, Joshua W.] Univ Calif San Diego, San Diego, CA 92103 USA. [McQuaid, John R.] San Francisco VA Med Ctr, San Francisco, CA USA. [McQuaid, John R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Doss, BD (reprint author), Univ Miami, Dept Psychol, POB 248185, Coral Gables, FL 33124 USA. EM bdoss@miami.edu NR 51 TC 14 Z9 14 U1 1 U2 6 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD MAR PY 2012 VL 43 IS 1 BP 216 EP 227 PG 12 WC Psychology, Clinical SC Psychology GA 897JQ UT WOS:000300647400019 PM 22304892 ER PT J AU Cholas, RH Hsu, HP Spector, M AF Cholas, Rahmatullah H. Hsu, Hu-Ping Spector, Myron TI The reparative response to cross-linked collagen-based scaffolds in a rat spinal cord gap model SO BIOMATERIALS LA English DT Article DE Collagen; Scaffold; Nerve tissue engineering; Nerve guide; Stem cells; Growth factors ID NEUROTROPHIC FACTOR GDNF; AXONAL REGENERATION; FUNCTIONAL RECOVERY; CORTICOSPINAL TRACT; NERVOUS-SYSTEM; SCAR FORMATION; GENE DELIVERY; IN-VITRO; INJURY; TRANSECTION AB Prior work demonstrated the improvement of peripheral nerve regeneration in gaps implanted with collagen scaffold-filled collagen tubes, compared with nerve autografts, and the promise of such implants for treating gaps in spinal cord injury (SCI) in rats. The objective of this study was to investigate collagen implants alone and incorporating select therapeutic agents in a 5-mm full-resection gap model in the rat spinal cord. Two studies were performed, one with a 6-week time point and one with a 2-week time point. For the 6-week study the groups included: (1) untreated control, (2) dehydrothermally (DHT)cross-linked collagen scaffold, (3) DHT-cross-linked collagen scaffold seeded with adult rat neural stem cells (NSCs), and (4) DHT-cross-linked collagen scaffold incorporating plasmid encoding glial cell linederived neurotropic factor (pGDNF). The 2-week study groups were: (1) nontreated control, (2) DHTcross-linked collagen scaffold; (3) DHT-cross-linked collagen scaffold containing laminin; and (4) carbodiimide-cross-linked collagen scaffold containing laminin. The tissue filling the defect of all groups at 6 weeks was largely composed of fibrous scar; however, the tissue was generally more favorably aligned with the long axis of the spinal cord in all of the treatment groups, but not in the control group. Quantification of the percentage of animals per group containing cystic cavities in the defect showed a trend toward fewer rats with cysts in the groups in which the scaffolds were implanted compared to control. All of the collagen implants were clearly visible and mostly intact after 2 weeks. A band of fibrous tissue filling the control gaps was not seen in the collagen implant groups. In all of the groups there was a narrowing of the spinal canal within the gap as a result of surrounding soft tissue collapse into the defect. The narrowing of the spinal canal occurred to a greater extent in the control and DHT scaffold alone groups compared to the DHT scaffold/laminin and EDAC scaffold/laminin groups. Collagen biomaterials can be useful in the treatment of SCI to: favorably align the reparative tissue with the long axis of the spinal cord; potentially reduce the formation of fluid-filled cysts; serve as a delivery vehicle for NSCs and the gene for GDNF; and impede the collapse of musculature and connective tissue into the defect. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Cholas, Rahmatullah H.; Hsu, Hu-Ping; Spector, Myron] VA Boston Healthcare Syst, Tissue Engn Labs, Boston, MA 02130 USA. [Cholas, Rahmatullah H.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hsu, Hu-Ping; Spector, Myron] Harvard Univ, Sch Med, Dept Orthoped Surg, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Spector, M (reprint author), VA Boston Healthcare Syst, Tissue Engn Labs, Mail Stop 151,150 S Huntington Ave, Boston, MA 02130 USA. EM mspector@rics.bwh.harvard.edu FU U.S. Department of Veterans Affairs; Veterans Health Administration; Rehabilitation Research and Development Service; Department of Defense; VA; Gates Millennium Scholars Program FX The research reported here was supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service and the Department of Defense. MS was supported by a VA Research Career Scientist Award, and RC received a fellowship from the Gates Millennium Scholars Program. The authors are grateful to Professor Martha C. Bohn, Ph.D., of Northwestern University for the pGDNF, and to the University of California San Diego for providing the HCN-A94-2 cells. NR 41 TC 26 Z9 31 U1 2 U2 26 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 MAR PY 2012 VL 33 IS 7 BP 2050 EP 2059 DI 10.1016/j.biomaterials.2011.11.028 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 895CN UT WOS:000300473900011 PM 22182744 ER PT J AU Zhang, JW Deng, XM Choi, HG Alessi, DR Gray, NS AF Zhang, Jinwei Deng, Xianming Choi, Hwan Geun Alessi, Dario R. Gray, Nathanael S. TI Characterization of TAE684 as a potent LRRK2 kinase inhibitor SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Parkinson's disease; LRRK2; TAE684 ID PARKINSONS-DISEASE; SELECTIVITY AB Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Zhang, Jinwei; Alessi, Dario R.] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland. [Deng, Xianming; Choi, Hwan Geun; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Deng, Xianming; Choi, Hwan Geun; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Alessi, DR (reprint author), Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dow St, Dundee DD1 5EH, Scotland. EM d.r.alessi@dundee.ac.uk; nathanael_gray@dfci.harvard.edu OI Alessi, Dario/0000-0002-2140-9185; Zhang, Jinwei/0000-0001-8683-509X FU NIH [P41 GM079575-03]; Medical Research Council; Michael J Fox foundation; AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer FX We wish to thank staff at the National Centre for Protein Kinase Profiling (www.kinase-screen.mrc.ac.uk) for undertaking Dundee kinase specificity screening as well as Nicholas Dzamko for providing the LRRK2 rabbit monoclonal antibodies. We also thank Faycal Hentati Institut National de Neurologie, Tunis, Tunisia as well as Alastair D. Reith GlaxoSmithKline Stevenage U.K. for providing the human lymphoblastoid cells, SAI Advantium for performing pharmacokinetic studies, and the antibody purification teams [Division of Signal Transduction Therapy (DSTT), University of Dundee] coordinated by Hilary McLauchlan and James Hastie for generation of antibodies. This work was supported by NIH grant P41 GM079575-03 (N. Gray) the Medical Research Council (D. Alessi), the Michael J Fox foundation for Parkinson's disease research (N. Gray & D. Alessi), the pharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer) (D. Alessi) NR 15 TC 40 Z9 41 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 MAR 1 PY 2012 VL 22 IS 5 BP 1864 EP 1869 DI 10.1016/j.bmcl.2012.01.084 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 894UA UT WOS:000300451200005 PM 22335897 ER PT J AU Wang, JQ Zhang, ZD Kuruppu, D Brownell, AL AF Wang, Ji-Quan Zhang, Zhaoda Kuruppu, Darshini Brownell, Anna-Liisa TI Radiosynthesis of PET radiotracer as a prodrug for imaging group II metabotropic glutamate receptors in vivo SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Group II mGluRs; mGluR2; mGluR3; PET; Prodrug ID PHARMACOLOGICAL CHARACTERIZATION; ACID LY354740; POTENT; ANTAGONIST; LIGANDS; LY341495; AGONISTS; EPILEPSY; TARGETS AB Group II metabotropic glutamate receptors (mGluRs) have been implicated in a variety of neurological and psychiatric disorders in recent studies. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers the possibility to visualize and study group II mGluRs in vivo under physiologic and pathologic conditions. We synthesized a PET tracer, (S,S,S)-2-(2-carboxycyclopropyl)-2-(3-[C-11]methoxyphenethyl) glycine dimethyl ester ([C-11]CMGDE), as a prodrug for group II mGluRs, and studied its preliminary biological properties in Sprague-Dawley rats to visualize group II mGluRs. The microPET studies demonstrated that [C-11]CMGDE readily penetrated into the brain and the radiotracer generated from [C-11]CMGDE had fast reversible binding in the group II mGluRs rich regions including striatum, hippocampus and different cortical areas. Blocking studies with LY341495 showed 20-30% decrease of binding of the radiotracer generated from [C-11]CMGDE in all brain areas with the highest decrease in the striatum 31.5 +/- 3.2%. The results show [C-11]CMGDE is the first PET tracer that is brain penetrating and can be used to image group II mGluRs in vivo. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Wang, Ji-Quan; Zhang, Zhaoda; Kuruppu, Darshini; Brownell, Anna-Liisa] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Biomed Imaging Ctr, Charlestown, MA USA. RP Brownell, AL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Biomed Imaging Ctr, 149 13th St, Charlestown, MA USA. EM abrownell@partners.org FU NIH-NIBIB [R01EB-012864]; NIH-NIMH [R01MH-091684] FX This work was supported by the NIH-NIBIB R01EB-012864 and NIH-NIMH R01MH-091684 to A-LB. NR 21 TC 7 Z9 7 U1 0 U2 5 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 MAR 1 PY 2012 VL 22 IS 5 BP 1958 EP 1962 DI 10.1016/j.bmcl.2012.01.039 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 894UA UT WOS:000300451200025 PM 22318160 ER PT J AU Hicks, JW Wilson, AA Rubie, EA Woodgett, JR Houle, S Vasdev, N AF Hicks, Justin W. Wilson, Alan A. Rubie, Elizabeth A. Woodgett, James R. Houle, Sylvain Vasdev, Neil TI Towards the preparation of radiolabeled 1-aryl-3-benzyl ureas: Radiosynthesis of [C-11-carbonyl] AR-A014418 by [C-11]CO2 fixation SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Glycogen synthase kinase; AR-A014418; Carbon-11; CO2 fixation; In vitro; PET ID PET; INHIBITORS; VERSATILE; MONOXIDE; CARRIER; AGENT; GSK3 AB The highly selective glycogen synthase kinase-3 (GSK-3) inhibitor N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl) urea (AR-A014418) was radiolabeled with carbon-11 (C-11; half-life = 20.4 min) at the urea moiety via [C-11]CO2 fixation. Reaction of [C-11]CO2 with 4-methoxybenzylamine in the presence of a CO2 fixating base was followed by dehydration with POCl3 and addition of 2-amino-5-nitrothiazole to prepare [C-11-carbonyl] AR-A014418. This reaction resulted in an 8% uncorrected radiochemical yield, based on [C-11]CO2, with high specific activity (4 Ci/mu mol) within 30 min. An in vitro GSK-3 beta enzyme activity assay revealed that AR-A014418 (K-i = 770 nM) is not as potent as previously claimed. The [C-11]CO2 fixation methodology described herein should prove generally applicable to preparing 1-aryl-3-benzyl-[C-11-carbonyl] ureas as radiotracers for positron emission tomography. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Hicks, Justin W.; Wilson, Alan A.; Houle, Sylvain; Vasdev, Neil] Univ Toronto, Inst Med Sci, Dept Psychiat, PET Ctr,Ctr Addict & Mental Hlth, Toronto, ON M5T 1R8, Canada. [Rubie, Elizabeth A.; Woodgett, James R.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Vasdev, N (reprint author), Massachusetts Gen Hosp, Dept Nucl Med & Mol Imaging, 55 Fruit St, Boston, MA 02114 USA. EM vasdev.neil@mgh.harvard.edu RI Wilson, Alan/A-1788-2011; Woodgett, Jim/F-1087-2010 OI Woodgett, Jim/0000-0003-3731-5797 FU Ontario Ministry of Research and Innovation FX The Ontario Ministry of Research and Innovation is acknowledged for financial support for this work in the form of an Early Researcher Award (N.V.). The authors thank Armando Garcia, Winston Stableford, and Min Wong for their expertise with the radiochemistry. NR 27 TC 13 Z9 13 U1 1 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 MAR 1 PY 2012 VL 22 IS 5 BP 2099 EP 2101 DI 10.1016/j.bmcl.2011.12.139 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 894UA UT WOS:000300451200051 PM 22321216 ER PT J AU Goodwin, JM Schmitt, AD McGinn, CM Fuchs, BC Kuruppu, D Tanabe, KK Lanuti, M AF Goodwin, Jonathan M. Schmitt, Anthony D. McGinn, Christopher M. Fuchs, Bryan C. Kuruppu, Darshini Tanabe, Kenneth K. Lanuti, Michael TI Angiogenesis Inhibition Using an Oncolytic Herpes Simplex Virus Expressing Endostatin in a Murine Lung Cancer Model SO CANCER INVESTIGATION LA English DT Article DE Herpes simplex virus; Viral oncolysis; Endostatin; Angiogenesis; Lung cancer ID MOUSE ENDOSTATIN; VIRAL ONCOLYSIS; TUMOR-GROWTH; PHASE-I; EFFICACY; THERAPY; MUTANT; CELLS; REPLICATION; COMBINATION AB Herpes-mediated viral oncolysis alone is not sufficient to completely eradicate tumors. In this study we used a replication conditional, endostatin-expressing herpes simplex virus-1 mutant (HSV-Endo) in a murine lung cancer model. We hypothesized that the anti-angiogenic action of endostatin would improve upon the oncolytic effect of HSV-1. HSV-Endo was evaluated in a pulmonary metastases and orthotopic flank model, where there was significantly less tumor burden and reduced microvessel density compared to a control virus. Endostatin expression appears to improve the anti-tumor effect of HSV-1 in a lung cancer model. C1 [Goodwin, Jonathan M.; Schmitt, Anthony D.; McGinn, Christopher M.; Lanuti, Michael] Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, Boston, MA 02114 USA. [Fuchs, Bryan C.; Kuruppu, Darshini; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lanuti, M (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. EM Mlanuti@partners.org FU Department of Surgery, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA FX This work was supported by departmental funds from the Department of Surgery, Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA. NR 32 TC 6 Z9 7 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0735-7907 J9 CANCER INVEST JI Cancer Invest. PD MAR PY 2012 VL 30 IS 3 BP 243 EP 250 DI 10.3109/07357907.2012.654870 PG 8 WC Oncology SC Oncology GA 897NI UT WOS:000300657200007 PM 22360364 ER PT J AU LeTourneau, JL Pinney, J Phillips, CR AF LeTourneau, Jennifer L. Pinney, Jamie Phillips, Charles R. TI Extravascular lung water predicts progression to acute lung injury in patients with increased risk SO CRITICAL CARE MEDICINE LA English DT Article DE acute lung injury; extravascular lung water; physiologic dead-space fraction; pulmonary edema; pulmonary permeability index; thermodilution; transpulmonary ID RESPIRATORY-DISTRESS-SYNDROME; RANDOMIZED CONTROLLED-TRIAL; CRITICALLY ILL PATIENTS; INTENSIVE-CARE-UNIT; LOWER TIDAL VOLUMES; TRANSPULMONARY THERMODILUTION; BODY-WEIGHT; CLINICAL-TRIAL; VENTILATION; SEVERITY AB Objectives: To compare the extravascular lung water index and other markers of disease severity in patients with acute lung injury vs. patients at risk for development of acute lung injury and to determine their ability to predict progression to acute lung injury in patients at risk. Design: Extravascular lung water index, dead space fraction, Pao(2)/Fio(2), and other markers of disease severity were measured prospectively in 29 patients daily for 5 days after admission to the intensive care unit. Patients had acute lung injury as defined by the American European Consensus Committee criteria or had risk factors for development of it. Setting: The intensive care units of an academic tertiary referral hospital. Measurements and Main Results: The mean extravascular lung water index on day 1 for patients who progressed to acute lung injury was higher than for those who did not (15.5 +/- 7.4 mL/kg vs. 8.7 +/- 2.3 mL/kg; p = .04). None of the other physiologic parameters tested discriminated progression to acute lung injury to include the mean physiologic dead space (0.61 +/- 0.06] vs. 0.59 +/- 0.10; p = .67), Pao(2)/Fio(2) ratio (322 +/- 35 vs. 267 +/- 98; p = .15), and static lung compliance (30.9 +/- 13.5 vs. 38.5 +/- 11.7; p = .24). An extravascular lung water index cutoff value on day 1 of 10 mL/kg had a 63% sensitivity, 88% specificity, positive predictive value of 83%, and negative predictive value of 70% to predict progression to acute lung injury. There was no difference in extravascular lung water index between those who progressed to acute lung injury vs. those who had acute lung injury (14.3 +/- 4.7 vs. 15.5 +/- 7.4; P = .97). Conclusions: Elevated extravascular lung water index is a feature of early acute lung injury and discriminates between those with acute lung injury and those without. Furthermore, extravascular lung water index predicts progression to acute lung injury in patients with risk factors for development of acute lung injury 2.6 +/- 0.3 days before the patients meet American European Consensus Committee criteria for it. These 2.6 +/- 0.3 days may then represent missed opportunity for therapeutic intervention and improved outcome. (Crit Care Med 2012; 40:847-854) C1 [LeTourneau, Jennifer L.] Portland VA Med Ctr, Pulm Dis Sect, Portland, OR 97239 USA. [LeTourneau, Jennifer L.; Pinney, Jamie; Phillips, Charles R.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Ctr Intens Care Res, Portland, OR 97201 USA. RP LeTourneau, JL (reprint author), Portland VA Med Ctr, Pulm Dis Sect, 3710 SW US Vet Hosp Rd,P3PULM, Portland, OR 97239 USA. EM Jennifer.Letourneau@va.gov FU Medical Research Foundation, Oregon Health & Science University, Portland, Oregon; Center of Excellence in Human Research, Oregon Health & Science University, Portland, Oregon; Oregon Clinical and Translational Research Institute (OCTRI); National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1 RR024140]; NIH Roadmap for Medical Research; MAB FX Supported, in part, by Medical Research Foundation, Oregon Health & Science University, Portland, Oregon; Center of Excellence in Human Research, Oregon Opportunity Funds, Oregon Health & Science University, Portland, Oregon; the Oregon Clinical and Translational Research Institute (OCTRI); grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH); and NIH Roadmap for Medical Research.; Dr. Phillips consulted for and received honoraria/speaking fees from MAB. The remaining authors have not disclosed any potential conflicts of interest. NR 43 TC 41 Z9 48 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 847 EP 854 DI 10.1097/CCM.0b013e318236f60e PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800019 PM 22036857 ER PT J AU Ackerman, HC Carroll, RW Casals-Pascual, C AF Ackerman, Hans C. Carroll, Ryan W. Casals-Pascual, Climent TI A better biomarker for cerebral malaria: In the eye of the beheld? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE angiopoietin; biomarker; cerebral malaria; endothelium; malaria; nitric oxide; retinopathy; sensitivity; specificity ID FALCIPARUM-MALARIA; AFRICAN CHILDREN; NITRIC-OXIDE; ANGIOPOIETIN-2; INDICATORS; LIGAND; TIE2 C1 [Ackerman, Hans C.] NIAID, Lab Malaria & Vector Res, Rockville, MD 20892 USA. [Carroll, Ryan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Crit Care Med, Boston, MA USA. [Carroll, Ryan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Anesthesiol Ctr Crit Care Res, Boston, MA USA. [Casals-Pascual, Climent] Wellcome Trust Ctr Human Genet, Oxford, England. RP Ackerman, HC (reprint author), NIAID, Lab Malaria & Vector Res, Rockville, MD 20892 USA. FU Intramural NIH HHS [ZIA AI001150-02]; Medical Research Council [G0701885] NR 18 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 1018 EP 1020 DI 10.1097/CCM.0b013e31823d7810 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800063 PM 22343865 ER PT J AU Kacmarek, RM Villar, J AF Kacmarek, Robert M. Villar, Jesus TI Noisy ventilation. When is it normal? Reply SO CRITICAL CARE MEDICINE LA English DT Letter C1 [Kacmarek, Robert M.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Multidisciplinary Organ Dysfunct Evaluat Res Netw, Las Palmas Gran Canaria, Spain. [Villar, Jesus] Inst Salud Carlos III, CIBER Enfermedades Resp, Las Palmas Gran Canaria, Spain. RP Kacmarek, RM (reprint author), Harvard Univ, Sch Med, Boston, MA 02215 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2012 VL 40 IS 3 BP 1036 EP 1036 DI 10.1097/CCM.0b013e31824102f6 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 895YO UT WOS:000300532800078 ER PT J AU Dudzinski, DM Mak, GS Hung, JW AF Dudzinski, David M. Mak, Gary S. Hung, Judy W. TI Pericardial Diseases SO CURRENT PROBLEMS IN CARDIOLOGY LA English DT Review ID EXPERIMENTAL CARDIAC-TAMPONADE; RECURRENT ACUTE PERICARDITIS; CONSTRICTIVE PERICARDITIS; CONSECUTIVE PATIENTS; ETIOLOGIC DIAGNOSIS; CONGENITAL ABSENCE; MEDICAL PATIENTS; PR-SEGMENT; MODERN-ERA; EFFUSION AB The pericardium provides an enclosed lubricated space for the beating heart and functions to fix the heart in the chest cavity relative to adjacent organs. Pericardial pathophysiology is often manifested in a spectrum of distinct cardiac and systemic disease states. The pericardial response to injury typically involves a spectrum of inflammation with both acute and chronic features and/or fluid accumulation. Recent advances in imaging methods have refined the diagnosis and therapy of pericardial disease. This article presents the anatomy and physiology of pericardial disease and the clinical approach for diagnosis and treatment. (Curr Probl Cardiol 2012;37:75-118.) C1 [Dudzinski, David M.; Mak, Gary S.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hung, Judy W.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Hung, Judy W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Dudzinski, DM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. FU Lippincott Williams and Wilkins FX David M. Dudzinski has received payment from Lippincott Williams and Wilkins for authorship of a medical review manual unrelated to this topic and has nothing else to disclose. Gary Mak and Judy Hung have no conflicts of interest to disclose. NR 82 TC 24 Z9 25 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0146-2806 J9 CURR PROB CARDIOLOGY JI Curr. Probl. Cardiol. PD MAR PY 2012 VL 37 IS 3 BP 75 EP 118 DI 10.1016/j.cpcardiol.2011.10.002 PG 44 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 895CZ UT WOS:000300475100002 PM 22289657 ER PT J AU Hansen, P Barry, D Restell, A Sylvia, D Magnin, O Dombkowski, D Preffer, F AF Hansen, P. Barry, D. Restell, A. Sylvia, D. Magnin, O. Dombkowski, D. Preffer, F. TI Physics of a rapid CD4 lymphocyte count with colloidal gold SO CYTOMETRY PART A LA English DT Article DE CD4 lymphocytes; nanoparticles; point of care; light scatter; cytometry AB The inherent surface charges and small diameters that confer colloidal stability to gold particle conjugates (immunogold) are detrimental to rapid cell surface labeling and distinct cluster definition in flow cytometric light scatter assays. Although the inherent immunogold surface charge prevents self aggregation when stored in liquid suspension, it also slows binding to cells to timeframes of hours and inhibits cell surface coverage. Although the small diameter of immunogold particles prevents settling when in liquid suspension, small particles have small light scattering cross sections and weak light scatter signals. We report a new, small particle lyophilized immunogold reagent that maintains activity after 42 degrees C storage for a year and can be rapidly dissolved into stable liquid suspension for use in labelling cells with larger particle aggregates that have enhanced scattering cross section. Labeling requires less than 1 min at 20 degrees C, which is similar to 30 times faster than customary fluorescent antibody labeling. The labeling step involves neutralizing the surface charge of immunogold and creating specifically bound aggregates of gold on the cell surface. This process provides distinct side-scatter cluster separation with blue laser light at 488 nm, which is further improved by using red laser light at 640 nm. Similar comparisons using LED light sources showed less improvement with red light, thereby indicating that coherent light scatter is of significance in enhancing side-scatter cluster separation. The physical principles elucidated here for this technique are compatible with most flow cytometers; however, future studies of its clinical efficacy should be of primary interest in point-of-care applications where robust reagents and rapid results are important. (C) 2011 International Society for Advancement of Cytometry C1 [Hansen, P.] Union Biometr Technol Inc, Canaan, NY 12029 USA. [Barry, D.; Restell, A.; Sylvia, D.] PointCare Technol Inc, Marlborough, MA USA. [Magnin, O.] C2 Diagnost, Montpellier, France. [Dombkowski, D.; Preffer, F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hansen, P (reprint author), Union Biometr Technol Inc, 121 Top Dean Hill Rd,PO 315, Canaan, NY 12029 USA. EM phansen5488@gmail.com NR 12 TC 1 Z9 1 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAR PY 2012 VL 81A IS 3 BP 222 EP 231 DI 10.1002/cyto.a.21139 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897SQ UT WOS:000300677100007 PM 21990088 ER PT J AU Wang, LM Lovejoy, NF Faustman, DL AF Wang, Limei Lovejoy, Nicholas Fraser Faustman, Denise L. TI Persistence of Prolonged C-peptide Production in Type 1 Diabetes as Measured With an Ultrasensitive C-peptide Assay SO DIABETES CARE LA English DT Article ID BETA-CELL FUNCTION; RESIDUAL INSULIN PRODUCTION; GLYCEMIC CONTROL; SECRETION; ONSET; AUTOANTIBODIES; PREVALENCE; DIAGNOSIS; CHILDREN; MELLITUS AB OBJECTIVE-To examine persistence of C-peptide production by ultrasensitive assay years after onset of type 1 diabetes and factors associated with preserving beta-cell function. RESEARCH DESIGN AND METHODS-Serum C-peptide levels, a marker of insulin production and surviving beta-cells, were measured in human subjects (n = 182) by ultrasensitive assay, as was beta-cell functioning. Twenty-two times more sensitive than standard assays, this assay's lower detection limit is 1.5 pmol/L. Disease duration, age at onset, age, sex, and autoantibody titers were analyzed by regression analysis to determine their relationship to C-peptide production. Another group of four patients was serially studied for up to 20 weeks to examine C-peptide levels and functioning. RESULTS-The ultrasensitive assay detected C-peptide in 10% of individuals 31-40 years after disease onset and with percentages higher at shorter duration. Levels as low as 2.8 +/- 1.1 pmol/L responded to hyperglycemia with increased C-peptide production, indicating residual beta-cell functioning. Several other analyses showed that beta-cells, whose C-peptide production was formerly undetectable, were capable of functioning. Multivariate analysis found disease duration (beta = -2.721; P = 0.005) and level of zinc transporter 8 autoantibodies (beta = 0.127; P = 0.015) significantly associated with C-peptide production. Unexpectedly, onset at >40 years of age was associated with low C-peptide production, despite short disease duration. CONCLUSIONS-The ultrasensitive assay revealed that C-peptide production persists for decades after disease onset and remains functionally responsive. These findings suggest that patients with advanced disease, whose beta-cell function was thought to have long ceased, may benefit from interventions to preserve beta-cell function or to prevent complications. C1 [Wang, Limei; Lovejoy, Nicholas Fraser; Faustman, Denise L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Immunobiol Labs, Boston, MA 02114 USA. RP Faustman, DL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Immunobiol Labs, Boston, MA 02114 USA. EM faustman@helix.mgh.harvard.edu FU Iacocca Foundation FX This study was supported by the Iacocca Foundation. NR 23 TC 51 Z9 51 U1 2 U2 6 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 MAR PY 2012 VL 35 IS 3 BP 465 EP 470 DI 10.2337/dc11-1236 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FI UT WOS:000300801400004 PM 22355018 ER PT J AU Cavallerano, JD Silva, PS Tolson, AM Francis, T Tolls, D Patel, B Eagan, S Aiello, LM Aiello, LP AF Cavallerano, Jerry D. Silva, Paolo S. Tolson, Ann M. Francis, Taniya Tolls, Dorothy Patel, Bina Eagan, Sharon Aiello, Lloyd M. Aiello, Lloyd P. TI Imager Evaluation of Diabetic Retinopathy at the Time of Imaging in a Telemedicine Program SO DIABETES CARE LA English DT Article AB OBJECTIVE-To evaluate the ability of certified retinal imagers to identify presence versus absence of sight-threatening diabetic retinopathy (stDR) (moderate nonproliferative diabetic retinopathy or worse or diabetic macular edema) at the time of retinal imaging in a telemedicine program. RESEARCH DESIGN AND METHODS-Diabetic patients in a primary care setting or specialty diabetes clinic received Joslin Vision Network protocol retinal imaging as part of their care. Trained nonphysician imagers graded the presence versus absence of stDR at the time of imaging. These gradings were compared with masked gradings of certified readers. RESULTS-Of 158 patients (316 eyes) imaged, all cases of stDR (42 eyes [13%]) were identified by the imagers at the time of imaging. Six eyes with mild nonproliferative diabetic retinopathy were graded by the imagers to have stDR (sensitivity 1.00, 95% CI 0.90-1.00; specificity 0.97, 0.94-0.99). CONCLUSIONS-Appropriately trained imagers can accurately identify stDR at the time of imaging. C1 [Cavallerano, Jerry D.; Silva, Paolo S.; Tolson, Ann M.; Francis, Taniya; Tolls, Dorothy; Patel, Bina; Eagan, Sharon; Aiello, Lloyd M.; Aiello, Lloyd P.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Cavallerano, Jerry D.; Silva, Paolo S.; Aiello, Lloyd M.; Aiello, Lloyd P.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Patel, Bina] New England Coll Optometry, Boston, MA USA. RP Silva, PS (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. EM paoloantonio.silva@joslin.havard.edu NR 13 TC 8 Z9 8 U1 1 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2012 VL 35 IS 3 BP 482 EP 484 DI 10.2337/dc11-1317 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FI UT WOS:000300801400007 PM 22238278 ER PT J AU Benedict, C Brooks, SJ Kullberg, J Burgos, J Kempton, MJ Nordenskjold, R Nylander, R Kilander, L Craft, S Larsson, EM Johansson, L Ahlstrom, H Lind, L Schioth, HB AF Benedict, Christian Brooks, Samantha J. Kullberg, Joel Burgos, Jonathan Kempton, Matthew J. Nordenskjold, Richard Nylander, Ruta Kilander, Lena Craft, Suzanne Larsson, Elna-Marie Johansson, Lars Ahlstrom, Hakan Lind, Lars Schioth, Helgi B. TI Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly SO DIABETES CARE LA English DT Article ID MIDDLE-AGED ADULTS; ALZHEIMERS-DISEASE; BRAIN; MEMORY; HUMANS; SEGMENTATION; PATHOGENESIS; RESISTANCE; LANGUAGE; ANATOMY AB OBJECTIVE-Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. RESEARCH DESIGN AND METHODS-Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants. also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume). RESULTS-The HOMA-IR was negatively correlated with verbal fluency performance, brain size, and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses. CONCLUSIONS-These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies. C1 [Benedict, Christian; Brooks, Samantha J.; Burgos, Jonathan; Schioth, Helgi B.] Uppsala Univ, Dept Neurosci, Uppsala, Sweden. [Kullberg, Joel; Nordenskjold, Richard; Nylander, Ruta; Larsson, Elna-Marie; Johansson, Lars; Ahlstrom, Hakan] Uppsala Univ, Dept Radiol, Uppsala, Sweden. [Kempton, Matthew J.] Kings Coll London, Dept Neuroimaging, London WC2R 2LS, England. [Kilander, Lena] Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden. [Craft, Suzanne] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Vet Affairs Puget Sound Hlth Care Syst,Geriatr Re, Seattle, WA 98195 USA. [Lind, Lars] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. RP Benedict, C (reprint author), Uppsala Univ, Dept Neurosci, Uppsala, Sweden. EM christian.benedict@neuro.uu.se RI Kempton, Matthew/F-8683-2011; OI Kempton, Matthew/0000-0003-3541-9947; Benedict, Christian/0000-0002-8911-4068 FU Swedish Research Council; Brain Research Foundation (Sweden); Olle Engkvist Byggmastare Foundation (Sweden); Tore Nilsons Foundation (Sweden); Gunvor och Josef Aners Foundation (Sweden); Ake Wibergs Foundation (Sweden); Ahlens Foundation (Sweden); Uppsala University (Sweden); Novo Nordisk (Denmark); AstraZeneca (Sweden) FX This study was funded by the Swedish Research Council, the Brain Research Foundation (Sweden), the Olle Engkvist Byggmastare Foundation (Sweden), the Tore Nilsons Foundation (Sweden), the Gunvor och Josef Aners Foundation (Sweden), the Ake Wibergs Foundation (Sweden), the Ahlens Foundation (Sweden), and Uppsala University (Sweden).; Funding for the study also was provided by Novo Nordisk (Denmark) and AstraZeneca (Sweden). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, or approval of the manuscript. No other potential conflicts of interest relevant to this article were reported. NR 41 TC 43 Z9 45 U1 0 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2012 VL 35 IS 3 BP 488 EP 494 DI 10.2337/dc11-2075 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FI UT WOS:000300801400009 PM 22301128 ER PT J AU Pittas, AG Nelson, J Mitri, J Hillmann, W Garganta, C Nathan, DM Hu, FB Dawson-Hughes, B AF Pittas, Anastassios G. Nelson, Jason Mitri, Joanna Hillmann, William Garganta, Cheryl Nathan, David M. Hu, Frank B. Dawson-Hughes, Bess CA Diabet Prevention Program Res Grp TI Plasma 25-Hydroxyvitamin D and Progression to Diabetes in Patients at Risk for Diabetes An ancillary analysis in the Diabetes Prevention Program SO DIABETES CARE LA English DT Article ID VITAMIN-D SUPPLEMENTATION; RANDOMIZED CONTROLLED-TRIAL; LIFE-STYLE; BASE-LINE; METABOLIC SYNDROME; CALCIUM INTAKE; BLOOD-GLUCOSE; SERUM; WOMEN; MELLITUS AB OBJECTIVE-To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes. RESEARCH DESIGN AND METHODS-Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying "lagged" covariates, as the mean of the previous and current visits at which diabetes status was assessed. RESULTS-After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56-0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52-0.94) versus lifestyle arm (0.80; 0.54-1.17). CONCLUSIONS-Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies. C1 [Pittas, Anastassios G.; Mitri, Joanna; Dawson-Hughes, Bess] Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA. [Nelson, Jason] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA USA. [Hillmann, William] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Garganta, Cheryl] Tufts Med Ctr, Floating Hosp Children, Boston, MA USA. [Nathan, David M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Nathan, David M.] Harvard Univ, Sch Med, Boston, MA USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hu, Frank B.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Dawson-Hughes, Bess] Tufts Univ, Bone Metab Lab, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Pittas, AG (reprint author), Tufts Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA USA. EM apittas@tuftsmedicalcenter.org FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-DK-76092, R01-DK-79003]; National Institutes of Health; National Institutes of Health Office of Dietary Supplements [UL1RR025752]; National Center for Research Resources; U.S. Department of Agriculture [58-1950-9001]; Endocrine Fellows Foundation; NIDDK [UO1-DK-48489]; Indian Health Service; National Institute of Child Health and Human Development; National Institute on Aging; National Eye Institute; National Heart, Lung, and Blood Institute; Office of Research on Women's Health; National Center for Minority Health and Human Disease; Centers for Disease Control and Prevention; American Diabetes Association FX This work was supported by grants R01-DK-76092 and R01-DK-79003 (to A.G.P.) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institutes of Health, and the National Institutes of Health Office of Dietary Supplements; Grant UL1RR025752 (to Tufts University) from the National Center for Research Resources; the U.S. Department of Agriculture Agreement 58-1950-9001 (to B.D.-H.); the Marilyn Fishman Grant for Diabetes Research (to J.M.) from the Endocrine Fellows Foundation; and Grant UO1-DK-48489 from the NIDDK to the DPP clinical centers and the Coordinating Center for the design and conduct of the DPP study. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, 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 was also provided by the National Institute of Child Health and Human Development; the National Institute on Aging; the National Eye Institute; the National Heart, Lung, and Blood Institute; the Office of Research on Women's Health; the National Center for Minority Health and Human Disease; the Centers for Disease Control and Prevention; the Indian Health Service; and the American Diabetes Association. NR 40 TC 56 Z9 60 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2012 VL 35 IS 3 BP 565 EP 573 DI 10.2337/dc11-1795 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FI UT WOS:000300801400022 PM 22323410 ER PT J AU Taylor, RM Tujios, S Jinjuvadia, K Davern, T Shaikh, OS Han, S Chung, RT Lee, WM Fontana, RJ AF Taylor, Ryan M. Tujios, Shannan Jinjuvadia, Kartik Davern, Timothy Shaikh, Obaid S. Han, Steve Chung, Raymond T. Lee, William M. Fontana, Robert J. TI Short and Long-Term Outcomes in Patients with Acute Liver Failure Due to Ischemic Hepatitis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Liver transplantation; Hypoxic hepatitis; Aminotransferase levels; Coagulopathy; Encephalopathy ID HYPOXIC HEPATITIS; TRANSPLANTATION; PROGNOSIS; DISEASE; INJURY AB The purpose of this study is to describe the incidence and presenting features of patients with acute liver failure (ALF) due to ischemic hepatitis and the prognostic factors associated with short (three-week) and long-term outcomes. Retrospective cohort analysis of adult patients enrolled in the Acute Liver Failure Study Group between 1998 and 2008 with ALF due to ischemic hepatitis. Predictors of adverse outcomes three weeks after presentation were identified by univariate and multivariate analysis. Ischemic hepatitis accounted for 51 (4.4%) of the 1147 ALF patients enrolled. Mean age was 50 years, 63% were female, and only 31% had known heart disease before presentation. However, a cardiopulmonary precipitant of hepatic ischemia was identified in 69%. Three-week spontaneous survival was 71%, two patients (4%) underwent liver transplantation, and the remaining 13 patients (25%) died of multi-organ failure. Adverse outcomes were more frequent in subjects with higher admission phosphate levels (HR 1.3, 95% CI 1.1-1.6, P = 0.008) and in subjects with grade 3/4 encephalopathy at presentation (HR: 8.4, 95% CI 1.1-66.5, P = 0.04). Nineteen of the 28 short-term survivors (68%) were still alive at a median follow-up of 3.7 years whereas nine (32%) others had died at a median follow-up of 2 months. A higher admission serum phosphate level and more advanced encephalopathy are associated with a lower likelihood of short-term survival of hospitalized patients with ALF due to ischemic hepatitis. Long-term outcomes are largely determined by underlying cardiovascular morbidity and mortality. C1 [Tujios, Shannan; Jinjuvadia, Kartik; Fontana, Robert J.] Univ Michigan, Sch Med, Dept Internal Med, Med Ctr,Taubman Ctr 3912, Ann Arbor, MI 48109 USA. [Taylor, Ryan M.] Univ Kansas, Dept Internal Med, Kansas City, KS USA. [Davern, Timothy] Calif Pacific Med Ctr, San Francisco, CA USA. [Shaikh, Obaid S.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Han, Steve] Univ Calif Los Angeles, Los Angeles, CA USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Fontana, RJ (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Med Ctr,Taubman Ctr 3912, Ann Arbor, MI 48109 USA. EM rtaylor2@kumc.edu; Shannan.Tujios@UTSouthwestern.edu; kartik.jinjuvadia@gmail.com; davernt@sutterhealth.org; obiad@pitt.edu; steven.han@ucla.edu; rtchung@partners.org; william.lee@utsouthwestern.edu; rfontana@med.umich.edu FU NIH [DK U-01 58369]; National Institute of Diabetes, Digestive, and Kidney Disease; Northwestern Medical Foundation; Southwestern Medical Foundation [T-32 DK007745-12] FX We gratefully acknowledge the support provided by the members of The Acute Liver Failure Study Group 1998-2008. This study was funded by NIH grant DK U-01 58369 for the Acute Liver Failure Study Group provided by the National Institute of Diabetes, Digestive, and Kidney Disease. Additional funding was provided by the Tips Fund of the Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation, and T-32 DK007745-12 to DD. NR 23 TC 11 Z9 13 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD MAR PY 2012 VL 57 IS 3 BP 777 EP 785 DI 10.1007/s10620-011-1918-1 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 896OQ UT WOS:000300578200026 PM 21948394 ER PT J AU Taborsky, GJ Mundinger, TO AF Taborsky, Gerald J., Jr. Mundinger, Thomas O. TI Minireview: The Role of the Autonomic Nervous System in Mediating the Glucagon Response to Hypoglycemia SO ENDOCRINOLOGY LA English DT Review ID PANCREATIC SYMPATHETIC-NERVES; INSULIN-INDUCED HYPOGLYCEMIA; DIABETIC-RATS; VENTROMEDIAL HYPOTHALAMUS; SECRETION; DOG; HORMONE; HUMANS; ISLETS; COUNTERREGULATION AB In type 1 diabetes, the impairment of the glucagon response to hypoglycemia increases both its severity and duration. In nondiabetic individuals, hypoglycemia activates the autonomic nervous system, which in turn mediates the majority of the glucagon response to moderate and marked hypoglycemia. The first goal of this minireview is therefore to illustrate and document these autonomic mechanisms. Specifically we describe the hypoglycemic thresholds for activating the three autonomic inputs to the islet (parasympathetic nerves, sympathetic nerves, and adrenal medullary epinephrine) and their magnitudes of activation as glucose falls from euglycemia to near fatal levels. The implication is that their relative contributions to this glucagon response depend on the severity of hypoglycemia. The second goal of this minireview is to discuss known and suspected down-regulation or damage to these mechanisms in diabetes. We address defects in the central nervous system, the peripheral nervous system, and in the islet itself. They are categorized as either functional defects caused by glucose dysregulation or structural defects caused by the autoimmune attack of the islet. In the last section of the minireview, we outline approaches for reversing these defects. Such reversal has both scientific and clinical benefit. Scientifically, one could determine the contribution of these defects to the impairment of glucagon response seen early in type 1 diabetes. Clinically, restoring this glucagon response would allow more aggressive treatment of the chronic hyperglycemia that is linked to the debilitating long-term complications of this disease. (Endocrinology 153: 1055-1062, 2012) C1 [Taborsky, Gerald J., Jr.; Mundinger, Thomas O.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Taborsky, GJ (reprint author), Div Endocrinol & Metab 151, 1660 S Columbian Way, Seattle, WA 98108 USA. EM taborsky@u.washington.edu FU NIDDK NIH HHS [P30 DK017047, R01 DK050154] NR 35 TC 38 Z9 38 U1 1 U2 12 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2012 VL 153 IS 3 BP 1055 EP 1062 DI 10.1210/en.2011-2040 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897JG UT WOS:000300645600012 PM 22315452 ER PT J AU Yang, JJ Caligioni, CS Chan, YM Seminara, SB AF Yang, Jasmine J. Caligioni, Claudia S. Chan, Yee-Ming Seminara, Stephanie B. TI Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men SO ENDOCRINOLOGY LA English DT Article ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; MONKEY MACACA-MULATTA; KALLMANN-SYNDROME; ARCUATE NUCLEUS; PREOPTIC AREA; GNRH NEURONS; GONADOTROPIN-SECRETION; TACHYKININ RECEPTORS; HORMONE RELEASE; TACR3 MUTATIONS AB Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3(-/-) mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, andfertility. Tacr3(-/-) mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3(-/-) males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3(-/-) females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3(-/-) females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3(-/-) females achieved fertility when mated. However, Tacr3(-/-) females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release. (Endocrinology 153: 1498-1508, 2012) C1 [Yang, Jasmine J.; Caligioni, Claudia S.; Chan, Yee-Ming; Seminara, Stephanie B.] Massachusetts Gen Hosp, Harvard Reprod Sci Ctr, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. RP Seminara, SB (reprint author), 55 Fruit St,Bartlett Hall Extens 5, Boston, MA 02114 USA. EM seminara.stephanie@mgh.harvard.edu FU National Institutes of Health (NIH) [U54 HD028138, T32 HD07396]; Charles A. King Trust; Children's Hospital Boston FX This work was supported by National Institutes of Health (NIH) Grant U54 HD028138, NIH Grant T32 HD07396 (to J.Y.Y. and C. S. C.), and a Charles A. King Trust Postdoctoral Fellowship and a Children's Hospital Boston Career Development Award (Y.-M.C.). NR 60 TC 50 Z9 51 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2012 VL 153 IS 3 BP 1498 EP 1508 DI 10.1210/en.2011-1949 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 897JG UT WOS:000300645600052 PM 22253416 ER PT J AU Demetri, GD Le Cesne, A Chawla, SP Brodowicz, T Maki, RG Bach, BA Smethurst, DP Bray, S Hei, YJ Blay, JY AF Demetri, George D. Le Cesne, Axel Chawla, Sant P. Brodowicz, Thomas Maki, Robert G. Bach, Bruce A. Smethurst, Dominic P. Bray, Sarah Hei, Yong-jiang Blay, Jean-Yves TI First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: A Phase I/II open-label and double-blind study SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Conatumumab; Doxorubicin; Soft tissue sarcomas; Death receptor 5; TRAIL ID IFOSFAMIDE PLUS DOXORUBICIN; STANDARD-DOSE DOXORUBICIN; DEATH RECEPTOR 5; EUROPEAN ORGANIZATION; SOLID TUMORS; II TRIAL; BONE; APOPTOSIS; CANCER; CHEMOTHERAPY AB Background: Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin +/- conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma. Methods: In Phase I, six patients received doxorubicin (75 mg/m(2)) with conatumumab (15 mg/kg) every 3 weeks. In Phase II, patients were randomised (2:1) to receive doxorubicin with either double-blind conatumumab 15 mg/kg (conatumumab-doxorubicin; n = 86) or placebo (placebo-doxorubicin; n = 42). Patients who progressed on placebo-doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy (n = 21). Findings: The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4 months in the conatumumab-doxorubicin and placebo-doxorubicin arms, respectively (stratified HR: 1.00; p = 0.973), with more early progressions noted in the first 3.5 months in the conatumumab-doxorubicin arm. Median overall survival was not reached after 8.6 months median follow-up in either arm. Common adverse events were nausea (conatumumab-doxorubicin: 66%; placebo-doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing. Interpretation: Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin. Funding: This study was supported by Amgen Inc. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Demetri, George D.] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. [Le Cesne, Axel] Inst Gustave Roussy, Villejuif, France. [Chawla, Sant P.] Sarcoma Oncol Ctr, Santa Monica, CA USA. [Brodowicz, Thomas] Med Univ Vienna, Gen Hosp, Vienna, Austria. [Maki, Robert G.] Mt Sinai Sch Med, New York, NY USA. [Bach, Bruce A.; Hei, Yong-jiang] Amgen Inc, Thousand Oaks, CA 91320 USA. [Smethurst, Dominic P.; Bray, Sarah] Amgen Ltd, Uxbridge, Middx, England. [Blay, Jean-Yves] Ctr Leon Berard, F-69373 Lyon, France. RP Demetri, GD (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 1212, Boston, MA 02215 USA. EM gdemetri@partners.org RI Blay, Jean-Yves/N-3966-2016; OI Blay, Jean-Yves/0000-0001-7190-120X; Bach, Bruce Allen/0000-0003-3535-9518 FU Amgen Inc. FX This study was supported by Amgen Inc. NR 29 TC 28 Z9 29 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2012 VL 48 IS 4 BP 547 EP 563 DI 10.1016/j.ejca.2011.12.008 PG 17 WC Oncology SC Oncology GA 898HD UT WOS:000300730300017 PM 22240283 ER PT J AU Refaat, MM Lubitz, SA Makino, S Islam, Z Frangiskakis, JM Mehdi, H Gutmann, R Zhang, ML Bloom, HL MacRae, CA Dudley, SC Shalaby, AA Weiss, R McNamara, DM London, B Ellinor, PT AF Refaat, Marwan M. Lubitz, Steven A. Makino, Seiko Islam, Zahid Frangiskakis, J. Michael Mehdi, Haider Gutmann, Rebecca Zhang, Michael L. Bloom, Heather L. MacRae, Calum A. Dudley, Samuel C. Shalaby, Alaa A. Weiss, Raul McNamara, Dennis M. London, Barry Ellinor, Patrick T. TI Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy SO HEART RHYTHM LA English DT Article DE Dilated cardiomyopathy; Genetics; Mutation; Single nucleotide polymorphism; RBM20 ID HEART-FAILURE; MUTATIONS; FREQUENCY; DISEASE; RELATIVES AB BACKGROUND Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous. OBJECTIVES We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes. METHODS Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of <= 30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects. RESULTS A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 +/- 13 years, 64% were males, and the mean follow-up time was 24.2 +/- 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44-0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047). CONCLUSIONS: Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers. C1 [Lubitz, Steven A.; Makino, Seiko; Zhang, Michael L.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Refaat, Marwan M.; Islam, Zahid; Frangiskakis, J. Michael; Mehdi, Haider; Gutmann, Rebecca; Shalaby, Alaa A.; McNamara, Dennis M.; London, Barry] Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Bloom, Heather L.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Dudley, Samuel C.] Univ Illinois, Cardiol Sect, Chicago, IL USA. [Weiss, Raul] Ohio State Univ, Med Ctr, Div Cardiovasc Med, Columbus, OH 43210 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM londonb@upmc.edu; pellinor@partners.org FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [UL1 RR024153]; NHLBI NIH HHS [R01 HL104156, R01 HL075431, K24 HL105780, R01 HL092577, R01 HL092577-04, R01 HL104156-03, K24 HL105780-03, R01 HL109264]; NIDA NIH HHS [R21 DA027021-02, R21 DA027021] NR 35 TC 35 Z9 36 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2012 VL 9 IS 3 BP 390 EP 396 DI 10.1016/j.hrthm.2011.10.016 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 898CJ UT WOS:000300712700019 PM 22004663 ER PT J AU Milan, DJ Acha, MR AF Milan, David J. Acha, Moshe Rav TI Recovery of myocardial tissue from extracted leads SO HEART RHYTHM LA English DT Editorial Material ID QT INTERVAL DURATION; COMMON VARIANTS; REPOLARIZATION; BIOMARKERS C1 [Milan, David J.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RP Milan, DJ (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM dmilan@partners.org NR 13 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 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2012 VL 9 IS 3 BP 405 EP 406 DI 10.1016/j.hrthm.2011.11.002 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 898CJ UT WOS:000300712700022 PM 22063082 ER PT J AU Armoundas, AA Mela, T Merchant, FM AF Armoundas, Antonis A. Mela, Theofanie Merchant, Faisal M. TI On the estimation of T-wave alternans using the spectral fast fourier transform method SO HEART RHYTHM LA English DT Article DE Arrhythmias; Alternans; Phase resetting; Random and colored noise ID SUDDEN CARDIAC DEATH; RISK STRATIFICATION; ISCHEMIC CARDIOMYOPATHY; ELECTRICAL ALTERNANS; HEART-FAILURE; VULNERABILITY; TRIAL; INFARCTION; PHASE AB BACKGROUND T-wave alternans (TWA) has been associated with increased vulnerability to ventricular tachyarrhythmias and sudden cardiac death. However, both random (white) noise and (patho)physiologic processes (ie, premature ventricular contractions and heart and respiration rates) may hamper TWA estimation and therefore lessen its clinical utility for risk stratification. OBJECTIVE To investigate the effect of random noise and certain (patho) physiologic processes on the estimation of TWA by using the fast Fourier transform method and to develop methods to overcome these potential sources of error. METHODS We used a combination of human electrocardiogram data and computer simulations to assess the effects of a premature ventricular contraction and random and colored noise on the accuracy of TWA estimation. RESULTS We quantitatively demonstrate that replacing a "bad" beat with an odd/even median beat is a more accurate approach than replacing it with the overall average or the overall median beat. We also show that phase resetting may have a significant effect on alternans estimation and that estimation of alternans by using frequencies >0.4922 cycles/beat in a 128-point fast Fourier transform provides the most accurate approach for estimating the alternans when phase resetting is likely to occur. In addition, our data demonstrate that the number of indeterminate TWA tests due to high levels of noise can be reduced when the alternans voltage exceeds a new higher threshold. Furthermore, the amplitude of random noise has a significant effect on alternans estimation and the alternans voltage threshold should be adjusted for noise levels >1.8 mu V. Finally, we quantitatively demonstrate that colored noise may lead to a false-positive or a false-negative result. We propose methods to estimate the effect of these (patho)physiologic processes on the alternans estimation in order to determine whether a TWA test is likely to be a true positive or a true negative. CONCLUSION This study introduces novel methods to overcome potential sources of error in the estimation of TWA. These methods may improve the utility of TWA either for ambulatory monitoring or for clinical risk stratification for ventricular arrhythmias and sudden cardiac death. C1 [Armoundas, Antonis A.; Mela, Theofanie; Merchant, Faisal M.] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Div Cardiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Armoundas, AA (reprint author), Harvard Univ, Sch Med, Cardiovasc Res Ctr, Div Cardiol,Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org FU American Heart Association [0635127N]; NIA [1R21 AG035128]; NIH [1RO1HL103961]; Center for Integration of Medicine and Innovative Technology (CIMIT); Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; Cardiovascular Research Society FX This work was supported by a Scientist Development Grant (0635127N) from the American Heart Association, NIA grant 1R21 AG035128, and NIH grant 1RO1HL103961. This work was also supported by a Fellowship and a Science Award from the Center for Integration of Medicine and Innovative Technology (CIMIT), the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke, and the Cardiovascular Research Society. T. Mela is involved with Medtronic, Boston Scientific, and St Jude. NR 21 TC 3 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD MAR PY 2012 VL 9 IS 3 BP 449 EP 456 DI 10.1016/j.hrthm.2011.10.013 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 898CJ UT WOS:000300712700029 PM 22001706 ER PT J AU Faghih, RT Savla, K Dahleh, MA Brown, EN AF Faghih, Rose T. Savla, Ketan Dahleh, Munther A. Brown, Emery N. TI Broad Range of Neural Dynamics From a Time-Varying FitzHugh-Nagumo Model and its Spiking Threshold Estimation SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Algorithms; biological system modeling; biomedical signal processing; parameter estimation ID CANONIC MODELS; OSCILLATORS; NEURONS; NERVE AB We study the use of the FitzHugh-Nagumo (FHN) model for capturing neural spiking. The FHN model is a widely used approximation of the Hodgkin-Huxley model that has significant limitations. In particular, it cannot produce the key spiking behavior of bursting. We illustrate that by allowing time-varying parameters for the FHN model, these limitations can be overcome while retaining its low-order complexity. This extension has applications in modeling neural spiking behaviors in the thalamus and the respiratory center. We demonstrate the use of the FHN model from an estimation perspective by presenting a novel parameter estimation method that exploits its multiple time-scale properties, and compare the performance of this method with the extended Kalman filter in several illustrative examples. We demonstrate that the dynamics of the spiking threshold can be recovered even in the absence of complete specifications for the system. C1 [Faghih, Rose T.; Dahleh, Munther A.] MIT, Lab Informat & Decis Syst, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Massachusetts Div Hlth Sci & Technol, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Faghih, Rose T.] MIT, Neurosci Stat Res Lab, Cambridge, MA 02139 USA. RP Faghih, RT (reprint author), MIT, Lab Informat & Decis Syst, Dept Elect Engn & Comp Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM rfaghih@mit.edu; ksavla@mit.edu; dahleh@mit.edu; enbrown1@mit.edu FU National Institutes of Health [DP1 OD003646]; National Science Foundation (NSF) [0836720]; Massachusetts Institute of Technology FX This work was supported in part by National Institutes of Health under Grant DP1 OD003646 and by the National Science Foundation (NSF) under Grant 0836720. The work of R. T. Faghih was supported in part by the Massachusetts Institute of Technology Fellowship in Control and NSF Graduate Fellowship. This paper was presented in part at the proceedings of the IEEE Engineering in Medicine and Biology Society Conference [5] and R. T. Faghih's Master's Thesis [6]. NR 23 TC 4 Z9 4 U1 2 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD MAR PY 2012 VL 59 IS 3 BP 816 EP 823 DI 10.1109/TBME.2011.2180020 PG 8 WC Engineering, Biomedical SC Engineering GA 895PK UT WOS:000300508400024 PM 22186931 ER PT J AU Growdon, WB Rauh-Hain, JJA Cordon, A Garrett, L Schorge, JO Goodman, A Boruta, DM Horowitz, NS del Carmen, MG AF Growdon, Whitfield B. Rauh-Hain, J. Jose A. Cordon, Adriana Garrett, Leslie Schorge, John O. Goodman, Annekathryn Boruta, David M. Horowitz, Neil S. del Carmen, Marcela G. TI Prognostic Determinants in Patients With Stage I Uterine Papillary Serous Carcinoma A 15-Year Multi-Institutional Review SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER LA English DT Article DE Uterine papillary serous cancer; Stage; Endometrial cancer; Surgery ID PLATINUM-BASED CHEMOTHERAPY; CLEAR-CELL CARCINOMA; PHASE-II; ENDOMETRIAL CARCINOMA; RADIATION-THERAPY; SURVIVAL OUTCOMES; ADJUVANT THERAPY; ONCOLOGY-GROUP; CANCER; UPSC AB Objective: The aim of this retrospective, multi-institutional study was to evaluate the importance of surgical staging for stage I uterine papillary serous carcinomas (UPSCs) to determine optimal management of this rare tumor. Methods: With institutional review board approval from both participating institutions, all patients with 2009 International Federation of Gynecology and Obstetrics stage I mixed serous and UPSC diagnosed between January 1, 1992, and December 31, 2007, were identified at the 2 institutions. Clinical factors were correlated using Spearman correlation coefficients, Kaplan-Meier survival estimates and a Cox proportional hazards model. Results: Of the 204 UPSC patients treated during this period, 84 were classified as stage I, with substages as follows: stage IA, n = 71; stage IB, n = 13. Thirty-seven patients (44%) had a history of a second cancer (22 breast tumors, 9 synchronous mullerian cancers). Surgical staging with at least hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and bilateral pelvic lymph node dissection was performed in 60 (71%) of 84 patients. The median survival for all patients was 10 years. Univariate analysis revealed surgical staging (P < 0.001), normal preoperative CA-125 (P < 0.001), and absence of additional cancers (P < 0.01) to be associated with improved survival. Age-adjusted multivariate analysis incorporating these factors revealed that advancing substage (hazard ratio, 4.59; P < 0.05), a second malignancy (hazard ratio, 2.75; P < 0.04), and surgical staging (hazard ratio, 0.18; P G 0.001) were independent factors associated with overall survival. In a subset analysis excluding patients with a second malignancy, substage (hazard ratio, 3.52; P < 0.05), and surgical staging (hazard ratio, 0.16; P < 0.001) were independent factors affecting overall survival. Conclusions: Independent of adjuvant chemotherapy or radiation, stage of disease, comprehensive surgical staging, and the presence of a second malignancy were predictors of overall survival. C1 [Growdon, Whitfield B.; Rauh-Hain, J. Jose A.; Cordon, Adriana; Garrett, Leslie; Schorge, John O.; Goodman, Annekathryn; Boruta, David M.; del Carmen, Marcela G.] Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, Boston, MA 02114 USA. [Rauh-Hain, J. Jose A.; Horowitz, Neil S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gynecol Oncol, Boston, MA 02115 USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Div Gynecol Oncol Vincent Obstet & Gynecol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 30 TC 17 Z9 18 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1048-891X J9 INT J GYNECOL CANCER JI Int. J. Gynecol. Cancer PD MAR PY 2012 VL 22 IS 3 BP 417 EP 424 DI 10.1097/IGC.0b013e31823c6e36 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 898IN UT WOS:000300735900013 PM 22237383 ER PT J AU Rombi, B Delaney, TF Macdonald, SM Huang, MS Ebb, DH Liebsch, NJ Raskin, KA Yeap, BY Marcus, KJ Tarbell, NJ Yock, TI AF Rombi, Barbara Delaney, Thomas F. Macdonald, Shannon M. Huang, Mary S. Ebb, David H. Liebsch, Norbert J. Raskin, Kevin A. Yeap, Beow Y. Marcus, Karen J. Tarbell, Nancy J. Yock, Torunn I. TI PROTON RADIOTHERAPY FOR PEDIATRIC EWING'S SARCOMA: INITIAL CLINICAL OUTCOMES SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Proton radiation; Ewing's sarcoma ID ACUTE MYELOID-LEUKEMIA; PRIMITIVE NEUROECTODERMAL TUMOR; CHILDRENS-ONCOLOGY-GROUP; LONG-TERM SURVIVORS; RADIATION-THERAPY; NEOADJUVANT CHEMOTHERAPY; STANDARD CHEMOTHERAPY; 2ND MALIGNANCIES; CHILDHOOD-CANCER; LOCAL THERAPY AB Purpose: Proton radiotherapy (PT) has been prescribed similarly to photon radiotherapy to achieve comparable disease control rates at comparable doses. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. We report the preliminary clinical outcomes including late effects on our pediatric Ewing's sarcoma patients treated with PT at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (Boston, MA). Methods and Materials: This was a retrospective review of the medical records of 30 children with Ewing's sarcoma who were treated with PT between April 2003 and April 2009. Results: A total of 14 male and 16 female patients with tumors in several anatomic sites were treated with PT at a median age of 10 years. The median dose was 54 Gy (relative biological effectiveness) with a median follow-up of 38.4 months. The 3-year actuarial rates of event-free survival, local control, and overall survival were 60%, 86%, and 89%, respectively. PT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At the time of writing, the only serious late effects have been four hematologic malignancies, which are known risks of topoisomerase and anthracyline exposure. Conclusions: Proton radiotherapy was well tolerated, with few adverse events. Longer follow-up is needed to more fully assess tumor control and late effects, but the preliminary results are encouraging. (C) 2012 Elsevier Inc. C1 [Delaney, Thomas F.; Macdonald, Shannon M.; Liebsch, Norbert J.; Tarbell, Nancy J.; Yock, Torunn I.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Sch Med, Boston, MA 02114 USA. [Huang, Mary S.; Ebb, David H.] Harvard Univ, Massachusetts Gen Hosp, Dept Pediat Hematol & Oncol, Sch Med, Boston, MA 02114 USA. [Yeap, Beow Y.] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med, Boston, MA 02114 USA. [Marcus, Karen J.] Childrens Hosp Boston, Div Radiat Oncol, Boston, MA USA. [Raskin, Kevin A.] Harvard Univ, Massachusetts Gen Hosp, Dept Orthopaed Surg, Sch Med, Boston, MA 02114 USA. [Rombi, Barbara] ATreP Prov Agcy Proton Therapy, Trento, Italy. RP Yock, TI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Sch Med, 100 Blossom St,Cox Bldg 341, Boston, MA 02114 USA. EM tyock@partners.org FU Massachusetts General Hospital on National Institutes of Health [C06 CA059267] FX Supported in part by the Federal Share of program income earned by Massachusetts General Hospital on National Institutes of Health Grant #C06 CA059267, Proton Therapy Research and Treatment Center. NR 44 TC 21 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2012 VL 82 IS 3 BP 1142 EP 1148 DI 10.1016/j.ijrobp.2011.03.038 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 894JR UT WOS:000300423500050 PM 21856094 ER PT J AU Hattangadi-Gluth, JA Wo, JY Nguyen, PL Raad, RFA Sreedhara, M Niemierko, A Freer, PE Georgian-Smith, D Bellon, JR Wong, JS Smith, BL Harris, JR Taghian, AG AF Hattangadi-Gluth, Jona A. Wo, Jennifer Y. Nguyen, Paul L. Raad, Rita F. Abi Sreedhara, Meera Niemierko, Andrzej Freer, Phoebe E. Georgian-Smith, Dianne Bellon, Jennifer R. Wong, Julia S. Smith, Barbara L. Harris, Jay R. Taghian, Alphonse G. TI BASAL SUBTYPE OF INVASIVE BREAST CANCER IS ASSOCIATED WITH A HIGHER RISK OF TRUE RECURRENCE AFTER CONVENTIONAL BREAST-CONSERVING THERAPY SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and Oncology (ASTRO) CY OCT 31-NOV 05, 2009 CL Chicago, IL SP Amer Soc Therapeut Radiol & Oncol (ASTRO) DE Basal; Biologic subtype; Breast cancer; Local recurrence; Elsewhere local recurrence; Triple negative; True recurrence ID 20-YEAR FOLLOW-UP; LOCAL RECURRENCE; CONSERVATIVE SURGERY; RADIATION-THERAPY; STAGE-I; ADJUVANT CHEMOTHERAPY; PROGESTERONE-RECEPTOR; DISTANT RECURRENCE; ESTROGEN-RECEPTOR; TUMOR RECURRENCE AB Purpose: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1-T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). Methods and Materials: From Jan 1998 to Dec 2003, 1,223 women with pT1-T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2-]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER- and PR- and HER-2+), and basal (ER- and PR- and HER-2-) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. Results: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8,p = 0.01), younger age at diagnosis (HR, 0.97;p = 0.05), and increasing tumor size (HR, 2.1;p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95;p = 0.01) significantly predicted for ELR. Conclusions: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1-T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored. (C) 2012 Elsevier Inc. C1 [Wo, Jennifer Y.; Raad, Rita F. Abi; Niemierko, Andrzej; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hattangadi-Gluth, Jona A.] Harvard Radiat Oncol Program, Boston, MA USA. [Nguyen, Paul L.; Sreedhara, Meera; Bellon, Jennifer R.; Wong, Julia S.; Harris, Jay R.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Freer, Phoebe E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Georgian-Smith, Dianne] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. EM ataghian@partners.org OI Freer, Phoebe/0000-0001-6886-7100 FU NCI NIH HHS [CA50628, P50 CA089393, P50CA089393, R01CA139118, R01 CA050628, R01 CA139118, R01 CA139118-01] NR 43 TC 27 Z9 28 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2012 VL 82 IS 3 BP 1185 EP 1191 DI 10.1016/j.ijrobp.2011.02.061 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 894JR UT WOS:000300423500056 PM 21601377 ER PT J AU Park, JJ Chen, MH Loffredo, M D'Amico, AV AF Park, Jessica J. Chen, Ming-Hui Loffredo, Marian D'Amico, Anthony V. TI PROSTATE-SPECIFIC ANTIGEN VELOCITY BEFORE AND AFTER ELIMINATION OF FACTORS THAT CAN CONFOUND THE PROSTATE-SPECIFIC ANTIGEN LEVEL SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Prostate cancer; PSA velocity; Prostate cancer-specific mortality; Prostate cancer management; High risk ID PREOPERATIVE PSA VELOCITY; BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; HIGH-RISK; BIOLOGICAL VARIATION; CANCER; SERUM; DEATH; MEN; FLUCTUATIONS AB Purpose: Prostate-specific antigen (PSA) velocity, like PSA level, can be confounded. In this study, we estimated the impact that confounding factors could have on correctly identifying a patient with a PSA velocity >2 ng/ml/y. Methods and Materials: Between 2006 and 2010, a total of 50 men with newly diagnosed PC comprised the study cohort. We calculated and compared the false-positive and false-negative PSA velocity >2 ng/ml/y rates for all men and those with low-risk disease using two approaches to calculate PSA velocity. First, we used PSA values obtained within 18 months of diagnosis; second, we used values within 18 months of diagnosis, substituting the prebiopsy PSA for a repeat, nonconfounded PSA that was obtained using the same assay and without confounders. Results: Using PSA levels pre-biopsy, 46% of all men had a PSA velocity >2 ng/ml/y; whereas this value declined to 32% when substituting the last prebiopsy PSA for a repeat, nonconfounded PSA using the same assay and without confounders. The false-positive rate for PSA velocity >2 ng/ml/y was 43% as compared with a false-negative rate of PSA velocity >2 ng/ml/y of 11% (p = 0.0008) in the overall cohort. These respective values in the low-risk subgroup were 60% and 16.7% (p = 0.09). Conclusion: This study provides evidence to explain the discordance in cancer-specific outcomes among groups investigating the prognostic significance of PSA velocity >2 ng/ml/y, and highlights the importance of patient education on potential confounders of the PSA test before obtaining PSA levels. (C) 2012 Elsevier Inc. C1 [Park, Jessica J.; Loffredo, Marian; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Park, Jessica J.; Loffredo, Marian; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. RP Park, JJ (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02115 USA. EM park16@fas.harvard.edu NR 21 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2012 VL 82 IS 3 BP 1217 EP 1221 DI 10.1016/j.ijrobp.2011.04.019 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 894JR UT WOS:000300423500060 PM 21640512 ER PT J AU Kang, J Chen, MH Zhang, YY Moran, BJ Dosoretz, DE Katin, MJ Braccioforte, MH Salenius, SA D'Amico, AV AF Kang, Josephine Chen, Ming-Hui Zhang, Yuanye Moran, Brian J. Dosoretz, Daniel E. Katin, Michael J. Braccioforte, Michelle H. Salenius, Sharon A. D'Amico, Anthony V. TI Type of Diabetes Mellitus and the Odds of Gleason Score 8 to 10 Prostate Cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Prostate cancer; Gleason score; Type II diabetes; Type I diabetes; PSA ID RISK; TESTOSTERONE; METAANALYSIS; MORTALITY; THERAPY AB Purpose: It has been recently shown that diabetes mellitus (DM) is significantly associated with the likelihood of presenting with high-grade prostate cancer (PCa) or Gleason score (GS) 8 to 10; however, whether this association holds for both Type 1 and 2 DM is unknown. In this study we evaluated whether DM Type 1, 2, or both are associated with high-grade PCa after adjusting for known predictors of high-grade disease. Methods and Materials: Between 1991 and 2010, a total of 15,330 men diagnosed with PCa and treated with radiation therapy were analyzed. A polychotomous logistic regression analysis was performed to evaluate whether Type 1 or 2 DM was associated with odds of GS 7 or GS 8 to 10 compared with 6 or lower PCa, adjusting for African American race, age, prostate-specific antigen (PSA) level, and digital rectal examination findings. Results: Men with Type 1 DM (adjusted odds ratio [AOR], 2.05; 95% confidence interval [CI], 1.28-3.27; p = 0.003) or Type 2 DM (AOR, 1.58; 95% CI, 1.26-1.99; p < 0.001) were significantly more likely to be diagnosed with GS 8 to 10 PCa compared with nondiabetic men. However this was not true for GS 7, for which these respective results were AOR, 1.30; 95% CI, 0.93-1.82; p = 0.12 and AOR, 1.13; 95% CI, 0.98-1.32; p = 0.10. Conclusion: Type 1 and 2 DM were associated with a higher odds of being diagnosed with Gleason score 8 to 10 but not 7 PCa. Pending validation, men who are diagnosed with Type I DM with GS 7 or lower should be considered for additional workup to rule out occult high-grade disease. (C) 2012 Elsevier Inc. C1 [Kang, Josephine; D'Amico, Anthony V.] Brigham & Womens Hosp, Harvard Radiat Oncol Program, Dept Radiat Oncol, Boston, MA 02115 USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Ming-Hui; Zhang, Yuanye] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Moran, Brian J.; Braccioforte, Michelle H.] Prostate Canc Fdn Chicago, Westmont, IL USA. [Dosoretz, Daniel E.; Katin, Michael J.; Salenius, Sharon A.] 21 Century Oncol Inc, Dept Radiat Oncol, Ft Myers, FL USA. RP Kang, J (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02115 USA. EM jkang3@partners.org RI zhang, yuanye/H-6315-2013 NR 22 TC 12 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2012 VL 82 IS 3 BP E463 EP E467 DI 10.1016/j.ijrobp.2011.07.003 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 894JR UT WOS:000300423500017 PM 21944463 ER PT J AU Merrick, GS Wallner, KE Butler, WM Galbreath, RW Taira, AV Orio, P Adamovich, E AF Merrick, Gregory S. Wallner, Kent E. Butler, Wayne M. Galbreath, Robert W. Taira, Al V. Orio, Peter Adamovich, Edward TI 20 GY VERSUS 44 GY OF SUPPLEMENTAL EXTERNAL BEAM RADIOTHERAPY WITH PALLADIUM-103 FOR PATIENTS WITH GREATER RISK DISEASE: RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Prostate cancer; Brachytherapy; Higher risk; Prospective randomized trial ID PERMANENT PROSTATE BRACHYTHERAPY; BIOCHEMICAL OUTCOMES; RADIATION-THERAPY; PARTIN TABLES; TARGET VOLUME; CANCER; EXTENSION AB Purpose: The necessity of external beam radiotherapy (EBRT) as a supplement to prostate brachytherapy remains unknown. We report brachytherapy outcomes for patients with higher risk features randomized to substantially different supplemental EBRT regimens. Methods and Materials: Between December 1999 and June 2004, 247 patients were randomized to 20 Gy vs. 44 Gy EBRT followed by a palladium-103 boost (115 Gy vs. 90 Gy). The eligibility criteria included clinically organ-confined disease with Gleason score 7-10 and/or pretreatment prostate-specific antigen (PSA) level 10-20 ng/mL. The median follow-up period was 9.0 years. Biochemical progression-free survival (bPFS) was defined as a PSA level of <= 0.40 ng/mL after nadir. The median day 0 prescribed dose covering 90% of the target volume was 125.7%; 80 men received androgen deprivation therapy (median, 4 months). Multiple parameters were evaluated for their effect on bPFS. Results: For the entire cohort, the cause-specific survival, bPFS, and overall survival rates were 97.7%, 93.2%, and 80.8% at 8 years and 96.9%, 93.2%, and 75.4% at 10 years, respectively. The bPFS rate was 93.1% and 93.4% for the 20-Gy and 44-Gy arms, respectively (p = .994). However, no statistically significant differences were found in cause-specific survival or overall survival were identified. When stratified by PSA level of <= 10 ng/mL vs. >10 ng/mL, Gleason score, or androgen deprivation therapy, no statistically significant differences in bPFS were discerned between the two EBRT regimens. On multivariate analysis, bPFS was most closely related to the preimplant PSA and clinical stage. For patients with biochemically controlled disease, the median PSA level was <0.02 ng/mL. Conclusion: The results of the present trial strongly suggest that two markedly different supplemental EBRT regimens result in equivalent cause-specific survival, bPFS, and overall survival. It is probable that the lack of benefit for a higher supplemental EBRT dose is the result of the high-quality brachytherapy dose distributions. (C) 2012 Elsevier Inc. C1 [Merrick, Gregory S.; Butler, Wayne M.; Galbreath, Robert W.] Wheeling Jesuit Univ, Schiffler Canc Ctr, Wheeling, WV USA. [Wallner, Kent E.] Univ Washington, Puget Sound Healthcare Corp, Seattle, WA 98195 USA. [Taira, Al V.] Western Radiat Oncol Inc, Mountain View, CA USA. [Orio, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Adamovich, Edward] Wheeling Hosp, Dept Pathol, Wheeling, WV 26003 USA. RP Merrick, GS (reprint author), Wheeling Hosp, Schiffler Canc Ctr, 1 Med Pk, Wheeling, WV 26003 USA. EM gmerrick@urologicresearchinstitute.org NR 23 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2012 VL 82 IS 3 BP E449 EP E455 DI 10.1016/j.ijrobp.2011.07.016 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 894JR UT WOS:000300423500015 PM 22196131 ER PT J AU Nordenstedt, H Younes, M El-Serag, HB AF Nordenstedt, Helena Younes, Mamoun El-Serag, Hashem B. TI Expression of Androgen Receptors in Barrett Esophagus SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Letter ID ADENOCARCINOMA; SEX; HORMONES; CANCER C1 [Nordenstedt, Helena; El-Serag, Hashem B.] Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [Nordenstedt, Helena; El-Serag, Hashem B.] Baylor Coll Med, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. [Nordenstedt, Helena] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Younes, Mamoun] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Nordenstedt, H (reprint author), Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. OI Younes, Mamoun/0000-0001-9618-3451 FU NCI NIH HHS [P30 CA125123, R01 CA116845]; NIDDK NIH HHS [K24 DK078154, T32 DK083266]; PHS HHS [R01 116845, NIDDK K24-04-107] NR 8 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD MAR PY 2012 VL 46 IS 3 BP 251 EP 252 DI 10.1097/MCG.0b013e318238353e PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 895TG UT WOS:000300518700014 PM 22327304 ER PT J AU Sonnenberg, A Boardman, CR AF Sonnenberg, Amnon Boardman, Charles R. TI Is it Justifiable to Withhold Endoscopic Information? SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Letter ID BARRETTS-ESOPHAGUS; DIAGNOSIS C1 [Sonnenberg, Amnon; Boardman, Charles R.] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Div Gastroenterol, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Div Gastroenterol, Portland, OR 97201 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD MAR PY 2012 VL 46 IS 3 BP 252 EP 253 DI 10.1097/MCG.0b013e318238e7d1 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 895TG UT WOS:000300518700015 PM 22186741 ER PT J AU Erickson, JI AF Erickson, Jeanette Ives TI Leading a Highly Visible Hospital Through a Serious Reportable Event SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article AB Most preventable adverse events result from systemic causes, not human error. The senior vice president for patient care/chief nurse at a leading hospital recounts the unnecessary death of a patient and the investigation that followed. Citing the critical importance of a "just culture,'' this case study offers a blueprint for managing a serious reportable event. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Erickson, JI (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 230, Boston, MA 02114 USA. EM jiveserickson@partners.org NR 7 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD MAR PY 2012 VL 42 IS 3 BP 131 EP 133 DI 10.1097/NNA.0b013e31824808b6 PG 3 WC Nursing SC Nursing GA 898HM UT WOS:000300731600003 PM 22361868 ER PT J AU Banister, G Winfrey, ME AF Banister, Gaurdia Winfrey, Marion E. TI Enhancing Diversity in Nursing A Partnership Approach SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article ID EDUCATION AB Recent census data highlight the ongoing shift toward greater levels of racial and ethnic diversity in the US population. In 2000, non-Hispanic whites accounted for 69% of the population. By 2010, this decreased to 64%. The Census Bureau predicts that minorities will become the majority over the upcoming decades. In nursing and other healthcare professions, however, a different picture emerges, with minorities consistently underrepresented. The authors describe the development, outcomes, and benefits of the clinical leadership collaborative for diversity in nursing. Strategies for overcoming barriers to increasing diversity in the nursing profession are addressed. C1 [Banister, Gaurdia] Massachusetts Gen Hosp, Inst Patient Care, Patient Care Serv, Boston, MA 02114 USA. [Winfrey, Marion E.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. RP Banister, G (reprint author), Massachusetts Gen Hosp, Inst Patient Care, Patient Care Serv, 55 Fruit St,FND 316, Boston, MA 02114 USA. EM gbanister@partners.org FU Partners HealthCare Chief Nurse Council FX The authors thank Jariza Rodriguez for her invaluable support of program operations; the members of the CLCDN steering committee for challenging us to make the program the best it can be; the Partners HealthCare Chief Nurse Council for their ongoing guidance and support; and Beth Kantz, MS, RN, of Corrigan Kantz Consulting for writing and editing support. NR 17 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD MAR PY 2012 VL 42 IS 3 BP 176 EP 181 DI 10.1097/NNA.0b013e3182480a97 PG 6 WC Nursing SC Nursing GA 898HM UT WOS:000300731600011 PM 22361876 ER PT J AU Gardiner, S Hartzell, TL AF Gardiner, Sonya Hartzell, Tristan L. TI Telemedicine and plastic surgery: A review of its applications, limitations and legal pitfalls SO JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY LA English DT Review DE Telemedicine; Plastic surgery; Medico-legal; Limitations ID MOBILE CAMERA-PHONE; RURAL TRAUMA CARE; MAXILLOFACIAL TRAUMA; DIGITAL PHOTOGRAPHY; CLINICAL-EXPERIENCE; SURGICAL TRAUMA; FOLLOW-UP; TELECONSULTATION; BURNS; MANAGEMENT AB Background: Telemedicine is a rapidly expanding technology involving the exchange of medical information to assist diagnosis and treatment at a distance. Within the field of plastic surgery, where visual examination contributes heavily to patient management decision-making, telemedicine has great potential. However, privacy and medico-legal issues must be considered when using electronic communication to assist our clinical practice. Methods: A comprehensive literature review of manuscripts published on telemedicine was performed. Articles were selected for relevance to plastic and reconstructive surgery and reviewed for applications, benefits and complications of telemedicine. In addition, the manuscripts were reviewed for conforming to current legal guidelines for the electronic transfer of patient information. Results: Twenty-nine articles met the inclusion criteria (11 trauma and burns, 4 hand, 5 wound-care, 5 maxillofacial, 1 digital replantation, 2 free-flap monitoring, and 1 technical application). Twenty-eight (96%) manuscripts reported a benefit of telemedicine (commonly including increased access to expertise and costs saved through reduction of unnecessary transfers). However only five (17%) reported a statistical benefit compared to a standard treatment cohort (face-to-face interactions). Fifteen (51%) reported on adverse effects, which included misdiagnosis, time consumption, training, technical and cost issues. Only four manuscripts (14%) discussed conforming to legal guidelines within their institution. Conclusions: Telemedicine can improve access to the specialty of plastic surgery by facilitating the provision of expertise at remote sites. Its application can be used in many situations and between a variety of healthcare professionals. However, there is little critical analysis on the benefits and risks of telemedicine. In addition, its legal implications need to be carefully considered if it is to be safely integrated into our daily practice. (C) 2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved. C1 [Gardiner, Sonya] Addenbrookes Hosp, Cambridge, England. [Hartzell, Tristan L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Gardiner, S (reprint author), Addenbrookes Hosp, Cambridge, England. EM sg410@cam.ac.uk NR 42 TC 21 Z9 23 U1 1 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1748-6815 EI 1878-0539 J9 J PLAST RECONSTR AES JI J. Plast. Reconstr. Aesthet. Surg. PD MAR PY 2012 VL 65 IS 3 BP E47 EP E53 DI 10.1016/j.bjps.2011.11.048 PG 7 WC Surgery SC Surgery GA 895VM UT WOS:000300524800001 PM 22178033 ER PT J AU King, G Wood, MJ AF King, Gerard Wood, Malissa J. TI The Right Ventricle of the Elite High End Endurance Athlete Cannot Be Underestimated SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Editorial Material ID MYOCARDIAL ADAPTATION; ARRHYTHMIAS; EXERCISE C1 [Wood, Malissa J.] Massachusetts Gen Hosp, Boston, MA 02214 USA. [King, Gerard] Eagle Lodge Cardiol, Limerick, Ireland. RP Wood, MJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Blake 256, Boston, MA 02214 USA. EM mjwood@partners.org NR 14 TC 1 Z9 1 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD MAR PY 2012 VL 25 IS 3 BP 272 EP 273 DI 10.1016/j.echo.2012.01.018 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 897FW UT WOS:000300633200007 PM 22353337 ER PT J AU Bettmann, MA White, RD Woodard, PK Abbara, S Atalay, MK Dorbala, S Haramati, LB Hendel, RC Martin, ET Ryan, T Steiner, RM AF Bettmann, Michael A. White, Richard D. Woodard, Pamela K. Abbara, Suhny Atalay, Michael K. Dorbala, Sharmila Haramati, Linda B. Hendel, Robert C. Martin, Edward T. Ryan, Thomas Steiner, Robert M. TI ACR Appropriateness Criteria (R) Acute Chest Pain-Suspected Pulmonary Embolism SO JOURNAL OF THORACIC IMAGING LA English DT Review DE Appropriateness Criteria; diagnosis of pulmonary embolism and DVT; CTPAgrams; ventilation and perfusion (V/Q) scan ID VENTILATION-PERFUSION SCINTIGRAPHY; RIGHT-VENTRICULAR DYSFUNCTION; COMPUTED-TOMOGRAPHY; SPIRAL CT; HELICAL CT; DIAGNOSIS; ANGIOGRAPHY; PREGNANCY; US AB Pulmonary embolism (PE) remains a common and important clinical condition that cannot be accurately diagnosed on the basis of signs, symptoms, and history alone. In the absence of high pretest probability and with a negative high-sensitivity D-dimer test, PE can be effectively excluded; in other situations, diagnostic imaging is necessary. The diagnosis of PE has been facilitated by technical advancements and multidetector computed tomography pulmonary angiography, which is the major diagnostic modality currently used. Ventilation and perfusion (V/Q) scans remain largely accurate and useful in certain settings. Lower-extremity ultrasound can substitute by demonstrating deep vein thrombosis; however, if negative, further studies to exclude PE are indicated. In all cases, correlation with the clinical status, particularly with risk factors, improves not only the accuracy of diagnostic imaging but also overall utilization. Other diagnostic tests have limited roles. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multi-disciplinary expert panel. The development and review of the guidelines include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Bettmann, Michael A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC USA. [White, Richard D.] Ohio State Univ, Med Ctr, Dept Radiol, Columbus, OH 43210 USA. [Woodard, Pamela K.] Washington Univ, Mallinckrodt Inst Radiol, Sch Med, St Louis, MS USA. [Abbara, Suhny] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Atalay, Michael K.] Brown Univ, Dept Diagnost Imaging, Warren Alpert Sch Med, Providence, RI 02912 USA. [Dorbala, Sharmila] Brigham & Womens Hosp, Dept Radiol, Soc Nucl Med, Boston, MA 02115 USA. [Haramati, Linda B.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Radiol, Bronx, NY 10467 USA. [Hendel, Robert C.] Univ Miami, Miller Sch Med, Amer Coll Cardiol, Outpatient Serv Cardiovasc Div, Miami, FL 33136 USA. [Martin, Edward T.] Oklahoma Heart Inst, Amer Coll Cardiol, Tulsa, OK USA. [Ryan, Thomas] Ohio State Univ, Amer Coll Cardiol, Heart & Vasc Ctr, Columbus, OH 43210 USA. [Steiner, Robert M.] Temple Univ Hlth Syst, Dept Radiol, Philadelphia, PA USA. RP Bettmann, MA (reprint author), Amer Coll Radiol, Dept Qual & Safety, 1891 Preston White Dr, Reston, VA 20191 USA. EM bettmann@wfubmc.edu OI White, Richard D./0000-0002-1133-7819 FU Astellas Pharma US Inc.; NIH FX Robert M. Steiner, is an consultant and course director Educational Symposium Inc. and also consultant to Johnson and Johnson Co. Sharmila Dorbala, has a research grant from Astellas Pharma US Inc. and funded by NIH, a K23 grant. The other authors declare no conflicts of interest. NR 28 TC 34 Z9 34 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0883-5993 J9 J THORAC IMAG JI J. Thorac. Imaging PD MAR PY 2012 VL 27 IS 2 BP W28 EP W31 DI 10.1097/RTI.0b013e31823efeb6 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 897EP UT WOS:000300628400002 PM 22343403 ER PT J AU Ochsenbauer, C Edmonds, TG Ding, HT Keele, BF Decker, J Salazar, MG Salazar-Gonzalez, JF Shattock, R Haynes, BF Shaw, GM Hahn, BH Kappes, JC AF Ochsenbauer, Christina Edmonds, Tara G. Ding, Haitao Keele, Brandon F. Decker, Julie Salazar, Maria G. Salazar-Gonzalez, Jesus F. Shattock, Robin Haynes, Barton F. Shaw, George M. Hahn, Beatrice H. Kappes, John C. TI Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 R5 ENVELOPES; CENTRAL-NERVOUS-SYSTEM; ANTIBODY NEUTRALIZATION; BIOLOGICAL PHENOTYPE; SEXUAL TRANSMISSION; VIRAL DETERMINANTS; LYMPHOID-TISSUES; FUSION INHIBITOR; TROPISM AB Genome sequences of transmitted/founder (T/F) HIV-1 have been inferred by analyzing single genome amplicons of acute infection plasma viral RNA in the context of a mathematical model of random virus evolution; however, few of these T/F sequences have been molecularly cloned and biologically characterized. Here, we describe the derivation and biological analysis of ten infectious molecular clones, each representing a T/F genome responsible for productive HIV-1 clade B clinical infection. Each of the T/F viruses primarily utilized the CCR5 coreceptor for entry and replicated efficiently in primary human CD4(+) T lymphocytes. This result supports the conclusion that single genome amplification-derived sequences from acute infection allow for the inference of T/F viral genomes that are consistently replication competent. Studies with monocyte-derived macrophages (MDM) demonstrated various levels of replication among the T/F viruses. Although all T/F viruses replicated in MDM, the overall replication efficiency was significantly lower compared to prototypic "highly macrophage-tropic" virus strains. This phenotype was transferable by expressing the env genes in an isogenic proviral DNA backbone, indicating that T/F virus macrophage tropism mapped to Env. Furthermore, significantly higher concentrations of soluble CD4 were required to inhibit T/F virus infection compared to prototypic macrophage-tropic virus strains. Our findings suggest that the acquisition of clinical HIV-1 subtype B infection occurs by mucosal exposure to virus that is not highly macrophage tropic and that the generation and initial biological characterization of 10 clade B T/F infectious molecular clones provides new opportunities to probe virus-host interactions involved in HIV-1 transmission. C1 [Ochsenbauer, Christina; Ding, Haitao; Decker, Julie; Salazar, Maria G.; Salazar-Gonzalez, Jesus F.; Kappes, John C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Edmonds, Tara G.; Kappes, John C.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL USA. [Keele, Brandon F.] NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. [Shattock, Robin] Univ London Imperial Coll Sci Technol & Med, London, England. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Med, Duke Human Vaccine Inst, Durham, NC 27706 USA. [Haynes, Barton F.] Duke Univ, Sch Med, Dept Immunol, Duke Human Vaccine Inst, Durham, NC USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Shaw, George M.; Hahn, Beatrice H.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. RP Kappes, JC (reprint author), Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. EM kappesjc@uab.edu RI Ghartouchent, malek/B-9088-2012 FU NIH Center for HIV/AIDS Vaccine Immunology (CHAVI) [UO1-AI067854]; Bill and Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium [38619]; Bill and Melinda Gates Foundation [37874]; facilities of the Virology, Biostatistics, and Genetic Sequencing cores of the UAB Center for AIDS Research [P30-AI-27767]; Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center [R24 DK-64400]; Department of Veterans Affairs Medical Center, Research Services; NIH [AI007439] FX This study was supported by the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI; UO1-AI067854); the Bill and Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/Comprehensive Antibody Vaccine Immune Monitoring Consortium (grant 38619); a Bill and Melinda Gates Foundation Grand Challenges grant (grant 37874); the facilities of the Virology, Biostatistics, and Genetic Sequencing cores of the UAB Center for AIDS Research (P30-AI-27767); and the Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center (R24 DK-64400). Research was also supported by a Merit Review Award (J.C.K.) and a Research Career Scientist Award (J.C.K.) from the Department of Veterans Affairs Medical Center, Research Services. T.G.E. is supported by NIH training grant AI007439. NR 71 TC 123 Z9 123 U1 2 U2 13 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 MAR PY 2012 VL 86 IS 5 BP 2715 EP 2728 DI 10.1128/JVI.06157-11 PG 14 WC Virology SC Virology GA 896AC UT WOS:000300536800029 PM 22190722 ER PT J AU Wright, JK Naidoo, VL Brumme, ZL Prince, JL Claiborne, DT Goulder, PJR Brockman, MA Hunter, E Ndung'u, T AF Wright, Jaclyn K. Naidoo, Vanessa L. Brumme, Zabrina L. Prince, Jessica L. Claiborne, Daniel T. Goulder, Philip J. R. Brockman, Mark A. Hunter, Eric Ndung'u, Thumbi TI Impact of HLA-B(star)81-Associated Mutations in HIV-1 Gag on Viral Replication Capacity SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE RESPONSE; CAPSID PROTEIN; COMPENSATORY MUTATION; CHRONIC INFECTION; ESCAPE MUTATIONS; CELL RESPONSES; HLA; EPITOPE; IMMUNE AB HIV-1 attenuation resulting from immune escape mutations selected in Gag may contribute to slower disease progression in HIV-1-infected individuals expressing certain HLA class I alleles. We previously showed that the protective allele HLA-B(star)81 and the HLA-B(star)81-selected Gag T186S mutation are strongly associated with a lower viral replication capacity of recombinant viruses encoding Gag-protease derived from individuals chronically infected with HIV-1 subtype C. In the present study, we directly tested the effect of this mutation on viral replication capacity. In addition, we investigated potential compensatory effects of various polymorphisms, including other HLA-B(star)81-associated mutations that significantly covary with the T186S mutation. Mutations were introduced into a reference subtype B backbone and into patient-derived subtype C sequences in subtype B and C backbones by site-directed mutagenesis. The exponential-phase growth of mutant and wild-type viruses was assayed by flow cytometry of a green fluorescent protein reporter T cell line or by measurement of HIV-1 reverse transcriptase activity in culture supernatants. Engineering of the T186S mutation alone into all patient-derived subtype C sequences failed to yield replication-competent viruses, while in the subtype B sequence, the T186S mutation resulted in impaired replication capacity. Only the T186S mutation in combination with the T190I mutation yielded replication-competent viruses for all virus backbones tested; however, these constructs replicated slower than the wild type, suggesting that only partial compensation is mediated by the T190I mutation. Constructs encoding the T186S mutation in combination with other putative compensatory mutations were attenuated or defective. These results suggest that the T186S mutation is deleterious to HIV-1 subtype C replication and likely requires complex compensatory pathways, which may contribute to the clinical benefit associated with HLA-B(star)81. C1 [Wright, Jaclyn K.; Naidoo, Vanessa L.; Goulder, Philip J. R.; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Durban, South Africa. [Brumme, Zabrina L.; Brockman, Mark A.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Brumme, Zabrina L.; Brockman, Mark A.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Prince, Jessica L.; Claiborne, Daniel T.; Hunter, Eric] Emory Univ, Dept Pathol & Lab Med, Emory Vaccine Ctr, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Goulder, Philip J. R.; Ndung'u, Thumbi] MIT, Ragon Inst, Massachusetts Gen Hosp, Boston, MA USA. [Goulder, Philip J. R.; Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. [Goulder, Philip J. R.] Univ Oxford, Nuffield Dept Med, Dept Paediat, Oxford, England. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, Durban, South Africa. EM ndungu@ukzn.ac.za RI Ghartouchent, malek/B-9088-2012; OI Ndung'u, Thumbi/0000-0003-2962-3992; Brockman, Mark/0000-0001-6432-1426 FU South African Department of Science and Technology through the National Research Foundation; Ragon Institute Fund for Innovation and New International Initiatives; Mark and Lisa Schwartz Foundation; NIH [ROI-AI 64060, 3 D43 TW000231 16S2]; National Research Foundation; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology; Harvard University; Columbia University-Southern African Fogarty through the Fogarty International Center; Canadian Institutes for Health Research (CIHR) FX This research was funded by the South African Department of Science and Technology through the National Research Foundation, the Ragon Institute Fund for Innovation and New International Initiatives, and the Mark and Lisa Schwartz Foundation. Additional funding came from the NIH (ROI-AI 64060) (E.H.). J.K.W. was funded by the National Research Foundation and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. V.L.N. was supported by the Columbia University-Southern African Fogarty AIDS International Training and Research Program (AITRP) through the Fogarty International Center, National Institutes of Health (grant 3 D43 TW000231 16S2). Z.L.B. was supported by a New Investigator Award from the Canadian Institutes for Health Research (CIHR). M.A.B. holds a Canada Research Chair, Tier 2, in Viral Pathogenesis and Immunity. T.N. holds the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS. NR 37 TC 27 Z9 27 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2012 VL 86 IS 6 BP 3193 EP 3199 DI 10.1128/JVI.06682-11 PG 7 WC Virology SC Virology GA 897GC UT WOS:000300634100027 PM 22238317 ER PT J AU Mohr, DC Young, GJ AF Mohr, David C. Young, Gary J. TI Slack Resources and Quality of Primary Care SO MEDICAL CARE LA English DT Article DE veterans health; personnel staffing and scheduling; workload; patient; satisfaction; vaccination; primary health care ID HEALTH-CARE; OF-CARE; ORGANIZATIONS; INTERVENTIONS; IMMUNIZATION; SATISFACTION; METAANALYSIS; PERFORMANCE; MANAGEMENT; INNOVATION AB Background: Research generally shows that greater resource utilization fails to translate into higher-quality healthcare. Organizational slack is defined as extra organizational resources needed to meet demand. Divergent views exist on organizational slack in healthcare. Some investigators view slack negatively because it is wasteful, inefficient, and costly, whereas others view slack positively because it allows flexibility in work practices, expanding available services, and protecting against environmental changes. Objective: We tested a curvilinear relationship between organizational slack and care quality. Methods: The study setting was primary care clinics (n = 568) in the Veterans Health Administration. We examined organizational slack using the patient panel size per clinic capacity ratio and support staff per provider ratio staffing guidelines developed by the Veterans Health Administration. Patient-level measures were influenza vaccinations, continuity of care, and overall quality of care ratings. We obtained 2 independent patient samples with approximately 28,000 and 62,000 observations for the analysis. We used multilevel modeling and examined the linear and quadratic terms for both organizational slack measures. Results: We found a significant curvilinear effect for panel size per clinic capacity for influenza vaccinations and overall quality of care. We also found support staff per provider exhibited a curvilinear effect for continuity of care and influenza vaccinations. Greater available resources led to better care, but at a certain point, additional resources provided minimal quality gains. Conclusions: Our findings highlight the importance of primary care clinic managers monitoring staffing levels. Healthcare systems managing a balanced provider workload and staff-mix may realize better patient care delivery and cost management. C1 [Mohr, David C.; Young, Gary J.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Dept Vet Affairs, Boston, MA USA. [Mohr, David C.] Boston Univ, Sch Med, Dept Hlth Policy & Management, Boston, MA 02118 USA. [Young, Gary J.] Northwestern Univ, Ctr Hlth Policy & Healthcare Res, Boston, MA USA. RP Mohr, DC (reprint author), VA Boston Healthcare Syst 152M, 150 S Huntington Ave, Boston, MA 02130 USA. EM david.mohr2@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development [IIR 05-221] FX Supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development for IIR 05-221. NR 53 TC 3 Z9 4 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2012 VL 50 IS 3 BP 203 EP 209 DI 10.1097/MLR.0b013e318241e3e6 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 896YF UT WOS:000300606600004 PM 22193414 ER PT J AU Curran, GM Bauer, M Mittman, B Pyne, JM Stetler, C AF Curran, Geoffrey M. Bauer, Mark Mittman, Brian Pyne, Jeffrey M. Stetler, Cheryl TI Effectiveness-implementation Hybrid Designs Combining Elements of Clinical Effectiveness and Implementation Research to Enhance Public Health Impact SO MEDICAL CARE LA English DT Article DE diffusion of innovation; implementation science; clinical trials; pragmatic designs ID HEALTH-SERVICES RESEARCH; QUERI SERIES; COLLABORATIVE CARE; BIPOLAR DISORDER; FORMATIVE EVALUATION; TRIALS; EFFICACY; INTERVENTION; PRINCIPLES; FRAMEWORK AB Objectives: This study proposes methods for blending design components of clinical effectiveness and implementation research. Such blending can provide benefits over pursuing these lines of research independently; for example, more rapid translational gains, more effective implementation strategies, and more useful information for decision makers. This study proposes a "hybrid effectiveness-implementation" typology, describes a rationale for their use, outlines the design decisions that must be faced, and provides several real-world examples. Results: An effectiveness-implementation hybrid design is one that takes a dual focus a priori in assessing clinical effectiveness and implementation. We propose 3 hybrid types: (1) testing effects of a clinical intervention on relevant outcomes while observing and gathering information on implementation; (2) dual testing of clinical and implementation interventions/strategies; and (3) testing of an implementation strategy while observing and gathering information on the clinical intervention's impact on relevant outcomes. Conclusions: The hybrid typology proposed herein must be considered a construct still in evolution. Although traditional clinical effectiveness and implementation trials are likely to remain the most common approach to moving a clinical intervention through from efficacy research to public health impact, judicious use of the proposed hybrid designs could speed the translation of research findings into routine practice. C1 [Curran, Geoffrey M.] Univ Arkansas Med Sci, Dept Psychiat, Div Hlth Serv Res, Little Rock, AR 72205 USA. [Curran, Geoffrey M.; Pyne, Jeffrey M.] Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. [Bauer, Mark] Harvard Univ, VA Boston Healthcare Syst, Sch Med, Boston, MA USA. [Mittman, Brian; Stetler, Cheryl] VA Greater Angeles Healthcare Syst, CIPRS, Los Angeles, CA USA. RP Curran, GM (reprint author), Univ Arkansas Med Sci, Dept Psychiat, Div Hlth Serv Res, 4301 W Markham St 755, Little Rock, AR 72205 USA. EM currangeoffreym@uams.edu FU Department of Veterans Affairs, Health Services Research and Development Service [MNT-05-152]; National Institute on Drug Abuse [K01 DA15102] FX Supported by a research grant for the Department of Veterans Affairs, Health Services Research and Development Service: MNT-05-152 (Pyne, PI) and also funded by a research grant from the National Institute on Drug Abuse: K01 DA15102 (Curran, PI). NR 39 TC 184 Z9 185 U1 4 U2 31 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2012 VL 50 IS 3 BP 217 EP 226 DI 10.1097/MLR.0b013e3182408812 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 896YF UT WOS:000300606600006 PM 22310560 ER PT J AU Keyhani, S Falk, R Bishop, T Howell, E Korenstein, D AF Keyhani, Salomeh Falk, Raphael Bishop, Tara Howell, Elizabeth Korenstein, Deborah TI The Relationship Between Geographic Variations and Overuse of Healthcare Services A Systematic Review SO MEDICAL CARE LA English DT Review DE quality of health care; small-area analysis; physicians practice pattern; Delphi Technique; Guidelines and topic; guideline adeherence; health services misuse ID ACUTE MYOCARDIAL-INFARCTION; SMALL-AREA VARIATIONS; REGIONAL-VARIATIONS; OUTCOMES; QUALITY AB Objective: To examine the relationship between overuse of healthcare services and geographic variations in medical care. Design: Systematic Review. Data Sources: Articles published in Medline between 1978, the year of publication of the first framework to measure quality, and January 1, 2009. Study Selection: Four investigators screened 114,830 titles and 2 investigators screened all selected abstracts and articles for possible inclusion and extracted all data. Data Extraction: We extracted data on rates of overuse in different geographic areas. We also extracted data on underuse, if available, for the same population in which overuse was measured. Results: Five papers examined the relationship between geographic variations and overuse of healthcare services. One study in 2008 compared the appropriateness of coronary angiography (CA) for acute myocardial infarction in high-cost areas versus low cost areas in the Medicare population and found largely similar rates of inappropriateness (12.2% vs. 16.2%). A study in 2000 using national data concluded that overuse of CA explained little of the geographic variations in the use of this procedure in the Medicare program. An older study of Medicare patients found similar rates of inappropriate use of CA (15% to 17% vs. 18%), endoscopy (15% vs. 18% 19%), and carotid endarterectomy (29% vs. 30%) in low-use and high-use regions. A small area reanalysis of data from this study of 3 procedures found no evidence of a relationship between inappropriate use of procedures and volume in 23 adjacent counties of California. Another 2008 study found that inappropriate chemotherapy for stage I cancer was less common in low-cost areas compared with high-cost areas (3.1% vs. 6.3%). Conclusions: The limited available evidence does not lend support to the hypothesis that inappropriate use of procedures is a major source of geographic variations in intensity and/or costs of care. More research is needed to improve our understanding of the relationship between geographic variations and the quality of care. C1 [Keyhani, Salomeh] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94121 USA. [Keyhani, Salomeh] San Francisco VA Med Ctr, WHSR & D Res Enhancement Award Program, San Francisco, CA USA. [Falk, Raphael] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94121 USA. [Howell, Elizabeth] Mt Sinai Sch Med, Dept Hlth Evidence & Policy, New York, NY USA. [Korenstein, Deborah] Mt Sinai Sch Med, Div Gen Internal Med, Dept Med, New York, NY USA. [Bishop, Tara] Weill Cornell Med Coll, Dept Publ Hlth & Med, New York, NY USA. RP Keyhani, S (reprint author), Univ Calif San Francisco, Div Gen Internal Med, San Francisco VA Med Ctr 4150,Clement 111A1, San Francisco, CA 94121 USA. EM salomeh.keyhani@ucsf.edu FU Commonwealth Fund; VA HSR&D Career Development Award FX Supported by the Commonwealth Fund. Dr Keyhani is also supported by a VA HSR&D Career Development Award. NR 14 TC 20 Z9 20 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2012 VL 50 IS 3 BP 257 EP 261 DI 10.1097/MLR.0b013e3182422b0f PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 896YF UT WOS:000300606600011 PM 22329997 ER PT J AU Burks, DJ Kobus, AM AF Burks, Derek J. Kobus, Amy M. TI The legacy of altruism in health care: the promotion of empathy, prosociality and humanism SO MEDICAL EDUCATION LA English DT Article ID US MEDICAL-STUDENTS; PATIENT-CENTEREDNESS; ACADEMIC MEDICINE; TEACH EMPATHY; BURNOUT; EDUCATION; PHYSICIANS; COMMUNICATION; VIEWPOINT; ATTITUDES AB OBJECTIVES This study aimed to examine concepts of altruism and empathy among medical students and professionals in conjunction with health care initiatives designed to support the maintenance of these qualities. METHODS We searched for the terms ` altruism', ` altruistic', ` helping', ` prosocial behaviour' and ` empathy' in the Englishlanguage literature published from 1980 to the present within the Ovid MEDLINE, PsycInfo and PubMed databases. We used conceptual analysis to examine the relationships among altruism, empathy and related prosocial concepts in health care in order to understand how such factors may relate to emotional and career burnout, cynicism, decreased helping and decreased patient- centredness in care. RESULTS Altruistic ideals and qualities of empathy appear to decrease among some medical students as they progress through their education. During this process, students face increasingly heavy workloads, deal with strenuous demands and become more acquainted with non- humanistic informal practices inherent in the culture of medicine. In combination, these factors increase the likelihood that emotional suppression, detachment from patients, burnout and other negative consequences may result, perhaps as a means of self-preservation. Alternatively, by making a mindful and intentional choice to endeavour for self-care and a healthy work-life balance, medical students can uphold humanistic and prosocial attitudes and behaviours. CONCLUSIONS Promoting altruism in the context of a compensated health care career is contradictory and misguided. Instead, an approach to clinical care that is prosocial and empathic is recommended. Training in mindfulness, self-reflection and emotion skills may help medical students and professionals to recognise, regulate and behaviourally demonstrate empathy within clinical and professional encounters. However, health care initiatives to increase empathy and other humanistic qualities will be limited unless more practical and feasible emotion skills training is offered to and accepted by medical students. Success will be further moderated by the culture of medicine's full acceptance of empathy and humanism into its customs, beliefs, values, interactions and daily practices. C1 [Burks, Derek J.] Portland VA Med Ctr, Dept Mental Hlth & Neurosci, Portland, OR USA. [Burks, Derek J.] VISN 20 Mental Illness Res Educ & Clin Ctr, Portland, OR USA. [Burks, Derek J.] Oregon Hlth & Sci Univ, Sch Med, Dept Clin Res, Portland, OR 97201 USA. [Kobus, Amy M.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. RP Burks, DJ (reprint author), Natl Ctr Telehlth & Technol, 9933 W Hayes St, Tacoma, WA 98431 USA. EM derekjburks@gmail.com NR 74 TC 23 Z9 24 U1 8 U2 50 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0308-0110 J9 MED EDUC JI Med. Educ. PD MAR PY 2012 VL 46 IS 3 BP 317 EP 325 DI 10.1111/j.1365-2923.2011.04159.x PG 9 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 895NW UT WOS:000300504100011 PM 22324531 ER PT J AU Conway, KE Cotten, JF AF Conway, Kevin E. Cotten, Joseph F. TI Covalent Modification of a Volatile Anesthetic Regulatory Site Activates TASK-3 (KCNK9) Tandem-Pore Potassium Channels SO MOLECULAR PHARMACOLOGY LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; DOMAIN K+ CHANNELS; GENERAL-ANESTHETICS; ISOFLURANE ANESTHESIA; INHIBITION; NEUROTRANSMITTERS; OSCILLATIONS; MODULATION; MECHANISMS; RECEPTORS AB TASK-3 (KCNK9) tandem-pore potassium channels provide a volatile anesthetic-activated and G alpha(q) protein-and acidic pHinhibited potassium conductance important in neuronal excitability. Met-159 of TASK-3 is essential for anesthetic activation and may contribute to the TASK-3 anesthetic binding site(s). We hypothesized that covalent occupancy of an anesthetic binding site would irreversibly activate TASK-3. We introduced a cysteine at residue 159 (M159C) and studied the rate and effect of Cys-159 modification by N-ethylmaleimide (NEM), a cysteine-selective alkylating agent. TASK-3 channels were transiently expressed in Fischer rat thyroid cells, and their function was studied in an Ussing chamber. NEM irreversibly activated M159C TASK-3, with minimal effects on wild-type TASK-3. NEM-modified M159C channels were resistant to inhibition by both acidic pH and active G alpha(q) protein. M159C channels that were first inhibited by G alpha(q) protein were more-slowly activated by NEM, which suggests protection of Cys159, and similar results were observed with isoflurane activation of wild-type TASK-3. M159W and M159F TASK-3 mutants behaved like NEM-modified M159C channels, with increased basal currents and resistance to inhibition by active G alpha(q) protein or acidic pH. TASK-3 wild-type/M159C dimers expressed as a single polypeptide demonstrated that modification of a single Cys-159 was sufficient for TASK-3 activation, and M159F/ M159C and M159W/M159C dimers provided evidence for cross-talk between subunits. The data are consistent with residue 159 contributing to an anesthetic regulatory site or sites, and they suggest that volatile anesthetics, through perturbations at a single site, increase TASK-3 channel activity and disrupt its regulation by active G alpha(q) protein, a determinant of central nervous system arousal and consciousness. C1 [Conway, Kevin E.; Cotten, Joseph F.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Cotten, JF (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444, Boston, MA 02114 USA. EM jcotten@partners.org FU Foundation for Anesthesia Education and Research; National Institutes of Health National Institute of General Medical Sciences [GM083216] FX This research was supported by grants from the Foundation for Anesthesia Education and Research and the National Institutes of Health National Institute of General Medical Sciences [Grant GM083216]. NR 24 TC 7 Z9 7 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X EI 1521-0111 J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2012 VL 81 IS 3 BP 393 EP 400 DI 10.1124/mol.111.076281 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 897CK UT WOS:000300618800013 PM 22147752 ER PT J AU Chang, SC Xie, P Anton, RF De Vivo, I Farrer, LA Kranzler, HR Oslin, D Purcell, SM Roberts, AL Smoller, JW Uddin, M Gelernter, J Koenen, KC AF Chang, S-C Xie, P. Anton, R. F. De Vivo, I. Farrer, L. A. Kranzler, H. R. Oslin, D. Purcell, S. M. Roberts, A. L. Smoller, J. W. Uddin, M. Gelernter, J. Koenen, K. C. TI No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples SO MOLECULAR PSYCHIATRY LA English DT Letter ID GENOMEWIDE LINKAGE SCAN; SEMISTRUCTURED ASSESSMENT; ALCOHOLISM SSADDA; DRUG-DEPENDENCE; ENVIRONMENT; RELIABILITY C1 [Chang, S-C; Roberts, A. L.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Xie, P.; Gelernter, J.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Xie, P.; Gelernter, J.] VA CT Healthcare Ctr, West Haven, CT USA. [Anton, R. F.] Med Univ S Carolina, Dept Psychiat, Ctr Alcohol & Drug Programs, Charleston, SC 29425 USA. [De Vivo, I.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [De Vivo, I.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Genet, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Med, Dept Genom Epidemiol & Biostat, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Genom Epidemiol & Biostat, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Genet, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Neurol, Boston, MA 02118 USA. [Farrer, L. A.] Boston Univ, Sch Publ Hlth, Dept Med, Boston, MA 02118 USA. [Kranzler, H. R.; Oslin, D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Kranzler, H. R.; Oslin, D.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Purcell, S. M.; Smoller, J. W.] Massachusetts Gen Hosp, Ctr Genet Res, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Purcell, S. M.; Smoller, J. W.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Purcell, S. M.] Broad Inst, Cambridge, MA USA. [Uddin, M.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Uddin, M.] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Gelernter, J.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Koenen, K. C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Chang, SC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM joel.gelernter@yale.edu; kck5@columbia.edu OI Farrer, Lindsay/0000-0001-5533-4225; Roberts, Andrea/0000-0001-5023-4399 NR 11 TC 25 Z9 25 U1 0 U2 2 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 MAR PY 2012 VL 17 IS 3 BP 239 EP 241 DI 10.1038/mp.2011.118 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 898BC UT WOS:000300709300004 PM 21912390 ER PT J AU Solit, DB Janne, PA AF Solit, David B. Jaenne, Pasi A. TI TRANSLATIONAL MEDICINE Primed for resistance SO NATURE LA English DT Editorial Material ID WILD-TYPE BRAF; INHIBITORS C1 [Solit, David B.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Solit, David B.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. RP Solit, DB (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. EM solitd@mskcc.org; pjanne@partners.org NR 12 TC 8 Z9 8 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 1 PY 2012 VL 483 IS 7387 BP 44 EP 45 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900HP UT WOS:000300877900040 PM 22382978 ER PT J AU Keller, TL Zocco, D Sundrud, MS Hendrick, M Edenius, M Yum, J Kim, YJ Lee, HK Cortese, JF Wirth, DF Dignam, JD Rao, A Yeo, CY Mazitschek, R Whitman, M AF Keller, Tracy L. Zocco, Davide Sundrud, Mark S. Hendrick, Margaret Edenius, Maja Yum, Jinah Kim, Yeon-Jin Lee, Hak-Kyo Cortese, Joseph F. Wirth, Dyann F. Dignam, John David Rao, Anjana Yeo, Chang-Yeol Mazitschek, Ralph Whitman, Malcolm TI Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase SO NATURE CHEMICAL BIOLOGY LA English DT Article ID AMINO-ACID-METABOLISM; GENE-EXPRESSION; CELL-DIFFERENTIATION; MAMMALIAN-CELLS; DENDRITIC CELLS; STRESS-RESPONSE; INFLAMMATION; SPECIFICITY; DEPRIVATION; LIMITATION AB Febrifugine, the bioactive constituent of one of the SO fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T(H)17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution. C1 [Keller, Tracy L.; Zocco, Davide; Hendrick, Margaret; Edenius, Maja; Yeo, Chang-Yeol; Whitman, Malcolm] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Sundrud, Mark S.; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sundrud, Mark S.; Rao, Anjana] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Yum, Jinah; Kim, Yeon-Jin; Yeo, Chang-Yeol] Ewha Womans Univ, Div Life & Pharmaceut Sci, Dept Life Sci, Seoul, South Korea. [Lee, Hak-Kyo] Hankyong Natl Univ, Genom Informat Ctr, Ansung, Kyongi Do, South Korea. [Cortese, Joseph F.; Wirth, Dyann F.; Mazitschek, Ralph] Broad Inst Harvard & MIT, Infect Dis Initiat, Cambridge, MA USA. [Wirth, Dyann F.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Dignam, John David] Univ Toledo, Coll Med, Dept Biochem & Canc Biol, Toledo, OH 43606 USA. [Mazitschek, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Keller, TL (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, 188 Longwood Ave, Boston, MA 02115 USA. EM tkeller@hms.harvard.edu; cyeo@ewha.ac.kr; rmazitschek@mgh.harvard.edu; mwhitman@hms.harvard.edu RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Yeo, Chang-Yeol/0000-0002-4440-1215 FU US National Institutes of Health (NIH) [GM089885]; Harvard Technology Accelerator Award; Rural Development Administration, Republic of Korea [PJ00812701, PJ008196]; NIH [AI40127, AI48213]; Juvenile Diabetes Research Foundation [17-2010-421] FX The authors would like to thank R. Copeland (Epizyme) for advice on the execution of tight-binding analysis, W Kilo Harvard Catalyst Laboratory for Innovative Translational Technologies for assistance with the establishment of qPCR assays, and C. Walsh (Harvard), T. Roberts (Dana-Farber Cancer Institute) anti S. Thomas (National Institute of Environmental Health Science, USA) for their valuable comments on the manuscript. This work was supported by US National Institutes of Health (NIH) grant GM089885 and a Harvard Technology Accelerator Award (to MW); by grants PJ00812701 and PJ008196 from The Next Generation BioGreen 21 Program, Rural Development Administration, Republic of Korea (to C.Y.Y. and H.K.L.); and by NIH grants AI40127 and AI48213 and Juvenile Diabetes Research Foundation 17-2010-421 (to A.R.). NR 50 TC 83 Z9 89 U1 1 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD MAR PY 2012 VL 8 IS 3 BP 311 EP 317 DI 10.1038/NCHEMBIO.790 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896VR UT WOS:000300600000017 PM 22327401 ER PT J AU Gordon, DJ Resio, B Pellman, D AF Gordon, David J. Resio, Benjamin Pellman, David TI Causes and consequences of aneuploidy in cancer SO NATURE REVIEWS GENETICS LA English DT Review ID ACUTE MYELOID-LEUKEMIA; MEROTELIC KINETOCHORE ORIENTATION; RETINOBLASTOMA TUMOR-SUPPRESSOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; MEDIATED CHROMOSOME TRANSFER; DOSAGE LETHAL SCREENS; GENETIC INSTABILITY; COLORECTAL CANCERS; DOWN-SYNDROME; HUMAN-CELLS AB Genetic instability, which includes both numerical and structural chromosomal abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. We also explore the role of aneuploidy in cellular transformation and discuss the possibility of developing aneuploidy-specific therapies. C1 [Gordon, David J.; Resio, Benjamin; Pellman, David] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Pellman, D (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU NCI NIH HHS [K08 CA160346]; NIGMS NIH HHS [R01 GM083299] NR 123 TC 246 Z9 251 U1 7 U2 67 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD MAR PY 2012 VL 13 IS 3 BP 189 EP 203 DI 10.1038/nrg3123 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 896ZI UT WOS:000300609900004 PM 22269907 ER PT J AU Goldberg, NRS Fields, V Pflibsen, L Salvatore, MF Meshul, CK AF Goldberg, Natalie R. S. Fields, Victoria Pflibsen, Lacey Salvatore, Michael F. Meshul, Charles K. TI Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Dopamine; Striatum; MPTP; Social enrichment; Tyrosine hydroxylase ID VESICULAR MONOAMINE TRANSPORTER; SLEEP BEHAVIOR DISORDER; POTENTIAL EARLY MARKERS; ADULT SUBSTANTIA-NIGRA; DOPAMINE TRANSPORTER; TYROSINE-HYDROXYLASE; STRIATAL DOPAMINE; NEURONAL DEATH; BASAL GANGLIA; MICE LACKING AB Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. in the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute l-DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute I-DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration. Published by Elsevier Inc. C1 [Goldberg, Natalie R. S.; Pflibsen, Lacey; Meshul, Charles K.] Portland VA Med Ctr, Portland, OR USA. [Fields, Victoria; Salvatore, Michael F.] Louisiana State Univ, Hlth Sci Ctr, Dept Pharmacol Toxicol & Neurosci, Shreveport, LA 71105 USA. [Meshul, Charles K.] Oregon Hlth & Sci Univ, Dept Behav Neurosci & Pathol, Portland, OR 97201 USA. RP Meshul, CK (reprint author), VA Med Ctr RD 29, 3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM meshulc@ohsu.edu FU Department of Veterans Affairs; Edward P Stiles Trust - LSUHSC - Shreveport; Biomedical Research Foundation of NW Louisiana FX Support was from the Department of Veterans Affairs Merit Review Program to CKM, and the Edward P Stiles Trust Fund - LSUHSC - Shreveport and Biomedical Research Foundation of NW Louisiana to MFS. We also thank Deborah Finn for consultation regarding statistical analyses. NR 122 TC 14 Z9 14 U1 1 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2012 VL 45 IS 3 BP 1051 EP 1067 DI 10.1016/j.nbd.2011.12.024 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 895TP UT WOS:000300519600023 PM 22198503 ER PT J AU Undurraga, J Baldessarini, RJ AF Undurraga, Juan Baldessarini, Ross J. TI Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE antidepressants; evidence-based medicine; depression; meta-analysis; controlled trials; secular changes ID DOUBLE-BLIND TRIAL; EXTENDED-RELEASE XR; SEROTONIN REUPTAKE INHIBITORS; SELEGILINE TRANSDERMAL SYSTEM; PAROXETINE-CONTROLLED TRIAL; DOSE FLUOXETINE THERAPY; TO-MODERATE DEPRESSION; ST-JOHNS-WORT; HYPERICUM EXTRACT; SUSTAINED-RELEASE AB Antidepressant-placebo response-differences (RDs) in controlled trials have been declining, potentially confounding comparisons among older and newer drugs. For clinically employed antidepressants, we carried out a meta-analytic review of placebo-controlled trials in acute, unipolar, major depressive episodes reported over the past three decades to compare efficacy (drug-placebo RDs) of individual antidepressants and classes, and to consider factors associated with year-of-reporting by bivariate and multivariate regression modeling. Observed drug-placebo differences were moderate and generally similar among specific drugs, but larger among older antidepressants, notably tricyclics, than most newer agents. This outcome parallels selective increases in placebo-associated responses as trial-size has increased in recent years. Study findings generally support moderate efficacy of clinically employed antidepressants for acute major depression, but underscore limitations of meta-analyses of controlled trials for ranking drugs by efficacy. We suggest that efficiency and drug-placebo differences may be improved with fewer sites and subjects, and better quality-control of diagnostic and clinical assessments. Neuropsychopharmacology (2012) 37, 851-864; doi: 10.1038/npp.2011.306; published online 14 December 2011 C1 [Undurraga, Juan; Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Psychopharmacol Program, Boston, MA 02115 USA. [Undurraga, Juan; Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Psychot & Mood Disorders Res, Mailman Res Ctr, McLean Div, Boston, MA 02114 USA. [Undurraga, Juan] Univ Barcelona, Bipolar Disorders Program, Dept Psychiat, Hosp Clin,IDIBAPS,CIBERSAM, Barcelona, Spain. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr 312, 115 Mill St, Belmont, MA 02478 USA. EM rbaldessarini@mclean.harvard.edu RI Undurraga, Juan/F-3438-2012 OI Undurraga, Juan/0000-0001-6958-2369 FU Bruce J Anderson Foundation; McLean Private Donors Psychopharmacology Research Fund; University of Barcelona; Fundacion Espanola de Psiquiatria y Salud Mental FX This work was supported by a grant from the Bruce J Anderson Foundation and by the McLean Private Donors Psychopharmacology Research Fund (to RJB), and by a Traveling Research Fellowship from the University of Barcelona and the Fundacion Espanola de Psiquiatria y Salud Mental (to JU). Leonardo Tondo, MD provided helpful technical advice. NR 135 TC 74 Z9 75 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2012 VL 37 IS 4 BP 851 EP 864 DI 10.1038/npp.2011.306 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 896PB UT WOS:000300580100001 PM 22169941 ER PT J AU Barry, MJ Edgman-Levitan, S AF Barry, Michael J. Edgman-Levitan, Susan TI Shared Decision Making - The Pinnacle of Patient-Centered Care SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Barry, Michael J.] Massachusetts Gen Hosp, Fdn Informed Med Decis Making, Boston, MA 02114 USA. Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care Innovat, Boston, MA 02114 USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Fdn Informed Med Decis Making, Boston, MA 02114 USA. NR 5 TC 461 Z9 467 U1 8 U2 58 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 MAR 1 PY 2012 VL 366 IS 9 BP 780 EP 781 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 900GI UT WOS:000300874300002 PM 22375967 ER PT J AU Kahn, R Gorgon, L Jones, K McSherry, F Glover, ED Anthenelli, RM Jackson, T Williams, J Murtaugh, C Montoya, I Yu, E Elkashef, A AF Kahn, Roberta Gorgon, Liza Jones, Karen McSherry, Frances Glover, Elbert D. Anthenelli, Robert M. Jackson, Thomas Williams, Jill Murtaugh, Cristin Montoya, Ivan Yu, Elmer Elkashef, Ahmed TI Selegiline Transdermal System (STS) as an Aid for Smoking Cessation SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID PLACEBO-CONTROLLED TRIAL; MONOAMINE-OXIDASE; CIGARETTE SMOKERS; DOUBLE-BLIND; ABSTINENCE; HYDROCHLORIDE; INHIBITION; DEPRESSION AB Introduction: This study examined the efficacy and safety of selegiline transdermal system (STS) and brief repeated behavioral intervention (BRBI) for smoking cessation in heavy smokers. We hypothesized that the quit rate of subjects who received STS and BRBI would be significantly greater than that of those who received placebo patch and BRBI. Methods: This was a double-blind, placebo-controlled parallel-group study in which 246 men and women were randomized to receive either STS (n = 121) or placebo patch (n = 125) for 9 weeks. Recruitment targeted heavy smokers, defined as individuals with self-reported use of = 15 cigarettes/day in the 30 days prior to enrollment, who had smoked cigarettes for the past 5 years, and had an expired CO level >= 9 ppm during screening. Results: Although STS was well tolerated, the overall results indicated that STS with BRBI was not more effective than placebo plus BRBI for smoking cessation (p = .58). Conclusions: The results are discussed in relation to interventions for heavy smokers. Although 2 trials using oral selegiline both showed trends toward improved abstinence, these results indicate that STS with BRBI was not an effective aid for smoking cessation at the end of treatment (10 weeks), 14, or 26 weeks. C1 [Kahn, Roberta; Gorgon, Liza; Montoya, Ivan; Elkashef, Ahmed] Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, Bethesda, MD 20892 USA. [Jones, Karen; McSherry, Frances; Murtaugh, Cristin] Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, Perry Point, MD USA. [Glover, Elbert D.] Univ Maryland, Ctr Hlth Behav Res, Dept Publ & Community Hlth, College Pk, MD 20742 USA. [Anthenelli, Robert M.] Univ Cincinnati, Tri State Tobacco & Alcohol Res Ctr, Cincinnati, OH USA. [Anthenelli, Robert M.] Cincinnati VA Med Ctr, Cincinnati, OH USA. [Jackson, Thomas] Univ Wisconsin, UW Ctr Tobacco Res & Intervent, Sch Med & Publ Hlth, Madison, WI USA. [Williams, Jill] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Yu, Elmer] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Kahn, R (reprint author), Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, 6001 Execut Blvd Room 4123,MSC 9551, Bethesda, MD 20892 USA. EM rkan@nida.nih.gov FU National Institutes of Health, National Institute on Drug Abuse through the Department of Veterans Affairs [Y1-DA4006] FX This study was supported by the National Institutes of Health, National Institute on Drug Abuse through the Department of Veterans Affairs Cooperative Studies Program (Interagency Agreement No. Y1-DA4006). NR 21 TC 9 Z9 9 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD MAR PY 2012 VL 14 IS 3 BP 377 EP 382 DI 10.1093/ntr/ntr143 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 898DB UT WOS:000300714500018 PM 21846661 ER PT J AU Reed, SD Guthrie, KA Joffe, H Shifren, JL Seguin, RA Freeman, EW AF Reed, Susan D. Guthrie, Katherine A. Joffe, Hadine Shifren, Jan L. Seguin, Rebecca A. Freeman, Ellen W. TI Sexual Function in Nondepressed Women Using Escitalopram for Vasomotor Symptoms A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the North-American-Menopause-Society (NAMS) CY SEP 21-24, 2011 CL Washington, DC SP N Amer Menopause Soc (NAMS) ID POSTMENOPAUSAL WOMEN; HOT FLASHES; DOUBLE-BLIND; INDEX FSFI; DYSFUNCTION; ANTIDEPRESSANTS; MENOPAUSE; EFFICACY; HEALTH; POPULATION AB OBJECTIVE: To evaluate sexual function in midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms. Selective serotonin reuptake inhibitors effectively treat vasomotor symptoms but adversely affect sexual function in depressed populations. Information on sexual function in nondepressed midlife women using selective serotonin reuptake inhibitors for vasomotor symptoms is lacking; any treatments that might impair function are of concern. METHODS: This was a randomized controlled trial comparing 8 weeks of escitalopram with placebo in women ages 40-62 years with 28 or more bothersome vasomotor symptoms per week. Change in Female Sexual Function Index composite score (ranges from 2 [not sexually active, no desire] to 36) and six sexual domains (desire, arousal, lubrication, orgasm, satisfaction, pain) and the Female Sexual Distress Scale, and a single-question of sexually-related personal distress from the Female Sexual Distress Scale, were compared between groups. RESULTS: Among all women, median composite baseline Female Sexual Function Index score was 18.1 (interquartile range 2.4-26.5, n=200) and among sexually active women was 22.8 (interquartile range 17.4-27.0, n=75) in the escitalopram group and 23.6 (interquartile range 14.9-31.0, n=70) in the placebo group. Treatment with escitalopram did not affect composite Female Sexual Function Index score at follow-up compared with placebo (P=.18 all women; P=.47 sexually active at baseline). Composite mean Female Sexual Function Index change from baseline to week 8 was 0.1 (95% confidence interval [CI] -1.5 to 1.7) for escitalopram and 2.0 (95% CI 0.2-3.8) for placebo. The Female Sexual Distress Scale results did not differ between groups (P=.73) nor did adverse reports of sexual function. At week 8, among those women sexually active at baseline, there was a small difference between groups in Female Sexual Function Index domain mean score change in lubrication (P=.02) and a marginal nonsignificant difference in orgasm (P=.07). CONCLUSION: Escitalopram, when used in the treatment of vasomotor symptoms, did not worsen overall sexual function among nondepressed midlife women. C1 Univ Washington, Sch Med, Dept Obstet & Gynecol, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, Seattle, WA 98104 USA. Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Univ Penn, Sch Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Reed, SD (reprint author), Epidemiol Univ Washington, Dept Obstet & Gynecol, 325 9th Ave,Box 359865, Seattle, WA 98104 USA. EM reeds@u.washington.edu FU NCRR NIH HHS [UL1 RR025761]; NHLBI NIH HHS [K01 HL108807]; NIA NIH HHS [U01 AG032669, U01AG032682, U01 AG032699-03, U01 AG032700, U01 AG032682, U01 AG032699, U01 AG032656-04, U01AG032669, U01AG032700, U01 AG032656, U01 AG032659, U01 AG032682-03, U01AG032699, U01AG032659] NR 33 TC 7 Z9 8 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 MAR PY 2012 VL 119 IS 3 BP 527 EP 538 DI 10.1097/AOG.0b013e3182475fa4 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 897GY UT WOS:000300637400007 PM 22353950 ER PT J AU Katon, J Reiber, G Williams, MA Yanez, D Miller, E AF Katon, Jodie Reiber, Gayle Williams, Michelle A. Yanez, David Miller, Edith TI Hemoglobin A(1c) and Postpartum Abnormal Glucose Tolerance Among Women With Gestational Diabetes Mellitus SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID GLYCATED HEMOGLOBIN; DCA 2000; A1C; MULTICENTER; INTOLERANCE; POPULATION; PREDICTORS; ANTEPARTUM; PREVENTION; ANALYZER AB OBJECTIVE: To analyze the association of hemoglobin A(1c) (HbA(1c)) at gestational diabetes mellitus (GDM) diagnosis with postpartum abnormal glucose in a cohort of women with GDM. METHODS: Women with singleton pregnancies treated for GDM at a large diabetes and pregnancy program located in Charlotte, North Carolina, who completed a postpartum 2-hour oral glucose tolerance test were eligible for inclusion in this retrospective cohort study. Clinical information, including maternal HbA(1c) at diagnosis, was abstracted from medical records. A parametric survival model was used to assess the association of HbA(1c) at GDM diagnosis with postpartum maternal abnormal glucose including impaired fasting glucose, impaired glucose tolerance, and any postpartum abnormal glucose. RESULTS: Of the 277 postpartum women with GDM, 75 (32%) had impaired fasting glucose, 61 (28%) had impaired glucose tolerance, and 15 (9%) were diagnosed with type 2 diabetes mellitus after delivery. After adjustment for clinic, maternal age, parity, prepregnancy body mass index 25 or higher, nonwhite race or ethnicity, and gestational week at first HbA(1c), we detected a trend of increased risk for impaired fasting glucose (P=.01), impaired glucose tolerance (P=.002), and any glucose abnormality (P<.001) associated with increased quartile of HbA1c at GDM diagnosis. CONCLUSION: Hemoglobin A1c measured at GDM diagnosis may be a useful tool for identifying patients with GDM at highest risk of developing postpartum abnormal glucose. LEVEL OF EVIDENCE: II (Obstet Gynecol 2012;119:566-74) DOI: 10.1097/AOG.0b013e3182475ac2 C1 [Katon, Jodie] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Carolinas Med Ctr, Diabet & Pregnancy Program, Charlotte, NC 28203 USA. RP Katon, J (reprint author), Univ Washington, Dept Epidemiol, Box 357236, Seattle, WA 98195 USA. EM jkaton@u.washington.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [T32 HD052462]; Seattle chapter of Achievement Rewards for College Scientists; Samuel and Althea Stroum Foundation; University of Washington Department of Epidemiology FX Dr. Katon was supported by grant number T32 HD052462 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; the Seattle chapter of Achievement Rewards for College Scientists; and the Samuel and Althea Stroum Foundation. This study was also funded by a grant from the University of Washington Department of Epidemiology. NR 35 TC 6 Z9 7 U1 0 U2 6 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 MAR PY 2012 VL 119 IS 3 BP 566 EP 574 DI 10.1097/AOG.0b013e3182475ac2 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 897GY UT WOS:000300637400012 PM 22353955 ER PT J AU Ter-Minassian, M Chan, JA Hooshmand, SM Brais, LK Daskalova, A Heafield, R Lin, XH Christiani, DC Kulke, MH AF Ter-Minassian, Monica Chan, Jennifer A. Hooshmand, Susanne M. Brais, Lauren K. Daskalova, Anastassia Heafield, Rachel Lin, Xihong Christiani, David C. Kulke, Matthew H. TI Prognostic Value of Chromogranin A and Alkaline Phosphatase in Patients with Advanced Neuroendocrine Tumor SO PANCREAS LA English DT Meeting Abstract C1 [Ter-Minassian, Monica; Chan, Jennifer A.; Hooshmand, Susanne M.; Brais, Lauren K.; Daskalova, Anastassia; Heafield, Rachel; Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2012 VL 41 IS 2 BP 341 EP 342 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 897ID UT WOS:000300641500050 ER PT J AU Chan, JA Ryan, DP Fuchs, CS Zhu, AX Abrams, TA Wolpin, BM Malinowski, P Regan, E Kulke, MH AF Chan, Jennifer A. Ryan, David P. Fuchs, Charles S. Zhu, Andrew X. Abrams, Thomas A. Wolpin, Brian M. Malinowski, Paige Regan, Eileen Kulke, Matthew H. TI Updated Results of a Phase I Study of Pasireotide (SOM230) in Combination with Everolimus in Patients (pts) with Advanced Neuroendocrine Tumors (NET) SO PANCREAS LA English DT Meeting Abstract C1 [Chan, Jennifer A.; Fuchs, Charles S.; Abrams, Thomas A.; Wolpin, Brian M.; Malinowski, Paige; Regan, Eileen; Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Chan, Jennifer A.; Fuchs, Charles S.; Abrams, Thomas A.; Wolpin, Brian M.; Kulke, Matthew H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ryan, David P.; Zhu, Andrew X.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2012 VL 41 IS 2 BP 344 EP 344 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 897ID UT WOS:000300641500057 ER PT J AU Kulke, MH O'Dorisio, T Phan, A Langdon, R Marek, B Ikhlaque, N Bergsland, E Freiman, J Law, L Banks, P Frazier, K Jackson, J Zambrowicz, B AF Kulke, Matthew H. O'Dorisio, Thomas Alexandria Phan Langdon, Robert, Jr. Marek, Billie Ikhlaque, Nadeem Bergsland, Emily Freiman, Joel Law, Linda Banks, Phillip Frazier, Kenny Jackson, Jessica Zambrowicz, Brian TI Efficacy of Telotristat Etiprate in Refractory Carcinoid Syndrome: Preliminary Results of a Randomized, Placebo-Controlled, Multicenter Study SO PANCREAS LA English DT Meeting Abstract C1 [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [O'Dorisio, Thomas] Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. [Alexandria Phan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Langdon, Robert, Jr.] Nebraska Methodist Hosp Syst, Omaha, NE USA. [Marek, Billie] Texas Oncol PA, McAllen, TX USA. [Ikhlaque, Nadeem] St Francis Mem Hosp, Grove Beach, IN USA. [Bergsland, Emily] Univ Calif San Francisco, Ctr Canc, San Francisco, CA 94143 USA. [Freiman, Joel; Law, Linda; Banks, Phillip; Frazier, Kenny; Jackson, Jessica; Zambrowicz, Brian] Lexicon Pharmaceut Inc, The Woodlands, TX 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 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2012 VL 41 IS 2 BP 346 EP 346 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 897ID UT WOS:000300641500064 ER PT J AU Townsend, E Pallotta, S AF Townsend, Elise Pallotta, Sheila TI Commentary on "Volumetric MRI and MRS and Early Motor Development of Infants Born Preterm" SO PEDIATRIC PHYSICAL THERAPY LA English DT Editorial Material ID BIRTH-WEIGHT INFANTS C1 [Townsend, Elise] MGH Inst Hlth Profess, Boston, MA USA. [Townsend, Elise; Pallotta, Sheila] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Townsend, E (reprint author), MGH Inst Hlth Profess, Boston, MA USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0898-5669 EI 1538-005X J9 PEDIATR PHYS THER JI Pediatr. Phys. Ther. PD SPR PY 2012 VL 24 IS 1 BP 44 EP 45 DI 10.1097/PEP.0b013e31823e0abb PG 3 WC Pediatrics; Rehabilitation SC Pediatrics; Rehabilitation GA 896IL UT WOS:000300558800007 ER PT J AU Tucker, JD Wong, FY Nehl, EJ Zhang, FJ AF Tucker, Joseph D. Wong, Frank Y. Nehl, Eric J. Zhang, Fujie TI HIV testing and care systems focused on sexually transmitted HIV in China SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID ANTIRETROVIRAL TREATMENT PROGRAM; HUMAN-IMMUNODEFICIENCY-VIRUS; FEMALE SEX WORKERS; COST-EFFECTIVENESS; INFECTION; PREVENTION; HEALTH; SERVICES; SYPHILIS; PROVINCE AB Background Over three-quarters of new HIV infections in China during 2009 were estimated to be from sexual transmission. Over half of those living with HIV do not know their serostatus and identifying and treating individuals with sexually transmitted HIV infection has been challenging. Objective This global assessment explores Chinese systems for detecting and treating those with HIV infection with a particular focus on groups at increased risk of sexually transmitted HIV. Methods Published literature, grey sources and non-governmental reports were reviewed to describe HIV testing and care systems in China. Results HIV testing and care in China involve several parallel health systems and have been largely successful in reaching large numbers of vulnerable individuals. Provider-initiated testing and counselling has been more effective than voluntary counselling and testing programmes for expanding HIV testing efforts in China. Individuals with sexually transmitted HIV infection are underrepresented in the antiretroviral care system compared with other high-risk groups. Conclusions Comprehensive HIV testing and care bring together a number of Chinese health systems, but there are still gaps and challenges. Research and programmes focused on HIV testing and care for those with increased sexual risk are needed. C1 [Tucker, Joseph D.] UNC Chapel Hill Sch Med, Dept Med, Div Infect Dis, Chapel Hill, NC USA. [Tucker, Joseph D.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02139 USA. [Wong, Frank Y.; Nehl, Eric J.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Zhang, Fujie] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing, Peoples R China. [Zhang, Fujie] Capital Med Med Univ, Ditan Hosp, Beijing, Peoples R China. RP Tucker, JD (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, 55 Fruit St,GRJ 504, Boston, MA 02139 USA. EM jtucker4@partners.org RI Ghartouchent, malek/B-9088-2012 FU NIH (US NIH) [1K01TW008200-01A1]; UNC [NIH FIC D43 TW01039]; UNC Social Science Research on HIV/AIDS in China (NIH NICHD) [R24 HD056670-01]; UNC Center for AIDS Research; Emory Center for AIDS Research [P30 AI050409] FX Financial support for this research came from an NIH Fogarty K01 award (US NIH 1K01TW008200-01A1), the UNC Fogarty AIDS International Research and Training Program (NIH FIC D43 TW01039), the UNC Social Science Research on HIV/AIDS in China (NIH NICHD R24 HD056670-01), the UNC Center for AIDS Research and the Emory Center for AIDS Research (P30 AI050409). NR 52 TC 12 Z9 12 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD MAR PY 2012 VL 88 IS 2 BP 116 EP 119 DI 10.1136/sextrans-2011-050135 PG 4 WC Infectious Diseases SC Infectious Diseases GA 897HH UT WOS:000300638300008 PM 22345024 ER PT J AU Narva, E Rahkonen, N Emani, MR Lund, R Pursiheimo, JP Nasti, J Autio, R Rasool, O Denessiouk, K Lahdesmaki, H Rao, A Lahesmaa, R AF Narva, Elisa Rahkonen, Nelly Emani, Maheswara Reddy Lund, Riikka Pursiheimo, Juha-Pekka Nasti, Juuso Autio, Reija Rasool, Omid Denessiouk, Konstantin Lahdesmaki, Harri Rao, Anjana Lahesmaa, Riitta TI RNA-Binding Protein L1TD1 Interacts with LIN28 via RNA and is Required for Human Embryonic Stem Cell Self-Renewal and Cancer Cell Proliferation SO STEM CELLS LA English DT Article DE L1TD1; Pluripotent stem cells; Embryonic stem cells; Embryonal carcinoma; Proliferation ID PROCESSING BODIES; CARCINOMA-CELLS; MESSENGER-RNAS; ES CELLS; P-BODIES; EXPRESSION; OCT4; REGULATOR; SITES; DIFFERENTIATION AB Human embryonic stem cells (hESC) have a unique capacity to self-renew and differentiate into all the cell types found in human body. Although the transcriptional regulators of pluripotency are well studied, the role of cytoplasmic regulators is still poorly characterized. Here, we report a new stem cell-specific RNA-binding protein L1TD1 (ECAT11, FLJ10884) required for hESC self-renewal and cancer cell proliferation. Depletion of L1TD1 results in immediate downregulation of OCT4 and NANOG. Furthermore, we demonstrate that OCT4, SOX2, and NANOG all bind to the promoter of L1TD1. Moreover, L1TD1 is highly expressed in seminomas, and depletion of L1TD1 in these cancer cells influences self-renewal and proliferation. We show that L1TD1 colocalizes and interacts with LIN28 via RNA and directly with RNA helicase A (RHA). LIN28 has been reported to regulate translation of OCT4 in complex with RHA. Thus, we hypothesize that L1TD1 is part of the L1TD1-RHA-LIN28 complex that could influence levels of OCT4. Our results strongly suggest that L1TD1 has an important role in the regulation of stemness. STEM CELLS 2012;30:452-460 C1 [Narva, Elisa; Rahkonen, Nelly; Emani, Maheswara Reddy; Lund, Riikka; Pursiheimo, Juha-Pekka; Nasti, Juuso; Autio, Reija; Rasool, Omid; Denessiouk, Konstantin; Lahesmaa, Riitta] Univ Turku, Turku Ctr Biotechnol, FIN-20521 Turku, Finland. [Narva, Elisa; Rahkonen, Nelly; Emani, Maheswara Reddy; Lund, Riikka; Pursiheimo, Juha-Pekka; Nasti, Juuso; Autio, Reija; Rasool, Omid; Denessiouk, Konstantin; Lahesmaa, Riitta] Abo Akad Univ, FIN-20521 Turku, Finland. [Autio, Reija; Lahdesmaki, Harri] Tampere Univ Technol, Dept Signal Proc, FIN-33101 Tampere, Finland. [Lahdesmaki, Harri] Aalto Univ, Dept Informat & Comp Sci, Espoo, Finland. [Rao, Anjana] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Rao, Anjana] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Rao, Anjana] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. RP Lahesmaa, R (reprint author), Univ Turku, Turku Ctr Biotechnol, POB 123, FIN-20521 Turku, Finland. EM riitta.lahesmaa@btk.fi RI Autio, Reija/D-2037-2014; OI Lund, Riikka/0000-0002-1068-5918 FU European Union; JDRF; Academy of Finland; Finnish Cancer Organizations; Turku Graduate School of Biomedical Sciences; Ida Montin Foundation; Finnish Cultural Foundation FX We thank Outi Hovatta (Karolinska Institute, Sweden) for the hESC lines; Peter Andrews (University of Sheffield, U. K.) for the EC cell lines, antibodies and plasmids; Jianliang Li (University of Sheffield, U. K.) for the NT2D1-TetR3 cell line; Anne-Mari Tveit, Joel Nystrom, Subhanjan Bhowmik, Kirsi Rautajoki, and technicians Marjo Hakkarainen, Paivi Junni, Arja Reinikainen, and Sarita Heinonen for the assistance with the experiments and data mining; Cell Imaging Core and The Finnish Microarray and Sequencing Centre. This study was supported by funding for the ESTOOLS consortium under the Sixth Research Framework Programme of the European Union, JDRF, The Academy of Finland, the Finnish Cancer Organizations, Turku Graduate School of Biomedical Sciences, Ida Montin Foundation, and Finnish Cultural Foundation. A. R. is currently affiliated with La Jolla Institute for Allergy and Immunology, La Jolla, CA. NR 46 TC 27 Z9 30 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAR PY 2012 VL 30 IS 3 BP 452 EP 460 DI 10.1002/stem.1013 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 896ZW UT WOS:000300611400013 PM 22162396 ER PT J AU Remer, EM Casalino, DD Arellano, RS Bishoff, JT Coursey, CA Dighe, M Fulgham, P Israel, GM Lazarus, E Leyendecker, JR Majd, M Nikolaidis, P Papanicolaou, N Prasad, S Ramchandani, P Sheth, S Vikram, R Karmazyn, B AF Remer, Erick M. Casalino, David D. Arellano, Ronald S. Bishoff, Jay T. Coursey, Courtney A. Dighe, Manjiri Fulgham, Pat Israel, Gary M. Lazarus, Elizabeth Leyendecker, John R. Majd, Massoud Nikolaidis, Paul Papanicolaou, Nicholas Prasad, Srinivasa Ramchandani, Parvati Sheth, Sheila Vikram, Raghunandan Karmazyn, Boaz TI ACR Appropriateness Criteria (R) Acute Onset of Scrotal Pain - Without Trauma, Without Antecedent Mass SO ULTRASOUND QUARTERLY LA English DT Article DE appropriateness criteria; acute scrotum/acute scrotal pain; testicular torsion; epididymoorchitis; ultrasound; MRI ID COLOR DOPPLER SONOGRAPHY; SEGMENTAL TESTICULAR INFARCTION; SPERMATIC CORD TORSION; EMERGENCY-DEPARTMENT; PEDIATRIC-PATIENTS; CLINICAL-OUTCOMES; CHILDREN; ULTRASOUND; US; ULTRASONOGRAPHY AB Men or boys, who present with acute scrotal pain without prior trauma or a known mass, most commonly suffer from torsion of the spermatic cord; epididymitis or epididymoorchitis; or torsion of the testicular appendages. Less common causes of pain include a strangulated hernia, segmental testicular infarction, or a previously undiagnosed testicular tumor. Ultrasound is the study of choice to distinguish these disorders; it has supplanted Tc-99 m scrotal scintigraphy for the diagnosis of spermatic cord torsion. MRI should be used in a problem solving role if the ultrasound examination is inconclusive. The ACR Appropriateness Criteria (R) are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. C1 [Remer, Erick M.] Cleveland Clin, Cleveland, OH 44106 USA. [Casalino, David D.; Nikolaidis, Paul] Northwestern Univ, Chicago, IL 60611 USA. [Arellano, Ronald S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bishoff, Jay T.] Intermt Urol Inst, Murray, UT USA. [Bishoff, Jay T.; Fulgham, Pat] Amer Urol Assoc, Linthicum, MD 21090 USA. [Coursey, Courtney A.] Emory Univ Hosp, Atlanta, GA 30322 USA. [Dighe, Manjiri] Univ Washington, Med Ctr, Seattle, WA 98195 USA. [Fulgham, Pat] Presbyterian Med Ctr, Dallas, TX USA. [Israel, Gary M.] Yale Univ, Sch Med, New Haven, CT USA. [Lazarus, Elizabeth] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Leyendecker, John R.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Majd, Massoud] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Majd, Massoud] Soc Nucl Med, Reston, VA USA. [Papanicolaou, Nicholas; Ramchandani, Parvati] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Prasad, Srinivasa] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Sheth, Sheila] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Vikram, Raghunandan] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Karmazyn, Boaz] Indiana Univ, James Whitcomb Riley Hosp Children, Indianapolis, IN USA. RP Remer, EM (reprint author), Cleveland Clin Fdn, Dept Radiol A21, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM remere1@ccf.org NR 63 TC 5 Z9 5 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 J9 ULTRASOUND Q JI Ultrasound Q. PD MAR PY 2012 VL 28 IS 1 BP 47 EP 51 DI 10.1097/RUQ.0b013e3182493c97 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 898GB UT WOS:000300725600007 PM 22357246 ER PT J AU O'Donovan, DJ Stokes-Rees, I Nam, Y Blacklow, SC Schroder, GF Brunger, AT Sliz, P AF O'Donovan, Daniel J. Stokes-Rees, Ian Nam, Yunsun Blacklow, Stephen C. Schroeder, Gunnar F. Brunger, Axel T. Sliz, Piotr TI A grid-enabled web service for low-resolution crystal structure refinement SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID PROTEIN DATA-BANK; CRYSTALLOGRAPHY; COMPLEX AB Deformable elastic network (DEN) restraints have proved to be a powerful tool for refining structures from low-resolution X-ray crystallographic data sets. Unfortunately, optimal refinement using DEN restraints requires extensive calculations and is often hindered by a lack of access to sufficient computational resources. The DEN web service presented here intends to provide structural biologists with access to resources for running computationally intensive DEN refinements in parallel on the Open Science Grid, the US cyberinfrastructure. Access to the grid is provided through a simple and intuitive web interface integrated into the SBGrid Science Portal. Using this portal, refinements combined with full parameter optimization that would take many thousands of hours on standard computational resources can now be completed in several hours. An example of the successful application of DEN restraints to the human Notch1 transcriptional complex using the grid resource, and summaries of all submitted refinements, are presented as justification. C1 [O'Donovan, Daniel J.; Stokes-Rees, Ian; Nam, Yunsun; Blacklow, Stephen C.; Sliz, Piotr] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Schroeder, Gunnar F.] Forschungszentrum Julich, Inst Complex Syst ICS 6, D-52425 Julich, Germany. [Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Brunger, Axel T.] Stanford Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Brunger, Axel T.] Stanford Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Brunger, Axel T.] Stanford Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. [Brunger, Axel T.] Stanford Sch Med, Dept Photon Sci, Stanford, CA 94305 USA. [Sliz, Piotr] Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA. RP Sliz, P (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM sliz@hkl.hms.harvard.edu RI Schroder, Gunnar/H-5261-2013; OI Schroder, Gunnar/0000-0003-1803-5431; Brunger, Axel/0000-0001-5121-2036; Stokes-Rees, Ian/0000-0002-6832-6168; Sliz, Piotr/0000-0002-6522-0835 FU National Science Foundation [0639193]; US Department of Energy's Office of Science FX This research was performed using resources provided by the Open Science Grid, which is supported by the National Science Foundation and the US Department of Energy's Office of Science. This work was supported by the National Science Foundation grant 0639193 (PS). NR 17 TC 12 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAR PY 2012 VL 68 BP 261 EP 267 DI 10.1107/S0907444912001163 PN 3 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 894RM UT WOS:000300444300008 PM 22349228 ER PT J AU Adeseun, GA Bonney, CC Rosas, SE AF Adeseun, Gbemisola A. Bonney, Christine C. Rosas, Sylvia E. TI Health Literacy Associated With Blood Pressre but not Other Cardiovascular Disease Risk Factors Among Dialysis Patients SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE blood pressure; cardiovascular disease; end-stage renal disease; health literacy; hemodialysis; hypertension; peritoneal dialysis ID BODY-MASS INDEX; HEMODIALYSIS-PATIENTS; ALL-CAUSE; MORTALITY; HYPERTENSION; KNOWLEDGE; CKD; PREVALENCE; CHOLESTEROL; SURVIVAL AB BACKGROUND Limited health literacy is prevalent and has been linked to adverse patient outcomes. We examined the relationship between health literacy and cardiovascular disease (CVD) risk factors, including blood pressure (BP) parameters, lipids, waist-to-hip ratio (WHR), body mass index (BMI), and tobacco utilization among dialysis patients. METHODS We conducted a cross-sectional study of 72 participants in a prospective cohort study of vascular calcification in newly initiated dialysis patients. Health literacy was assessed using the Short Test of Functional Health Literacy (S-TOFHLA) in Adults. The study population was dichotomized into those with and without adequate literacy. Linear and logistic regression analyses were used to predict continuous and dichotomous cardiovascular risk factor variables, respectively. RESULTS Twenty-one percent had limited health literacy. Compared to limited health literacy, adequate health literacy was associated with lower BP parameters in multivariable analyses (systolic blood pressure (SBP): beta-16.8, s.e. 6.7, P = 0.01; diastolic blood pressure (DBP):beta-13.8, s.e. 4.1, P = 0.001; mean arterial pressure (MAP):beta-14.8, s.e. 4.6, P = 0.002). Health literacy was not a statistically significant predictor of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, WHR, BMI, or tobacco utilization. CONCLUSIONS Limited health literacy is common in individuals on dialysis. Individuals with adequate health literacy skills had DBP readings that were on average 13.8 mm Hg lower and MAP that was 14.8 mm Hg lower than those with inadequate health literacy. Prospective studies to elucidate if improvements in health literacy skills will lead to improvement in BP control are needed. C1 [Adeseun, Gbemisola A.; Bonney, Christine C.; Rosas, Sylvia E.] Univ Penn, Dept Med, Div Renal Electrolyte & Hypertens, Philadelphia, PA 19104 USA. [Rosas, Sylvia E.] Philadelphia Vet Adm Med Ctr, Dept Med, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Rosas, SE (reprint author), Univ Penn, Dept Med, Div Renal Electrolyte & Hypertens, Philadelphia, PA 19104 USA. EM sylvia.rosas@uphs.upenn.edu RI Rosas, Sylvia/D-1106-2009 FU NIH [R21 HL 086971]; Veterans Health Administration; National Center for Research Resources [UL1RR024134]; [R01 DK 080033] FX This work was supported by NIH grants R21 HL 086971. Salary support was provided by the Veterans Health Administration and R01 DK 080033 (Dr Rosas). The project described was supported by Grant Number 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. Funding sources had no involvement in study design, data collection, analysis, and interpretation, writing of the report, or decision to submit the paper for publication. NR 38 TC 14 Z9 14 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAR PY 2012 VL 25 IS 3 BP 348 EP 353 DI 10.1038/ajh.2011.252 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 893VN UT WOS:000300385900013 PM 22237154 ER PT J AU Yang, X Cao, W Zhang, L Zhang, W Zhang, X Lin, H AF Yang, X. Cao, W. Zhang, L. Zhang, W. Zhang, X. Lin, H. TI Targeting 14-3-3zeta in cancer therapy SO CANCER GENE THERAPY LA English DT Review DE 14-3-3zeta; apoptosis; cancer therapy; cell cycle; invasion ID SQUAMOUS-CELL CARCINOMA; MULTIDIMENSIONAL LIQUID-CHROMATOGRAPHY; ISOFORM-SPECIFIC EXPRESSION; TANDEM MASS-SPECTROMETRY; LUNG-CANCER; PROTEOMIC ANALYSIS; INDUCED APOPTOSIS; HUMAN ASTROCYTOMA; DOWN-REGULATION; BREAST-CANCER AB An effective therapeutic target is imperative for cancer treatment, including gene therapy. 14-3-3zeta, a member of the 14-3-3 protein family, acts as a suppressor of apoptosis and has a central role in tumor genesis and progression. Owing to its wide upregulation in human tumors and its involvement in cancer progression and treatment resistance, 14-3-3zeta is currently undergoing extensive investigation as a novel therapeutic target. In this review, we widely investigate the role of 14-3-3zeta in cancer and suggest a potential therapeutic target for new anticancer interventions. Cancer Gene Therapy (2012) 19, 153-159; doi:10.1038/cgt.2011.85; published online 23 December 2011 C1 [Yang, X.; Cao, W.; Zhang, L.; Zhang, W.; Zhang, X.; Lin, H.] Fourth Mil Med Univ, Inst Neurosurg, Xijing Hosp, Xian 710032, Shaanxi Provinc, Peoples R China. [Zhang, W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg,Mol Neurosurg Lab,Brain Tumor Res, Boston, MA USA. RP Zhang, X (reprint author), Fourth Mil Med Univ, Inst Neurosurg, Xijing Hosp, Changle Western Rd 127, Xian 710032, Shaanxi Provinc, Peoples R China. EM xzhang@fmmu.edu.cn FU Scientific and Technological Project of ShaanXi Province [2008K09-09]; National Natural Science Foundation of China [81072083] FX Supported by Scientific and Technological Project of ShaanXi Province (No: 2008K09-09) and National Natural Science Foundation of China (No: 81072083). NR 77 TC 20 Z9 23 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD MAR PY 2012 VL 19 IS 3 BP 153 EP 159 DI 10.1038/cgt.2011.85 PG 7 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 893VK UT WOS:000300385600001 PM 22193627 ER PT J AU Yamada, S Kuroda, T Fuchs, BC He, X Supko, JG Schmitt, A McGinn, CM Lanuti, M Tanabe, KK AF Yamada, S. Kuroda, T. Fuchs, B. C. He, X. Supko, J. G. Schmitt, A. McGinn, C. M. Lanuti, M. Tanabe, K. K. TI Oncolytic Herpes simplex virus expressing yeast cytosine deaminase: relationship between viral replication, transgene expression, prodrug bioactivation SO CANCER GENE THERAPY LA English DT Article DE cytosine deaminase; HSV-1; pharmacokinetics; viral oncolysis ID POSITRON-EMISSION-TOMOGRAPHY; ADENOVIRUS-MEDIATED TRANSFER; IN-VIVO; GENE-THERAPY; URACIL PHOSPHORIBOSYLTRANSFERASE; CHEMOTHERAPEUTIC-AGENTS; COLORECTAL-CANCER; CYP2B1 TRANSGENE; TUMOR-REGRESSION; SUICIDE GENE AB Yeast cytosine deaminase (yCD) is a well-characterized prodrug/enzyme system that converts 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU), and has been combined with oncolytic viruses. However, in vivo studies of the interactions between 5-FC bioactivation and viral replication have not been previously reported, nor have the kinetics of transgene expression and the pharmacokinetics of 5-FC and 5-FU. We constructed a replication-conditional Herpes simplex virus 1 (HSV-1) expressing yCD and examined cytotoxicity when 5-FC was initiated at different times after viral infection, and observed that earlier 5-EC administration led to greater cytotoxicity than later 5-EC administration in vitro and in vivo. In animal models, 12 days of 5-FC administration was superior to 6 days, but dosing beyond 12 days did not further enhance efficacy. Consistent with the dosing-schedule results, both viral genomic DNA copy number and viral titers were observed to peak on Day 3 after viral injection and gradually decrease thereafter. The virus is replication-conditional and was detected in tumors for as long as 2 weeks after viral injection. The maximum relative extent of yCD conversion of 5-EC to 5-FU in tumors was observed on Day 6 after viral injection and it decreased progressively thereafter. The observation that 5-FU generation within tumors did not lead to appreciable levels of systemic 5-FU (<10 ng ml(-1)) is important and has not been previously reported. The approaches used in these studies of the relationship between the viral replication kinetics, transgene expression, prodrug administration and anti-tumor efficacy are useful in the design of clinical trials of armed, oncolytic viruses. Cancer Gene Therapy (2012) 19, 160-170; doi:10.1038/cgt.2011.70; published online 11 November 2011 C1 [Yamada, S.; Kuroda, T.; Fuchs, B. C.; Tanabe, K. K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. [Yamada, S.; Kuroda, T.; Fuchs, B. C.; He, X.; Supko, J. G.; Schmitt, A.; McGinn, C. M.; Lanuti, M.; Tanabe, K. K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [He, X.; Supko, J. G.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. [Schmitt, A.; McGinn, C. M.; Lanuti, M.] Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, Boston, MA 02114 USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Yawkey 7-924,55 Fruit St, Boston, MA 02114 USA. EM ktanabe@partners.org OI Kuroda, Toshihiko/0000-0001-6660-8930 FU NIH [R01CA76183, 5K01CA140861] FX This work was supported by NIH grants R01CA76183 (KKT) and 5K01CA140861 (BCF). NR 46 TC 8 Z9 9 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD MAR PY 2012 VL 19 IS 3 BP 160 EP 170 DI 10.1038/cgt.2011.70 PG 11 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 893VK UT WOS:000300385600002 PM 22076044 ER PT J AU Heddleston, JM Wu, Q Rivera, M Minhas, S Lathia, JD Sloan, AE Iliopoulos, O Hjelmeland, AB Rich, JN AF Heddleston, J. M. Wu, Q. Rivera, M. Minhas, S. Lathia, J. D. Sloan, A. E. Iliopoulos, O. Hjelmeland, A. B. Rich, J. N. TI Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE hypoxia; MLL1; cancer stem cell; HIF2 alpha; epigenetics ID MYELOID-LEUKEMIA; GENE-EXPRESSION; GLIOBLASTOMA; MLL; IDENTIFICATION; NEUROGENESIS; ACTIVATION; SUBCLASSES; PATHWAYS; SURVIVAL AB Normal stem cells reside in functional niches critical for self-renewal and maintenance. Neural and hematopoietic stem cell niches, in particular, are characterized by restricted availability of oxygen and the resulting regulation by hypoxia-inducible factors (HIFs). Glioblastoma multiforme (GBM) is the most common malignant brain tumor and also contains high degrees of hypoxia. Heterogeneity within the neoplastic compartment has been well characterized in GBM and may be derived from genetic and epigenetic sources that co-evolve during malignant progression. Recent experimental evidence has supported the importance of hypoxia in glioma stem cell (GSC) niches. We hypothesized that HIFs require epigenetic-modifying proteins to promote tumor malignancy in GBM. Here we demonstrate that in GBM the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is induced by hypoxia and enhances hypoxic responses. Loss of MLL1 reduces the expression of HIF transcripts and HIF2 alpha protein. Targeting MLL1 by RNA interference inhibited the expression of HIF2 alpha and target genes, including vascular endothelial growth factor (VEGF). GSCs expressed higher levels of MLL1 than matched non-stem tumor cells and depletion of MLL1 reduced GSC self-renewal, growth, and tumorigenicity. These studies have uncovered a novel mechanism mediating tumor hypoxic responses linking microenvironmental regulation of epigenetic-modifying proteins to cellular heterogeneity and provide rationale for the design of more sophisticated clinical approaches targeting epigenetic regulation. Cell Death and Differentiation (2012) 19, 428-439; doi: 10.1038/cdd.2011.109; published online 12 August 2011 C1 [Heddleston, J. M.; Wu, Q.; Rivera, M.; Minhas, S.; Lathia, J. D.; Hjelmeland, A. B.; Rich, J. N.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44106 USA. [Sloan, A. E.] Case Comprehens Canc Ctr, Univ Hosp Case Med Ctr, Dept Neurol Surg, Cleveland, OH USA. [Sloan, A. E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Iliopoulos, O.] Massachusetts Gen Hosp, Ctr Canc, Ctr Canc Res, Charlestown, MA USA. RP Rich, JN (reprint author), Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, 9500 Euclid Ave,Mailstop NE30, Cleveland, OH 44106 USA. EM richj@ccf.org FU McDonnell Foundation; NIH [NS054276, CA129958, CA116659, CA154130, CA151522]; National Brain Tumor Society; American Brain Tumor Association; Joelle Syverson Fund; NCI [F32 CA142159]; CWRU; Cleveland Clinic Foundation Tissue Procurement Service; Tissue Procurement and Biorepository Cores at University Hospitals; Case Comprehensive Cancer Center; [RO1 CA122591]; [CA137443]; [CA116257]; [HHS N2612010] FX We thank Cathy Shemo, Moneen Morgan, and Sage O'Bryant for flow cytometry assistance; Linda Vargo for histology assistance; and the members of the Rich laboratory for technical assistance and critical review of the manuscript. Work in the Rich laboratory is supported by the McDonnell Foundation and NIH Grants NS054276, CA129958, CA116659, and CA154130. AH is supported by the National Brain Tumor Society and the NIH Grant CA151522. JDL is supported by an American Brain Tumor Association Basic Research Fellowship (sponsored by the Joelle Syverson Fund) and a National Service Research Award (NCI F32 CA142159). OI is supported by RO1 CA122591. AS is supported by CA137443, CA116257, HHS N2612010, the Kimble Fund and Cristal Chair at CWRU. Studies were also supported by the Cleveland Clinic Foundation Tissue Procurement Service and the Tissue Procurement and Biorepository Cores at University Hospitals and the Case Comprehensive Cancer Center, and we also thank S Staugatis, R Weil, and M McGraw for their assistance. NR 40 TC 43 Z9 45 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAR PY 2012 VL 19 IS 3 BP 428 EP 439 DI 10.1038/cdd.2011.109 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 892SF UT WOS:000300305200007 PM 21836617 ER PT J AU Anglaret, X Minga, A Gabillard, D Ouassa, T Messou, E Morris, B Traore, M Coulibaly, A Freedberg, KA Lewden, C Menan, H Abo, Y Dakoury-Dogbo, N Toure, S Seyler, C AF Anglaret, Xavier Minga, Albert Gabillard, Delphine Ouassa, Timothee Messou, Eugene Morris, Brandon Traore, Moussa Coulibaly, Ali Freedberg, Kenneth A. Lewden, Charlotte Menan, Herve Abo, Yao Dakoury-Dogbo, Nicole Toure, Siaka Seyler, Catherine CA ANRS 12222 Morbidity Mortality Stu TI AIDS and Non-AIDS Morbidity and Mortality Across the Spectrum of CD4 Cell Counts in HIV-Infected Adults Before Starting Antiretroviral Therapy in Cote d'Ivoire SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; AFRICAN GOLD MINERS; SHORT-TERM RISK; TRIMETHOPRIM-SULFAMETHOXAZOLE; SOUTH-AFRICA; COTRIMOXAZOLE PROPHYLAXIS; OPPORTUNISTIC INFECTIONS; HIV-1-INFECTED PATIENTS; NAIVE INDIVIDUALS; VIRAL LOAD AB Background. In WesternEurope, NorthAmerica, andAustralia, large cohort collaborations have been able to estimate the short-term CD4 cell count-specific risk of AIDS or death in untreated human immunodeficiency virus (HIV)infected adults with high CD4 cell counts. In sub-Saharan Africa, these CD4 cell count-specific estimates are scarce. Methods. From 1996 through 2006, we followed up 2 research cohorts of HIV-infected adults in Cote d'Ivoire. This included follow-up off antiretroviral therapy (ART) across the entire spectrum of CD4 cell counts before the ART era, and only in patients with CD4 cell counts > 200 cells/mu L once ART became available. Data were censored at ART initiation. We modeled the CD4 cell count decrease using an adjusted linear mixed model. CD4 cell count-specific rates of events were obtained by dividing the number of first events occurring in a given CD4 cell count stratum by the time spent in that stratum. Results. Eight hundred sixty patients were followed off ART over 2789 person-years (PY). In the >= 650, 500-649, 350-499, 200-349, 100-199, 50-99, and 0-49 cells/mu L CD4 cell count strata, the rates of AIDS or death were 0.9, 1.7, 3.7, 10.4, 30.9, 60.8, and 99.9 events per 100 PY, respectively. In patients with CD4 cell counts >= 200 CD4 cells/mu L, the most frequent AIDS-defining disease was tuberculosis (decreasing from 4.0 to 0.6 events per 100 PY for 200-349 and >= 650 cells/mu L, respectively), and the most frequent HIV non-AIDS severe diseases were visceral bacterial diseases (decreasing from 9.1 to 3.6 events per 100 PY). Conclusions. Rates of AIDS or death, tuberculosis, and invasive bacterial diseases are substantial in patients with CD4 cell counts >= 200 cells/mu L. Tuberculosis and bacterial diseases should be the most important outcomes in future trials of early ART in sub-Saharan Africa. C1 [Anglaret, Xavier; Minga, Albert; Gabillard, Delphine; Ouassa, Timothee; Messou, Eugene; Traore, Moussa; Coulibaly, Ali; Lewden, Charlotte; Menan, Herve; Abo, Yao; Dakoury-Dogbo, Nicole; Toure, Siaka; Seyler, Catherine] CHU Treichville, Programme PAC CI, Abidjan, Cote Ivoire. [Ouassa, Timothee] CHU Treichville, Ctr Diagnost & Rech SIDA CeDReS, Abidjan, Cote Ivoire. [Anglaret, Xavier; Minga, Albert; Gabillard, Delphine; Messou, Eugene; Lewden, Charlotte] INSERM U897, Bordeaux, France. [Anglaret, Xavier; Minga, Albert; Gabillard, Delphine; Messou, Eugene; Lewden, Charlotte] Univ Bordeaux Segalen, Bordeaux, France. [Seyler, Catherine] Hop La Timone, Serv Sante Publ & Informat Med, Marseille, France. [Freedberg, Kenneth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Univ Ctr AIDS Res,Div Infect Dis, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Univ Ctr AIDS Res,Div Gen Med, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Univ Ctr AIDS Res,Med Practice Evaluat Ct, Boston, MA USA. [Morris, Brandon; Freedberg, Kenneth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Univ Ctr AIDS Res,Dept Med, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Anglaret, X (reprint author), CHU Treichville, Programme PAC CI, 18 BP 1954, Abidjan, Cote Ivoire. EM xavier.anglaret@pacci.ci RI Ghartouchent, malek/B-9088-2012; Van de Perre, Philippe/B-9692-2008; Nagot, Nicolas/I-9467-2014; Anglaret, Xavier/F-7333-2013; OI Van de Perre, Philippe/0000-0002-3912-0427; DENOEUD-NDAM, Lise/0000-0002-9482-1461 FU French Agence Nationale de Recherche sur le SIDA et les hepatites virales, Paris, France) [ANRS 1203, ANRS 1220, ANRS 12222]; US National Institute of Allergy and Infectious Diseases [NIAID AI058736] FX This work was supported by the French Agence Nationale de Recherche sur le SIDA et les hepatites virales, Paris, France (grants ANRS 1203, ANRS 1220, and ANRS 12222) and the US National Institute of Allergy and Infectious Diseases (grant NIAID AI058736). NR 29 TC 45 Z9 45 U1 1 U2 6 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 MAR 1 PY 2012 VL 54 IS 5 BP 714 EP 723 DI 10.1093/cid/cir898 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 891PE UT WOS:000300228300022 PM 22173233 ER PT J AU Gandhi, RT Deeks, SG AF Gandhi, Rajesh T. Deeks, Steven G. TI Plasma HIV-1 RNA Levels During Antiretroviral Therapy: How Low Is Low Enough? SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID RALTEGRAVIR INTENSIFICATION; VIREMIA; SUPPRESSION; ADHERENCE; DURATION; HAART; RISK C1 [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol & Harvard, Charlestown, MA USA. [Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. RP Deeks, SG (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA 94110 USA. EM sdeeks@php.ucsf.edu RI Ghartouchent, malek/B-9088-2012 FU NIAID NIH HHS [2P30 AI060354-06, K24 AI069994, K24AI069994, P0 AI27763, P30 AI027763, P30 AI060354, R01 AI066992, R01 AI066992-04A1, R01 AI087145, U01 AI 694722, U19 AI096109]; NLM NIH HHS [G08 LM008830, G08LM008830-01] NR 16 TC 11 Z9 11 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 MAR 1 PY 2012 VL 54 IS 5 BP 733 EP 735 DI 10.1093/cid/cir933 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 891PE UT WOS:000300228300024 PM 22238162 ER PT J AU Pfab, F Nowak-Machen, M Napadow, V Fleckenstein, J AF Pfab, Florian Nowak-Machen, Martina Napadow, Vitaly Fleckenstein, Johannes TI Alternatives to prokinetics to move the pylorus and colon SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Review DE critically ill; motility; mu-opioid receptor antagonists; prokinetics; therapies ID CRITICALLY-ILL PATIENTS; OPIOID-INDUCED CONSTIPATION; INDUCED BOWEL DYSFUNCTION; FUNCTIONAL GASTROINTESTINAL DISORDERS; ACUPUNCTURE-POINT STIMULATION; RANDOMIZED CONTROLLED-TRIAL; INTENSIVE-CARE UNITS; ENTERAL NUTRITION; CRITICAL ILLNESS; ELECTRICAL-STIMULATION AB Purpose of review Gastrointestinal motility disorders (GMDs) are common in the ICU. When encountering these problems, one typically thinks of prokinetics. This review summarizes current evidence of treatments. Recent findings Prokinetics are not the first-line therapy for GMDs. In fact, the clinical implications of using prokinetic agents are rather controversial. Current evidence on alternative treatment modalities such as fluid and electrolyte management, laxatives, opioid antagonists, purgative enemas, acupuncture, physical therapies and probiotics is growing. Summary Current state of the art to treat GMDs is primarily focused at the elimination of underlying trigger factors. Fluid and electrolyte management as well as laxatives and peripherally acting m-opioid receptor antagonists are the recommended first-line therapies that can be complemented with prokinetics. Acupuncture as well as physical modalities, such as massage or warming of the abdomen, is promising with few side-effects and should be considered as well. C1 [Pfab, Florian] Tech Univ Munich, Dept Prevent & Rehabil Sports Med, D-80809 Munich, Germany. [Pfab, Florian; Napadow, Vitaly] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Martinos Ctr Biomed Imaging, Cambridge, MA 02138 USA. [Pfab, Florian] Tech Univ Munich, Dept Dermatol & Allergy, D-80809 Munich, Germany. [Pfab, Florian] Harvard Univ, Brigham & Womens Hosp, Sch Med, CK CARE, Boston, MA 02115 USA. [Nowak-Machen, Martina] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Anesthesiol, Boston, MA 02115 USA. [Fleckenstein, Johannes] Univ Munich, Klinikum Grosshadern, Dept Anesthesiol, D-8000 Munich, Germany. RP Pfab, F (reprint author), Tech Univ Munich, Dept Prevent & Sports Med, Conollystr 32, D-80809 Munich, Germany. EM pfab@sport.med.tum.de OI Fleckenstein, Johannes/0000-0003-3442-0380 NR 80 TC 3 Z9 3 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD MAR PY 2012 VL 15 IS 2 BP 166 EP 173 DI 10.1097/MCO.0b013e32834f3000 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 894FD UT WOS:000300411600013 PM 22234164 ER PT J AU Dummer, R Flaherty, KT AF Dummer, Reinhard Flaherty, Keith T. TI Resistance patterns with tyrosine kinase inhibitors in melanoma: new insights SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE molecular classification of melanoma; resistance; targeted therapy; tyrosine kinase inhibitor ID METASTATIC MELANOMA; SOMATIC MUTATIONS; IMATINIB MESYLATE; UVEAL MELANOMA; BRAF; RAF; KIT; PATHWAY; CANCER; CELLS AB Purpose of review After years of therapeutic approaches with limited effects in metastatic melanoma, new inhibitors of serine-threonine and tyrosine kinases have demonstrated impressive clinical efficacy and improved survival. Recent findings This review explains the molecular background for the development of specific kinase inhibitors and briefly summarizes their clinical impact on advanced melanoma. Summary Despite robust early clinical efficacy, the antiproliferative effect of these kinase inhibitors is limited. The resistance mechanisms are explored currently and will help to identify new targets for melanoma therapy. C1 [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Dummer, R (reprint author), Univ Zurich Hosp, Dept Dermatol, Gloriastr 31, CH-8091 Zurich, Switzerland. EM reinhard.dummer@usz.ch FU Gottfried und Julia Bangerter-Rhyner-Stiftung; G+B Schwyzer Stiftung FX This work was supported in part by the Gottfried und Julia Bangerter-Rhyner-Stiftung and by G+B Schwyzer Stiftung. NR 41 TC 36 Z9 36 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-8746 EI 1531-703X J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAR PY 2012 VL 24 IS 2 BP 150 EP 154 DI 10.1097/CCO.0b013e32834fca92 PG 5 WC Oncology SC Oncology GA 894DG UT WOS:000300406600007 PM 22316627 ER PT J AU Kuijk, EW van Tol, LTA Van de Velde, H Wubbolts, R Welling, M Geijsen, N Roelen, BAJ AF Kuijk, Ewart W. van Tol, Leni T. A. Van de Velde, Hilde Wubbolts, Richard Welling, Maaike Geijsen, Niels Roelen, Bernard A. J. TI The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos SO DEVELOPMENT LA English DT Article DE FGF; Lineage segregation; MAP kinase; Epiblast; Hypoblast; Bovine; Human ID PLURIPOTENT STEM-CELLS; PRIMITIVE ENDODERM; DEVELOPMENTAL BIOLOGY; MOUSE BLASTOCYST; RAT BLASTOCYSTS; GROUND-STATE; SELF-RENEWAL; NANOG; DIFFERENTIATION; MAMMALS AB At the blastocyst stage of mammalian pre-implantation development, three distinct cell lineages have formed: trophectoderm, hypoblast (primitive endoderm) and epiblast. The inability to derive embryonic stem (ES) cell lines in a variety of species suggests divergence between species in the cell signaling pathways involved in early lineage specification. In mouse, segregation of the primitive endoderm lineage from the pluripotent epiblast lineage depends on FGF/MAP kinase signaling, but it is unknown whether this is conserved between species. Here we examined segregation of the hypoblast and epiblast lineages in bovine and human embryos through modulation of FGF/MAP kinase signaling pathways in cultured embryos. Bovine embryos stimulated with FGF4 and heparin form inner cell masses (ICMs) composed entirely of hypoblast cells and no epiblast cells. Inhibition of MEK in bovine embryos results in ICMs with increased epiblast precursors and decreased hypoblast precursors. The hypoblast precursor population was not fully ablated upon MEK inhibition, indicating that other factors are involved in hypoblast differentiation. Surprisingly, inhibition of FGF signaling upstream of MEK had no effects on epiblast and hypoblast precursor numbers in bovine development, suggesting that GATA6 expression is not dependent on FGF signaling. By contrast, in human embryos, inhibition of MEK did not significantly alter epiblast or hypoblast precursor numbers despite the ability of the MEK inhibitor to potently inhibit ERK phosphorylation in human ES cells. These findings demonstrate intrinsic differences in early mammalian development in the role of the FGF/MAP kinase signaling pathways in governing hypoblast versus epiblast lineage choices. C1 [van Tol, Leni T. A.; Roelen, Bernard A. J.] Univ Utrecht, Fac Vet Med, Dept Farm Anim Hlth, NL-3584 CM Utrecht, Netherlands. [Kuijk, Ewart W.; Welling, Maaike; Geijsen, Niels] Royal Netherlands Acad Arts & Sci, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Kuijk, Ewart W.; Welling, Maaike; Geijsen, Niels] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Van de Velde, Hilde] Vrije Univ Brussel, Dept Embryol & Genet, B-1090 Brussels, Belgium. [Van de Velde, Hilde] UZ Brussel, Ctr Reprod Med, B-1090 Brussels, Belgium. [Wubbolts, Richard] Univ Utrecht, Fac Vet Med, Ctr Cellular Imaging, Dept Biochem & Cell Biol, NL-3584 CM Utrecht, Netherlands. [Geijsen, Niels] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Geijsen, Niels] Univ Utrecht, Fac Vet Med, Dept Clin Sci Compan Anim, NL-3584 CM Utrecht, Netherlands. [Roelen, Bernard A. J.] Univ Utrecht, Fac Vet Med, Dept Equine Sci, NL-3584 CM Utrecht, Netherlands. RP Roelen, BAJ (reprint author), Univ Utrecht, Fac Vet Med, Dept Farm Anim Hlth, Yalelaan 104, NL-3584 CM Utrecht, Netherlands. EM b.a.j.roelen@uu.nl OI Kuijk, Ewart/0000-0002-1385-6516 FU Hubrecht Imaging Center; Netherlands Organization for Scientific Research (NWO); National Institutes of Health (NIH) FX We are very grateful to the support of Ir. Anko de Graaff of the Hubrecht Imaging Center.; N.G. was supported by funding from the Netherlands Organization for Scientific Research (NWO) and by the National Institutes of Health (NIH). Deposited in PMC for release after 12 months. NR 49 TC 82 Z9 82 U1 0 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 1 PY 2012 VL 139 IS 5 BP 871 EP 882 DI 10.1242/dev.071688 PG 12 WC Developmental Biology SC Developmental Biology GA 894BQ UT WOS:000300402400004 PM 22278923 ER PT J AU Ricks, J Molnar, MZ Kovesdy, CP Shah, A Nissenson, AR Williams, M Kalantar-Zadeh, K AF Ricks, Joni Molnar, Mildos Z. Kovesdy, Csaba P. Shah, Anuja Nissenson, Allen R. Williams, Mark Kalantar-Zadeh, Kamyar TI Glycemic Control and Cardiovascular Mortality in Hemodialysis Patients With Diabetes A 6-Year Cohort Study SO DIABETES LA English DT Article ID MAINTENANCE HEMODIALYSIS; GLYCOSYLATED HEMOGLOBIN; GLUCOSE CONTROL; SURVIVAL; MELLITUS; INSULIN; DISEASE; ASSOCIATION; RISK; COMPLICATIONS AB Previous observational studies using differing methodologies have yielded inconsistent results regarding the association between glycemic control and outcomes in diabetic patients receiving maintenance hemodialysis (MHD). We examined mortality predictability of A1C and random serum glucose over time in a contemporary cohort of 54,757 diabetic MHD patients (age 63 +/- 13 years, 51% men, 30% African Americans, 19% Hispanics). Adjusted all-cause death hazard ratio (HR) for baseline A1C increments of 8.0-8.9, 9.0-9.9, and >= 10%, compared with 7.0-7.9% (reference), was 1.06 (95% CI 1.01-1.12), 1.05 (0.99-1.12), and 1.19 (1.12-1.28), respectively, and for time-averaged A1C was 1.11 (1.05-1.16), 1.36 (1.27-1.45), and 1.59 (1.46-1.72). A symmetric increase in mortality also occurred with time-averaged A1C levels in the low range (6.0-6.9%, HR 1.05 [95% CI 1.01-1.08]; 5.0-5.9%, 1.08 [1.04-1.11], and <= 5%, 1.35 [1.29-1.42]) compared with 7.0-7.9% in fully adjusted models. Adjusted all-cause death HR for time-averaged blood glucose 175-199, 200-249, 250-299, and >= 300 mg/dL, compared with 150-175 mg/dL (reference), was 1.03 (95% CI 0.99-1.07), 1.14 (1.10-1.19), 1.30 (1.23-1.37), and 1.66 (1.56-1.76), respectively. Hence, poor glycemic control (A1C >= 8% or serum glucose >= 200 mg/dL) appears to be associated with high all-cause and cardiovascular death in MHD patients. Very low glycemic levels are also associated with high mortality risk. Diabetes 61:708-715, 2012 C1 [Ricks, Joni; Molnar, Mildos Z.; Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Harold Simmons Ctr Chron Dis Res & Epidemiol, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Molnar, Mildos Z.] Semmelweis Univ, Inst Pathophysiol, Budapest, Hungary. [Kovesdy, Csaba P.] Salem VA Med Ctr, Div Nephrol, Salem, VA USA. [Kovesdy, Csaba P.] Univ Virginia, Div Nephrol, Charlottesville, VA USA. [Shah, Anuja; Kalantar-Zadeh, Kamyar] Harbor UCLA Med Ctr, Div Nephrol & Hypertens, Torrance, CA 90509 USA. [Nissenson, Allen R.] DaVita Inc, Denver, CO USA. [Nissenson, Allen R.; Kalantar-Zadeh, Kamyar] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Williams, Mark] Harvard Univ, Sch Med, Joslin Diabet Ctr, Renal Unit, Boston, MA 02115 USA. [Kalantar-Zadeh, Kamyar] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. RP Kalantar-Zadeh, K (reprint author), Harbor UCLA Med Ctr, Harold Simmons Ctr Chron Dis Res & Epidemiol, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. EM kamkal@ucla.edu OI Molnar, Miklos Z/0000-0002-9665-330X; Kalantar-Zadeh, Kamyar/0000-0002-8666-0725 FU National Institutes of Health [DK077341]; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [R01 DK078106]; National Developmental Agency [KTIA-OTKA-EU 7KP-HUMAN-MB08-A-81231]; Hungarian Kidney Foundation; DaVita Inc. FX This study was partly supported by a research grant from the National Institutes of Health (DK077341) to K.K.-Z. K.K-Z. also receives funding from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R01 DK078106) and a philanthropic grant from Mr. Harold Simmons. M.Z.M. received grants from the National Developmental Agency (KTIA-OTKA-EU 7KP-HUMAN-MB08-A-81231) from the Research and Technological Innovation Fund and was also supported by the Hungarian Kidney Foundation.; This study was also supported by a research grant from DaVita Inc. (to K.K.-Z.). No other potential conflicts of interest relevant to this article were reported. NR 38 TC 56 Z9 57 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2012 VL 61 IS 3 BP 708 EP 715 DI 10.2337/db11-1015 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FA UT WOS:000300800600022 PM 22315308 ER PT J AU Qi, QB Liang, LM Doria, A Hu, FB Qi, L AF Qi, Qibin Liang, Liming Doria, Alessandro Hu, Frank B. Qi, Lu TI Genetic Predisposition to Dyslipidemia and Type 2 Diabetes Risk in Two Prospective Cohorts SO DIABETES LA English DT Article ID CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; PHYSICAL-ACTIVITY; MELLITUS; BEZAFIBRATE; WOMEN; LOCI; MEN; ATHEROSCLEROSIS; CLASSIFICATION AB Dyslipidemia has been associated with type 2 diabetes, but it remains unclear whether dyslipidemia plays a causal role in type 2 diabetes. We aimed to examine the association between the genetic predisposition to dyslipdemia and type 2 diabetes risk. The current study included 2,447 patients with type 2 diabetes and 3,052 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-up Study. Genetic predisposition to dyslipidemia was estimated by three genotype scores of lipids (LDL cholesterol, HDL cholesterol, and triglycerides) on the basis of the established loci for blood lipids. Linear relation analysis indicated that the HDL cholesterol and triglyceride genotype scores, but not the LDL cholesterol genotype score, were linearly related to elevated type 2 diabetes risk. Each point of the HDL cholesterol and triglyceride genotype scores was associated with a 3% (odds ratio [OR] 1.03 [95% CI 1.01-1.04]) and a 2% (1.02 [1.00-1.04]) increased risk of developing type 2 diabetes, respectively. The ORs were 1.39 (1.17-1.65) and 1.19 (1.01-1.41) for type 2 diabetes by comparing extreme quartiles of the HDL cholesterol genotype score and triglyceride genotype score, respectively. In conclusion, genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk. Diabetes 61:745-752, 2012 C1 [Qi, Qibin; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Liang, Liming; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Doria, Alessandro] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu RI Qi, Qibin/H-9055-2012 FU National Institutes of Health [HL-71981, HL-073168, U01-HG-004399, DK-58845, DK-46200]; American Heart Association [0730094N] FX This study was supported by grants HL-71981, HL-073168, U01-HG-004399, DK-58845, and DK-46200 from the National Institutes of Health. L.Q. is a recipient of the American Heart Association Scientist Development Award (0730094N). NR 30 TC 25 Z9 25 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2012 VL 61 IS 3 BP 745 EP 752 DI 10.2337/db11-1254 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 899FA UT WOS:000300800600026 PM 22315312 ER PT J AU Bind, MA Baccarelli, A Zanobetti, A Tarantini, L Suh, H Vokonas, P Schwartz, J AF Bind, Marie-Abele Baccarelli, Andrea Zanobetti, Antonella Tarantini, Letizia Suh, Helen Vokonas, Pantel Schwartz, Joel TI Air Pollution and Markers of Coagulation, Inflammation, and Endothelial Function Associations and Epigene-environment Interactions in an Elderly Cohort SO EPIDEMIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; DNA METHYLATION; CARDIOVASCULAR-DISEASE; ADHESION MOLECULES; PARTICULATE MATTER; RESPONSES; EXPOSURE; RISK; ACTIVATION; EXPRESSION AB Background: Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states. Methods: We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short-and intermediateterm air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-like receptor 2 (TLR-2), and ICAM-1. Results: We found effects of particle number, black carbon, nitrogen dioxide (NO2), and carbon monoxide (CO) on fibrinogen. Ozone was a predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO2, CO, PM2.5, and sulfates were associated with ICAM-1 and VCAM-1. An interquartile range increase in 24-hour exposure for NO2 was associated with a 1.7% (95% confidence interval = 0.2%-3.3%) increase in fibrinogen for ozone; a 10.8% (2.2%-20.0%) increase in C-reactive protein for particle number; a 5.9% (3.6%-8.3%) increase in ICAM-1; and for PM2.5, a 3.7% (1.7%-5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status. Conclusion: We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution. C1 [Bind, Marie-Abele] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Exposure Epidemiol & Risk Program,Landmark Ctr, Boston, MA 02115 USA. [Tarantini, Letizia] Univ Milan, IRCCS Ca Granda Osped Maggiore Policlin Fdn, Ctr Mol & Genet Epidemiol, Milan, Italy. [Tarantini, Letizia] Univ Milan, Dept Environm & Occupat Hlth, Milan, Italy. [Vokonas, Pantel] Boston Univ, Sch Med, VA Normat Aging Study, VA Boston Healthcare Syst, Boston, MA 02118 USA. [Vokonas, Pantel] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP Bind, MA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Exposure Epidemiol & Risk Program,Landmark Ctr, 401 Pk Dr,Suite 415, Boston, MA 02115 USA. EM mbind@hsph.harvard.edu OI Baccarelli, Andrea/0000-0002-3436-0640 FU U.S. Environmental Protection Agency [EPA R827353, R832416]; National Institute of Environmental Health Sciences (NIEHS) [RO1-ES015172, 2RO1-ES015172, ES014663, ES00002, PO1_ES008925, RD-83479701]; Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs FX Supported by the U.S. Environmental Protection Agency grants EPA R827353 and R832416; National Institute of Environmental Health Sciences (NIEHS) grants RO1-ES015172, 2RO1-ES015172, ES014663, ES00002, PO1_ES008925 and Clean Air Act (CLARC) grant RD-83479701. The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center, Boston, Massachusetts. The authors reported no other financial interests related to this research. NR 41 TC 92 Z9 97 U1 7 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2012 VL 23 IS 2 BP 332 EP 340 DI 10.1097/EDE.0b013e31824523f0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 894VX UT WOS:000300456500024 PM 22237295 ER PT J AU Scheffel, H Stolzmann, P Schlett, CL Engel, LC Major, GP Karolyi, M Do, S Maurovich-Horvat, P Hoffmann, U AF Scheffel, Hans Stolzmann, Paul Schlett, Christopher L. Engel, Leif-Christopher Major, Gyoengi Petra Karolyi, Mihaly Do, Synho Maurovich-Horvat, Pal Hoffmann, Udo TI Coronary artery plaques: Cardiac CT with model-based and adaptive-statistical iterative reconstruction technique SO EUROPEAN JOURNAL OF RADIOLOGY LA English DT Article DE Adaptive statistical iterative reconstruction; Model-based iterative reconstruction; CT angiography; Plaque visualization; Image quality ID MULTIDETECTOR COMPUTED-TOMOGRAPHY; IMPROVED IMAGE QUALITY; INTRAVASCULAR ULTRASOUND; INTRACORONARY ULTRASOUND; ANGIOGRAPHY; ACCURACY; EXPERIENCE; CHEST; CALCIUM; DISEASE AB Objectives: To compare image quality of coronary artery plaque visualization at CT angiography with images reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model based iterative reconstruction (MBIR) techniques. Methods: The coronary arteries of three ex vivo human hearts were imaged by CT and reconstructed with FBP, ASIR and MBIR. Coronary cross-sectional images were co-registered between the different reconstruction techniques and assessed for qualitative and quantitative image quality parameters. Readers were blinded to the reconstruction algorithm. Results: A total of 375 triplets of coronary cross-sectional images were co-registered. Using MBIR, 26% of the images were rated as having excellent overall image quality, which was significantly better as compared to ASIR and FBP (4% and 13%, respectively, all p < 0.001). Qualitative assessment of image noise demonstrated a noise reduction by using ASIR as compared to FBP (p < 0.01) and further noise reduction by using MBIR (p < 0.001). The contrast-to-noise-ratio (CNR) using MBIR was better as compared to ASIR and FBP (44 +/- 19, 29 +/- 15, 26 +/- 9, respectively; all p < 0.001). Conclusions: Using MBIR improved image quality, reduced image noise and increased CNR as compared to the other available reconstruction techniques. This may further improve the visualization of coronary artery plaque and allow radiation reduction. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02144 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02144 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02144 USA. EM uhoffmann@partners.org OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU GE Healthcare FX This study was partially funded by an unrestricted research grant of GE Healthcare. NR 20 TC 59 Z9 62 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0720-048X J9 EUR J RADIOL JI Eur. J. Radiol. PD MAR PY 2012 VL 81 IS 3 BP E363 EP E369 DI 10.1016/j.ejrad.2011.11.051 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 894DV UT WOS:000300408100033 PM 22197733 ER PT J AU Stephenson, AJ Bolla, M Briganti, A Cozzarini, C Moul, JW Roach, M van Poppel, H Zietman, A AF Stephenson, Andrew J. Bolla, Michel Briganti, Alberto Cozzarini, Cesare Moul, Judd W. Roach, Mack, III van Poppel, Hein Zietman, Anthony TI Postoperative Radiation Therapy for Pathologically Advanced Prostate Cancer After Radical Prostatectomy SO EUROPEAN UROLOGY LA English DT Article DE Prostatic neoplasms; Prostate-specific antigen; Radiotherapy; Radiotherapy, adjuvant; Salvage therapy; Neoplasm recurrence, local; Prostatectomy; Radiotherapy; Treatment outcome ID RANDOMIZED CONTROLLED-TRIAL; BICALUTAMIDE 150 MG; TERM-FOLLOW-UP; ADJUVANT RADIOTHERAPY; SALVAGE RADIOTHERAPY; ANDROGEN SUPPRESSION; LOCAL RECURRENCE; RETROPUBIC PROSTATECTOMY; 10-YEAR PROBABILITY; CLINICAL-TRIAL AB Context: Approximately 15-25% of men who undergo radical prostatectomy for localized prostate cancer (PCa) will experience recurrence of their cancer; men with poorly differentiated cancer, non-organ-confined disease, and positive surgical margins are at the highest risk. Objective: Review accumulating evidence indicating that postoperative radiotherapy (RT) to the prostate bed favorably influences the course of disease in men with adverse pathologic features. Evidence acquisition: Three phase 3 randomized trials of adjuvant RT versus observation have reported improved freedom from biochemical recurrence (BCR) and local control: Southwest Oncology Group (SWOG) 8794, European Organization for Research and Treatment of Cancer (EORTC) 22911, and the German Cancer Society (ARO 96-02). Evidence synthesis: Conflicting evidence from these trials suggests that adjuvant RT can have a favorable impact on systemic progression, PCa-specific mortality, or overall survival. Observational studies have reported durable responses to salvage RT in a substantial proportion of high-risk patients (provided that it is administered at the earliest evidence of BCR) and reduced PCa-specific mortality. There is consensus that the outcome of patients receiving postoperative RT is best when the prostate-specific antigen (PSA) level is the lowest. However, it is unclear if better outcomes will be achieved administering adjuvant RT to all patients at increased risk for recurrent PCa who have an undetectable postoperative PSA level compared to close observation and timely salvage RT at the earliest indications of BCR. Conclusions: Given the absence of data from randomized trials demonstrating superiority of one approach over the other in terms of quantity and quality of life, we advocate multidisciplinary input and shared and informed decision making among patients, urologists, and radiation oncologists based on the relative advantages and disadvantages of each approach. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Stephenson, Andrew J.] Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44195 USA. [Bolla, Michel] Univ Grenoble, Ctr Hosp Reg, Grenoble, France. [Briganti, Alberto] Univ Vita Salute San Raffaele, Dept Urol, Milan, Italy. [Cozzarini, Cesare] Ist Sci San Raffaele, Dept Radiotherapy, I-20132 Milan, Italy. [Moul, Judd W.] Duke Univ, Div Urol, Durham, NC USA. [Roach, Mack, III] Univ Calif San Francisco, Dept Radiat Oncol, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [van Poppel, Hein] Katholieke Univ Leuven, Dept Urol, Univ Hosp Gasthuisberg, Louvain, Belgium. [Zietman, Anthony] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Stephenson, AJ (reprint author), Cleveland Clin, Glickman Urol & Kidney Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM stephea2@ccf.org OI Cozzarini, Cesare/0000-0002-7006-8196 NR 60 TC 69 Z9 69 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAR PY 2012 VL 61 IS 3 BP 443 EP 451 DI 10.1016/j.eururo.2011.10.010 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 891CM UT WOS:000300194000013 PM 22036777 ER PT J AU Bachmann, A Muir, GH Collins, EJ Choi, BB Tabatabaei, S Reich, OM Gomez-Sancha, F Woo, HH AF Bachmann, Alexander Muir, Gordon H. Collins, Edward J. Choi, Benjamin B. Tabatabaei, Shahin Reich, Oliver M. Gomez-Sancha, Fernando Woo, Henry H. TI 180-W XPS GreenLight Laser Therapy for Benign Prostate Hyperplasia: Early Safety, Efficacy, and Perioperative Outcome After 201 Procedures SO EUROPEAN UROLOGY LA English DT Article DE BPH; BPE; Laser therapy; GreenLight; Photoselective vaporisation; XPS; HPS; KTP; TURP; Laser prostatectomy ID HPS 120-W LASER; PHOTOSELECTIVE VAPORIZATION PROSTATECTOMY; RANDOMIZED CLINICAL-TRIAL; URINARY-TRACT SYMPTOMS; TRANSURETHRAL RESECTION; FOLLOW-UP; COMPLICATIONS; EXPERIENCE; MULTICENTER; RETENTION AB Background: Photoselective vaporisation of the prostate has evolved from the GreenLight 80-W KTP powered laser to the latest 180-W XPS laser involving a MoXy fibre. Objective: Evaluate the prevalence of perioperative complications and short-term outcome for the first time with the XPS laser in men with lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE). Design, setting, and participants: Prospective data were collected from consecutive patients at seven centres worldwide during June 2010 and March 2011. Indication for surgery was based on the European Association of Urology and the American Urological Association guidelines. Patients receiving anticoagulants or those with retention were included and analysed separately. Intervention: 180-W XPS GreenLight laser prostatectomy using the MoXy fibre. Measurements: Standard parameters associated with transurethral prostate surgery and perioperative prevalence of surgery-associated problems or complications were documented. Results and limitations: A total of 201 patients were included in the study. Mean follow-up was 5.8 mo (standard deviation [SD]: 2.8; range: 1-12 mo). A quarter of the patients had a prostate volume >= 80 ml. For prostates between 51 and 60 ml, a mean of 300 kJ (SD: 112) of energy was applied (lasing time: 35.0 min; SD: 15). Statistically significant improvements were noted in all key parameters postoperatively. The prevalence of perioperative complications was low. Limitations of the study are short duration of follow-up and limited number of available patients for the functional follow-up. Conclusions: The 180-W GreenLight XPS laser is a new effective treatment option with a low prevalence of perioperative complications for patients suffering from LUTS due to BPE. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved. C1 [Bachmann, Alexander] Univ Basel, Univ Basel Hosp, Dept Urol, CH-4031 Basel, Switzerland. [Muir, Gordon H.] Kings Coll Hosp London, Dept Urol, London, England. [Collins, Edward J.] Calif Urol Serv, San Francisco, CA USA. [Choi, Benjamin B.] Cornell Univ, Weill Med Coll, Dept Urol, New York, NY 10021 USA. [Tabatabaei, Shahin] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Reich, Oliver M.] Univ Munich, Harlaching Hosp, Dept Urol, Munich, Germany. [Gomez-Sancha, Fernando] Inst Adv Urol Surg, Madrid, Spain. [Woo, Henry H.] Univ Sydney, Sydney Adventist Hosp Clin Sch, Sydney, NSW 2006, Australia. RP Bachmann, A (reprint author), Univ Basel, Univ Basel Hosp, Dept Urol, Spitalstr 21, CH-4031 Basel, Switzerland. EM bachmanna@uhbs.ch NR 28 TC 74 Z9 75 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD MAR PY 2012 VL 61 IS 3 BP 600 EP 607 DI 10.1016/j.eururo.2011.11.041 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 891CM UT WOS:000300194000041 PM 22153927 ER PT J AU LaVela, SL Gering, J Schectman, G Weaver, FM AF LaVela, Sherri L. Gering, Jeffrey Schectman, Gordon Weaver, Frances M. TI Optimizing Primary Care Telephone Access and Patient Satisfaction SO EVALUATION & THE HEALTH PROFESSIONS LA English DT Article DE access to care; patient satisfaction; patient-centered care; quality improvement; telephone medicine ID CONSULTATION; SERVICES; TRIAGE AB Telephone medicine is often preferred by patients to meet primary care needs and may be associated with high patient satisfaction. This article presents findings about incoming patient calls to primary care for medically based reasons during office hours and reports factors independently associated with telephone encounter satisfaction, considering patient characteristics, call reasons, and staff responsiveness, for a national cohort of primary care users. Interviews were conducted with patients from 18 nationwide primary care clinics during the fall of 2009. Calling for an urgent medical issue was associated with dissatisfaction. Odds of call satisfaction were greater when patients thought staff was friendly (10x), call answer was timely (5x), and needed medical information was provided (7x). These findings can be used for interventions to optimize telephone access and patient satisfaction which is beneficial because satisfactory telephone encounters reduce primary care use and satisfied patients are more likely to be engaged in their health care. C1 [LaVela, Sherri L.; Weaver, Frances M.] US Dept Vet Affairs, Ctr Management Complex Chron Care, Edward Hines Jr VA Hosp, Hines, IL 60141 USA. [LaVela, Sherri L.] Northwestern Univ, Feinberg Sch Med, Inst Healthcare Studies, Chicago, IL 60611 USA. [Gering, Jeffrey] Chillicothe Vet Affairs Med Ctr, Chillicothe, OH 45601 USA. [Gering, Jeffrey] Ohio Univ, Chillicothe, OH USA. [Schectman, Gordon] Vet Affairs Cent Off, Off Patient Care Serv, Washington, DC USA. [Schectman, Gordon] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Weaver, Frances M.] Loyola Univ, Stritch Sch Med, Program Hlth Serv Res, Maywood, IL 60153 USA. RP LaVela, SL (reprint author), US Dept Vet Affairs, Ctr Management Complex Chron Care, Edward Hines Jr VA Hosp, 5000 S 5th Ave,151-H, Hines, IL 60141 USA. EM sherri.lavela@va.gov FU Office of Systems Redesign of the Department of Veterans Affairs FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This material is based upon work supported by the Office of Systems Redesign of the Department of Veterans Affairs. This paper reflects only the authors' opinions and does not necessarily reflect the official position of the Department of Veterans Affairs. NR 19 TC 8 Z9 8 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0163-2787 J9 EVAL HEALTH PROF JI Eval. Health Prof. PD MAR PY 2012 VL 35 IS 1 BP 77 EP 86 DI 10.1177/0163278711411479 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 894HJ UT WOS:000300417400005 PM 21685222 ER PT J AU Konstantinidis, IT Bajpai, S Kambadakone, AR Tanabe, KK Berger, DL Zheng, H Sahani, DV Lauwers, GY Fernandez-del Castillo, C Warshaw, AL Ferrone, CR AF Konstantinidis, Ioannis T. Bajpai, Surabhi Kambadakone, Avinash R. Tanabe, Kenneth K. Berger, David L. Zheng, Hui Sahani, Dushyant V. Lauwers, Gregory Y. Fernandez-del Castillo, Carlos Warshaw, Andrew L. Ferrone, Cristina R. TI Gallbladder Lesions Identified on Ultrasound. Lessons from the Last 10 Years SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Gallbladder mass; Gallbladder polyp; Gallbladder adenocarcinoma; Ultrasonographic characteristics ID POLYPOID LESIONS; FOLLOW-UP; NATURAL-HISTORY; CLINICOPATHOLOGICAL FEATURES; OPERATIVE INDICATIONS; GALL-BLADDER; DIAGNOSIS; PREVALENCE AB Possible mass lesions identified on ultrasound (US) of the gallbladder may prompt an aggressive surgical intervention due to the possibility of a malignant neoplasm. This study aims to utilize a large modern series of patients with gallbladder lesions identified on US to evaluate imaging characteristics consistent with malignancy. A retrospective review was conducted of gallbladder ultrasound reports and clinicopathologic data of patients with a mass identified on US. Approximately 59,271 abdominal ultrasounds and 9,117 cholecystectomies were performed between February 2000 and February 2010. We identified 213 patients with a questionable gallbladder neoplasm on ultrasonography who underwent surgical exploration. Median age was 52 years (range = 11-87 years) and 147 (69%) were females. Final pathology demonstrated no neoplasm in 130 patients (61%), while 32 patients (15%) had a wall adenomyoma, 36 (17%) had a polyp (five of which were malignant), 14 (7%) had an adenocarcinoma not arising from a polyp, and one patient had a cystic papillary neoplasm. The smaller the lesion, the more likely it was to be a pseudo-mass. For lesions measuring < 5 mm on US, 83% had no lesion found on final pathology. Significant predictors of malignancy were age > 52 years (p < 0.001), presence of gallstones on US (p = 0.004), size > 9 mm (p < 0.001), evidence of invasion at the liver interface (p < 0.001), and wall thickening > 5 mm (p < 0.001). Shape (sessile or penduculated), echogenicity (echogenic or isoechoic), or presence of flow on Doppler were not predictors of malignancy. An US size of a parts per thousand currency sign9 mm had a negative predictive value of 100% for malignancy. Despite improvements in imaging, most apparent lesions measuring < 5 mm on US are not identified in the surgical specimen. US size > 9 mm, age > 52 years, US suggestion of invasion at the liver interface, and wall thickening > 5 mm, especially in the presence of gallstones, should raise the suspicion of malignancy. C1 [Konstantinidis, Ioannis T.; Tanabe, Kenneth K.; Berger, David L.; Fernandez-del Castillo, Carlos; Warshaw, Andrew L.; Ferrone, Cristina R.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Konstantinidis, Ioannis T.; Bajpai, Surabhi; Kambadakone, Avinash R.; Tanabe, Kenneth K.; Berger, David L.; Zheng, Hui; Sahani, Dushyant V.; Lauwers, Gregory Y.; Fernandez-del Castillo, Carlos; Warshaw, Andrew L.; Ferrone, Cristina R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bajpai, Surabhi; Kambadakone, Avinash R.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Ferrone, CR (reprint author), Massachusetts Gen Hosp, Dept Surg, Wang Ambulatory Care Ctr 460,15 Parkman St, Boston, MA 02114 USA. EM cferrone@partners.org NR 24 TC 15 Z9 16 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD MAR PY 2012 VL 16 IS 3 BP 549 EP 553 DI 10.1007/s11605-011-1696-2 PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 892NU UT WOS:000300293700014 PM 22108768 ER PT J AU Al Natour, RH Saund, MS Sanchez, VM Whang, EE Sharma, AM Huang, Q Boosalis, VA Gold, JS AF Al Natour, Riad H. Saund, Mandeep S. Sanchez, Vivian M. Whang, Edward E. Sharma, Ashish M. Huang, Qin Boosalis, Valia A. Gold, Jason S. TI Tumor Size and Depth Predict Rate of Lymph Node Metastasis in Colon Carcinoids and Can Be Used to Select Patients for Endoscopic Resection SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article DE Colon carcinoid; Neuroendocrine tumors; Lymph node metastasis ID NEUROENDOCRINE TUMORS; GUIDELINES; SYSTEM; RECTUM AB Regional lymphadenectomy is recommended for all colon carcinoids, whereas resection without lymphadenectomy is accepted for selected appendiceal and rectal carcinoids. We examined the relation of tumor size and depth to lymph node metastasis in order to determine whether colon carcinoids could be selected for endoscopic resection. Patients were identified from the Surveillance Epidemiology and End Results Registry. The Pearson chi-square and the log rank tests were used. P < 0.05 was considered significant. We identified 929 patients who underwent resection of localized colon carcinoids without distant metastasis diagnosed from 1973 to 2006. The diagnosis of small and superficial tumors increased over time (p < 0.001). The presence of lymph node metastasis was adversely associated with survival (p < 0.001); however, there was only a trend toward independence on multivariate analysis (p = 0.054). Tumor size and depth were associated with lymph node metastasis (p < 0.001, p < 0.001). Tumors were subgrouped by size and depth to find cases with a low risk of lymph node metastasis. Intramucosal tumors < 1 cm had a 4% rate of lymph node metastasis, while all other subgroups had rates a parts per thousand yen14%. Tumor size and depth predict lymph node metastasis for colon carcinoids. Endoscopic resection may be appropriate for intramucosal tumors < 1 cm. C1 [Al Natour, Riad H.; Saund, Mandeep S.; Whang, Edward E.; Huang, Qin; Gold, Jason S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Al Natour, Riad H.; Saund, Mandeep S.; Sanchez, Vivian M.; Whang, Edward E.; Gold, Jason S.] VA Boston Healthcare Syst, Surg Serv, W Roxbury, MA 02132 USA. [Huang, Qin] VA Boston Healthcare Syst, Pathol Serv, W Roxbury, MA 02132 USA. [Huang, Qin] Harvard Univ, Sch Med, W Roxbury, MA 02132 USA. [Sharma, Ashish M.; Boosalis, Valia A.] VA Boston Healthcare Syst, Med Serv, W Roxbury, MA 02132 USA. [Sanchez, Vivian M.; Sharma, Ashish M.; Boosalis, Valia A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Gold, JS (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM jgold4@partners.org RI Gold, Jason/O-5112-2014; OI Gold, Jason/0000-0002-2925-4755; Sanchez, Vivian/0000-0001-5565-9687 FU Department of Veterans Affairs Office of Research and Development FX This work was supported by the Department of Veterans Affairs Office of Research and Development through a Career Development Award-2 (JSG). NR 18 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD MAR PY 2012 VL 16 IS 3 BP 595 EP 602 DI 10.1007/s11605-011-1786-1 PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 892NU UT WOS:000300293700020 PM 22143420 ER PT J AU Bogoch, II Robbins, GK AF Bogoch, Isaac I. Robbins, Gregory K. TI Varicella zoster mimicking infectious tenosynovitis SO JOURNAL OF INFECTION LA English DT Letter C1 [Bogoch, Isaac I.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Bogoch, II (reprint author), Massachusetts Gen Hosp, Div Infect Dis, COX 5,55 Fruit St, Boston, MA 02114 USA. EM ibogoch@partners.org NR 2 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD MAR PY 2012 VL 64 IS 3 BP 341 EP 342 DI 10.1016/j.jinf.2011.12.001 PG 2 WC Infectious Diseases SC Infectious Diseases GA 892BA UT WOS:000300260300014 PM 22178586 ER PT J AU Waisbren, SE Potter, NL Gordon, CM Green, RC Greenstein, P Gubbels, CS Rubio-Gozalbo, E Schomer, D Welt, C Anastasoaie, V D'Anna, K Gentile, J Guo, CY Hecht, L Jackson, R Jansma, BM Li, YJ Lip, V Miller, DT Murray, M Power, L Quinn, N Rohr, F Shen, YP Skinder-Meredith, A Timmers, I Tunick, R Wessel, A Wu, BL Levy, H Elsas, L Berry, GT AF Waisbren, Susan E. Potter, Nancy L. Gordon, Catherine M. Green, Robert C. Greenstein, Patricia Gubbels, Cynthia S. Rubio-Gozalbo, Estela Schomer, Donald Welt, Corrine Anastasoaie, Vera D'Anna, Kali Gentile, Jennifer Guo, Chao-Yu Hecht, Leah Jackson, Roberta Jansma, Bernadette M. Li, Yijun Lip, Va Miller, David T. Murray, Michael Power, Leslie Quinn, Nicolle Rohr, Frances Shen, Yiping Skinder-Meredith, Amy Timmers, Inge Tunick, Rachel Wessel, Ann Wu, Bai-Lin Levy, Harvey Elsas, Louis Berry, Gerard T. TI The adult galactosemic phenotype SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID CLASSICAL GALACTOSEMIA; FEMALE-PATIENTS; CHILDREN; ADOLESCENTS AB Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. Thirty-three adults (mean age = 32.6 +/- 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 +/- 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults. C1 [Waisbren, Susan E.; Gordon, Catherine M.; Anastasoaie, Vera; D'Anna, Kali; Gentile, Jennifer; Guo, Chao-Yu; Hecht, Leah; Li, Yijun; Lip, Va; Miller, David T.; Quinn, Nicolle; Rohr, Frances; Shen, Yiping; Tunick, Rachel; Wessel, Ann; Wu, Bai-Lin; Levy, Harvey] Childrens Hosp, Boston, MA 02115 USA. [Potter, Nancy L.; Power, Leslie; Skinder-Meredith, Amy] Washington State Univ, Pullman, WA 99164 USA. [Green, Robert C.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Greenstein, Patricia; Schomer, Donald] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Gubbels, Cynthia S.; Rubio-Gozalbo, Estela; Timmers, Inge] Maastricht Univ Med Ctr, Maastricht, Netherlands. [Welt, Corrine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jackson, Roberta] Eastern Washington Univ, Seattle, WA USA. [Jansma, Bernadette M.] Maastricht Univ, Maastricht, Netherlands. [Murray, Michael] Brigham & Womens Hosp, Boston, MA 02115 USA. [Elsas, Louis] Univ Miami, Coral Gables, FL 33124 USA. [Berry, Gerard T.] Harvard Univ, Sch Med, Manton Ctr Orphan Dis Res, Childrens Hosp Boston, Boston, MA USA. RP Waisbren, SE (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM Susan.Waisbren@childrens.harvard.edu RI Timmers, Inge/H-1887-2011; rubio, estela/H-1833-2011; OI Berry, Gerard/0000-0001-5299-3313; Welt, Corrine/0000-0002-8219-5504 FU Parents of Galactosemic Children, USA; National Center for Research Resources, National Institutes of Health [UL1 RR025758-01] FX This project was funded in part by a research grant from the Parents of Galactosemic Children, USA, and in part by the grant UL1 RR025758-01 from the National Center for Research Resources, National Institutes of Health, to the Harvard Catalyst Clinical & Translational Science Center (Harvard Catalyst). The authors thank the CTSU staff of Children's Hospital Boston for their superb assistance and the patients with galactosemia and their families who traveled to Boston from around the U.S.A. and participated in this study. We thank the Parents of Galactosemic Children, USA for their support. We also thank Al Ozonoff, Linda Manis, Michelle Fowler, Judith Muir, Catherine Arnold, Brian Deutsch, Stephanie Kon, Anya Kwasnik, and Rebecca Owen for their invaluable help. NR 38 TC 45 Z9 47 U1 0 U2 12 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 MAR PY 2012 VL 35 IS 2 BP 279 EP 286 DI 10.1007/s10545-011-9372-y PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 893FT UT WOS:000300342300008 PM 21779791 ER PT J AU Ng, K Kim, R Kesari, S Carter, B Chen, CC AF Ng, Kimberly Kim, Ryan Kesari, Santosh Carter, Bob Chen, Clark C. TI Genomic profiling of glioblastoma: convergence of fundamental biologic tenets and novel insights SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Glioblastoma; TCGA; Genomics; RTK; RB; p53; IDH1; Telomerase; Angiogenesis; Invasion; Subtype; Cancer ID RECEPTOR TYROSINE KINASES; ENDOTHELIAL GROWTH-FACTOR; GENE-EXPRESSION; MALIGNANT GLIOMAS; CLINICALLY-RELEVANT; TUMOR-SUPPRESSOR; DIFFUSE GLIOMAS; IDH2 MUTATIONS; CANCER-THERAPY; CELLS AB With advances in genomic profiling and sequencing technology, we are beginning to understand the landscape of the genetic events that accumulated during the neoplastic process. The insights gleamed from these genomic profiling studies with regards to glioblastoma etiology has been particularly satisfying because it cemented the clinical pertinence of major concepts in cancer biology-concepts developed over the past three decades. This article will review how the glioblastoma genomic data set serves as an illustrative platform for the concepts put forward by Hanahan and Weinberg on the cancer phenotype. The picture emerging suggests that most glioblastomas evolve along a multitude of pathways rather than a single defined pathway. In this context, the article will further provide a discussion of the subtypes of glioblastoma as they relate to key principles of developmental neurobiology. C1 [Chen, Clark C.] Univ Calif San Diego, Div Neurosurg, La Jolla, CA 92093 USA. [Ng, Kimberly; Chen, Clark C.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Kim, Ryan; Kesari, Santosh] Univ Calif San Diego, Moores UCSD Canc Ctr, Dept Neurol, La Jolla, CA 92093 USA. [Carter, Bob; Chen, Clark C.] Univ Calif San Diego, Ctr Theoret & Appl Neurooncol, La Jolla, CA 92093 USA. RP Chen, CC (reprint author), Univ Calif San Diego, Div Neurosurg, 3855 Hlth Sci Dr 0987, La Jolla, CA 92093 USA. EM clarkchen@ucsd.edu RI Kesari, Santosh/E-8461-2013 NR 78 TC 19 Z9 19 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2012 VL 107 IS 1 BP 1 EP 12 DI 10.1007/s11060-011-0714-2 PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 892VG UT WOS:000300313100001 PM 22002595 ER PT J AU Drappatz, J Lee, EQ Hammond, S Grimm, SA Norden, AD Beroukhim, R Gerard, M Schiff, D Chi, AS Batchelor, TT Doherty, LM Ciampa, AS LaFrankie, DC Ruland, S Snodgrass, SM Raizer, JJ Wen, PY AF Drappatz, J. Lee, E. Q. Hammond, S. Grimm, S. A. Norden, A. D. Beroukhim, R. Gerard, M. Schiff, D. Chi, A. S. Batchelor, T. T. Doherty, L. M. Ciampa, A. S. LaFrankie, D. C. Ruland, S. Snodgrass, S. M. Raizer, J. J. Wen, P. Y. TI Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Panobinostat; Bevacizumab; High-grade glioma; Vascular endothelial growth factor; Histone deacetylase inhibitor ID HISTONE DEACETYLASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; TYROSINE KINASE INHIBITOR; MALIGNANT GLIOMAS; PLUS IRINOTECAN; GLIOBLASTOMA; GROWTH; VITRO; ANGIOGENESIS; APOPTOSIS AB Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway. C1 [Drappatz, J.; Lee, E. Q.; Hammond, S.; Norden, A. D.; Beroukhim, R.; Gerard, M.; Doherty, L. M.; Ciampa, A. S.; LaFrankie, D. C.; Ruland, S.; Wen, P. Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02215 USA. [Grimm, S. A.; Raizer, J. J.] Northwestern Univ, Chicago, IL 60611 USA. [Schiff, D.] Univ Virginia, Charlottesville, VA USA. [Chi, A. S.; Batchelor, T. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Snodgrass, S. M.] Novartis Pharmaceut, E Hanover, NJ USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, 450 Brookline Ave,SW 430, Boston, MA 02215 USA. EM pwen@partners.org FU Novartis; Genentech/Roche FX E.Q. Lee has served on the advisory board of Novartis and Genentech/Roche. T. T. Batchelor has served on the advisory board for Genentech/Roche. R. Beroukhim has received research support from Novartis. S. M. Snodgrass is an employee of Novartis. J.J. Raizer has received research support from Novartis and Genentech/Roche, served on the advisory boards of both Novartis and Genentech/Roche and is on the speaker's bureau of Genentech/Roche. P.Y. Wen has received research support from Novartis and Genentech/Roche and served on the advisory boards of both Novartis and Genentech/Roche. NR 29 TC 34 Z9 34 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2012 VL 107 IS 1 BP 133 EP 138 DI 10.1007/s11060-011-0717-z PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 892VG UT WOS:000300313100014 PM 21984064 ER PT J AU Reardon, DA Herndon, JE Peters, K Desjardins, A Coan, A Lou, E Sumrall, A Turner, S Sathornsumetee, S Rich, JN Boulton, S Lipp, ES Friedman, HS Vredenburgh, JJ AF Reardon, David A. Herndon, James E., II Peters, Katherine Desjardins, Annick Coan, April Lou, Emil Sumrall, Ashley Turner, Scott Sathornsumetee, Sith Rich, Jeremy N. Boulton, Susan Lipp, Eric S. Friedman, Henry S. Vredenburgh, James J. TI Outcome after bevacizumab clinical trial therapy among recurrent grade III malignant glioma patients SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Malignant glioma; Angiogenesis; Bevacizumab; Vascular endothelial growth factor; Anaplastic astrocytoma ID PHASE-II; METRONOMIC CHEMOTHERAPY; PLUS IRINOTECAN; ANAPLASTIC ASTROCYTOMA; GLIOBLASTOMA; PROGRESSION; ERLOTINIB; PROGNOSIS; PATTERNS; OLIGODENDROGLIOMA AB Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy (n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy (n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation. C1 [Reardon, David A.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02215 USA. [Herndon, James E., II] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Dept Canc Ctr Biostat, Durham, NC USA. [Peters, Katherine; Desjardins, Annick; Vredenburgh, James J.] Duke Univ, Med Ctr, Dept Med, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Coan, April] Duke Univ, Med Ctr, Dept Pathol, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Lou, Emil; Sumrall, Ashley; Turner, Scott; Boulton, Susan; Lipp, Eric S.] Duke Univ, Med Ctr, Dept Surg, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Sathornsumetee, Sith] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med Neurol, Bangkok 10700, Thailand. [Rich, Jeremy N.] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44106 USA. Duke Univ, Med Ctr, Dept Pediat, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. RP Reardon, DA (reprint author), Dana Farber Canc Inst, Ctr Neurooncol, 450 Brookline Ave,SW 460F, Boston, MA 02215 USA. EM david_reardon@dfci.harvard.edu OI Sykes, April/0000-0002-7667-8155 FU NIH [P50-NS20023-29, R37- CA11898-42]; Genentech Pharmaceuticals FX This work was supported by NIH Grants P50-NS20023-29 and R37- CA11898-42; and a grant from Genentech Pharmaceuticals. NR 35 TC 15 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD MAR PY 2012 VL 107 IS 1 BP 213 EP 221 DI 10.1007/s11060-011-0740-0 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 892VG UT WOS:000300313100024 PM 21997879 ER PT J AU Blackham, KA Meyers, PM Abruzzo, TA Alberquerque, FC Fiorella, D Fraser, J Frei, D Gandhi, CD Heck, DV Hirsch, JA Hsu, DP Jayaraman, M Narayanan, S Prestigiacomo, C Sunshine, JL AF Blackham, K. A. Meyers, P. M. Abruzzo, T. A. Alberquerque, F. C. Fiorella, D. Fraser, J. Frei, D. Gandhi, C. D. Heck, D. V. Hirsch, J. A. Hsu, D. P. Jayaraman, M. Narayanan, S. Prestigiacomo, C. Sunshine, J. L. CA Soc NeuroInterventional Surg TI Endovascular therapy of acute ischemic stroke: report of the Standards of Practice Committee of the Society of NeuroInterventional Surgery SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID INTRAARTERIAL THROMBOLYTIC THERAPY; TISSUE-PLASMINOGEN ACTIVATOR; CEREBRAL-ARTERY OCCLUSION; RANDOMIZED CONTROLLED-TRIALS; CLINICAL-PRACTICE GUIDELINES; PERIPHERAL-VASCULAR-DISEASE; BRAIN ATTACK COALITION; QUALITY-OF-CARE; INTRAVENOUS THROMBOLYSIS; COMPUTED-TOMOGRAPHY AB Objective To summarize and classify the evidence for the use of endovascular techniques in the treatment of patients with acute ischemic stroke. Methods Recommendations previously published by the American Heart Association (AHA) (Guidelines for the early management of adults with ischemic stroke (Circulation 2007) and Scientific statement indications for the performance of intracranial endovascular neurointerventional procedures (Circulation 2009)) were vetted and used as a foundation for the current process. Building on this foundation, a critical review of the literature was performed to evaluate evidence supporting the endovascular treatment of acute ischemic stroke. The assessment was based on guidelines for evidence based medicine proposed by the Stroke Council of the AHA and the University of Oxford, Centre for Evidence Based Medicine (CEBM). Procedural safety, technical efficacy and impact on patient outcomes were specifically examined. C1 [Blackham, K. A.; Hirsch, J. A.; Sunshine, J. L.] Case Western Reserve Univ, Dept Radiol, Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Meyers, P. M.] Columbia Univ, Coll Phys & Surg, Neuroendovasc Serv New York Presbyterian Columbia, Dept Radiol & Neurol Surg,Neurol Inst New York, New York, NY USA. [Abruzzo, T. A.] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. [Alberquerque, F. C.] Barrow Neurosurg Associates LTD, Div Neurol Surg, Phoenix, AZ USA. [Fiorella, D.] SUNY Stony Brook, Med Ctr, Dept Neurol Surg, Stony Brook, NY 11794 USA. [Fraser, J.] Univ Kentucky, Dept Neurol Surg, Lexington, KY USA. [Frei, D.] Radiol Imaging Associates, Intervent Neuroradiol, Englewood, CO USA. [Gandhi, C. D.] UMDNJ New Jersey Med Sch, Dept Neurol Surg, Newark, NJ USA. [Heck, D. V.] Forsyth Radiol Associates, Dept Radiol, Winston Salem, NC USA. [Hirsch, J. A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jayaraman, M.] Brown Univ, Warren Alpert Sch Med, Rhode Isl Hosp, Providence, RI 02912 USA. [Narayanan, S.] Wayne State Univ, Detroit Med Ctr, Dept Neurosurg, Detroit, MI USA. [Narayanan, S.] Wayne State Univ, Detroit Med Ctr, Dept Neurol, Detroit, MI USA. [Prestigiacomo, C.] Univ Med & Dent New Jersey, Dept Neurol Surg, Newark, NJ 07103 USA. RP Blackham, KA (reprint author), Case Western Reserve Univ, Dept Radiol, Univ Hosp Cleveland, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM kristine.blackham@uhhospitals.org OI Fraser, Justin/0000-0002-5980-3989 NR 83 TC 25 Z9 28 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAR PY 2012 VL 4 IS 2 BP 87 EP 93 DI 10.1136/neurintsurg-2011-010243 PG 7 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 891KU UT WOS:000300216600006 PM 22278933 ER PT J AU Gupta, AC Hirsch, JA Chaudhry, ZA Chandra, RV Pulli, B Galinsky, JG Hirsch, AE Yoo, AJ AF Gupta, Amar C. Hirsch, Joshua A. Chaudhry, Zeshan A. Chandra, Ronil V. Pulli, Benjamin Galinsky, Janice G. Hirsch, Ariel E. Yoo, Albert J. TI Evaluating the safety and effectiveness of percutaneous acetabuloplasty SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID BONE METASTASIS; RECONSTRUCTION; CEMENTOPLASTY; ACETABULUM; ABLATION; SCALE; PAIN AB Purpose To evaluate the safety and effectiveness of percutaneous acetabuloplasty in treating the pain and disability related to metastatic lesions of the acetabulum. Materials and methods This institutional review board approved retrospective study examined 11 patients who underwent percutaneous acetabuloplasty in our hospital from April 2007 to June 2010. All patients gave informed consent prior to the procedure, and all records were HIPAA compliant. Chart review was performed to collect patient demographics and to assess pre- and post-treatment patient performance on the Visual Analog Scale, Functional Mobility Scale and Analgesic Scale. Paired testing comparing the pre-and post-treatment scores for each patient was performed using the Wilcoxon signed rank test. Results There were 11 procedures: 10 performed under CT guidance and one using fluoroscopic guidance. There was a statistically significant decrease in patient Visual Analog Scale score (p=0.001) and Functional Mobility Scale score (p=0.03) after treatment. There was no change in median Analgesic Scale scores pre-and post-treatment although paired testing revealed a trend towards reduced analgesic use postoperatively (p=0.06). There were no clinically significant complications in this series. Conclusion Percutaneous acetabuloplasty appears to be safe and effective for improving the pain and decreased mobility secondary to metastatic lesions of the acetabulum. C1 [Gupta, Amar C.; Hirsch, Joshua A.; Chaudhry, Zeshan A.; Chandra, Ronil V.; Pulli, Benjamin; Galinsky, Janice G.; Hirsch, Ariel E.; Yoo, Albert J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yoo, AJ (reprint author), Massachusetts Gen Hosp, Gray 241,55 Fruit St, Boston, MA 02114 USA. EM ajyoo@partners.org NR 22 TC 7 Z9 7 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAR PY 2012 VL 4 IS 2 BP 134 EP 138 DI 10.1136/jnis.2011.004879 PG 5 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 891KU UT WOS:000300216600018 PM 21990476 ER PT J AU Manchikanti, L Hirsch, JA AF Manchikanti, Laxmaiah Hirsch, Joshua A. TI Patient Protection and Affordable Care Act of 2010: a primer for NeuroInterventionalists SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Review ID INTERVENTIONAL PAIN MANAGEMENT; HEALTH-CARE; REFORM; INSURANCE; DECADE AB The Patient Protection and Affordable Care Act (the ACA, for short) became law on 23 March 2010. It represents the most significant transformation of the American healthcare system since Medicare and Medicaid. Essentials of ACA include: (1) a mandate for individuals and businesses requiring as a matter of law that nearly every American has an approved level of health insurance or pay a penalty; (2) a system of federal subsidies to completely or partially pay for the now required health insurance for similar to 34 million Americans who are currently uninsured-subsidized through Medicaid and Exchanges; (3) extensive new requirements on the health insurance industry and (4) changes in the practice of medicine. The Act is divided into 10 titles. It contains provisions that went into effect starting on 21 June 2010 with many of the provisions going into effect in 2014 and later. The ACA goes well beyond insurance and payment reform. Practicing physicians will potentially be impacted by the Independent Payment Advisory Board and the Patient Centered Outcomes Research Institute. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY 42003 USA. [Manchikanti, Laxmaiah] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept NeuroIntervent Radiol, Boston, MA USA. RP Manchikanti, L (reprint author), Pain Management Ctr Paducah, 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com NR 31 TC 26 Z9 26 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD MAR PY 2012 VL 4 IS 2 BP 141 EP 146 DI 10.1136/neurintsurg-2011-010036 PG 6 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 891KU UT WOS:000300216600020 PM 21990501 ER PT J AU Morgans, AK Hancock, ML Barnette, KG Steiner, MS Morton, RA Smith, MR AF Morgans, Alicia K. Hancock, Michael L. Barnette, K. Gary Steiner, Mitchell S. Morton, Ronald A. Smith, Matthew R. TI Racial Differences in Bone Mineral Density and Fractures in Men Receiving Androgen Deprivation Therapy for Prostate Cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; androgens; bone density; fractures, bone; survival rate ID OLDER MEN; VERTEBRAL FRACTURES; HORMONE AGONISTS; WHITE MEN; OSTEOPOROSIS; BLACK; RISK; PREVENTION; CARCINOMA; HEALTH AB Purpose: Whether race influences bone loss and fracture risk during androgen deprivation therapy for prostate cancer is unknown. Using data from a prospective clinical trial we compared bone mineral density and fracture between African-American and Caucasian men receiving androgen deprivation therapy. Materials and Methods: A total of 516 subjects were in the placebo group of a 2-year randomized placebo controlled fracture prevention trial, and were African-American (68) or Caucasian (448). We compared baseline characteristics, changes in bone mineral density and rates of new fractures between races. Results: Compared to Caucasian men, African-American men had higher baseline hip bone mineral density (mean +/- SD 0.98 +/- 0.15 vs 0.91 +/- 0.15 gm/m(2), p = 0.001) and similar spine bone mineral density (1.09 +/- 0.22 vs 1.11 +/- 0.22, p = 0.51). There was no difference in prevalent vertebral fractures between African-American and Caucasian men (7.4% vs 15.0%, p = 0.13). The percentage change in hip bone mineral density at 2 years was similar between African-American and Caucasian men (mean +/- SE -2.21% +/- 0.59% vs -2.54% +/- 0.26%, p = 0.65). Changes in bone mineral density of the lumbar spine were also similar between African-American and Caucasian men (-1.74% +/- 0.69% vs -1.30% +/- 0.33%, p = 0.64). No new vertebral fractures were reported in African-American men but 2 fractures were reported in Caucasian men. Conclusions: In a clinical trial African-American men receiving androgen deprivation therapy for prostate cancer have a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. Despite a lower baseline risk of osteoporosis and fracture, African-American men experience a decrease in bone mineral density similar to that of Caucasian men. C1 [Morgans, Alicia K.; Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Hancock, Michael L.; Barnette, K. Gary; Steiner, Mitchell S.; Morton, Ronald A.] GTx Inc, Memphis, TN USA. RP Morgans, AK (reprint author), Massachusetts Gen Hosp, Ctr Canc, POB 221, Boston, MA 02114 USA. EM amorgans@partners.org FU NCI NIH HHS [K24 CA121990] NR 24 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD MAR PY 2012 VL 187 IS 3 BP 889 EP 893 DI 10.1016/j.juro.2011.10.136 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 892CY UT WOS:000300265500038 PM 22245322 ER PT J AU Palevsky, PM AF Palevsky, Paul M. TI Chronic-on-acute kidney injury SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID ACUTE-RENAL-FAILURE; DIALYSIS; DISEASE AB Although older teaching suggested that patients who survived an episode of acute kidney injury (AKI) had a benign course, recent studies have demonstrated that AKI is strongly associated with increased risk for development of progressive chronic kidney disease (CKD) and longer-term mortality. Much as we understand that CKD predisposes to the development of AKI, we must recognize that the relationship is bidirectional and that our patients with AKI are at risk for chronic-on-acute kidney disease. Kidney International (2012) 81, 430-431. doi:10.1038/ki.2011.435 C1 [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Renal Sect, Room 7E123 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 10 TC 14 Z9 15 U1 0 U2 1 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 MAR PY 2012 VL 81 IS 5 BP 430 EP 431 DI 10.1038/ki.2011.435 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 893SY UT WOS:000300377000002 PM 22333743 ER PT J AU Barnard, ZR Walcott, BP Kahle, KT Nahed, BV Coumans, JV AF Barnard, Zachary R. Walcott, Brian P. Kahle, Kristopher T. Nahed, Brian V. Coumans, Jean Valery TI Hyponatremia associated with Ipilimumab-induced hypophysitis SO MEDICAL ONCOLOGY LA English DT Article DE Pituitary gland; Melanoma; Antibodies; Monoclonal; Inappropriate ADH syndrome ID ANTIGEN-4 BLOCKADE; TUMOR-REGRESSION; AUTOIMMUNITY; CTLA-4 AB A 75-year-old woman with a history of stage IV metastatic melanoma underwent treatment with the CTLA-4 blocking agent Ipilimumab. She presented 2 months after initiating treatment with a severe headache. Laboratories were consistent with severe hyponatremia. MRI of the brain revealed enlargement of the pituitary gland, enhancement of the infundibulum, and an enhancing, centrally necrotic foci in the anterior pituitary. Based on the clinical and radiographic findings, she was diagnosed with treatment-related syndrome of inappropriate antidiuretic hormone secretion (SIADH). Effective treatment consisted of fluid restriction, hyperosmolar therapy, and steroids. C1 [Barnard, Zachary R.; Walcott, Brian P.; Kahle, Kristopher T.; Nahed, Brian V.; Coumans, Jean Valery] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Barnard, Zachary R.; Walcott, Brian P.; Kahle, Kristopher T.; Nahed, Brian V.; Coumans, Jean Valery] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,White Bldg,Room 502, Boston, MA 02114 USA. EM walcott.brian@mgh.harvard.edu NR 19 TC 17 Z9 18 U1 0 U2 0 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 MAR PY 2012 VL 29 IS 1 BP 374 EP 377 DI 10.1007/s12032-010-9794-7 PG 4 WC Oncology SC Oncology GA 892WV UT WOS:000300317200056 PM 21264545 ER PT J AU Tombini, M Rigosa, J Zappasodi, F Porcaro, C Citi, L Carpaneto, J Rossini, PM Micera, S AF Tombini, Mario Rigosa, Jacopo Zappasodi, Filippo Porcaro, Camillo Citi, Luca Carpaneto, Jacopo Rossini, Paolo Maria Micera, Silvestro TI Combined Analysis of Cortical (EEG) and Nerve Stump Signals Improves Robotic Hand Control SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE robotic hand prosthesis; LIFE; ERS/ERD analysis ID PHANTOM LIMB PAIN; INTRANEURAL ELECTRODES; AMPUTEES; MOTOR; SYNCHRONIZATION; CLASSIFICATION; FEEDBACK AB Background. Interfacing an amputee's upper-extremity stump nerves to control a robotic hand requires training of the individual and algorithms to process interactions between cortical and peripheral signals. Objective. To evaluate for the first time whether EEG-driven analysis of peripheral neural signals as an amputee practices could improve the classification of motor commands. Methods. Four thin-film longitudinal intrafascicular electrodes (tf-LIFEs-4) were implanted in the median and ulnar nerves of the stump in the distal upper arm for 4 weeks. Artificial intelligence classifiers were implemented to analyze LIFE signals recorded while the participant tried to perform 3 different hand and finger movements as pictures representing these tasks were randomly presented on a screen. In the final week, the participant was trained to perform the same movements with a robotic hand prosthesis through modulation of tf-LIFE-4 signals. To improve the classification performance, an event-related desynchronization/synchronization (ERD/ERS) procedure was applied to EEG data to identify the exact timing of each motor command. Results. Real-time control of neural (motor) output was achieved by the participant. By focusing electroneurographic (ENG) signal analysis in an EEG-driven time window, movement classification performance improved. After training, the participant regained normal modulation of background rhythms for movement preparation (alpha/beta band desynchronization) in the sensorimotor area contralateral to the missing limb. Moreover, coherence analysis found a restored alpha band synchronization of Rolandic area with frontal and parietal ipsilateral regions, similar to that observed in the opposite hemisphere for movement of the intact hand. Of note, phantom limb pain (PLP) resolved for several months. Conclusions Combining information from both cortical (EEG) and stump nerve (ENG) signals improved the classification performance compared with tf-LIFE signals processing alone; training led to cortical reorganization and mitigation of PLP. C1 [Tombini, Mario] Univ Campus Biomed, Neurol Clin, I-00128 Rome, Italy. [Rigosa, Jacopo; Citi, Luca; Carpaneto, Jacopo; Micera, Silvestro] Scuola Super Sant Anna, BioRobot Inst, Pisa, Italy. [Zappasodi, Filippo] Univ G DAnnunzio, Chieti, Italy. [Porcaro, Camillo] Osped Fatebenefratelli, ISTC CNR, Rome, Italy. [Porcaro, Camillo] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Citi, Luca] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Rossini, Paolo Maria] IRCCS S Raffaele Pisana, Rome, Italy. [Rossini, Paolo Maria] Casa Cura S Raffaele, Cassino, Italy. [Rossini, Paolo Maria] Catholic Univ, Rome, Italy. [Micera, Silvestro] Swiss Fed Inst Technol, Zurich, Switzerland. RP Tombini, M (reprint author), Univ Campus Biomed, Neurol Clin, Via Alvaro Portillo 200, I-00128 Rome, Italy. EM m.tombini@unicampus.it RI Citi, Luca/G-2270-2011; Rossini, Paolo /D-4994-2013; OI Citi, Luca/0000-0001-8702-5654; Rossini, Paolo /0000-0003-2665-534X; Tombini, Mario/0000-0002-0328-7815; Porcaro, Camillo/0000-0003-4847-163X FU Commission of the European Community [FP6-IST-001917]; TIME [FP7-ICT-224012] FX This study was partially supported by the Commission of the European Community within the projects NEUROBOTICS (Contract No. FP6-IST-001917) and TIME (Contract No. FP7-ICT-224012). None of these funding sources had a role in the study design, data collection, data analysis, data interpretation, or writing. NR 21 TC 15 Z9 15 U1 2 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD MAR-APR PY 2012 VL 26 IS 3 BP 275 EP 281 DI 10.1177/1545968311408919 PG 7 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 894OD UT WOS:000300435300008 PM 21730360 ER PT J AU Huang, SP Bao, BY Wu, MT Choueiri, TK Goggins, WB Liu, CC Huang, CY Pu, YS Yu, CC Wu, TT Huang, CN Huang, CH Wu, WJ AF Huang, Shu-Pin Bao, Bo-Ying Wu, Ming-Tsang Choueiri, Toni K. Goggins, William B. Liu, Chia-Chu Huang, Chao-Yuan Pu, Yeong-Shiau Yu, Chia-Cheng Wu, Tony T. Huang, Chun-Nung Huang, Chun-Hsiung Wu, Wen-Jeng TI Significant associations of prostate-specific antigen nadir and time to prostate-specific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy SO AGING MALE LA English DT Article DE Prostate cancer; androgen-deprivation therapy; metastatic prostate cancer; prostate-specific antigen kinetics; time to prostate-specific antigen nadir; prostate-specific antigen nadir ID BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; PROGNOSTIC-SIGNIFICANCE; POSTRADICAL PROSTATECTOMY; ANTIANDROGEN WITHDRAWAL; HORMONAL-THERAPY; PSA VELOCITY; RECEPTOR; RISK; POLYMORPHISMS AB Objective. The influence of prostate-specific antigen (PSA) kinetics on the outcome of metastatic prostate cancer (PCa) after androgen-deprivation therapy (ADT) remains poorly characterised. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their interactive effect on prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT. Methods. A total of 650 men with advanced or metastatic PCa treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on PCSM and ACM were analysed using Kaplan-Meier analysis and the Cox regression model. Results. On multivariate analysis, clinical M1 stage, Gleason Score 8-10, PSA nadir >= 0.2 ng/ml and time to PSA nadir 5 10 months were independent predictors of PCSM and ACM. The combined analysis showed that patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk of PCSM and ACM compared to those with lower PSA nadir and longer time to PSA nadir (hazard ratios = 6.30 and 4.79, respectively, all P < 0.001). Conclusions. Our results suggest that higher PSA nadir level and faster time to reach PSA nadir after ADT were associated with shorter survival for PCa. C1 [Huang, Shu-Pin; Huang, Chun-Hsiung; Wu, Wen-Jeng] Kaohsiung Med Univ, Dept Urol, Fac Med, Coll Med, Kaohsiung 807, Taiwan. [Huang, Shu-Pin; Liu, Chia-Chu; Huang, Chun-Nung; Huang, Chun-Hsiung; Wu, Wen-Jeng] Kaohsiung Med Univ Hosp, Dept Urol, Kaohsiung, Taiwan. [Huang, Shu-Pin] Kaohsiung Med Univ Hosp, Ctr Canc, Kaohsiung, Taiwan. [Bao, Bo-Ying] China Med Univ, Dept Pharm, Taichung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ Hosp, Dept Family Med, Kaohsiung, Taiwan. [Wu, Ming-Tsang] Kaohsiung Med Univ, Grad Inst Occupat Safety & Hlth, Kaohsiung 807, Taiwan. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goggins, William B.] Chinese Univ Hong Kong, Div Biostat, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Huang, Chao-Yuan; Pu, Yeong-Shiau] Natl Taiwan Univ, Dept Urol, Taipei 10764, Taiwan. [Yu, Chia-Cheng; Wu, Tony T.] Kaohsiung Vet Gen Hosp, Div Urol, Dept Surg, Kaohsiung, Taiwan. RP Huang, SP (reprint author), Kaohsiung Med Univ, Dept Urol, Fac Med, Coll Med, 100 Shih Chuan 1st Rd, Kaohsiung 807, Taiwan. EM shpihu@yahoo.com.tw RI Wu, Ming-Tsang/G-5637-2012; Bao, Bo-Ying/D-1789-2012; OI Bao, Bo-Ying/0000-0001-5510-6513; HUANG, CHAO-YUAN/0000-0002-9322-6062; PU, YEONG-SHIAU/0000-0002-2859-3966 FU Taiwan National Science Council [NSC 95-2314-B-037-053-MY2, NSC 96-2314-B-037-012-MY3, NSC 99-2314-B-037-018-MY3]; Kaohsiung Medical University Hospital [KMUH96-6G27, KMUH96-6G28]; Kaohsiung Municipal Hsiao-Kang Hospital [kmhk-96-009, kmhk-97-008] FX This study was supported by grants from the Taiwan National Science Council (NSC 95-2314-B-037-053-MY2, NSC 96-2314-B-037-012-MY3 and NSC 99-2314-B-037-018-MY3), Kaohsiung Medical University Hospital (KMUH96-6G27 and KMUH96-6G28) and Kaohsiung Municipal Hsiao-Kang Hospital (kmhk-96-009 and kmhk-97-008). The authors thank Ms. Chao-Shih Chen and Professor Hung-Yi Chuang for their help on data analyses. NR 38 TC 8 Z9 10 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1368-5538 J9 AGING MALE JI Aging Male PD MAR PY 2012 VL 15 IS 1 BP 34 EP 41 DI 10.3109/13685538.2011.580398 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 886GB UT WOS:000299840800006 PM 21615239 ER PT J AU Anderson, RM Weindruch, R AF Anderson, Rozalyn M. Weindruch, Richard TI The caloric restriction paradigm: Implications for healthy human aging SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Article ID GENE-EXPRESSION PROFILE; RANDOMIZED CONTROLLED-TRIAL; TERM DIETARY RESTRICTION; RHESUS-MONKEYS; LIFE-SPAN; ADIPOSE-TISSUE; METABOLIC-DISORDERS; ENERGY-INTAKE; MITOCHONDRIAL BIOGENESIS; SKELETAL-MUSCLE AB Underlying the importance of research on the biology of aging is the fact that many nations face the demographic reality of a rapidly aging populace and the looming healthcare challenges that it brings. This reality is a result of aging itself being the most significant risk factor for a range of the most prevalent diseases, including many cancers, cardiovascular disease, and diabetes. Accordingly, interventions are sorely needed that would be able to delay or prevent diseases and disorders associated with the aging process and thereby increase the period of time that aging individuals are in good health (the health-span). Caloric restriction (CR) has emerged as a model of major interest as it is widely agreed that CR is the most potent environmental intervention that delays the onset of aging and extends life span in diverse experimental organisms. A better understanding of the mechanisms by which CR delays aging will reveal new insights into the aging process and the underlying causes of disease vulnerability with age. These novel insights will allow the development of novel treatments and preventive measures for age-associated diseases and disorders. Am. J. Hum. Biol. 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Anderson, Rozalyn M.; Weindruch, Richard] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Anderson, Rozalyn M.; Weindruch, Richard] William S Middleton Mem Vet Adm Med Ctr, Geriatr Educ Res & Clin Ctr, Madison, WI USA. RP Anderson, RM (reprint author), Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. EM rmanderson@medicine.wisc.edu FU NIH [NIA P01AG11915, R01AG037000]; NCRR/CTSA [UL1RR025011] FX Contract grant sponsor: NIH; Contract grant numbers: NIA P01AG11915, R01AG037000, and NCRR/CTSA UL1RR025011. NR 66 TC 57 Z9 59 U1 2 U2 19 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 MAR-APR PY 2012 VL 24 IS 2 BP 101 EP 106 DI 10.1002/ajhb.22243 PG 6 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 888IQ UT WOS:000299997500001 PM 22290875 ER PT J AU Ackerman, KE Skrinar, GS Medvedova, E Misra, M Miller, KK AF Ackerman, Kathryn E. Skrinar, Gary S. Medvedova, Eva Misra, Madhusmita Miller, Karen K. TI Estradiol levels predict bone mineral density in male collegiate athletes: a pilot study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID ANOREXIA-NERVOSA; SERUM TESTOSTERONE; PHYSICAL-ACTIVITY; DISTANCE RUNNERS; ADOLESCENT GIRLS; YOUNG-ADULTS; MEN; WOMEN; MASS; ESTROGEN AB Objective Strenuous training commonly results in amenorrhoea, which contributes to bone loss in some female collegiate athletes. However, the impact of athletic training on endocrine function and bone mineral density (BMD) in male collegiate athletes is less well understood. The objective of the study was to investigate the specific endocrine determinants of BMD in male collegiate runners and wrestlers, including the potential impact of gonadal steroid levels. Design Cross-sectional study. Patients Twenty-six division I collegiate male athletes (wrestlers, runners and golfers). Measurements Main outcome measures included (i) BMD endpoints measured by dual energy x-ray absorptiometry (DXA); (ii) endocrine end-points: total and free oestradiol, total and free testosterone; (iii) body composition end-points: lean and fat mass, measured by DXA; and (iv) exercise end-points: maximal oxygen uptake (VO2 max), number of miles run weekly and grip strength. Results Free and total oestradiol levels were important positive determinants of BMD. In contrast, total and free testosterone levels were not significant predictors of BMD at any skeletal site (except for free testosterone at the radius). In addition, lean body mass, % ideal body weight, total body weight, body mass index (BMI) and hours per week of resistance training were positive predictors of BMD. VO2 max was a negative predictor of BMD. Mean BMD was higher at all skeletal sites in the wrestlers compared with the runners and a comparison group (golfers). Conclusions Our data suggest that oestradiol levels, BMI, and resistance training are more important determinants of BMD in male collegiate athletes than testosterone. C1 [Ackerman, Kathryn E.; Medvedova, Eva; Misra, Madhusmita; Miller, Karen K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Ackerman, Kathryn E.; Medvedova, Eva; Misra, Madhusmita; Miller, Karen K.] Harvard Univ, Sch Med, Boston, MA USA. [Ackerman, Kathryn E.] Childrens Hosp Boston, Div Sports Med, Boston, MA USA. [Skrinar, Gary S.] Boston Univ, Dept Hlth Sci GSS, Boston, MA 02215 USA. [Misra, Madhusmita] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. MIT, Gen Clin Res Ctr, Cambridge, MA 02139 USA. RP Ackerman, KE (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Bulfinch 457B, Boston, MA 02114 USA. EM KEAckerman@partners.org FU [MO1 RR01066] FX We thank the nurses and bionutritionists of the Massachusetts Institute of Technology General Clinical Research Center, and we thank the athletes for their participation in this study. The authors have no conflicts of interest. This work was supported in part by the following grant: MO1 RR01066. The authors have nothing else to declare. NR 38 TC 5 Z9 6 U1 0 U2 3 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 MAR PY 2012 VL 76 IS 3 BP 339 EP 345 DI 10.1111/j.1365-2265.2011.04212.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 887RF UT WOS:000299946000005 PM 21942923 ER PT J AU Gill, TJ Van de Velde, SK Carroll, KM Robertson, WJ Heyworth, BE AF Gill, Thomas J. Van de Velde, Samuel K. Carroll, Kaitlin M. Robertson, William J. Heyworth, Benton E. TI Surgical Technique: Aperture Fixation in PCL Reconstruction: Applying Biomechanics to Surgery SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID POSTERIOR CRUCIATE LIGAMENT; TIBIAL INLAY TECHNIQUES; FOLLOW-UP; SINGLE-BUNDLE; TRANSTIBIAL TECHNIQUES; DEFICIENT KNEE; TENDON GRAFT; INJURIES; TRANSLATION; KINEMATICS AB Biomechanical studies suggest reducing the effective graft length during transtibial posterior cruciate ligament (PCL) reconstruction by augmenting the distal tibial fixation with a proximal screw near the tibial tunnel aperture could increase graft stiffness and provide a more stable reconstruction. However, it remains unknown to what extent this mechanical theory influences in vivo graft performance over time. We developed a technique to augment tibial distal fixation with a proximal screw near the tibial tunnel aperture to shorten the effective graft length and increase graft stiffness. We retrospectively reviewed all 10 patients who had isolated PCL reconstructions with combined distal and proximal tibial fixation from 2003 to 2007. Mean age of the patients was 36.5 years. We measured ROM and obtained Tegner, International Knee Documentation Committee (IKDC), and Lysholm scores. Anteroposterior stability was evaluated with a KT-2000 arthrometer. Minimum followup was 1 year (mean, 2.5 years; range, 1-4.8 years). Mean Tegner scores before injury and at last followup were 7.3 and 6.5, respectively. Mean postoperative IKDC score was 87 versus a preoperative IKDC score of 43. Mean Lysholm score was 89 at last followup. All patients achieved full terminal extension. No patient had greater than a 5-mm difference in anterior or posterior displacement from the contralateral knee as measured by a KT-2000 arthrometer postoperatively (0.93 +/- A 0.79 mm). In this small series, augmentation of tibial distal fixation with a proximal screw near the tibial tunnel aperture during reconstruction of the isolated PCL rupture restored function, motion, and stability. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Gill, Thomas J.; Van de Velde, Samuel K.; Carroll, Kaitlin M.; Robertson, William J.; Heyworth, Benton E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Sports Med Serv, Boston, MA 02114 USA. RP Gill, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Sports Med Serv, 175 Cambridge St,4th Floor, Boston, MA 02114 USA. EM tgill@partners.org FU National Institutes of Health [NIH F32AR056451] FX One or more of the authors (SKV) received financial support from the National Institutes of Health: NIH F32AR056451. NR 35 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAR PY 2012 VL 470 IS 3 BP 853 EP 860 DI 10.1007/s11999-011-2100-y PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 889EF UT WOS:000300055600028 PM 21997781 ER PT J AU Steele, SR Stein, SL Bordeianou, LG Johnson, E Herzig, DO Champagne, BJ AF Steele, Scott R. Stein, Sharon L. Bordeianou, Liliana G. Johnson, Eric Herzig, Dan O. Champagne, Bradley J. CA Amer Soc Colon & Rectal Surg Young TI The impact of practice environment on laparoscopic colectomy utilization following colorectal residency: a survey of the ASCRS Young Surgeons SO COLORECTAL DISEASE LA English DT Article DE Laparoscopy; colectomy; fellowship; university; private practice ID COLON-CANCER; RANDOMIZED-TRIAL; POSTOPERATIVE COMPLICATIONS; EXPERIENCE; OUTCOMES; RESECTION; VOLUME AB Aim It is often thought that practice patterns are different in private (PP) vs university hospital (UH) settings. We aimed to describe the impact of practice environment on the type of laparoscopic colectomy procedures performed by graduating colorectal surgeons. Method A review was carried out of prospectively gathered self-reported questionnaire data. Graduates of American Society of Colon and Rectal Surgeons' (ASCRS)-approved colorectal residencies from 2004 to 2008 underwent an on-line survey, developed by the ASCRS Young Surgeons' Committee. Results About 177 (52%) of 342 graduates surveyed responded. Practice setting data were available for 157 (89%) surgeons. Gender, geographical location and age were similar in both cohorts. PP surgeons utilized a laparoscopic approach more often for rectal cancer (37% vs 19%; P = 0.003). There was no significant difference in the rate of laparoscopic surgery in colon cancer, diverticular disease, inflammatory bowel disease, Clostridium difficile or emergency surgery. PP surgeons operated more often with a partner (43% vs 8%) or surgical assistant (13% vs 4%; both P < 0.001), while UH surgeons had a colorectal resident (10% vs 21%) or general surgery resident (15% vs 55%; both P < 0.001). Impediments to performing laparoscopic surgery for PP surgeons included a perceived lack of hospital equipment (33% vs 20%) and support (29% vs 17%; both P < 0.05). Perception of personal experience, access to trained assistants, financial reimbursement, length of surgery and patient availability were equivalent in both groups. Conclusion While differences such as type of assistant and impediments to laparoscopic utilization exist between PP-and UH-based practices, early laparoscopic practice patterns remain similar. PP surgeons more frequently perform laparoscopic resection for rectal cancer and with hand-assistance. Despite differences, newly trained colorectal surgeons in both settings utilize and require laparoscopic skills. C1 [Steele, Scott R.] Madigan Army Med Ctr, Dept Surg, Tacoma, WA 98431 USA. [Stein, Sharon L.; Champagne, Bradley J.] Case Western Reserve Univ, Dept Surg, Div Colorectal Surg, Cleveland, OH 44106 USA. [Bordeianou, Liliana G.] Massachusetts Gen Hosp, Dept Surg, Colorectal Surg Program, Boston, MA 02114 USA. [Johnson, Eric] Dwight D Eisenhower Army Med Ctr, Dept Surg, Div Colorectal Surg, Augusta, GA USA. [Herzig, Dan O.] Oregon Hlth & Sci Univ, Dept Surg, Div Colorectal Surg, Portland, OR 97201 USA. RP Steele, SR (reprint author), 9606 Piperhill Dr SE, Olympia, WA 98513 USA. EM harkersteele@mac.com NR 31 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-8910 J9 COLORECTAL DIS JI Colorectal Dis. PD MAR PY 2012 VL 14 IS 3 BP 374 EP 381 DI 10.1111/j.1463-1318.2011.02614.x PG 8 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 887SE UT WOS:000299949100029 PM 21689306 ER PT J AU Bergen, SE Petryshen, TL AF Bergen, Sarah E. Petryshen, Tracey L. TI Genome-wide association studies of schizophrenia: does bigger lead to better results? SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE association; genetic; genome-wide association studies; risk gene; schizophrenia ID COMMON VARIANTS; MACULAR DEGENERATION; CONFERRING RISK; STEM-CELLS; GENETICS; SUSCEPTIBILITY; LOCI; PSYCHOSIS; DISEASE; TCF4 AB Purpose of review Numerous genome-wide association studies (GWAS) of schizophrenia have been published in the past 6 years, with a number of key reports published in the last year. The studies have evolved in scale from small individual samples to large collaborative endeavors. This review aims to critically assess whether the results have improved as the sample size and scale of genetic association studies have grown. Recent findings Genomic genotyping and increasing sample sizes for schizophrenia association studies have led to parallel increases in the number of risk genes discovered with high statistical confidence. Nearly 20 genes or loci have surpassed the genome-wide significance threshold (P = 5 x 10(-8)) in a single study, and several have been replicated in more than one GWAS. Summary Identifying the genetic underpinnings of complex diseases offers insight into the etiological mechanisms leading to manifestation of the disease. New and more effective treatments for schizophrenia are desperately needed, and the ability to target the relevant biological processes grows with our understanding of the genes involved. As the size of GWAS samples has increased, more genes have been identified with high confidence that have begun to provide insight into the etiological and pathophysiological foundations of this disorder. C1 [Bergen, Sarah E.; Petryshen, Tracey L.] Harvard Univ, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. [Bergen, Sarah E.; Petryshen, Tracey L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Bergen, Sarah E.; Petryshen, Tracey L.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Petryshen, TL (reprint author), Harvard Univ, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Massachusetts Gen Hosp,Med Sch, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM petryshen@chgr.mgh.harvard.edu RI Bergen, Sarah/I-8313-2012; OI Bergen, Sarah/0000-0002-5888-0034 FU US National Institutes of Health [MH080272]; Stanley Medical Research Institute FX This work was supported by the US National Institutes of Health (grant MH080272) and the Stanley Medical Research Institute. NR 52 TC 30 Z9 30 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAR PY 2012 VL 25 IS 2 BP 76 EP 82 DI 10.1097/YCO.0b013e32835035dd PG 7 WC Psychiatry SC Psychiatry GA 888ZG UT WOS:000300042700002 PM 22277805 ER PT J AU AhnAllen, CG AF AhnAllen, Christopher G. TI The role of the alpha 7 nicotinic receptor in cognitive processing of persons with schizophrenia SO CURRENT OPINION IN PSYCHIATRY LA English DT Review DE alpha7; cognition; nicotinic agonists; positive allosteric modulators; schizophrenia ID ACETYLCHOLINE-RECEPTORS; ENHANCEMENT THERAPY; CIGARETTE-SMOKING; DEFAULT NETWORK; AGONIST; TROPISETRON; DISEASE; TRIAL; ENDOPHENOTYPES; ASSOCIATION AB Purpose of review Cognitive abilities are established as major deficits in those with schizophrenia and represent significant impediments toward successful psychosocial functioning within the community. Pharmacological treatments have historically focused on reducing the positive and negative symptoms of schizophrenia, with recent increased attention to developing agents to improve cognition as a treatment outcome. This review will highlight the recent advances in developing agents that act at neuronal alpha 7 nicotinic acetylcholine receptors (nAChRs). Recent findings A number of agents have demonstrated improvements in cognitive deficits in studies using both preclinical and clinical models. Evidence suggests that alpha 7 nAChR activation impacts rule acquisition and initial learning in preclinical models. Preclinical studies indicate improved spatial working memory and reversal of phencyclidine-induced learning and memory deficits. Clinical studies indicate normalization of neuronal default network activity using functional magnetic resonance imaging methods. In addition, research on new agents developed to improve cognition suggests improved cognitive functioning in multiple domains (e. g., attention, memory, executive functioning, sensory gating and overall cognition) and promising safety profiles of additional agents. Summary Improvements in cognitive functioning within preclinical and clinical studies of schizophrenia are evident through the use of alpha 7 nAChR agonists, while positive allosteric modulators may gain increased attention in the future. C1 [AhnAllen, Christopher G.] VA Boston Healthcare Syst, Inpatient Mental Hlth Serv, Brockton Div, Ward 23B, Brockton, MA 02301 USA. [AhnAllen, Christopher G.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP AhnAllen, CG (reprint author), VA Boston Healthcare Syst, Inpatient Mental Hlth Serv, Brockton Div, Ward 23B, 940 Belmont St, Brockton, MA 02301 USA. EM Christopher.AhnAllen@va.gov NR 49 TC 18 Z9 20 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD MAR PY 2012 VL 25 IS 2 BP 103 EP 108 DI 10.1097/YCO.0b013e3283503637 PG 6 WC Psychiatry SC Psychiatry GA 888ZG UT WOS:000300042700006 PM 22262029 ER PT J AU Igoillo-Esteve, M Marselli, L Cunha, DA Ladriere, L Ortis, F Grieco, FA Dotta, F Weir, GC Marchetti, P Eizirik, DL Cnop, M AF Igoillo-Esteve, M. Marselli, L. Cunha, D. A. Ladriere, L. Ortis, F. Grieco, F. A. Dotta, F. Weir, G. C. Marchetti, P. Eizirik, D. L. Cnop, M. TI Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes (vol 53, pg 1395, 2010) SO DIABETOLOGIA LA English DT Correction C1 [Igoillo-Esteve, M.; Cunha, D. A.; Ladriere, L.; Ortis, F.; Eizirik, D. L.; Cnop, M.] Univ Libre Bruxelles, Expt Med Lab, B-1070 Brussels, Belgium. [Marselli, L.; Marchetti, P.] Univ Pisa, Dept Endocrinol & Metab, Metab Unit, Pisa, Italy. [Grieco, F. A.; Dotta, F.] Univ Siena, Dept Internal Med, I-53100 Siena, Italy. [Grieco, F. A.; Dotta, F.] Umberto Di Mario Fdn, Siena, Italy. [Weir, G. C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Cnop, M.] Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, B-1070 Brussels, Belgium. RP Cnop, M (reprint author), Univ Libre Bruxelles, Expt Med Lab, CP-618,Route Lennik 808, B-1070 Brussels, Belgium. EM mcnop@ulb.ac.be RI Dotta, Francesco/H-3788-2012; Ortis, Fernanda/K-7917-2014; Marchetti, Piero/J-7439-2013 OI Marchetti, Piero/0000-0003-4907-0635 NR 1 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD MAR PY 2012 VL 55 IS 3 BP 863 EP 863 DI 10.1007/s00125-011-2389-9 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 887IX UT WOS:000299921200041 ER PT J AU Cullen, G Bader, C Korzenik, JR Sands, BE AF Cullen, Garret Bader, Caroline Korzenik, Joshua R. Sands, Bruce E. TI Serological response to the 2009 H1N1 influenza vaccination in patients with inflammatory bowel disease SO GUT LA English DT Article ID CROHNS-DISEASE; IMMUNE-RESPONSE; ANTIBODY-RESPONSE; CONTROLLED-TRIAL; DOUBLE-BLIND; EFFICACY; SAFETY; VIRUS; IMMUNOGENICITY; IMMUNIZATION AB Background Influenza vaccination is recommended for patients with inflammatory bowel disease (IBD). The 2009 H1N1 influenza vaccine produced seroprotection rates of >85% in the general population but there are no data on the immunogenicity of the vaccine in patients with IBD. Methods An observational prospective open-label study was conducted to examine the immunogenicity of the 2009 H1N1 influenza vaccine in 108 patients with IBD. Patient details, medications and disease activity were recorded. Pre- and post-vaccination haemagglutinin inhibition titres and geometric mean titres were measured. A functional assay of T lymphocyte activity was measured at vaccination in a subset of patients as an alternative measure of immunosuppression. Subjects were followed for 6 months post-vaccination. Results Of 108 patients enrolled, 105 completed the study. The post-vaccination seroprotection rate was 50%. Immunosuppressed subjects had a lower rate of seroprotection than non-immunosuppressed subjects (44% vs 64%, p=0.06). The proportion with seroprotection was significantly lower in subjects on combination immunosuppression than in those receiving no immunosuppression (36% vs 64%, p=0.02). Patients receiving combined immunosuppression had a significantly lower fold increase in geometric mean titres than those on monotherapy immunosuppression (3.5 vs 11.5, p=0.03). An assay of T lymphocyte activity was performed in a subgroup of 48 subjects. Those with intermediate activity had lower seroprotection than those with high activity (28% vs 61%, p=0.02). The vaccine was well tolerated. Conclusions Patients with IBD vaccinated with the 2009 H1N1 influenza vaccine had a low rate of seroprotection, particularly among those who were immunosuppressed. Although there is a need for studies of the clinical benefit of vaccines in this population, patients with IBD need to be aware of this reduced immunogenicity. C1 [Cullen, Garret; Bader, Caroline; Korzenik, Joshua R.] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. [Cullen, Garret; Bader, Caroline; Korzenik, Joshua R.] Harvard Univ, Sch Med, Boston, MA USA. [Sands, Bruce E.] Mt Sinai Sch Med, Dr Henry D Janowitz Div Gastroenterol, New York, NY USA. RP Cullen, G (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Boston, MA 02114 USA. EM gcullen@bidmc.harvard.edu FU Sanofi Pasteur, USA; Crohn's and Colitis Center; Massachusetts General Hospital, Boston FX Sanofi Pasteur, USA provided an educational grant to the Crohn's and Colitis Center, Massachusetts General Hospital, Boston to part-fund the cost of the haemagglutinin inhibition assays that were performed at the Laboratory for Specialized Clinical Studies at Cincinnati Children's Hospital Medical Center. BES NR 26 TC 30 Z9 31 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD MAR PY 2012 VL 61 IS 3 BP 385 EP 391 DI 10.1136/gutjnl-2011-300256 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 889FH UT WOS:000300058500009 PM 21757451 ER PT J AU Lu, XM Tompkins, RG Fischman, AJ AF Lu, X. -M. Tompkins, R. G. Fischman, A. J. TI SILAM for quantitative proteomics of liver Akt1/PKB alpha after burn injury SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE Akt1/PKB alpha; SILAM; MS/MS; burn injury ID PROTEIN-KINASE-B/AKT; SKELETAL-MUSCLE DIFFERENTIATION; INSULIN-RECEPTOR SUBSTRATE-1; S-NITROSYLATED PROTEINS; NITRIC-OXIDE PRODUCTION; CAPLC-Q-TOFMICRO; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; THERMAL-INJURY; STABLE-ISOTOPES AB Akt1/protein kinase B alpha (Akt1/PKB alpha) is a downstream mediator of the insulin signaling system. In this study we explored mechanism(s) for its role in burn injury. Akt1/PKB alpha in liver extracts from mice with burn injury fed with (H-2(7))-L-Leu was immunoprecipitated and isolated with SDS-PAGE. Two tryptic peptides, one in the kinase loop and a control peptide just outside of the loop were sequenced via nano-LC interfaced with quadruple time-of-flight tandem mass spectrometry (Q-TOF tandem MS). Their relative isotopologue abundances were determined by stable isotope labeling by amino acids in mammalians (SILAM). Relative quantifications based on paired heavy/light peptides were obtained in 3 steps. The first step included homogenization of mixtures of equal amounts of tissue from burned and sham-treated animals (i.e., isotope dilution) and acquisition of uncorrected data based on parent monoisotopic MS ion ratios. The second step included determination of isotopic enrichment of the kinase from burned mice on Day 7 and the third step enrichment correction of partially labeled heavy and light monoisotopic MS ion ratios for relative quantification of bioactivity (loop peptide) and expression level (control peptide). Protein synthesis and enrichment after injury were found to be dependent on tissue and turnover of individual proteins. Three heavy and light monoisotopic ion ratios for albumin peptides from burned mice indicated similar to 55% enrichment and similar to 16.7-fold downregulation. In contract, serum amyloid P had similar to 66% enrichment and was significantly upregulated. Akt1/PKB alpha had similar to 56% enrichment and kinase level in response to the burn injury was upregulated compared with the control peptide. However, kinase bioactivity, represented by the Cys(296) peptide, was significantly reduced. Overall, we demonstrated that i) quantitative proteomics can be performed without completely labeled mice; ii) measurement of enrichment of acyl-tRNAs is unnecessary and iii) Cys(296) plays an important role in kinase activity after burn injury. C1 [Lu, X. -M.; Tompkins, R. G.; Fischman, A. J.] Shriners Hosp Children, Boston, MA 02114 USA. [Lu, X. -M.; Tompkins, R. G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lu, X. -M.; Tompkins, R. G.; Fischman, A. J.] Harvard Univ, Sch Med, Boston, MA USA. RP Fischman, AJ (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM aajjff@gmail.com FU National Institutes of Health [NIGMS P50 GM21000]; Shriners Hospitals for Children FX This study was supported in part by grants from the National Institutes of Health (NIGMS P50 GM21000) and Shriners Hospitals for Children. We would like to thank Dr E.A. Carter and Ms. F. Lin for their assistance with these studies. NR 63 TC 3 Z9 3 U1 0 U2 5 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD MAR PY 2012 VL 29 IS 3 BP 461 EP 471 DI 10.3892/ijmm.2011.861 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 889ZV UT WOS:000300115800019 PM 22179310 ER PT J AU Wang, JI Hui, P Zeng, MS Rabkin, SD Liu, RB AF Wang, Jiani Hui, Pan Zeng, Musheng Rabkin, Samuel D. Liu, Renbin TI Oncolytic herpes simplex virus treatment of metastatic breast cancer SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE breast cancer; pulmonary metastatic breast cancer; oncolytic herpes simplex virus; immortalized breast cells; pulmonary metastatic model ID TERM-FOLLOW-UP; NODE METASTASES; THERAPY; GENE; CARCINOMA; VECTORS; CELLS; GAMMA-134.5; PROGRESSION; MUTANT AB The high prevalence and poor prognosis of breast cancer provides a strong rationale for developing new treatment strategies and preventive and therapeutic agents. Oncolytic replication-competent herpes simplex virus (HSV) can infect tumor cells, replicating and killing the cells by direct cytopathic effect and then spreading within the tumor. Replication of oncolytic HSV leads to the destruction of the infected tumor cell and release of new virions, which are able to infect adjacent cells until potentially all tumor cells are destroyed. In this study, the cytotoxicity of a third-generation oncolytic HSV vector, designated G47 Delta, was examined in human breast cancer cell lines, as well as in immortalized and normal breast cells. A pulmonary metastatic model of breast cancer established in Balb/c nude mice was used to evaluate the efficacy of G47 Delta treatment. Systemic treatment by intravenous administration of G47 Delta for metastatic lung tumors was initiated 14 days after injection of tumor cells. On Day 56, the mice were sacrificed and tumor nodules on the surface of the lung were counted. G47 Delta was highly cytotoxic to breast cancer and immortalized breast cells in vitro at low multiplicities of infection (MOI), while normal breast cells remained viable 5 days after infection. In the pulmonary metastatic model, the average number ;of surface lung tumor nodules in the G47 Delta-treated group was approximately 9-fold less than in the control-treated group. X-gal staining illustrated viral replication and spread in the tumor cells in vitro and in vivo. In conclusion, G47 Delta effectively killed human breast cancer cells and immortalized breast cells but not normal breast cells. Systemic administration of G47 Delta by tail vein injection was effective in inhibiting the growth of established breast cancer lung metastases. C1 [Wang, Jiani; Hui, Pan; Liu, Renbin] Sun Yat Sen Univ, Breast Canc Ctr, Affiliated Hosp 3, Guangzhou 510630, Guangdong, Peoples R China. [Zeng, Musheng] Sun Yat Sen Univ, Dept Lab Med, Tumor Hosp, Guangzhou 510630, Guangdong, Peoples R China. [Rabkin, Samuel D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurosurg Lab, Boston, MA USA. RP Liu, RB (reprint author), Sun Yat Sen Univ, Breast Canc Ctr, Affiliated Hosp 3, 600 Tianhe Rd, Guangzhou 510630, Guangdong, Peoples R China. EM liur@vip.163.com RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 FU NSF of China [30672410]; Guangdong Natural Science Foundation [06104599] FX This study was supported by the NSF of China (30672410) and the Guangdong Natural Science Foundation (06104599). NR 27 TC 7 Z9 7 U1 0 U2 15 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD MAR PY 2012 VL 40 IS 3 BP 757 EP 763 DI 10.3892/ijo.2011.1266 PG 7 WC Oncology SC Oncology GA 890AT UT WOS:000300118200017 PM 22108767 ER PT J AU Roach, NT Lieberman, DE Gill, TJ Palmer, WE Gill, TJ AF Roach, Neil Thomas Lieberman, Daniel E. Gill, Thomas J. Palmer, William E. Gill, Thomas J., III TI The effect of humeral torsion on rotational range of motion in the shoulder and throwing performance SO JOURNAL OF ANATOMY LA English DT Review DE glenohumeral joint; humeral retroversion; humeral rotation; humeral torsion; throwing ID PROFESSIONAL BASEBALL PITCHERS; GLENOHUMERAL INTERNAL-ROTATION; TENNIS PLAYERS; PITCHING MECHANICS; HEAD RETROVERSION; INJURIES; ATHLETE; BIOMECHANICS; JOINT; ELBOW AB Several recent studies have found that throwing athletes typically have lower humeral torsion (retroversion) and a greater range of external rotation at the shoulder than non-athletes. How these two parameters are related is debated. This study uses data from a sample of both throwers and non-throwers to test a new model that predicts torsion values from a range of motion data. The model proposes a series of predicted regressions which can help provide new insight into the factors affecting rotational range of motion at the shoulder. Humeral torsion angles were measured from computed tomography scans collected from 25 male subjects. These values are compared to predicted torsion values for the same subjects calculated from both kinematic and goniometric range-of-motion data. Results show that humeral torsion is negatively correlated (goniometric: r = -0.409, P = 0.047; kinematic: r = -0.442, P = 0.035) with external rotational range of motion and positively correlated (goniometric: r = 0.741, P < 0.001; kinematic: r = 0.559, P = 0.006) with internal rotational range of motion. The predicted torsion values are highly correlated (goniometric: r = 0.815, P < 0.001; kinematic: r = 0.617, P = 0.006) with actual torsion values. Deviations in the data away from predicted equations highlight significant differences between high torsion and low torsion individuals that may have significant functional consequences. The method described here may be useful for non-invasively assessing the degree of torsion in studies of the evolution and biomechanics of the shoulder and arm, and for testing hypotheses about the etiology of repetitive stress injuries among athletes and others who throw frequently. C1 [Roach, Neil Thomas; Lieberman, Daniel E.] Harvard Univ, Dept Human Evolutionary Biol, Cambridge, MA 02138 USA. [Gill, Thomas J.; Gill, Thomas J., III] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Gill, Thomas J.; Palmer, William E.; Gill, Thomas J., III] Harvard Univ, Sch Med, Boston, MA USA. [Palmer, William E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Roach, NT (reprint author), Harvard Univ, Dept Human Evolutionary Biol, 11 Div Ave, Cambridge, MA 02138 USA. EM ntroach@fas.harvard.edu FU Hintze Family Charitable Trust; American School for Prehistoric Research; National Science Foundation [BCS 0961943] FX The authors would like to thank the subjects who volunteered their time, the staff at the MGH Imaging Service, Michelle Cardillo, Louise Borda and Isabella Suzarte for their help making this study possible. The authors would also like to thank the two reviewers for their helpful comments and criticisms. Generous funding for the Qualisys Oqus camera system was provided by the Hintze Family Charitable Trust and the American School for Prehistoric Research. External funding was provided by the National Science Foundation (BCS 0961943). NR 60 TC 14 Z9 15 U1 0 U2 17 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-8782 J9 J ANAT JI J. Anat. PD MAR PY 2012 VL 220 IS 3 BP 293 EP 301 DI 10.1111/j.1469-7580.2011.01464.x PG 9 WC Anatomy & Morphology SC Anatomy & Morphology GA 889BJ UT WOS:000300048200008 PM 22257273 ER PT J AU Smith, DJ AF Smith, D. J. TI Prospects in Caries Vaccine Development SO JOURNAL OF DENTAL RESEARCH LA English DT Editorial Material DE mucosal immunity; Streptococcus mutans; vaccine(s); adjuvants; dental caries; DNA vaccines ID STREPTOCOCCUS-MUTANS; ESCHERICHIA-COLI; IMMUNIZATION; INFECTION C1 Forsyth Inst, Cambridge, MA 02146 USA. RP Smith, DJ (reprint author), Forsyth Inst, 245 1st St, Cambridge, MA 02146 USA. EM dsmith@forsyth.org NR 12 TC 5 Z9 7 U1 2 U2 16 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 MAR PY 2012 VL 91 IS 3 BP 225 EP 226 DI 10.1177/0022034511425928 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 888HF UT WOS:000299993800001 PM 22027715 ER PT J AU Bleier, BS Mulligan, RM Schlosser, RJ AF Bleier, Benjamin S. Mulligan, Ryan M. Schlosser, Rodney J. TI Primary human sinonasal epithelial cell culture model for topical drug delivery in patients with chronic rhinosinusitis with nasal polyposis SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article DE chronic rhinosinusitis; in-vitro model; nasal polyposis; primary human sinonasal epithelial cell culture; topical drug delivery ID CILIARY BEAT FREQUENCY; IN-VITRO; CHRONIC SINUSITIS; INTERLEUKIN-8; EXPRESSION; TRANSPORT; BETA AB Objectives The primary human sinonasal epithelial cell culture (HSNEC) allows for in-vitro modelling of mucosal responses to topical therapy. Cultures grown from healthy donors may underestimate changes in individuals with chronic sinonasal disease thereby yielding inaccurate results with respect to this large patient population. The purpose of this study was to analyse HSNECs derived from patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) to determine whether expected disease dependent variables salient to topical drug delivery persist in culture. Methods Cultures were grown from patients with CRSwNP. Ciliary beat frequency (CBF) (basal and stimulated), permeability (trans and paracellular), inflammatory response, and glucocorticoid dose response were measured and compared with healthy controls. Key findings Methylcholine stimulated CBF was greater in CRSwNP versus controls (Delta CBF60min 7.25 +/- 1.02 vs 0.89 +/- 1.04 Hz, respectively). Paracellular permeability was greater in CRSwNP versus controls (basolateral dextran(120min) 18.97 +/- 3.90 vs 11.31 +/- 4.35 mu g/ml, respectively). Lipopolysaccharide (0.1 mg/ml) stimulated interleukin-6 (IL-6) and IL-8 secretion was increased in CRSwNP versus controls (IL-6 Delta baseline 1738.72 +/- 654.82 vs 1461.61 +/- 533.51%, respectively; IL-8 Delta baseline 137.11 +/- 0.83 vs 111.27 +/- 0.67%, respectively). CRSwNP cultures were more sensitive than controls to dexamethasone (1 mu g/ml) dependent IL-6 and IL-8 suppression. Conclusions HSNECs derived from patients with CRSwNP retained their primary phenotype with respect to ciliary function, epithelial permeability, irritant induced inflammatory cytokine secretion, and glucocorticoid dose response. C1 [Bleier, Benjamin S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Mulligan, Ryan M.; Schlosser, Rodney J.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC 29425 USA. RP Bleier, BS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM bleierb@gmail.com FU Flight Attendant Medical Research Institute FX These studies were supported by grants to Rodney J. Schlosser from the Flight Attendant Medical Research Institute. NR 19 TC 8 Z9 8 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3573 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD MAR PY 2012 VL 64 IS 3 BP 449 EP 456 DI 10.1111/j.2042-7158.2011.01409.x PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 886XW UT WOS:000299889100016 PM 22309277 ER PT J AU Psaros, C Kagan, L Auba, E Alert, M Park, ER AF Psaros, Christina Kagan, Leslee Auba, Enrique Alert, Marissa Park, Elyse R. TI A brief report of depressive symptoms and health promoting behaviors among women with infertility attending a clinical mind-body program SO JOURNAL OF PSYCHOSOMATIC OBSTETRICS AND GYNECOLOGY LA English DT Article DE Mind-body influences; consequences of infertility; depression; infertility; mental health ID IN-VITRO FERTILIZATION; PSYCHOLOGICAL INTERVENTIONS; GENERAL-POPULATION; MENTAL-HEALTH; COUPLES; DISORDERS; ANXIETY; STYLE; CARE; PREVALENCE AB Diagnosis of infertility or treatment for infertility can result in distress, including for some women, depressive symptoms. Integrative infertility treatment programs are gaining recognition and popularity, and many women may seek this kind of care. However, depressive symptoms may be a barrier to fully engaging in and benefiting from mind-body infertility programs. The aim of this retrospective, cross-sectional chart review, was to describe the baseline level of depressive symptoms and differences in baseline health promoting behaviors by level of depressive symptoms among women (n = 104) presenting to a mind-body infertility program in the clinical setting. Depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II), and health promoting behaviors were assessed using the Health Promoting Lifestyle Profile-II (HPLP-II). The mean BDI-II score for the sample was 16.3 (+/- 8.5). Participants scoring in the moderate-severe range on the BDI-II had significantly lower scores on Spiritual Growth, Interpersonal Relations, Stress Management and Nutrition subscales of the HPLP-II. There were no significant differences on the Physical Activity or Health Responsibility subscales. These findings may have implications for the treatment of women with infertility, particularly those who seek an integrative approach to treatment. C1 [Psaros, Christina; Park, Elyse R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kagan, Leslee; Alert, Marissa] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. [Auba, Enrique] Univ Navarra, Sch Med, Dept Psychiat & Med Psychol, E-31080 Pamplona, Spain. [Park, Elyse R.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. RP Psaros, C (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM cpsaros@partners.org FU Centers for Disease Control, Atlanta, GA [5R01DP00039] FX This publication resulted (in part) from Centers for Disease Control, Atlanta, GA [Grant #5R01DP00039]. NR 31 TC 4 Z9 4 U1 1 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0167-482X J9 J PSYCHOSOM OBST GYN JI J. Psychosomat. Obstet. Gynecol. PD MAR PY 2012 VL 33 IS 1 BP 32 EP 36 DI 10.3109/0167482X.2011.643933 PG 5 WC Psychology, Clinical; Obstetrics & Gynecology; Psychiatry SC Psychology; Obstetrics & Gynecology; Psychiatry GA 887AM UT WOS:000299897500005 PM 22214290 ER PT J AU Larauche, M AF Larauche, M. TI Novel insights in the role of peripheral corticotropin-releasing factor and mast cells in stress-induced visceral hypersensitivity SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE mast cells; peripheral corticotropin releasing factor; stress-induced visceral hypersensitivity ID IRRITABLE-BOWEL-SYNDROME; COLONIC EPITHELIAL BARRIER; FACTOR SIGNALING PATHWAYS; LIGHT-CHAIN KINASE; PSYCHOLOGICAL STRESS; MATERNAL-DEPRIVATION; IBS PATIENTS; GASTROINTESTINAL-TRACT; RECTAL DISTENSION; PROTEASE ACTIVITY AB Visceral hypersensitivity is one of the hallmarks in irritable bowel syndrome (IBS) pathophysiology. Stress is well known to affect visceral sensitivity in humans and rodents, an effect which is associated in part with alterations of intestinal epithelial permeability in rodents. Although the pathophysiology of visceral hypersensitivity is still unclear, two key factors have been identified as playing a major role in its modulation, namely peripheral corticotropin-releasing factor (CRF) and mast cells. In a recent study in Neurogastroenterology and Motility, van den Wijngaard etal. demonstrate that the mast-cell dependent visceral hypersensitivity observed in maternally separated rats after an acute exposure to a psychological stress can be prevented but not reversed by the peripherally restricted CRF receptor antagonist, a-helical CRF941. They further show that the preventive effect of the CRF receptor antagonist is linked to a stabilization of mast cells and maintenance of the epithelial barrier at the colonic level. These data suggest that post stress mast cell activation and subsequent visceral hypersensitivity are not targeted by peripheral CRF receptor antagonists. These novel insights in the role of peripheral CRF in the modulation of stress-induced visceral hypersensitivity add to our growing understanding of the mechanisms that may lie at the origin of visceral pain disturbances following stress and will contribute to enhance the development of drugs that may have potential therapeutic benefits for IBS patients. C1 [Larauche, M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Oppenheimer Family Ctr Neurobiol Stress,Dept Med, Los Angeles, CA 90073 USA. [Larauche, M.] VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA USA. RP Larauche, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Oppenheimer Family Ctr Neurobiol Stress,Dept Med, Los Angeles, CA 90073 USA. EM mlarauche@mednet.ucla.edu OI Larauche, Muriel/0000-0003-3320-3675 NR 53 TC 15 Z9 17 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD MAR PY 2012 VL 24 IS 3 BP 201 EP 205 DI 10.1111/j.1365-2982.2011.01867.x PG 5 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 888JX UT WOS:000300000900006 PM 22316289 ER PT J AU Giuliari, GP Sadaka, A AF Paolo Giuliari, Gian Sadaka, Ama TI Uveal metastatic disease: Current and new treatment options (Review) SO ONCOLOGY REPORTS LA English DT Article DE ocular malignancy; uveal metastasis; choroidal metastasis; ocular masquerade syndrome; vascular endothelial growth factor; bevacizumab ID CHOROIDAL METASTASIS; BREAST-CARCINOMA; INTRAVITREAL BEVACIZUMAB; COMPLETE REGRESSION; TUMOR METASTASIS; LUNG-CANCER; FOLLOW-UP; EYE; RADIOTHERAPY; SECONDARY AB Choroidal metastasis represents the most common form of intraocular malignancies. It may occur in up to 10% of patients with systemic metastasis with almost half of the patients developing central nervous system disease. The most common primary sites of ocular metastasis are breast cancer in women and lung cancer in men. In most cases, these lesions tend to be asymptomatic and are not evaluated by an ophthalmologist. The diagnosis is generally made by the history of present or prior malignancies and an ophthalmological examination with slit-lamp biomicroscopy and indirect ophthalmoscopy. As with other malignancies, management may vary with each patient. Small tumors, that do not compromise the vision and that have responded previously to systemic treatment, may be closely observed. For larger lesions and for symptomatic ones, external beam radiation offers an excellent alternative to save the eye and stabilize vision. Bevacizumab (Avastin), a potent monoclonal antibody that has also been employed for the treatment of ocular vaso-proliferative diseases, has been used in the treatment of choroidal metastasis and has shown promising results. C1 [Paolo Giuliari, Gian] Ctr Cirugia Oftalmol CECOF, Caracas, Venezuela. [Paolo Giuliari, Gian] Domingo Luciani Hosp, Dept Ophthalmol, Caracas, Venezuela. [Sadaka, Ama] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Giuliari, GP (reprint author), Ctr Cirugia Oftalmol CECOF, Av Francisco de Miranda,Torre Cavendes,Piso 6,Ofi, Caracas, Venezuela. EM gpgiuliari@gmail.com NR 58 TC 5 Z9 5 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD MAR PY 2012 VL 27 IS 3 BP 603 EP 607 DI 10.3892/or.2011.1563 PG 5 WC Oncology SC Oncology GA 890AY UT WOS:000300118700001 PM 22134585 ER PT J AU Biederman, J Spencer, T Lomedico, A Day, H Petty, CR Faraone, SV AF Biederman, J. Spencer, T. Lomedico, A. Day, H. Petty, C. R. Faraone, S. V. TI Deficient emotional self-regulation and pediatric attention deficit hyperactivity disorder: a family risk analysis SO PSYCHOLOGICAL MEDICINE LA English DT Article DE ADHD; deficient emotional self-regulation; pediatric ID CHILD-BEHAVIOR CHECKLIST; BIPOLAR DISORDER; ADHD; CBCL; DIAGNOSES; PREDICTS; ADULTS AB Background. Although deficient emotional self-regulation (DESR) is associated with attention deficit hyperactivity disorder (ADHD), little research investigates this association and little is known about its etiology. Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR in children. Method. Subjects were 242 children with ADHD and 224 children without ADHD. DESR was operationalized using an aggregate score >= 180 and <210 in the anxious/depressed, attention and aggression scales (AAA profile) of the Child Behavior Checklist (CBCL), termed the CBCL-DESR profile. The CBCL-bipolar (CBCL-BP) profile was defined as >= 210 on the CBCL-AAA scale. We examined the familial transmission of ADHD and the CBCL-AAA scale in families selected through probands with and without these conditions. Results. We found a linear increase in the prevalence of CBCL-DESR in siblings as indexed by the Control, ADHD, ADHD + CBCL-DESR and ADHD + CBCL-BP proband groups. While the ADHD siblings were at elevated risk for both the CBCL-DESR and CBCL-BP compared with non-ADHD siblings, a significantly higher rate of CBCL-BP in the siblings of ADHD + CBCL-BP probands was found compared with siblings of the Control probands. Conclusions. ADHD shows the same degree of familial transmission in the presence or absence of DESR. CBCL-DESR and CBCL-BP are familial, but further work is needed to determine if these definitions are distinctly familial or represent a continuum of the same psychopathology. C1 [Biederman, J.; Spencer, T.; Lomedico, A.; Day, H.; Petty, C. R.] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. [Biederman, J.; Spencer, T.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care, YAW-6A-6900,32 Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Shire Pharmaceuticals; Elminda; Janssen; McNeil; Next Wave Pharmaceuticals; Shire; Fundacion Dr Manuel; Cipher Pharmaceuticals Inc.; Fundacion Areces; Medice Pharmaceuticals; Spanish Child Psychiatry Association; Abbott; Alza; Bristol-Myers Squibb; Celltech; Cephalon; Eli Lilly and Co.; Esai; Forest; Glaxo; Gliatech; Merck; NARSAD; NIDA; New River; NICHD; NIMH; Novartis; Noven; Neurosearch; Organon; Otsuka; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma, Inc.; Wyeth; Shire Laboratories, Inc; Eli Lilly Company; GlaxoSmithKline; Janssen Pharmaceutical; McNeil Pharmaceutical; Novartis Pharmaceuticals; National Institute of Mental Health; National Institutes of Health (NIH); Guilford Press FX Shire Pharmaceuticals provided support for this analysis.; Dr J. Biederman is currently receiving research support from the following sources: Elminda, Janssen, McNeil, Next Wave Pharmaceuticals and Shire. In 2011, Dr Biederman gave a single unpaid talk for Juste Pharmaceutical Spain, and received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. He also received an honorarium from Cambridge University Press for a chapter publication. In 2010, Dr Biederman received a speaker's fee from Fundacion Dr Manuel Camelo A. C., provided single consultations for Shionogi Pharma Inc. and Cipher Pharmaceuticals Inc. and received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course. In 2009, Dr Biederman received a speaker's fee from the following sources: Fundacion Areces, Medice Pharmaceuticals and the Spanish Child Psychiatry Association. In previous years, Dr Biederman received research support, consultation fees or speaker's fees for/from the following additional sources: Abbott, Alza, AstraZeneca, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, Merck, NARSAD, NIDA, New River, NICHD, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc. and Wyeth.; Dr T. Spencer has received research support from, has been a speaker for or on a speaker's bureau or has been an Advisor or on an Advisory Board of the following sources: Shire Laboratories, Inc, Eli Lilly & Company, GlaxoSmithKline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Cephalon, Pfizer, the National Institute of Mental Health and royalties on adult ADHD scales (research support).; In the past year, Dr Faraone received consulting fees and was on Advisory Boards for Shire Development and received research support from Shire and the National Institutes of Health (NIH). In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by: Shire, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. In previous years he received research support from Eli Lilly, Shire, Pfizer and the NIH. Dr Faraone receives royalties from a book published by Guilford Press: Straight Talk about Your Child's Mental Health. NR 26 TC 22 Z9 24 U1 1 U2 16 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD MAR PY 2012 VL 42 IS 3 BP 639 EP 646 DI 10.1017/S0033291711001644 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 886XC UT WOS:000299886500017 PM 21861953 ER PT J AU Seker, E Berdichevsky, Y Staley, KJ Yarmush, ML AF Seker, Erkin Berdichevsky, Yevgeny Staley, Kevin J. Yarmush, Martin L. TI Microfabrication-Compatible Nanoporous Gold Foams as Biomaterials for Drug Delivery SO ADVANCED HEALTHCARE MATERIALS LA English DT Article ID MECHANICAL-PROPERTIES; SIGNALS; ARRAYS C1 [Seker, Erkin] Univ Calif Davis, Dept Elect & Comp Engn, Livermore, CA 95616 USA. [Seker, Erkin; Yarmush, Martin L.] Harvard Univ, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Seker, Erkin; Yarmush, Martin L.] Massachusetts Gen Hosp, Shriners Hosp Children, Boston, MA 02114 USA. [Berdichevsky, Yevgeny; Staley, Kevin J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Berdichevsky, Yevgeny; Staley, Kevin J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Seker, E (reprint author), Univ Calif Davis, Dept Elect & Comp Engn, Livermore, CA 95616 USA. EM eseker@ucdavis.edu OI Seker, Erkin/0000-0003-2401-3562 FU Massachusetts General Hospital (MGH) Fund for Medical Discovery award [217035]; University of California, Davis-College of Engineering; National Institutes of Health (NIH) [AI063795, EB002503] FX ES acknowledges support by Massachusetts General Hospital (MGH) Fund for Medical Discovery award 217035, facilities at Harvard University-Center for Nanoscale Systems, and start-up funds from University of California, Davis-College of Engineering. MLY acknowledges support by National Institutes of Health (NIH) awards AI063795 and EB002503. We acknowledge the help of Dr. Gavrielle Price (MGH) with endothelial cell culture, Dr. Hansang Cho (MGH) with microglia culture, and Dr. Eloise Hudry (MGH) with cortical neuron culture. NR 22 TC 15 Z9 15 U1 0 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2192-2640 J9 ADV HEALTHC MATER JI Adv. Healthc. Mater. PD MAR PY 2012 VL 1 IS 2 BP 172 EP 176 DI 10.1002/adhm.201200002 PG 5 WC Engineering, Biomedical; Nanoscience & Nanotechnology; Materials Science, Biomaterials SC Engineering; Science & Technology - Other Topics; Materials Science GA 092HN UT WOS:000315111100006 PM 23184720 ER PT J AU Benson, A Maust, DT Tanh, D Mavandadi, S Streim, JE DiFilippo, S Oslin, D AF Benson, Amy Maust, Donovan T. Tanh, Daniel Mavandadi, Shahrzad Streim, Joel E. DiFilippo, Suzanne Oslin, David TI Self-reported Reasons for New Psychotropic Medications in Asymptomatic Older Adults SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Benson, Amy; Maust, Donovan T.; Tanh, Daniel; Mavandadi, Shahrzad; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Mavandadi, Shahrzad; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr VISN4, Philadelphia, PA USA. FU Pennsylvania Department of Aging, PACE Program FX This research was funded by: Funded by the Pennsylvania Department of Aging, PACE Program. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 48 BP S95 EP S95 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500098 ER PT J AU Cohen, CI Kasckow, J Vahia, I Jeste, DV AF Cohen, Carl I. Kasckow, John Vahia, Ipsit Jeste, Dilip V. TI NEW RESEARCH ADVANCES IN LATE LIFE SCHIZOPHRENIA SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Kasckow, John] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Kasckow, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Cohen, Carl I.] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Vahia, Ipsit; Jeste, Dilip V.] Univ Calif San Diego, San Diego, CA USA. FU Astra Zeneca FX John Kasckow, MD, PhD; Research Support: Astra Zeneca 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA 307 BP S31 EP S31 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500031 ER PT J AU Kasckow, J Golshan, S Zisook, S AF Kasckow, John Golshan, Shahrokh Zisook, Sidney TI Subsyndromal Depressive Symptoms in Middle Aged and Older Patients with Schizophrenia: Relationship to Suicidal Ideation SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Kasckow, John] VA Pittsburgh Hlth Care Syst, Pittsburgh, PA USA. [Kasckow, John] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Golshan, Shahrokh; Zisook, Sidney] Univ Calif San Diego, San Diego, CA 92103 USA. FU VISN 4; 22 MIRECC; [MH6398] FX This research was funded by: Supported by MH6398 (SZ, JWK), the VISN 4 and 22 MIRECC. The contents do not represent the views of the Dept of Veterans Affairs of the US government. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA NR 1 BP S121 EP S121 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500126 ER PT J AU Maust, DT Benson, A Mavandadi, S Streim, JE Glasenberg, J DiFilippo, S Oslin, D AF Maust, Donovan T. Benson, Amy Mavandadi, Shahrzad Streim, Joel E. Glasenberg, Jenna DiFilippo, Suzanne Oslin, David TI Who Gets Prescribed Antipsychotic Monotherapy versus Combination Therapy with an Antidepressant in a Community Sample of Older Persons? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Maust, Donovan T.; Benson, Amy; Mavandadi, Shahrzad; Streim, Joel E.; Glasenberg, Jenna; DiFilippo, Suzanne; Oslin, David] Univ Penn, Philadelphia, PA 19104 USA. [Mavandadi, Shahrzad; Streim, Joel E.; DiFilippo, Suzanne; Oslin, David] Philadelphia VA Med Ctr, Philadelphia, PA USA. FU PACE Program, Pennsylvania Department of Aging, Harrisburg, PA FX This research was funded by: PACE Program, Pennsylvania Department of Aging, Harrisburg, PA. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 49 BP S96 EP S97 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500099 ER PT J AU Mavandadi, S Benson, A Tanh, D DiFilippo, S Streim, JE Oslin, D AF Mavandadi, Shahrzad Benson, Amy Tanh, Daniel DiFilippo, Suzanne Streim, Joel E. Oslin, David TI The Association between Caregiver Burden and Neuropsychiatric Symptom Severity among Community-Dwelling Older Adults with Dementia SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Mavandadi, Shahrzad; DiFilippo, Suzanne; Streim, Joel E.; Oslin, David] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Mavandadi, Shahrzad; Benson, Amy; Tanh, Daniel; DiFilippo, Suzanne; Streim, Joel E.; Oslin, David] Univ Penn, Philadelphia, PA 19104 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA NR 27 BP S142 EP S143 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500152 ER PT J AU Melrose, RJ Harwood, DG Khoo, T Mandelkern, MA Sultzer, D AF Melrose, Rebecca J. Harwood, Dylan G. Khoo, Theresa Mandelkern, Mark A. Sultzer, David TI The association between regional cerebral metabolism and visuoconstructive skills in probable Alzheimer's Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Melrose, Rebecca J.; Harwood, Dylan G.; Khoo, Theresa; Sultzer, David] VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA USA. [Melrose, Rebecca J.; Harwood, Dylan G.; Sultzer, David] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv, Los Angeles, CA USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. FU Dept. of Veterans Affairs FX This research was funded by: Supported by the Dept. of Veterans Affairs (Career Development Award to R. Melrose; Office of R&D Merit Review) 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 39 BP S88 EP S89 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500089 ER PT J AU Metti, AL Cauley, JA Newman, AB Ayonayon, H Barry, LC Kuller, LM Satterfield, S Simonsick, EM Yaffe, K AF Metti, Andrea L. Cauley, Jane A. Newman, Anne B. Ayonayon, Hilsa Barry, Lisa C. Kuller, Lewis M. Satterfield, Suzanne Simonsick, Eleanor M. Yaffe, Kristine TI Plasma Beta Amyloid Level and Depression in Older Adults SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Metti, Andrea L.; Cauley, Jane A.; Newman, Anne B.; Kuller, Lewis M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Ayonayon, Hilsa; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Barry, Lisa C.] Yale Univ, Sch Med, New Haven, CT USA. [Satterfield, Suzanne] Univ Tennessee Memphis, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. FU National Institute of Aging (NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIA [R01-AG028050, 2T32AG000181]; NINR [R01-NR012459]; Intramural Research Program on the NIH, National Institute of Aging FX This research was funded by: This research was supported by National Institute of Aging (NIA) Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG-6-2106; NIA grant R01-AG028050, and NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program on the NIH, National Institute of Aging. Andrea Metti is supported by NIA Training Grant 2T32AG000181. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 66 BP S109 EP S110 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500114 ER PT J AU Murray, PS Kirkwood, CM Gray, MC Ikonomovic, MD Paljug, WR Abrahamson, EE Hamilton, RL Kofler, JK Klunk, WE Lopez, OL Penzes, P Sweet, RA AF Murray, Patrick S. Kirkwood, Caitlin M. Gray, Megan C. Ikonomovic, Milos D. Paljug, William R. Abrahamson, Eric E. Hamilton, Ronald L. Kofler, Julia K. Klunk, William E. Lopez, Oscar L. Penzes, Peter Sweet, Robert A. TI Increased ratio of beta-amyloid 42/40 and reduced Kalirin expression in prefrontal cortex in Alzheimer disease with psychosis SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Murray, Patrick S.; Ikonomovic, Milos D.; Paljug, William R.; Abrahamson, Eric E.; Hamilton, Ronald L.; Kofler, Julia K.; Klunk, William E.; Lopez, Oscar L.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kirkwood, Caitlin M.; Gray, Megan C.] Univ Pittsburgh, Pittsburgh, PA USA. [Murray, Patrick S.; Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Penzes, Peter] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. FU Veterans Health Administration [5I01BX000452]; National Institute on Aging [5P50AG005133, 5R01AG027224]; National Institute of Mental Health [5T32MH019986] FX This research was funded by: Supported by Grants 5I01BX000452 from the Veterans Health Administration and by 5P50AG005133 and 5R01AG027224 from the National Institute on Aging. Patrick Murray is supported by 5T32MH019986 from the National Institute of Mental Health. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 40 BP S89 EP S90 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500090 ER PT J AU Okereke, O Hoang, T Qiu, W Byers, AL AF Okereke, Olivia Hoang, Tina Qiu, Wendy (Wei Qiao) Byers, Amy L. TI LIFESTYLE FACTORS AND TRAJECTORIES OF LATE-LIFE MENTAL HEALTH SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Okereke, Olivia] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA. [Byers, Amy L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hoang, Tina; Byers, Amy L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Qiu, Wendy (Wei Qiao)] Boston Univ, Sch Med, Boston, MA 02118 USA. [Okereke, Olivia] Harvard Sch Publ Hlth, 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA 320 BP S39 EP S39 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500042 ER PT J AU Park, M Huang, DL AF Park, Mijung Huang, Deborah L. TI More Variety In Sources of Social Support is Better for Late-Life Depression Outcome SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Park, Mijung; Huang, Deborah L.] Univ Washington, Seattle, WA 98195 USA. [Huang, Deborah L.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. FU Geriatric Mental Health Research Fellowship [NIMH 2 T32 MH 73553-6]; VA Advanced Fellowship in Geriatrics, VA Puget Sound Health Care System, Seattle, Washington FX This research was funded by: Dr. Park is supported by Geriatric Mental Health Research Fellowship (NIMH 2 T32 MH 73553-6). Dr. Huang is supported by VA Advanced Fellowship in Geriatrics, VA Puget Sound Health Care System, Seattle, Washington. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 13 BP S68 EP S69 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500063 ER PT J AU Ravven, S Bader, C Azar, AR Rudolph, JL AF Ravven, Simha Bader, Caroline Azar, Armin R. Rudolph, James L. TI Depression after CABG Surgery: A Meta-analysis SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Ravven, Simha] Harvard Med Sch, Cambridge Hlth Alliance, Cambridge, MA USA. [Bader, Caroline] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Azar, Armin R.] Povidence VA Med Ctr, Geriatr & Extended Care, Providence, RI USA. [Rudolph, James L.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. FU VA Rehabilitation Career Development Award; American Federation for Aging Research; Boston MSTAR; NIH [AG038027-01]; Harvard Medical School Kaplan Depression Fellowship FX This research was funded by: Dr. Rudolph is funded by a VA Rehabilitation Career Development Award. Ms Bader and Dr. Rudolph received support provided by the American Federation for Aging Research, the Boston MSTAR, and NIH grants (AG038027-01). Dr Azara(sic)(TM) S effort was supported by a Harvard Medical School Kaplan Depression Fellowship. The authors retained full independence in the conduct of this work. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 32 BP S84 EP S84 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500082 ER PT J AU Streim, JE DiFilippo, S TenHave, T Mavandadi, S Weintraub, D Oslin, D AF Streim, Joel E. DiFilippo, Suzanne TenHave, Thomas Mavandadi, Shahrzad Weintraub, Daniel Oslin, David TI Antidepressant Discontinuation Associated with Cognitive Decline in Older Adult Residents of Long-term Care Facilities SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Streim, Joel E.; DiFilippo, Suzanne; Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Geriatr Psychiat Sect, Philadelphia, PA 19104 USA. [TenHave, Thomas] Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Streim, Joel E.; DiFilippo, Suzanne; Mavandadi, Shahrzad; Weintraub, Daniel; Oslin, David] Dept Vet Affairs Med Ctr, VISN Mental Illness Res Educ & Clin Ctr MIRECC 4, Philadelphia, PA 19104 USA. [Oslin, David] Univ Penn, Dept Psychiat, Perelman Sch Med, Treatment Res Ctr, Philadelphia, PA 19104 USA. FU National Institute for Mental Health [R01 MH051247-13]; Department of Veterans Affairs (VA) VISN 4 Mental Illness Research Education and Clinical Center (MIRECC) FX This research was funded by: This work was supported by the National Institute for Mental Health (grant no. R01 MH051247-13) and partially supported by the Department of Veterans Affairs (VA) VISN 4 Mental Illness Research Education and Clinical Center (MIRECC) 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA NR 34 BP S147 EP S148 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500159 ER PT J AU Sultzer, D Leskin, LS Melrose, RJ Harwood, DG Narvaez, T Ando, T Walston, A Bussel, N Mandelkern, MA AF Sultzer, David Leskin, Lorraine S. Melrose, Rebecca J. Harwood, Dylan G. Narvaez, Theresa Ando, Timothy Walston, Amy Bussel, Natalya Mandelkern, Mark A. TI Delusions, memory, and insight in Alzheimer's disease: clinical associations and relationships with FDG-PET cortical metabolic activity SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Sultzer, David; Leskin, Lorraine S.; Melrose, Rebecca J.; Harwood, Dylan G.; Narvaez, Theresa; Ando, Timothy; Walston, Amy; Bussel, Natalya; Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Sultzer, David; Melrose, Rebecca J.; Harwood, Dylan G.; Walston, Amy] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA USA. [Mandelkern, Mark A.] UC Irvine, Dept Phys, Irvine, CA USA. FU NIMH; Department of Veterans Affairs FX This research was funded by: Supported in part by the NIMH and the Department of Veterans Affairs 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA NR 25 BP S140 EP S141 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500150 ER PT J AU Valdez, K Brown, GK Johnson, JC Oslin, D AF Valdez, Karen Brown, Gregory K. Johnson, Jerry C. Oslin, David TI Comparison of Two Screening Instruments in the Detection of Suicidal Ideation in Older Primary Care Veterans: Paykel Questionnaire and Patient Health Questionnaire-9 SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Valdez, Karen; Brown, Gregory K.; Oslin, David] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Johnson, Jerry C.] Univ Penn, Dept Geriatr Med, Philadelphia, PA 19104 USA. [Oslin, David] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Oslin, David] VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Philadelphia, PA USA. FU Philadelphia Veterans Affairs Medical Center; VISN 4 Mental Illness Research, Education, and Clinical Center (MIRECC) FX This research was funded by: Poster funding by Philadelphia Veterans Affairs Medical Center and the VISN 4 Mental Illness Research, Education, and Clinical Center (MIRECC) 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 16 BP S70 EP S71 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500066 ER PT J AU Wang, S Luo, XD Barnes, D Sano, M Yaffe, K AF Wang, Sophia Luo, Xiaodong Barnes, Deborah Sano, Mary Yaffe, Kristine TI The Effects of Late Life Physical Activity on Cognition over 20 Years in Oldest Old Women SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Wang, Sophia; Sano, Mary] James J Peters VA, Bronx, NY USA. [Wang, Sophia; Luo, Xiaodong; Sano, Mary] Mt Sinai Sch Med, New York, NY USA. [Barnes, Deborah; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Barnes, Deborah; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. FU NIA; Alzheimer's Association; University of California, San Francisco, School of Medicine; NIA [K24 AG 031155]; National Institutes of Health [AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, 2 R01 AG027574-22A1, 5 R01AG026720-04] FX This research was funded by: SW is a VA Neurosciences Research Fellow. XL is supported by a NIA funded ADRC grant. DB is supported by the Alzheimer's Association and the University of California, San Francisco, School of Medicine. MS is supported by a NIA funded ADRC grant and CTSA grant. KY is supported by a NIA grant K24 AG 031155 and an Independent Investigator Award from the Alzheimer's Association. The Study of Osteoporotic Fractures (SOF) and the SOF-WISE are supported by grants AG05407, AR35582, AG05394, AR35584, AR35583, R01 AG005407, R01 AG027576-22, 2 R01 AG005394-22A1, 2 R01 AG027574-22A1, and 5 R01AG026720-04 from the National Institutes of Health. 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 69 BP S112 EP S112 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500117 ER PT J AU Wu, P Read, S Biscow, M AF Wu, Pauline Read, Stephen Biscow, Mark TI Sustained Cognitive Benefit in Mild Alzheimer's Disease with Pioglitazone - Case Report of a 4.5 Year Treatment Trial SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of American-Association-for-Geriatric-Psychiatry CY MAR 16-19, 2012 CL Washington, DC C1 [Wu, Pauline; Read, Stephen] Univ Calif Los Angeles, Los Angeles, CA USA. [Wu, Pauline; Read, Stephen] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Biscow, Mark] St Johns Hlth Ctr, Santa Monica, CA 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 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2012 VL 20 IS 3 SU 1 MA EI 41 BP S90 EP S90 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V45WK UT WOS:000209846500091 ER PT J AU Serrano, NA Trenite, GN Yueh, B Farwell, G Futran, ND Mendez, E AF Serrano, Nicholas A. Trenite, Gilean N. Yueh, Bevan Farwell, Gregory Futran, Neal D. Mendez, Eduardo TI Risk Factors Associated With Repair of Orbital and Lateral Skull Defects SO ARCHIVES OF FACIAL PLASTIC SURGERY LA English DT Article ID FREE-FLAP RECONSTRUCTION; MYOCUTANEOUS FREE-FLAP; FREE-TISSUE TRANSFER; MICROVASCULAR RECONSTRUCTION; CLASSIFICATION-SYSTEM; BASE RECONSTRUCTION; MIDFACIAL DEFECTS; EXENTERATION; NECK; HEAD AB Objective: To explore the complications and associated risks factors after orbital exenteration and lateral skull base defect repair. Methods: Patients who had undergone a reconstruction of their orbital cavity and lateral skull base defects were selected from our departmental database. The outcome of interest was postoperative complications. The risks factors were defined as age, sex, history of radiation therapy, and intracranial involvement (with and without dural involvement). Information was collected on the type of reconstruction used after the orbital cavity repair. The chi(2) test and logistic regression were used to analyze associations between postoperative complications and the various risks factors. Results: Of the 32 identified patients, 19 had intracranial involvement (9 with dural involvement). Twenty-four patients underwent reconstruction with free tissue transfer in the same setting. Reconstruction with free tissue transfer was significantly associated with fewer major postoperative complications (P < .053). There was a trend toward more complications with a history of radiation therapy or intracranial involvement. Conclusions: Reconstruction of the orbital cavity and lateral skull base can be challenging, especially if there is a history of radiation therapy and intracranial involvement. Free tissue transfer is a safe and effective method for reconstruction of such defects. C1 [Mendez, Eduardo] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Clin Res, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. [Mendez, Eduardo] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Mendez, Eduardo] Vet Affairs Puget Sound Hlth Care Syst, Surg & Perioperat Care Serv, Seattle, WA USA. [Serrano, Nicholas A.] Univ Washington, Sch Med, Seattle, WA USA. [Trenite, Gilean N.] Onze Lieve Vrouw Hosp, Dept Surg, Amsterdam, Netherlands. [Yueh, Bevan] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, Minneapolis, MN USA. [Farwell, Gregory] Univ Calif Davis, Sacramento, CA 95817 USA. RP Mendez, E (reprint author), Univ Washington, Fred Hutchinson Canc Res Ctr, Div Clin Res, Dept Otolaryngol Head & Neck Surg, 1959 NE Pacific St,Mailbox 356515, Seattle, WA 98195 USA. EM edmendez@u.washington.edu OI Yueh, Bevan/0000-0003-1380-1053 NR 25 TC 3 Z9 3 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1521-2491 J9 ARCH FACIAL PLAST S JI Arch. Facial Plast. Surg. PD MAR-APR PY 2012 VL 14 IS 2 BP 97 EP 103 DI 10.1001/archfacial.2011.1301 PG 7 WC Surgery SC Surgery GA 914LI UT WOS:000301951100005 PM 22183060 ER PT J AU Abbott, AL Adelman, MAA Alexandrov, AV Barnett, HJM Beard, J Bell, P Bjorck, M Blacker, D Buckley, CJ Cambria, RP Comerota, AJ Connolly, S Davies, AH Eckstein, HH Faruqi, R Fraedrich, G Gloviczki, P Hankey, GJ Harbaugh, RE Heldenberg, E Kittner, SJ Kleinig, TJ Mikhailidis, DP Moore, WS Naylor, R Nicolaides, A Paraskevas, KI Pelz, DM Prichard, JW Purdie, G Ricco, JB Riles, T Rothwell, P Sandercock, P Sillesen, H Spence, JD Spinelli, F Tan, A Thapar, A Veith, FJ Zhou, W AF Abbott, Anne L. Adelman, Mark A. A. Alexandrov, Andrei V. Barnett, Henry J. M. Beard, Jonathan Bell, Peter Bjorck, Martin Blacker, David Buckley, Clifford J. Cambria, Richard P. Comerota, Anthony J. Connolly, Sander, Jr. Davies, Alun H. Eckstein, Hans-Henning Faruqi, R. Fraedrich, Gustav Gloviczki, Peter Hankey, Graeme J. Harbaugh, Robert E. Heldenberg, E. Kittner, Steven J. Kleinig, Timothy J. Mikhailidis, Dimitri P. Moore, Wesley S. Naylor, R. Nicolaides, Andrew Paraskevas, Kosmas I. Pelz, David M. Prichard, James W. Purdie, Grant Ricco, Jean-Baptiste Riles, Thomas Rothwell, Peter Sandercock, Peter Sillesen, Henrik Spence, J. David Spinelli, Francesco Tan, Aron Thapar, Ankur Veith, Frank J. Zhou, Wei TI Why the United States Center for Medicare and Medicaid Services (CMS) should not extend reimbursement indications for carotid artery angioplasty/stenting SO BRAIN AND BEHAVIOR LA English DT Review DE Carotid angioplasty; carotid endarterectomy; carotid stenting; carotid surgery; health economics; public health; vascular disease medical intervention AB In recent years, many important discoveries have been made to challenge current policy, guidelines, and practice regarding how best to prevent stroke associated with atherosclerotic stenosis of the origin of the internal carotid artery. The United States Center for Medicare and Medicaid Services (CMS), for instance, is calling for expert advice as to whether its current policies should be modified. Using a thorough review of literature, 41 leading academic stroke-prevention clinicians from the United States and other countries, have united to advise CMS not to extend current reimbursement indications for carotid angioplasty/stenting (CAS) to patients with asymptomatic carotid stenosis or to patients with symptomatic carotid stenosis considered to be at "low or standard risk from carotid endarterectomy (CEA)." It was concluded that such expansion of reimbursement indications would have disastrous health and economic consequences for the United States and any other country that may follow such inappropriate action. This was an international effort because the experts to best advise CMS are relatively few and scattered around the world. In addition, US health policy, practice, and research have tended to have strong influences on other countries. C1 [Abbott, Anne L.] Baker IDI Heart & Diabet Inst, Melbourne, Vic 3004, Australia. [Abbott, Anne L.] Florey Neurosci Inst, Melbourne, Vic, Australia. [Adelman, Mark A. A.] NYU, Langone Med Ctr, New York, NY 10003 USA. [Alexandrov, Andrei V.] Univ Alabama Hosp & Clin, South Birmingham, AL USA. [Barnett, Henry J. M.] Univ Western Ontario, Robarts Res Inst, Toronto, ON, Canada. [Beard, Jonathan] No Gen Hosp, Sheffield Vasc Inst, Sheffield S5 7AU, S Yorkshire, England. [Bell, Peter] Univ Leicester, Leicester, Leics, England. [Bell, Peter] Univ Leicester Hosp, Leicester, Leics, England. [Bjorck, Martin] Uppsala Univ, Uppsala, Sweden. [Blacker, David] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia. [Buckley, Clifford J.] Texas A&M Hlth Sci Ctr, Coll Med, Scott & White Hlth Care Syst, Bryan, TX USA. [Buckley, Clifford J.] Cent Texas Vet Hlth Care Syst, Arlington, TX USA. [Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cambria, Richard P.] Harvard Univ, Sch Med, Boston, MA USA. [Comerota, Anthony J.] Toledo Hosp, Jobst Vasc Inst, Toledo, OH USA. [Connolly, Sander, Jr.] Columbia Univ, New York, NY 10027 USA. [Davies, Alun H.] Charing Cross Hosp, Imperial Coll Sch Med, London, England. [Eckstein, Hans-Henning] Tech Univ Munich, D-80290 Munich, Germany. [Eckstein, Hans-Henning] Tech Univ Munich, Klinikum Rechts Isar, D-80290 Munich, Germany. [Faruqi, R.] Stanford Univ, Univ Calif, Stanford, CA 94305 USA. [Faruqi, R.] Kaiser Permanente Med Ctr, Los Angeles, CA USA. [Fraedrich, Gustav] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Gloviczki, Peter] Mayo Clin, Rochester, MN USA. [Hankey, Graeme J.] Royal Perth Hosp, Perth, WA, Australia. [Harbaugh, Robert E.] Penn State Univ, Penn State Inst Neurosci, Hershey, PA USA. [Heldenberg, E.] Assaf Harofeh Med Ctr, IL-70300 Zerifin, Israel. [Kittner, Steven J.] Univ Maryland, Sch Med, Baltimore, MD USA. [Kleinig, Timothy J.] Univ Adelaide, Royal Adelaide & Lyell McEwin Hosp, Adelaide, SA, Australia. [Mikhailidis, Dimitri P.] UCL, Sch Med, London W1N 8AA, England. [Moore, Wesley S.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Naylor, R.] Leicester Royal Infirm, Leicester, Leics, England. [Nicolaides, Andrew] Univ London Imperial Coll Sci Technol & Med, Vasc Diagnost Ctr, London, England. [Paraskevas, Kosmas I.] Klinikum Nurnberg Sud, Nurnberg, Germany. [Pelz, David M.; Spence, J. David] Univ Western Ontario, London, ON, Canada. [Prichard, James W.] Yale Univ, Sch Med, New Haven, CT USA. [Purdie, Grant] Queen Elizabeth Hosp, Adelaide, SA, Australia. [Ricco, Jean-Baptiste] Univ Poitiers, Poitiers, France. [Riles, Thomas] NYU, Sch Med, New York, NY 10003 USA. [Rothwell, Peter] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford OX1 2JD, England. [Sandercock, Peter] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. [Sillesen, Henrik] Univ Copenhagen, DK-1168 Copenhagen, Denmark. [Spence, J. David] Robarts Res Inst, London, ON N6A 5C1, Canada. [Spinelli, Francesco] Univ Messina, Messina, Italy. [Tan, Aron] Queen Elizabeth & Lyell McEwin Hosp, Adelaide, SA, Australia. [Thapar, Ankur] Charing Cross Hosp, Royal Coll Surg, London, England. [Veith, Frank J.] NYU, Case Western Reserve Univ, Univ Hlth Sci, Sch Med,Cleveland Clin,Edward Hebert Sch Med, New York, NY 10003 USA. [Zhou, Wei] Stanford Univ, Stanford, CA 94305 USA. [Zhou, Wei] Palo Alto VA Hlth Care Syst, Stanford, CA USA. RP Abbott, AL (reprint author), Baker IDI Heart & Diabet Inst, 75 Commercial Rd, Melbourne, Vic 3004, Australia. EM Anne.L.Abbott@gmail.com; Mark.Adelman@nyumc.org; avalexandrov@att.net; hjmb@bell.net; j.d.beard@btinternet.com; peterrfbell@googlemail.com; martin@bjorck.pp.se; David.Blacker@health.wa.gov.au; Clifford.Buckley@VA.GOV; RCAMBRIA@PARTNERS.ORG; anthony.comerotamd@promedica.org; esc5@columbia.edu; a.h.davies@imperial.ac.uk; HHEckstein@web.de; Rishad.Faruqi@kp.org; gustav.fraedrich@i-med.ac.at; gloviczki.peter@mayo.edu; gjhankey@cyllene.uwa.edu.au; rharbaugh@psu.edu; eitanh@asaf.health.gov.il; skittner@umaryland.edu; tkleinig@hotmail.com; MIKHAILIDIS@aol.com; WMoore@mednet.ucla.edu; ross.naylor@uhl-tr.nhs.uk; anicolaides1@gmail.com; paraskevask@hotmail.com; Pelz@uwo.ca; james.prichard@yale.edu; Grant.Purdie@health.sa.gov.au; jeanbaptistericco@gmail.com; Thomas.Riles@nyumc.org; peter.rothwell@clneuro.ox.ac.uk; Peter.sandercock@ed.ac.uk; sillesen@mac.com; dspence@robarts.ca; f.spinelli@mac.com; Aaron.Tan@health.sa.gov.au; a.thapar09@imperial.ac.uk; fjvmd@msn.com; weizhou@stanford.edu RI Spence, J. David/K-6396-2013; Hankey, Graeme /H-4968-2014; OI Spence, J. David/0000-0001-7478-1098; Hankey, Graeme /0000-0002-6044-7328; Alexandrov, Andrei V/0000-0001-8871-1023; Eckstein, Hans-Henning/0000-0002-0743-1642 FU Australian National Health and Medical Research Council (NHMRC) Fellowship [472700] FX Anne Abbott's time on this project has been supported by an Australian National Health and Medical Research Council (NHMRC) Fellowship (ID: 472700). NR 57 TC 0 Z9 0 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2162-3279 J9 BRAIN BEHAV JI Brain Behav. PD MAR PY 2012 VL 2 IS 2 BP 200 EP 207 DI 10.1002/brb3.32 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V35UQ UT WOS:000209173900009 ER PT J AU Au, DH Udris, EM Engelberg, RA Diehr, PH Bryson, CL Reinke, LE Curtis, JR AF Au, David H. Udris, Edmunds M. Engelberg, Ruth A. Diehr, Paula H. Bryson, Christopher L. Reinke, Lynn E. Curtis, J. Randall TI A Randomized Trial to Improve Communication About End-of-Life Care Among Patients With COPD SO CHEST LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; ADVANCE DIRECTIVE EDUCATION; LUNG-CANCER; PALLIATIVE CARE; HEALTH; REHABILITATION; EFFICACY; QUALITY; DEATH; QUESTIONNAIRE AB Objective: Patients with COPD consistently express a desire to discuss end-of-life care with clinicians, but these discussions rarely occur. We assessed whether an intervention using patient-specific feedback about preferences for discussing end-of-life care would improve the occurrence and quality of communication between patients with COPD and their clinicians. Methods: We performed a cluster-randomized trial of clinicians and patients from the outpatient clinics at the Veterans Affairs Puget Sound Health Care System. Using self-reported questionnaires, we assessed patients' preferences for communication, life-sustaining therapy, and experiences at the end of life. The intervention clinicians and patients received a one-page patient-specific feedback form, based on questionnaire responses, to stimulate conversations. The control group completed questionnaires but did not receive feedback. Patient-reported occurrence and quality of end-of-life communication (QOC) were assessed within 2 weeks of a targeted visit. Intention-to-treat regression analyses were performed with generalized estimating equations to account for clustering of patients within clinicians. Results: Ninety-two clinicians contributed 376 patients. Patients in the intervention arm reported nearly a threefold higher rate of discussions about end-of-life care (unadjusted, 30% vs 11%; P<.001). Baseline end-of-life communication was poor (intervention group QOC score, 23.3; 95% CI, 19.9-26.8; control QOC score, 19.2; 95% CI, 15.9-22.4). Patients in the intervention arm reported higher-quality end-of-life communication that was statistically significant, although the overall improvement was small (Cohen effect size, 0.21). Conclusions: A one-page patient-specific feedback form about preferences for end-of-life care and communication improved the occurrence and quality of communication from patients' perspectives. Trial Registry: ClinicalTrials.gov; No.: NCT00106080; URL: www.clinicaltrials.gov CHEST 2012; 141(3):726-735 C1 [Au, David H.; Udris, Edmunds M.; Bryson, Christopher L.; Reinke, Lynn E.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98101 USA. [Au, David H.; Engelberg, Ruth A.; Bryson, Christopher L.; Curtis, J. Randall] Univ Washington, Dept Med, Seattle, WA USA. [Diehr, Paula H.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Diehr, Paula H.] Univ Washington, Sch Publ Hlth & Community Med, Dept Hlth Serv, Seattle, WA 98195 USA. RP Au, DH (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM David.Au@VA.gov FU Department of Veterans Affairs [IIR-02-292]; Veterans Affairs Health Services Research and Development Career Development Award; National Heart Lung and Blood Institute [K24 HL068593] FX This study was funded by the Department of Veterans Affairs [Grant IIR-02-292]. Dr Au was funded during the trial period by a Veterans Affairs Health Services Research and Development Career Development Award. Dr Curtis was funded by a K24 Award from that National Heart Lung and Blood Institute [Grant K24 HL068593]. NR 29 TC 38 Z9 38 U1 1 U2 7 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2012 VL 141 IS 3 BP 726 EP 735 DI 10.1378/chest.11-0362 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 120KO UT WOS:000317169400025 PM 21940765 ER PT J AU Muzaffar, SAF Christiani, DC AF Muzaffar, Saeher A. F. Christiani, David C. TI Frontiers in Occupational and Environmental Lung Disease Research SO CHEST LA English DT Article ID GENOME-WIDE ASSOCIATION; NECROSIS-FACTOR-ALPHA; CHRONIC BERYLLIUM DISEASE; IDIOPATHIC PULMONARY-FIBROSIS; EXHALED BREATH CONDENSATE; TOBACCO-SMOKE EXPOSURE; CHILDHOOD ASTHMA; GENETIC SUSCEPTIBILITY; DIISOCYANATE EXPOSURE; POLYMORPHISMS MODIFY AB Two central challenges in the field of occupational and environmental epidemiology include accurately measuring biologic responses to exposure and preventing subsequent disease. As exposure-related lung diseases continue to be identified, advances in exposure biology have introduced toxicogenomic approaches that detect biomarkers of exposure at the gene, protein, and metabolite levels. Moreover, genetic epidemiology research has focused more recently on common, low-penetrant (ie, low-relative-risk) genetic variants that may interact with commonly encountered exposures. A number of such gene by environment interactions have been identified for airways and interstitial lung diseases, with the goal of preventing disease among susceptible populations that may not otherwise have been identified. Exhaled breath condensate analysis has provided another noninvasive means of assessing toxicant exposures and systemic effects. As these technologies become more refined, clinicians and public health practitioners will need to appreciate the social implications of the individual- and population-level risks conferred by certain genetic polymorphisms or by biomarker evidence of exposure. At present, the primary approach to occupational and environmental lung disease prevention remains elimination or reduction of known hazardous exposures and requires continued application of local and international resources toward exposure control. CHEST 2012; 141(3):772-781 C1 [Muzaffar, Saeher A. F.] Hosp Univ Penn, Div Pulm Allergy & Crit Care Med, Philadelphia, PA 19104 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Christiani, David C.] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care Med, 665 Huntington Ave,SPH I-1407, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu NR 84 TC 1 Z9 1 U1 0 U2 2 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2012 VL 141 IS 3 BP 772 EP 781 DI 10.1378/chest.11-0156 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 120KO UT WOS:000317169400030 PM 22396562 ER PT J AU Goel, S Wong, AHK Jain, RK AF Goel, Shom Wong, Andus Hon-Kit Jain, Rakesh K. TI Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; HEREDITARY HEMORRHAGIC TELANGIECTASIA; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; INTERSTITIAL FLUID PRESSURE; FACTOR RECEPTOR-2 BLOCKADE; INDUCIBLE-FACTOR 1-ALPHA; SUPPRESSES TUMOR-GROWTH; ANTI-VEGF TREATMENT AB Pathological angiogenesis-driven byan imbalance of pro-and antiangiogenic signaling-is a hallmark of many diseases, both malignant and benign. Unlike in the healthy adult in which angiogenesis is tightly regulated, such diseases are characterized by uncontrolled new vessel formation, resulting in a microvascular network characterized by vessel immaturity, with profound structural and functional abnormalities. The consequence of these abnormalities is further modification of the microenvironment, often serving to fuel disease progression and attenuate response to conventional therapies. In this article, we present the "vascular normalization" hypothesis, which states that antiangiogenic therapy, by restoring the balance between pro-and antiangiogenic signaling, can induce a more structurally and functionally normal vasculature in a variety of diseases. We present the preclinical and clinical evidence supporting this concept and discuss how it has contributed to successful treatment of both solid tumors and several benign conditions. C1 [Goel, Shom; Wong, Andus Hon-Kit; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin Steele Lab Tumor Biol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin Steele Lab Tumor Biol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Wong, Hon-Kit/G-3944-2014 OI Wong, Hon-Kit/0000-0003-0049-8454 FU Australian-American Fulbright Commission; American Society for Clinical Oncology; U.S. National Institutes of Health (NIH) [P01-CA80124, R01-CA85140, R01-CA115767, R01-CA126642]; Federal Share/NCI Proton Beam Program Income; National Foundation for Cancer Research; Department of Defense [W81XWH-10-1-0016]; AstraZeneca; Dyax; MedImmune; Roche FX S.G. is supported by the Australian-American Fulbright Commission and an American Society for Clinical Oncology Young Investigator Award. The research of R.K.J. is supported by the U.S. National Institutes of Health (NIH) grants P01-CA80124, R01-CA85140, R01-CA115767, and R01-CA126642, Federal Share/NCI Proton Beam Program Income, National Foundation for Cancer Research, and Department of Defense Breast Cancer Research Innovator Award (W81XWH-10-1-0016).; R.K.J. has served in a consultant or advisory role to Astellas, AstraZeneca, Dyax, Genzyme, Noxxon Pharma, Regeneron, and SynDevRx, has equity in SynDevRx, has received honoraria from Genzyme, and has received research funding from AstraZeneca, Dyax, MedImmune, and Roche. NR 189 TC 70 Z9 72 U1 6 U2 14 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD MAR PY 2012 VL 2 IS 3 AR a006486 DI 10.1101/cshperspect.a006486 PG 24 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080WL UT WOS:000314274700005 PM 22393532 ER PT J AU Porichis, F Kaufmann, DE AF Porichis, Filippos Kaufmann, Daniel E. TI Role of PD-1 in HIV Pathogenesis and as Target for Therapy SO CURRENT HIV/AIDS REPORTS LA English DT Article DE HIV; AIDS; Chronic viral infection; T-cell exhaustion; Programmed-death 1 (PD-1); Programmed death-ligand 1 (PD-L1); Programmed death-ligand 2 AB Major advances in Antiretroviral Therapy (ART) have resulted in a dramatic decline in HIV-related deaths. However, no current treatment regimen leads to viral eradication or restoration of HIV-specific immune responses capable of durable viral control after cessation of ART. Thus, there is a need for novel interventions that could complement ART in order to eliminate virus or reach a state of " functional cure." It has been shown in murine models and humans that the negative co-signaling molecule programmed-death 1 (PD-1) plays an active and reversible role in mediating T-cell exhaustion in chronic infections. This review summarizes recent advances in our understanding of the PD-1 pathway in HIV infection, and the lessons learned from studies in the SIV model and cancer. We discuss the potential of immunotherapeutic interventions targeting PD-1 in order to augment immune responses or facilitate viral eradication. We also present the challenges to therapies targeting immunoregulatory networks. C1 [Porichis, Filippos; Kaufmann, Daniel E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Kaufmann, Daniel E.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kaufmann, Daniel E.] Massachusetts Gen Hosp E, Ragon Inst MGH MIT & Harvard, Charlestown, MA 02129 USA. RP Kaufmann, DE (reprint author), Massachusetts Gen Hosp E, Ragon Inst MGH MIT & Harvard, Room 5239,149 13th St, Charlestown, MA 02129 USA. EM dkaufmann@partners.org FU National Institutes of Health [NIH RO1 HL 092565, P01AI-080192]; Executive Committee on Research of the Massachusetts General Hospital (ECOR) FX D.E.K. is supported by grants from the National Institutes of Health (NIH RO1 HL 092565 and P01AI-080192). F.P. is supported by a fellowship grant from Executive Committee on Research of the Massachusetts General Hospital (ECOR). NR 77 TC 35 Z9 36 U1 0 U2 7 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 MAR PY 2012 VL 9 IS 1 BP 81 EP 90 DI 10.1007/s11904-011-0106 PG 10 WC Infectious Diseases SC Infectious Diseases GA V32TS UT WOS:000208974100010 PM 22198819 ER PT J AU Ham, M Moss, AC AF Ham, Maggie Moss, Alan C. TI Mesalamine in the treatment and maintenance of remission of ulcerative colitis SO EXPERT REVIEW OF CLINICAL PHARMACOLOGY LA English DT Article DE 5-ASA; inflammatory bowel disease; mesalamine; ulcerative colitis AB Ulcerative colitis (UC) is a chronic disease of the GI tract that is characterized by mucosal inflammation in the colon. Mesalamine (mesalazine) is a 5-aminosalicylic acid compound that is the first-line treatment for patients with mild-to-moderate UC. There are multiple formulations of mesalamine available, primarily differentiated by their means of delivering active mesalamine to the colon. Mesalamine has been demonstrated in randomized controlled trials to induce both clinical response and remission, and maintain clinical remission, in these patients. It has few serious adverse effects and is generally well tolerated by patients. The main areas of uncertainty with use of mesalamine in patients with UC center on the optimal dose for induction of response, how to maintain patient adherence and the role of mesalamine in cancer chemoprophylaxis. Generic forms of mesalamine have yet to be approved by regulatory bodies in the USA. C1 [Ham, Maggie; Moss, Alan C.] Harvard Univ, Sch Med, BIDMC, Ctr Inflammatory Bowel Dis, Boston, MA 02215 USA. RP Moss, AC (reprint author), Harvard Univ, Sch Med, BIDMC, Ctr Inflammatory Bowel Dis, 330 Brookline Ave, Boston, MA 02215 USA. EM amoss@bidmc.harvard.edu FU Salix; Shire; Procter Gamble; NIH [K23DK084338] FX AC Moss has received research funding from Salix, Shire and Procter & Gamble, and is supported by NIH grant K23DK084338. 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 85 TC 18 Z9 22 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1751-2433 EI 1751-2441 J9 EXPERT REV CLIN PHAR JI Expert Rev. Clin. Pharmacol. PD MAR PY 2012 VL 5 IS 2 BP 113 EP 123 DI 10.1586/ECP.12.2 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V37PO UT WOS:000209287900007 PM 22390554 ER PT J AU Pulliam, SJ Weinstein, MM Wakamatsu, MM AF Pulliam, Samantha J. Weinstein, Milena M. Wakamatsu, May M. TI Minimally Invasive Apical Sacropexy: A Retrospective Review of Laparoscopic and Robotic Operating Room Experiences SO FEMALE PELVIC MEDICINE AND RECONSTRUCTIVE SURGERY LA English DT Article DE minimally invasive surgery; sacral colpopexy; learning curve; robotic colpopexy; laparoscopic colpopexy AB Objectives: Minimally invasive apical sacropexies (MI-APSC) can be performed using robotics or laparoscopy. We hypothesized that operative characteristics of MI-APSC, laparoscopic (LSC) and robotic (RSC), were similar. The objective of our study was to compare operative characteristics, objective prolapse outcomes, and robotic learning curve. Methods: Ninety-two women planning MI-APSC for treatment of apical pelvic organ prolapse from 2006 to 2010 were included in the study. The primary outcome was operative time. The secondary outcomes included estimated blood loss, rate of conversion, intraoperative complications, hospital stay, and objective prolapse outcome. We also analyzed the robotic learning curve. Statistical analysis included independent samples t test, Wilcoxon rank sum test, chi(2), and multiple logistic regressions; significance was set at P < 0.05. Learning curve was graphed with moving average and analyzed with moving block technique. Results: Forty-eight RSCs and 43 LSCs were analyzed. Mean operative times were LSC, 238 +/- 59 minutes; and RSC, 242 +/- 54 minutes. Robotic MI-APSC setup was longer (P = 0.02). Complications, conversions, estimated blood loss and hospital stay were low and similar between groups. Patients' characteristics were similar. Concomitant procedures produced longer operative times. Conclusions: Operating room experiences with laparoscopic- and robotic-assisted approaches to MI-APSC were similar, but setup time is longer for the robotic-assisted approach. The robotic learning curve is short for surgeons who have experience with LSC. C1 [Pulliam, Samantha J.; Weinstein, Milena M.; Wakamatsu, May M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Urogynecol & Reconstruct Pelv Surg,Dept Vince, Boston, MA USA. RP Weinstein, MM (reprint author), 55 Fruit St,Founders 5, Boston, MA 02114 USA. EM mweinstein2@partners.org FU Vincent Memorial Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, MA FX Departmental funding was received from Vincent Memorial Obstetrics and Gynecology Service, Massachusetts General Hospital, Boston, MA. NR 27 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 2151-8378 J9 FEMALE PELVIC MED RE JI Female Pelvic Med. Reconstr. Surg. PD MAR-APR PY 2012 VL 18 IS 2 BP 122 EP 126 DI 10.1097/SPV.0b013e31824a3995 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA V35XH UT WOS:000209178000012 PM 22453324 ER PT J AU Roberts, SR Crigler, J Lafferty, WE Bonham, AJ Hunter, JL Smith, AJ Banderas, JW Early, GL King, RK AF Roberts, Shauna R. Crigler, Jane Lafferty, William E. Bonham, Aaron J. Hunter, Jennifer L. Smith, Andrew J. Banderas, Julie W. Early, Gerald L. King, Roderick K. TI Addressing Social Determinants to Improve HealthCare Quality and Reduce Cost SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE Care/Disease; Management; Continuum of Care; Delivery Models; Social Work; Urban AB Most healthcare quality improvement and cost reduction efforts currently focus on care processes, or transitions-for example, the hospital discharge process. While identification and adoption of best practices to address these aspects of healthcare are essential, more is needed for systems that serve vulnerable populations: to account for social factors that often inhibit patients' ability to take full advantage of available healthcare. Our urban safety net healthcare system developed and implemented an innovative quality improvement approach. The programs, Guided Chronic Care (TM), and Passport to Wellness, use Assertive Care and provide social support for patients between medical encounters, enabling patients to make better use of the healthcare system and empowering them to better manage their conditions. Results: The majority of patients reported problems with mobility and nearly half reported anxiety or depression. Early indications show improved quality of care and significant reduction in costs. Challenges encountered and lessons learned in implementing the programs are described, to assist others developing similar interventions. C1 [Roberts, Shauna R.] Qual Truman Med Ctr, Kansas City, MO 64108 USA. [Roberts, Shauna R.] Univ Missouri Kansas City, Dept Med, Sch Med, Kansas City, MO USA. [Lafferty, William E.] Univ Missouri Kansas City, Off Hlth Serv & Publ Hlth Outcomes Res, Sch Med, Kansas City, MO USA. [Bonham, Aaron J.] Univ Missouri Kansas City, Sch Med, Hicklin Off Hlth Serv & Publ Hlth Outcomes Res, Kansas City, MO USA. [Hunter, Jennifer L.] Univ Missouri Kansas City, Sch Nursing, Kansas City, MO USA. [Smith, Andrew J.] Univ Missouri Kansas City, Sch Pharm, Kansas City, MO USA. [Smith, Andrew J.; Early, Gerald L.] Truman Med Ctr, Kansas City, MO USA. [Banderas, Julie W.; Early, Gerald L.] Univ Missouri Kansas City, Sch Med, Kansas City, MO USA. [King, Roderick K.] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. [King, Roderick K.] Next Generat Consulting Grp, Boston, MA USA. [King, Roderick K.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. RP Roberts, SR (reprint author), Qual Truman Med Ctr, Kansas City, MO 64108 USA. EM shauna.roberts@tmcmed.org NR 25 TC 4 Z9 4 U1 0 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 MAR-APR PY 2012 VL 34 IS 2 BP 12 EP 20 DI 10.1111/j.1945-1474.2011.00179.x PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OM UT WOS:000209221000003 PM 23552199 ER PT J AU Dillon, AR Dell'Italia, LJ Tillson, M Killingsworth, C Denney, T Hathcock, J Botzman, L AF Dillon, A. Ray Dell'Italia, Louis J. Tillson, Michael Killingsworth, Cheryl Denney, Thomas Hathcock, John Botzman, Logan TI Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs SO JOURNAL OF VETERINARY CARDIOLOGY LA English DT Review DE Cardiac remodeling; Volume overload; Extracellular matrix AB Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. (C) 2012 Elsevier B.V. All rights reserved. C1 [Dillon, A. Ray; Tillson, Michael; Hathcock, John; Botzman, Logan] Auburn Univ, Coll Vet Med, Auburn, AL 36849 USA. [Dell'Italia, Louis J.; Killingsworth, Cheryl] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Dell'Italia, Louis J.] Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL 35294 USA. [Denney, Thomas] Auburn Univ, Coll Engn, Auburn, AL 36849 USA. [Denney, Thomas] Auburn Univ, MRI Ctr, Auburn, AL 36849 USA. RP Dillon, AR (reprint author), Auburn Univ, Coll Vet Med, Auburn, AL 36849 USA. EM dilloar@auburn.edu NR 43 TC 9 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1760-2734 EI 1875-0834 J9 J VET CARDIOL JI J. Vet. Cardiol. PD MAR PY 2012 VL 14 IS 1 BP 73 EP 92 DI 10.1016/j.jvc.2012.01.012 PG 20 WC Veterinary Sciences SC Veterinary Sciences GA V31VG UT WOS:000208910500008 PM 22386719 ER PT J AU Morone, NE Lynch, CP Losasso, VJ Liebe, K Greco, CM AF Morone, Natalia E. Lynch, Cheryl P. Losasso, Vincent J., III Liebe, Karl Greco, Carol M. TI Mindfulness to Reduce Psychosocial Stress SO MINDFULNESS LA English DT Article DE Psychosocial stress; Mindfulness; Meditation; Qualitative AB While the adverse impact of stress on health states has been established, effective stress reduction programs are largely underused in clinical settings. In an area with little published information, this study identifies themes that describe the process of applying mindfulness methods to cope with psychosocial stressors in participants of the Mindfulness-Based Stress Reduction (MBSR) program. The study design is a qualitative investigation with a phenomenological approach using participant feedback from 11 MBSR 8-week programs. Participants were 74 adults from the greater Pittsburgh area. Content analysis was used to inductively generate thematic categories. Four themes were identified that described the process and results of learning mindfulness to adapt to psychosocial stressors. We categorized participants' feedback into interrelated themes of awareness (subdivided into self-discovery-" step back from my thoughts in order to view them more clearly", and being in the present), coping-" pause, take a breath", serenity-" increased feeling of calm, centeredness", and change in perspective-" different understanding interpersonally and intrapersonally." In addition, a brief section describes specific health benefits identified by participants. Participants found the mindfulness-based approach effective for stress reduction. The learning process allowed them to routinely apply mindfulness strategies that provided multiple benefits. C1 [Morone, Natalia E.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Morone, Natalia E.] Univ Pittsburgh, Translat Sci Inst, Pittsburgh, PA 15213 USA. [Morone, Natalia E.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Lynch, Cheryl P.] Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Div Populat, Charleston, SC USA. [Lynch, Cheryl P.] Med Univ S Carolina, Dept Med, Div Gen Internal Med, Charleston, SC 29425 USA. [Losasso, Vincent J., III] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. [Liebe, Karl] HealthSouth Harmarville Rehabil Hosp, Dept Med Phys & Rehabil, Pittsburgh, PA USA. [Greco, Carol M.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. RP Morone, NE (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15213 USA. EM moronene@upmc.edu NR 21 TC 4 Z9 5 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1868-8527 EI 1868-8535 J9 MINDFULNESS JI Mindfulness PD MAR PY 2012 VL 3 IS 1 BP 22 EP 29 DI 10.1007/s12671-011-0076-z PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA V33HM UT WOS:000209009900004 ER PT J AU Dastani, Z Hivert, MF Timpson, N Perry, JRB Yuan, X Scott, RA Henneman, P Heid, IM Kizer, JR Lyytikainen, LP Fuchsberger, C Tanaka, T Morris, AP Small, K Isaacs, A Beekman, M Coassin, S Lohman, K Qi, L Kanoni, S Pankow, JS Uh, HW Wu, Y Bidulescu, A Rasmussen-Torvik, LJ Greenwood, CMT Ladouceur, M Grimsby, J Manning, AK Liu, CT Kooner, J Mooser, VE Vollenweider, P Kapur, KA Chambers, J Wareham, NJ Langenberg, C Frants, R Willems-vanDijk, K Oostra, BA Willems, SM Lamina, C Winkler, TW Psaty, BM Tracy, RP Brody, J Chen, I Viikari, J Kahonen, M Pramstaller, PP Evans, DM St Pourcain, B Sattar, N Wood, AR Bandinelli, S Carlson, OD Egan, JM Bohringer, S van Heemst, D Kedenko, L Kristiansson, K Nuotio, ML Loo, BM Harris, T Garcia, M Kanaya, A Haun, M Klopp, N Wichmann, HE Deloukas, P Katsareli, E Couper, DJ Duncan, BB Kloppenburg, M Adair, LS Borja, JB Wilson, JG Musani, S Guo, XQ Johnson, T Semple, R Teslovich, TM Allison, MA Redline, S Buxbaum, SG Mohlke, KL Meulenbelt, I Ballantyne, CM Dedoussis, GV Hu, FB Liu, YM Paulweber, B Spector, TD Slagboom, PE Ferrucci, L Jula, A Perola, M Raitakari, O Florez, JC Salomaa, V Eriksson, JG Frayling, TM Hicks, AA Lehtimaki, T Smith, GD Siscovick, DS Kronenberg, F van Duijn, C Loos, RJF Waterworth, DM Meigs, JB Dupuis, J Richards, JB AF Dastani, Zari Hivert, Marie-France Timpson, Nicholas Perry, John R. B. Yuan, Xin Scott, Robert A. Henneman, Peter Heid, Iris M. Kizer, Jorge R. Lyytikainen, Leo-Pekka Fuchsberger, Christian Tanaka, Toshiko Morris, Andrew P. Small, Kerrin Isaacs, Aaron Beekman, Marian Coassin, Stefan Lohman, Kurt Qi, Lu Kanoni, Stavroula Pankow, James S. Uh, Hae-Won Wu, Ying Bidulescu, Aurelian Rasmussen-Torvik, Laura J. Greenwood, Celia M. T. Ladouceur, Martin Grimsby, Jonna Manning, Alisa K. Liu, Ching-Ti Kooner, Jaspal Mooser, Vincent E. Vollenweider, Peter Kapur, Karen A. Chambers, John Wareham, Nicholas J. Langenberg, Claudia Frants, Rune Willems-vanDijk, Ko Oostra, Ben A. Willems, Sara M. Lamina, Claudia Winkler, Thomas W. Psaty, Bruce M. Tracy, Russell P. Brody, Jennifer Chen, Ida Viikari, Jorma Kahonen, Mika Pramstaller, Peter P. Evans, David M. St Pourcain, Beate Sattar, Naveed Wood, Andrew R. Bandinelli, Stefania Carlson, Olga D. Egan, Josephine M. Bohringer, Stefan van Heemst, Diana Kedenko, Lyudmyla Kristiansson, Kati Nuotio, Marja-Liisa Loo, Britt-Marie Harris, Tamara Garcia, Melissa Kanaya, Alka Haun, Margot Klopp, Norman Wichmann, H. -Erich Deloukas, Panos Katsareli, Efi Couper, David J. Duncan, Bruce B. Kloppenburg, Margreet Adair, Linda S. Borja, Judith B. Wilson, James G. Musani, Solomon Guo, Xiuqing Johnson, Toby Semple, Robert Teslovich, Tanya M. Allison, Matthew A. Redline, Susan Buxbaum, Sarah G. Mohlke, Karen L. Meulenbelt, Ingrid Ballantyne, Christie M. Dedoussis, George V. Hu, Frank B. Liu, Yongmei Paulweber, Bernhard Spector, Timothy D. Slagboom, P. Eline Ferrucci, Luigi Jula, Antti Perola, Markus Raitakari, Olli Florez, Jose C. Salomaa, Veikko Eriksson, Johan G. Frayling, Timothy M. Hicks, Andrew A. Lehtimaki, Terho Smith, George Davey Siscovick, David S. Kronenberg, Florian van Duijn, Cornelia Loos, Ruth J. F. Waterworth, Dawn M. Meigs, James B. Dupuis, Josee Richards, J. Brent CA DIAGRAM Consortium MAGIC Consortium GLGC Investigators MuTHER Consortium TI Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; LIPID CONCENTRATIONS; ADIPOSE-TISSUE; GENETIC-BASIS; RISK; POPULATION; RECEPTOR; VARIANTS AB Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P=4.5 x 10(-8)-1.2 x 10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3 x 10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p=4.3 x 10(-3), n = 22,044), increased triglycerides (p=2.6 x 10(-14), n = 93,440), increased waist-to-hip ratio (p=1.8 x 10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p=4.4 x 10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p=4.5x10(-13), n = 96,748) and decreased BMI (p= 1.4 x 10(-14), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance. C1 [Dastani, Zari] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3T 1E2, Canada. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France; Grimsby, Jonna; Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Timpson, Nicholas; Evans, David M.; Smith, George Davey] Univ Bristol, MRC CAiTE Ctr, Bristol, Avon, England. [Timpson, Nicholas; Evans, David M.; St Pourcain, Beate; Smith, George Davey] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England. [Perry, John R. B.; Morris, Andrew P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Perry, John R. B.; Wood, Andrew R.; Frayling, Timothy M.] Univ Exeter, Peninsula Med Sch, Exeter, Devon, England. [Yuan, Xin; Mooser, Vincent E.; Waterworth, Dawn M.] GlaxoSmithKline, King Of Prussia, PA USA. [Scott, Robert A.; Wareham, Nicholas J.; Langenberg, Claudia; Loos, Ruth J. F.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Henneman, Peter; Frants, Rune; Willems-vanDijk, Ko] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [Heid, Iris M.; Winkler, Thomas W.] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, Regensburg, Germany. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Kizer, Jorge R.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Lyytikainen, Leo-Pekka; Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Lyytikainen, Leo-Pekka; Kahonen, Mika; Lehtimaki, Terho] Tampere Univ Hosp, Tampere, Finland. [Fuchsberger, Christian; Teslovich, Tanya M.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Small, Kerrin; Spector, Timothy D.; Richards, J. Brent] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Small, Kerrin; Kanoni, Stavroula; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Isaacs, Aaron; Willems, Sara M.; van Duijn, Cornelia] Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands. [Isaacs, Aaron; Oostra, Ben A.; van Duijn, Cornelia] Ctr Med Syst Biol, Leiden, Netherlands. [Beekman, Marian; van Heemst, Diana; Meulenbelt, Ingrid] Leiden Univ, Med Ctr, Sect Mol Epidemiol, Leiden, Netherlands. [Beekman, Marian; Meulenbelt, Ingrid] Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Leiden, Netherlands. [Coassin, Stefan; Lamina, Claudia; Haun, Margot; Kronenberg, Florian] Innsbruck Med Univ, Div Genet Epidemiol, Innsbruck, Austria. [Lohman, Kurt; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Qi, Lu; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Wu, Ying; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Bidulescu, Aurelian] Morehouse Sch Med, Cardiovasc Res Inst, Atlanta, GA 30310 USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Greenwood, Celia M. T.] McGill Univ, Dept Oncol, Lady Davis Inst Med Res, Montreal, PQ, Canada. [Grimsby, Jonna; Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Manning, Alisa K.; Liu, Ching-Ti; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kooner, Jaspal] Ealing Gen Hosp, Natl Hlth Serv NHS Trust, London, England. [Vollenweider, Peter] Univ Lausanne, Dept Internal Med, Lausanne, Switzerland. [Kapur, Karen A.; Johnson, Toby] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland. [Chambers, John] Univ London Imperial Coll Sci Technol & Med, London, England. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Psaty, Bruce M.; Brody, Jennifer] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98195 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Burlington, VT 05405 USA. [Chen, Ida] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Viikari, Jorma] Turku Univ Hosp, FIN-20520 Turku, Finland. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Pramstaller, Peter P.; Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, Bolzano, Italy. [Pramstaller, Peter P.] Univ Lubeck, Dept Neurol, Lubeck, Germany. [Sattar, Naveed] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow, Lanark, Scotland. [Bandinelli, Stefania] ASF, Geriatr Unit, Florence, Italy. [Carlson, Olga D.; Egan, Josephine M.] NIA, Clin Invest Lab, Baltimore, MD 21224 USA. [Kedenko, Lyudmyla; Paulweber, Bernhard] Paracelsus Private Med Univ Salzburg, Dept Internal Med 1, St Johann Spital, Salzburg, Austria. [Kristiansson, Kati; Nuotio, Marja-Liisa; Perola, Markus] Univ Helsinki, Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Publ Hlth Genom Unit, Helsinki, Finland. [Kristiansson, Kati; Nuotio, Marja-Liisa; Perola, Markus] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland. [Loo, Britt-Marie; Jula, Antti] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Populat Studies Unit, Turku, Finland. [Harris, Tamara; Garcia, Melissa] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kanaya, Alka] Univ Calif San Francisco, Womens Hlth Clin Res Ctr, Div Gen Internal Med, San Francisco, CA 94143 USA. [Klopp, Norman; Wichmann, H. -Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Klinikum Grosshadern, Munich, Germany. [Katsareli, Efi; Dedoussis, George V.] Harokopio Univ, Athens, Greece. [Couper, David J.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Duncan, Bruce B.] Univ Fed Rio Grande do Sul, Sch Med, Porto Alegre, RS, Brazil. [Duncan, Bruce B.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Kloppenburg, Margreet] Dept Rheumatol, Leiden, Netherlands. [Kloppenburg, Margreet] Leiden Univ Hosp, Dept Clin Epidemiol, Leiden, Netherlands. [Adair, Linda S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Borja, Judith B.] Univ San Carlos, Off Populat Studies Fdn, Cebu, Philippines. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Musani, Solomon] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Guo, Xiuqing] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Johnson, Toby] CHU Vaudois, Univ Inst Social & Preventat Med, Lausanne, Switzerland. [Johnson, Toby] Swiss Inst Bioinformat, Lausanne, Switzerland. [Semple, Robert] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Metab Res Labs, Cambridge CB2 2QQ, England. [Allison, Matthew A.] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Redline, Susan] Brigham & Womens Hosp, Boston, MA 02115 USA. [Buxbaum, Sarah G.] Jackson State Univ, Jackson Heart Study Coordinating Ctr, Jackson, MS USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Ballantyne, Christie M.] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol, FIN-20520 Turku, Finland. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland. [Eriksson, Johan G.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Diabet Prevent Unit, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Ctr Hosp, Unit Gen Practice, Helsinki, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Vaasa Cent Hosp, Vaasa, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Dupuis, Josee] Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Biostat, Montreal, PQ H3T 1E2, Canada. [Oostra, Ben A.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Psaty, Bruce M.; Brody, Jennifer] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. RP Dastani, Z (reprint author), McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3T 1E2, Canada. EM brent.richards@mcgill.ca RI Erdmann, Jeanette/P-7513-2014; Buxbaum, Sarah/E-1970-2013; Slagboom, P. Eline/R-4790-2016; Davey Smith, George/A-7407-2013; Naitza, Silvia/D-5620-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Lyytikainen, Leo-Pekka/C-8544-2016; Aulchenko, Yurii/M-8270-2013; Rudan, Igor/I-1467-2012; Ejebe, Kenechi/I-9238-2016; Smith, Albert/K-5150-2015; Kyvik, Kirsten /K-5680-2016; Visvikis-Siest, Sophie/H-2324-2014; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; Hayward, Caroline/M-8818-2016; Schwarz, Peter/B-5127-2013; Fox, Laura /C-6249-2016; Johansson, Asa/G-5270-2011; Palmer, Lyle/K-3196-2014; Bidulescu, Aurelian/N-2617-2014; Fouchier, Sigrid/A-8310-2011; Kronenberg, Florian/B-1736-2008; SIMPSON, LAILA/O-7281-2014; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Polasek, Ozren/B-6002-2011; Meitinger, Thomas/O-1318-2015; Prokopenko, Inga/H-3241-2014; Singleton, Andrew/C-3010-2009; Fuchsberger, Christian/C-9646-2010; Deloukas, Panos/B-2922-2013; Evans, David/H-6325-2013; Hide, Winston Hide/C-7217-2009; Pramstaller, Peter/C-2357-2008; Thorand, Barbara/B-5349-2014; Elliott, Amanda/G-5120-2012; Cooper, Matthew/J-4420-2014; Colaus, PsyColaus/K-6607-2013; van Hoek, Mandy/B-9325-2014; Meisinger, Christine/B-5358-2014; OI Coin, Lachlan/0000-0002-4300-455X; Karpe, Fredrik/0000-0002-2751-1770; Navarro, Pau/0000-0001-5576-8584; Jorgensen, Torben/0000-0001-9453-2830; Watkins, Hugh/0000-0002-5287-9016; Allison, Matthew/0000-0003-0777-8272; Small, Kerrin/0000-0003-4566-0005; Marmot, Michael/0000-0002-2431-6419; Evans, David/0000-0003-0663-4621; Mitchell, Braxton/0000-0003-4920-4744; Ziegler, Andreas/0000-0002-8386-5397; Franks, Paul/0000-0002-0520-7604; Semple, Robert/0000-0001-6539-3069; Kumari, Meena/0000-0001-9716-1035; Rivadeneira, Fernando/0000-0001-9435-9441; Palmer, Colin/0000-0002-6415-6560; Meisinger, Christa/0000-0002-9026-6544; Melzer, David/0000-0002-0170-3838; Klein, Ronald/0000-0002-4428-6237; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Zeggini, Eleftheria/0000-0003-4238-659X; Becker, James/0000-0003-4425-4726; Kristiansson, Kati/0000-0003-4688-107X; Seedorf, Udo/0000-0003-4652-5358; Erdmann, Jeanette/0000-0002-4486-6231; Dupuis, Josee/0000-0003-2871-3603; Luben, Robert/0000-0002-5088-6343; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; sanna, serena/0000-0002-3768-1749; Kivimaki, Mika/0000-0002-4699-5627; Buxbaum, Sarah/0000-0002-4886-3564; Johnson, Toby/0000-0002-5998-3270; Janssens, A Cecile/0000-0002-6153-4976; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Beekman, Marian/0000-0003-0585-6206; Aihie Sayer, Avan/0000-0003-1283-6457; Seielstad, Mark/0000-0001-5783-1401; Pichler, Irene/0000-0001-8251-0757; Willems van Dijk, Ko/0000-0002-2172-7394; Griffin, Simon/0000-0002-2157-4797; Paolisso, Giuseppe/0000-0002-2137-455X; Sladek, Robert/0000-0002-2730-1204; Magi, Reedik/0000-0002-2964-6011; Marre, Michel/0000-0002-3071-1837; Slagboom, P. Eline/0000-0002-2875-4723; Davey Smith, George/0000-0002-1407-8314; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Willer, Cristen/0000-0001-5645-4966; Nuotio, Marja-Liisa/0000-0002-6688-027X; Kaakinen, Marika/0000-0002-9228-0462; Cupples, L. Adrienne/0000-0003-0273-7965; Marroni, Fabio/0000-0002-1556-5907; Fuchsberger, Christian/0000-0002-5918-8947; Sijbrands, Eric/0000-0001-8857-7389; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Aulchenko, Yurii/0000-0002-7899-1575; Rudan, Igor/0000-0001-6993-6884; Ejebe, Kenechi/0000-0002-6090-8657; Smith, Albert/0000-0003-1942-5845; Kyvik, Kirsten /0000-0003-2981-0245; Visvikis-Siest, Sophie/0000-0001-8104-8425; Bochud, Murielle/0000-0002-5727-0218; Hayward, Caroline/0000-0002-9405-9550; Schwarz, Peter/0000-0001-6317-7880; Johansson, Asa/0000-0002-2915-4498; Palmer, Lyle/0000-0002-1628-3055; Bidulescu, Aurelian/0000-0001-8211-8309; Kronenberg, Florian/0000-0003-2229-1120; SIMPSON, LAILA/0000-0001-7189-4791; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Polasek, Ozren/0000-0002-5765-1862; Prokopenko, Inga/0000-0003-1624-7457; Deloukas, Panos/0000-0001-9251-070X; Hide, Winston Hide/0000-0002-8621-3271; Thorand, Barbara/0000-0002-8416-6440; Cooper, Matthew/0000-0003-1139-3682; Lawlor, Debbie A/0000-0002-6793-2262; Tai, E Shyong/0000-0003-2929-8966; de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020; Dehghan, Abbas/0000-0001-6403-016X FU NIH, National Institute on Aging; MedStar Research Institute; Netherlands Organisation for Scientific Research, Erasmus MC; Centre for Medical Systems Biology (CMSB); European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium; National Heart, Lung, and Blood Institute [N01-HC-25195, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL087652, HL105756, HL094555]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; "Tiroler Wissenschaftsfonds" [UNI-0407/29]; Helmholtz Zentrum Munchen; NIH subcontract from the Children's Hospital, Boston, US [1 R01 DK075787-01A1]; German National Genome Research Net NGFN2 and NGFNplus [01GS0823]; Wellcome Trust; European Commission [FP7/2007-2013, HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; Arthritis Research Campaign, Chronic Disease Research Foundation; National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre; St Thomas' NHS Foundation Trust in partnership with King's College London; Biotechnology and Biological Sciences Research Council [G20234]; National Institute of Neurological Disorders and Stroke; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491, R01DK056918]; NHLBI [R01-HL085251]; Academy of Finland [114382, 126775, 127437, 129255, 129306, 130326, 209072, 210595, 213225, 216374, 126925, 121584, 124282, 129378, 117787, 41071, 125973, 129322, 129494, 139635, 129907, 135072]; Finnish Diabetes Research Society; Finnish Foundation for Pediatric Research; Samfundet Folkhalsan; Juho Vainio Foundation; Novo Nordisk Foundation; Finska Lakaresallskapet; Paivikki; Sakari Sohlberg Foundation; Signe and Ane Gyllenberg Foundation; Yrjo Jahnsson Foundation; Finnish Academy [118065]; Social Insurance Institution of Finland, Kuopio; Tampere; Turku University Hospital; Paavo Nurmi Foundation; Finnish Foundation of Cardiovascular Research; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Finnish Cultural Foundation; Orion-Farmos Research Foundation; Finnish Foundation for Cardiovascular Research; Sigrid Juselius Foundation; Medical Research Council; Support for Science Funding programme; CamStrad; National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-65226, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, RC2 HL102419]; National Heart, Lung, and Blood Institute, through contracts with Jackson State University [N01-HC-95170]; University of Mississippi Medical Center [N01-HC-95171]; Tougaloo College [N01-HC-95172]; National Institutes of Health, National Center for Research Resources (NCRR) [UL1 RR025008]; NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Institutes of Health [HHSN268200782096C, DK078150, TW05596, HL085144, RR20649, ES10126, DK56350]; NIH, National Institute on Aging. Genetics, Arthrosis, and Progression; Leiden University Medical Centre; Dutch Arthritis Association; Pfizer; Groton; CT; USA; Netherlands Organization of Scientific Research [MW 904-61-095, 911-03-016, 917 66344, 911-03-012]; Centre of Medical System Biology; Netherlands Consortium for Healthy Aging; TI-Pharma; National Human Genome Research Institute [U01HG004402]; a component of the National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; "Austrian Genome Research Programme" (GEN-AU); Medizinische Forschungsgesellschaft Salzburg; "Kamillo Eisner Stiftung" (Switzerland); General Secretary of Research and Technology [PENED 03, EPSILON, DELTA. 474]; Canadian Foundation for Innovation; Canadian Institutes of Health Research (CIHR); Fonds de la recherche en sante du Quebec; Lady Davis Institute; Ministere du Developpement economique; de l'Innovation et de l'Exportation du Quebec; Jewish General Hospital; [092447/Z/10/Z]; [N01 HC-95159]; [N01-HC-95160]; [N01-HC-95161]; [N01-HC-95162]; [N01-HC-95163]; [N01-HC-95164]; [N01-HC-95165]; [N01-HC-95166]; [N01-HC-95167]; [N01-HC-95168]; [N01-HC-95169]; [RR-024156] FX Baltimore Longitudinal Study of Aging (BLSA): The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through an R&D contract with MedStar Research Institute. Erasmus Rucphen Family (ERF). The ERF study was supported by grants from The Netherlands Organisation for Scientific Research, Erasmus MC and the Centre for Medical Systems Biology (CMSB), and the European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium. Invecchaire in Chianti (InCHIANTI). JRB Perry is a Sir Henry Wellcome Postdoctoral Research Fellow (092447/Z/10/Z). Framingham Heart Study (FHS): This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The Collaborative Health Research in the Region of Augsburg (KORA F3): This study was partially funded by the "Tiroler Wissenschaftsfonds" (Project UNI-0407/29) and by the "Genomics of Lipid-associated Disorders - GOLD" of the "Austrian Genome Research Programme GEN-AU" to F Kronenberg. The MONICA/KORA Augsburg cohort study was financed by the Helmholtz Zentrum Munchen. It was further funded by the NIH subcontract from the Children's Hospital, Boston, US, (H-E Wichmann and IM Heid, prime grant 1 R01 DK075787-01A1 to JN Hirschhorn) and the German National Genome Research Net NGFN2 and NGFNplus (H-E Wichmann 01GS0823). TwinsUK: Study was funded by the Wellcome Trust, European Commission Framework (FP7/2007-2013), ENGAGE project HEALTH-F4-2007-201413, and the FP5 GenomEUtwin Project (QLG2-CT-2002-01254). It also receives support from the Arthritis Research Campaign, Chronic Disease Research Foundation, the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London, and a Biotechnology and Biological Sciences Research Council project grant (G20234). Cardiovascular Health Study (CHS): The CHS research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652, HL105756, and HL094555 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center, NHLBI R01-HL085251.; Helsinki Birth Cohort Study (HBCS): HBCS has been supported by grants from Academy of Finland (project numbers 114382, 126775, 127437, 129255, 129306, 130326, 209072, 210595, 213225, 216374), Finnish Diabetes Research Society, Finnish Foundation for Pediatric Research, Samfundet Folkhalsan, Juho Vainio Foundation, Novo Nordisk Foundation, Finska Lakaresallskapet, Paivikki and Sakari Sohlberg Foundation, Signe and Ane Gyllenberg Foundation, and Yrjo Jahnsson Foundation. DILGOM survey was funded by the Finnish Academy, grant number 118065. Cardiovascular Risk in Young Finns (YFS): The Young Finns Study has been financially supported by the Academy of Finland: grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds, Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research (T. L., OT.R), Tampere Tuberculosis Foundation (Te.Le., Mik, Ka), the Emil Aaltonen Foundation (T. L.) and Finnish Cultural Foundation. The expert technical assistance in the statistical analyses by Irina Lisinen and Ville Aalto are gratefully acknowledged. Dietary, Lifestyle, and Genetic determinants of Obesity and Metabolic syndrome (DILGOM): K Kristiansson was supported by the Orion-Farmos Research Foundation and the Academy of Finland (grant no. 125973). M Perola and V Salomaa were supported by the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and the Academy of Finland (grants 129322, 129494 and 139635). JG Eriksson was supported by the Academy of Finland (grants 126775, 129255, 129907, and 135072). Fenland study: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Multiethnic Study of Atherosclerosis (MESA): The MESA project is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, and RR-024156. Funding for CARe genotyping was provided by NHLBI Contract N01-HC-65226. Jackson Heart Study (JHS): The Jackson Heart Study is supported by the National Heart, Lung, and Blood Institute, through contracts with Jackson State University (N01-HC-95170), the University of Mississippi Medical Center (N01-HC-95171), and Tougaloo College (N01-HC-95172). Adiponectin measurements used in the current study were funded by PHS Award UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources (NCRR). Health ABC: This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C.; This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Genetics, Arthrosis, and Progression) study (GARP): This study was supported the Leiden University Medical Centre and the Dutch Arthritis Association. Pfizer, Groton, CT, USA supported the inclusion of the GARP study. The genotypic work was supported by the Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917 66344 and 911-03-012), Leiden University Medical Centre and the Centre of Medical System Biology and Netherlands Consortium for Healthy Aging both in the framework of the Netherlands Genomics Initiative (NGI). The adiponectin measurements were supported by TI-Pharma. Atherosclerosis Risk in Communities (ARIC): The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, and RC2 HL102419; National Human Genome Research Institute contract U01HG004402; National Institutes of Health contract HHSN268200625226C; and National Institute of Diabetes and Digestive and Kidney Diseases R01DK056918. Infrastructure was partly supported by Grant Number UL1RR025005,a component of the National Institutes of Health and NIH Roadmap for Medical Research. Salzburg Atherosclerosis Prevention Program in subjects at High Individual Risk (SHAPIR): Part of this work was funded by the "Genomics of Lipid-associated Disorders" (GOLD) of the "Austrian Genome Research Programme" (GEN-AU) to Florian Kronenberg, and grants from the "Medizinische Forschungsgesellschaft Salzburg" and the "Kamillo Eisner Stiftung" (Switzerland) to Bernhard Paulweber. THISEAS: The genotyping of the THISEAS study was funded by the Wellcome Trust. The recruitment was partially supported by the General Secretary of Research and Technology (PENED 03, EPSILON., DELTA. 474). We are grateful to all the volunteers for their time and help, the medical staff of the hospitals and the field investigators, Eirini Theodoraki, Maria Dimitriou and Kathy Stirrups for her assistance in the genotyping. Cebu Longitudinal Health and Nutrition Survey (CLHNS): We thank the Office of Population Studies Foundation research and data collection teams and the study participants who generously provided their time for this study. This work was supported by National Institutes of Health grants DK078150, TW05596, HL085144, RR20649, ES10126, and DK56350. Coordinating Centre: McGill University. This work was supported by grants from the Canadian Foundation for Innovation, the Canadian Institutes of Health Research (CIHR), Fonds de la recherche en sante du Quebec, the Lady Davis Institute, the Ministere du Developpement economique, de l'Innovation et de l'Exportation du Quebec and the Jewish General Hospital. JB Richards and Z Dastani are supported by the CIHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 151 Z9 154 U1 2 U2 51 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 MAR PY 2012 VL 8 IS 3 AR e1002607 DI 10.1371/journal.pgen.1002607 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800080 PM 22479202 ER PT J AU White, YAR Woods, DC Takai, Y Ishihara, O Seki, H Tilly, JL AF White, Yvonne A. R. Woods, Dori C. Takai, Yasushi Ishihara, Osamu Seki, Hiroyuki Tilly, Jonathan L. TI Oogonial Stem Cells Isolated from Adult Human Ovaries Generate Oocytes In Vitro and In Vivo SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [White, Yvonne A. R.; Woods, Dori C.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. [Takai, Yasushi; Ishihara, Osamu; Seki, Hiroyuki] Saitama Med Sch, Saitama Med Ctr, Dept Obstet & Gynecol, Saitama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 73A EP 73A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543601003 ER PT J AU Wang, N White, YA Woods, DC Tilly, JL AF Wang, Ning White, Yvonne Ar Woods, Dori C. Tilly, Jonathan L. TI Steroid Hormone Regulation of Ovarian Germline Stem Cell Differentiation SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Wang, Ning; White, Yvonne Ar; Woods, Dori C.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 79A EP 80A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543601024 ER PT J AU Woods, DC White, YAR Rueda, BR Tilly, JL AF Woods, Dori C. White, Yvonne A. R. Rueda, Bo R. Tilly, Jonathan L. TI Tumorigenic Potential of Oogonial Stem Cells Is Actively Suppressed by the Intraovarian Microenvironment. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Woods, Dori C.; White, Yvonne A. R.; Rueda, Bo R.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 93A EP 93A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543601071 ER PT J AU Wang, N Satirapod, C Tilly, JL AF Wang, Ning Satirapod, Chonthicha Tilly, Jonathan L. TI Progressive Decline of Oogonial Stem Cell Activity Contributes to Ovarian Aging. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Wang, Ning; Satirapod, Chonthicha; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 110A EP 110A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543601129 ER PT J AU Stanic, AK Attaman, JA Kim, M Styer, AK Rueda, BR AF Stanic, Aleksandar K. Attaman, Jill A. Kim, Minji Styer, Aaron K. Rueda, Bo R. TI Characterization of Immune Cell Populations in Murine Endometriosis-Like Lesions SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Stanic, Aleksandar K.; Attaman, Jill A.; Kim, Minji; Styer, Aaron K.; Rueda, Bo R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent Dept Obstet & Gyn, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 142A EP 143A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543601240 ER PT J AU Faustino, LR Woods, DC White, YAR Tilly, JL AF Faustino, Luciana R. Woods, Dori C. White, Yvonne A. R. Tilly, Jonathan L. TI Oogonial Stem Cells Increase in Numbers in Aged Mouse Ovaries SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Faustino, Luciana R.; Woods, Dori C.; White, Yvonne A. R.; Tilly, Jonathan L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Bosotn, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 224A EP 224A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543602123 ER PT J AU Groeneweg, JW Woods, DC White, YAR Takai, Y Tilly, JL AF Groeneweg, Jolijn W. Woods, Dori C. White, Yvonne A. R. Takai, Yasushi Tilly, Jonathan L. TI Characterization of Meiosis in Ovarian Germ Cells of Reproductive-Age Women SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Groeneweg, Jolijn W.; Woods, Dori C.; White, Yvonne A. R.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol, Boston, MA USA. [Takai, Yasushi] Saitama Med Ctr, Dept Obstet & Gynecol, Saitama, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 225A EP 225A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543602125 ER PT J AU Shalowitz, DI Unger, C Saadi, A Shelton, K Leffert, L Albrecht, M Wylie, B AF Shalowitz, David I. Unger, Cecile Saadi, Altaf Shelton, Kenneth Leffert, Lisa Albrecht, Meredith Wylie, Blair TI Intrapartum Pulse Pressure, Volume Status and Response to Epidural SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Shalowitz, David I.; Unger, Cecile; Saadi, Altaf; Shelton, Kenneth; Leffert, Lisa; Albrecht, Meredith; Wylie, Blair] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 233A EP 233A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543602153 ER PT J AU Chattergoon, NN Louey, S Giraud, GD Thornburg, KL AF Chattergoon, Natasha N. Louey, Samantha Giraud, George D. Thornburg, Kent L. TI Myocardial Thyroid Hormone Deiodinases Are Regulated by Fetal T-3. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Chattergoon, Natasha N.; Louey, Samantha; Giraud, George D.; Thornburg, Kent L.] Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA. [Louey, Samantha; Giraud, George D.; Thornburg, Kent L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Giraud, George D.] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 252A EP 252A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543602219 ER PT J AU Edlow, A Kaimal, A Lee, H Felsenstein, D Riley, L AF Edlow, Andrea Kaimal, Anjali Lee, Hang Felsenstein, Donna Riley, Laura TI Screening for Herpes Simplex Virus in Pregnancy Does Not Impact Quality of Life. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Edlow, Andrea; Kaimal, Anjali; Riley, Laura] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Lee, Hang; Felsenstein, Donna] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 279A EP 279A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543602309 ER PT J AU Doyle, J Lee, HJ Selesniemi, K Ghazal, S Rueda, B Tilly, J AF Doyle, Joseph Lee, Ho Joon Selesniemi, Kaisa Ghazal, Sanaz Rueda, Bo Tilly, Jonathan TI Effect of Vitrification on Aurora Kinase A Expression and Germinal Vesicle Breakdown in Isolated Mouse Oocytes SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract C1 [Doyle, Joseph; Lee, Ho Joon; Selesniemi, Kaisa; Ghazal, Sanaz; Rueda, Bo; Tilly, Jonathan] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 336A EP 336A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543603123 ER PT J AU Young, BC Panda, B Madden, E Bryant, A AF Young, Brett C. Panda, Britta Madden, Erin Bryant, Allison TI What Happens after the Puerperium? The Impact of Pregnancy on the Duration of Future Hospitalization SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 59th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 21-24, 2012 CL San Diego, CA SP Soc Gynecol Invest C1 [Young, Brett C.; Panda, Britta; Bryant, Allison] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Madden, Erin] VCIRE, Vet Res Inst, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 374A EP 374A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543603253 ER PT J AU Young, BC Panda, B Madden, E Bryant, A AF Young, Brett C. Panda, Britta Madden, Erin Bryant, Allison TI To Bleed or Not To Bleed: What Are Risk Factors for Early Delivery with Placenta Previa? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 59th Annual Scientific Meeting of the Society-for-Gynecologic-Investigation (SGI) CY MAR 21-24, 2012 CL San Diego, CA SP Soc Gynecol Invest C1 [Young, Brett C.; Panda, Britta; Bryant, Allison] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Madden, Erin] VCIRE, Vet Res Inst, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2012 VL 19 IS S3 SU 3 BP 374A EP 375A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 287LP UT WOS:000329543603254 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI Can nurses place esophageal temperature probes? What is the procedure to place an esophageal probe? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter C1 Massachusetts Gen Hosp, Neurosci ICU, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Neurosci ICU, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD MAR 1 PY 2012 VL 2 IS 1 BP 45 EP 45 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA V38PJ UT WOS:000209355000012 ER PT J AU Borba, CPC DePadilla, L McCarty, FA von Esenwein, SA Druss, BG Sterk, CE AF Borba, Christina P. C. DePadilla, Lara McCarty, Frances A. von Esenwein, Silke A. Druss, Benjamin G. Sterk, Claire E. TI A Qualitative Study Examining the Perceived Barriers and Facilitators to Medical Healthcare Services among Women with a Serious Mental Illness SO WOMENS HEALTH ISSUES LA English DT Article AB Objective: This qualitative study investigates the barriers and facilitators to accessing and utilizing healthcare services among women with a serious mental illness (SMI). Methods: A purposive sample of 30 poor, urban, predominantly African-American women with a diagnosis of an SMI was recruited. Interviews were audio-taped and transcribed verbatim. Data analysis was guided by a modified constant comparison approach. Results: The findings highlight a variety of nonmedical factors that serve as both barriers and facilitators to accessing and utilizing medical healthcare services, such as a trusting relationship with a mental health provider and a women's social network. Conclusion: Nonmedical factors and personal circumstances seem to be important factors influencing pathways to healthcare services among women with an SMI. Efforts to better engage and retain women with an SMI into healthcare will need to better acknowledge and incorporate the larger social context of the women's lives. Copyright (C) 2012 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Borba, Christina P. C.; DePadilla, Lara; Druss, Benjamin G.; Sterk, Claire E.] Emory Univ, Rollins Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. [Borba, Christina P. C.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [McCarty, Frances A.] Georgia State Univ, Coll Hlth & Human Sci, Inst Publ Hlth, Atlanta, GA 30303 USA. [von Esenwein, Silke A.; Druss, Benjamin G.] Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. RP Borba, CPC (reprint author), 25 Staniford St, Boston, MA 02114 USA. EM cborba@partners.org NR 51 TC 12 Z9 12 U1 2 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 MAR-APR PY 2012 VL 22 IS 2 BP E217 EP E224 DI 10.1016/j.whi.2011.10.001 PG 8 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33SQ UT WOS:000209038900015 PM 22172651 ER PT J AU Oshima, M Deitiker, PR Smith, RG Mosier, D Atassi, MZ AF Oshima, Minako Deitiker, Philip R. Smith, R. Glenn Mosier, Dennis Atassi, M. Zouhair TI T-cell recognition of acetylcholine receptor provides a reliable means for monitoring autoimmunity to acetylcholine receptor in antibody-negative myasthenia gravis patients SO AUTOIMMUNITY LA English DT Article DE Myasthenia gravis; acetylcholine receptor; seronegative; T cells; synthetic peptides ID PERIPHERAL-BLOOD LYMPHOCYTES; HIGH-RESOLUTION; ALPHA-SUBUNIT; IN-VITRO; HLA-DQ; EXTRACELLULAR PART; CHAIN PEPTIDES; UNITED-STATES; ASSOCIATION; DQB1-ASTERISK-0502 AB Myasthenia gravis (MG) is an autoimmune disease usually associated with autoantibodies (auto-Abs) against nicotinic acetylcholine receptor (AChR). Some MG patients appear negative for anti-AChR Abs (seronegative), and a fraction of these have auto-Abs against muscle-specific kinase. The remaining patients, although displaying MG symptoms, show no detectable auto-Abs. We describe here a possible association of a rare human leukocyte antigen (HLA)-DQ type and AChR Ab-negative MG. We also found that the majority of seronegative patients exhibit an anti-AChR autoimmune T lymphocyte response. We investigated the existence of AChR-reactive T cells in peripheral blood lymphocytes from seronegative patients by their proliferative responses against a mixture of 18 overlapping synthetic peptides encompassing the extracellular part of human AChR a-chain. Of the 10 samples, eight exhibited positive T-cell proliferative responses against the peptide mixtures. The proliferative assay was equally efficient using a mixture of eight peptides frequently recognized by MG T cells. This T-cell proliferative assay should provide a reliable method for monitoring seronegative MG patients. C1 [Oshima, Minako; Deitiker, Philip R.; Atassi, M. Zouhair] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Smith, R. Glenn] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA. [Mosier, Dennis] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Atassi, M. Zouhair] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA. [Mosier, Dennis] ME DeBakey VA Med Ctr, Neurol Serv, Houston, TX 77030 USA. [Mosier, Dennis] ME DeBakey VA Med Ctr, Med Res Serv, Houston, TX 77030 USA. RP Atassi, MZ (reprint author), Baylor Coll Med, Dept Biochem & Mol Biol, 1 Baylor Plaza,BCM125, Houston, TX 77030 USA. EM matassi@bcm.edu FU Muscular Dystrophy Association; Welch Foundation [Q-0007] FX This study was partly supported by grants from the Muscular Dystrophy Association. The support of the Welch Foundation (Grant Q-0007), due to the award to M.Z. Atassi of the Robert A. Welch Chair of Chemistry, is also gratefully acknowledged. NR 31 TC 6 Z9 9 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0891-6934 J9 AUTOIMMUNITY JI Autoimmunity PD MAR PY 2012 VL 45 IS 2 BP 153 EP 160 DI 10.3109/08916934.2011.611550 PG 8 WC Immunology SC Immunology GA 885AA UT WOS:000299748800005 PM 21985279 ER PT J AU Yu, HE Hawash, K Picker, J Stoler, J Urion, D Wu, BL Shen, Y AF Yu, H. E. Hawash, K. Picker, J. Stoler, J. Urion, D. Wu, B-L Shen, Y. TI A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism SO CLINICAL GENETICS LA English DT Article DE 2q13-autism spectrum disorders; developmental delay; DNA copy number variant; dysmorphism ID COPY NUMBER; MICRODELETION SYNDROMES; REARRANGEMENTS; DIAGNOSIS; AUTISM; BCL-2 AB Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Many of these genomic imbalances have since been shown to associate with developmental delay, intellectual disability and congenital malformation. Here we identified five unrelated individuals who have a recurrent 1.71 Mb deletion/ duplication at 2q13 (Human Genome Build 19: 111,392,197-113,102,594). Four of these individuals have developmental issues, four have cranial dysmorphism. Literature review revealed 14 more cases that had similar genomic imbalances at 2q13. Many of them had developmental delay and dysmorphism. Taken together, 93% and 63% of individuals with this genomic imbalance displayed impaired developmental skills and/ or abnormal facial features respectively. This copy number variant (CNV) has not been reported in normal control databases. We, therefore, propose that CNV in this region is a risk factor for developmental delay and dysmorphism. C1 [Yu, H. E.; Wu, B-L; Shen, Y.] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Hawash, K.; Urion, D.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Hawash, K.; Picker, J.; Stoler, J.; Urion, D.; Wu, B-L; Shen, Y.] Harvard Univ, Sch Med, Boston, MA USA. [Picker, J.; Stoler, J.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Wu, B-L] Fudan Univ, Shanghai 200433, Peoples R China. [Shen, Y.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Shen, Y (reprint author), Geisinger Hlth Syst, Dept Lab Med, Danville, PA 17822 USA. EM yiping.shen@childrens.harvard.edu FU Genetic Diagnostic Laboratory at Children's Hospital Boston; Children's Tumor Foundation; Harvard Medical School; Fudan University; Chinese National "973" project on Population and Health [2010CB529601]; Science and Technology Council of Shanghai [09JC1402400] FX The authors thank the members of the Genetic Diagnostic Laboratory at Children's Hospital Boston for support. Y. S. holds a Young Investigator Award from the Children's Tumor Foundation and Catalyst Award from Harvard Medical School. B. L. W. holds a Fudan Scholar Research Award from Fudan University and a grant from Chinese National "973" project on Population and Health (Grant Number: 2010CB529601) and a grant from Science and Technology Council of Shanghai (Grant Number: 09JC1402400.) NR 21 TC 17 Z9 18 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD MAR PY 2012 VL 81 IS 3 BP 257 EP 264 DI 10.1111/j.1399-0004.2011.01637.x PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 884HB UT WOS:000299694400008 PM 21255006 ER PT J AU Cayabyab, MJ Kashino, SS Campos-Neto, A AF Cayabyab, Mark J. Kashino, Suely S. Campos-Neto, Antonio TI Robust immune response elicited by a novel and unique Mycobacterium tuberculosis protein using an optimized DNA/protein heterologous prime/boost protocol SO IMMUNOLOGY LA English DT Article DE Mycobacterium tuberculosis; prime; boost; vaccine ID BACILLE CALMETTE-GUERIN; VACCINIA VIRUS ANKARA; T-CELL RESPONSES; ACTIVE PULMONARY TUBERCULOSIS; CROSS-PRESENTATION; ENHANCED IMMUNOGENICITY; PROTECTIVE EFFICACY; EXOGENOUS ANTIGENS; DENDRITIC CELLS; LEUKEMIA-VIRUS AB An efficacious tuberculosis (TB) vaccine will probably need to induce both CD4 and CD8 T-cell responses specific to a protective Mycobacterium tuberculosis antigen(s). To achieve this broad cellular immune response we tested a heterologous DNA/protein combination vaccine strategy. We used a purified recombinant protein preparation of a unique M. tuberculosis antigen (rMT1721) found in the urine of TB patients, an optimized plasmid DNA expressing this protein (DNA-MT1721), and a Toll-like receptor 4 agonist adjuvant. We found that priming mice with DNA-MT1721 and subsequently boosting with rMT1721 elicited high titres of specific IgG1 and IgG2a antibodies as well as high magnitude and polyfunctional CD4+ T-cell responses. However, no detectable CD8+ T-cell response was observed using this regimen of immunization. In contrast, both CD4+ and CD8+ T-cell responses were detected after a prime/boost vaccination regimen using rMT1721 as the priming antigen and DNA-MT1721 as the boosting immunogen. These findings support the exploration of heterologous DNA/protein immunization strategies in vaccine development against TB and possibly other infectious diseases. C1 [Cayabyab, Mark J.; Kashino, Suely S.; Campos-Neto, Antonio] Forsyth Inst, Global Infect Dis Res Ctr, Cambridge, MA 02142 USA. [Cayabyab, Mark J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Campos-Neto, A (reprint author), Forsyth Inst, Global Infect Dis Res Ctr, 245 1st St, Cambridge, MA 02142 USA. EM acampos@forsyth.org RI Kashino, Suely/F-4171-2012 FU Colorado State University (NIAID/NIH) [1-A125174]; National Institutes of Health [R01 AI076425] FX We thank Dr John Beslile, Dr Angelo Izzo and Dr Karen Dobos, Colorado State University (NIAID/NIH Tuberculosis Research Materials contract no. 1-A125174), for kindly supplying M. tuberculosis culture filtrate proteins and Dr Lizeng Qin for his expert help with the intracellular cytokine staining assay and analysis.; This work was supported by the following grant from the National Institutes of Health: R01 AI076425 to A. Campos-Neto. NR 42 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD MAR PY 2012 VL 135 IS 3 BP 216 EP 225 DI 10.1111/j.1365-2567.2011.03525.x PG 10 WC Immunology SC Immunology GA 880PC UT WOS:000299418400005 PM 22043824 ER PT J AU Hardy, DC Ross, JH Schuyler, CA Leite, RS Slate, EH Huang, Y AF Hardy, Douglas C. Ross, Jonathan H. Schuyler, Corinne A. Leite, Renata S. Slate, Elizabeth H. Huang, Yan TI Matrix metalloproteinase-8 expression in periodontal tissues surgically removed from diabetic and non-diabetic patients with periodontal disease SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE diabetes mellitus; gene expression; metalloproteinase-8; periodontal diseases ID GINGIVAL CREVICULAR FLUID; NEUTROPHIL COLLAGENASE ACTIVITY; CHAIR-SIDE TEST; IN-VIVO; MMP-8; INTERLEUKIN-6; LIPOPOLYSACCHARIDE; MELLITUS; OBESITY; CELLS AB Background: Although it is known that periodontal matrix metalloproteinase-8 (MMP-8) expression is associated with periodontal disease, the information concerning the periodontal MMP-8 expression in diabetic patients with periodontal disease is insufficient. Materials and Methods: Periodontal tissue specimens were collected from seven patients without periodontal disease and diabetes (Group 1), 15 patients with periodontal disease alone (Group 2) and 10 patients with both periodontal disease and diabetes (Group 3). The frozen sections were prepared and MMP-8 protein expression was detected using immunohistochemistry and quantified. For in vitro study, human U937 mononuclear cells were pre-exposed to normal or high glucose and then treated with lipopolysaccharide (LPS). Results: The nonparametric Kruskal-Wallis test showed that the difference in MMP-8 protein levels among the three groups were statistically significant (p = 0.003). Nonparametric analysis using Jonckheere-Terpstra test showed a tendency of increase in periodontal MMP-8 levels across Group 1 to Group 2 to Group 3 (p = 0.0002). In vitro studies showed that high glucose and LPS had a synergistic effect on MMP-8 expression. Conclusion: Our current study showed an increasing trend in MMP-8 protein expression levels across patients without both periodontal disease and diabetes, patients with periodontal disease alone and patients with both diseases. C1 [Huang, Yan] Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29403 USA. [Hardy, Douglas C.; Ross, Jonathan H.] Med Univ S Carolina, Coll Dent Med, Dept Stomatol, Div Periodont, Charleston, SC 29403 USA. [Leite, Renata S.; Slate, Elizabeth H.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29403 USA. [Huang, Yan] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29403 USA. RP Huang, Y (reprint author), Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Affairs Med Ctr, 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU NIH [DE016353]; Department of Veterans Affairs FX There is no conflict of interest to declare. This study was supported by NIH grant DE016353 and Merit Review Grant from Department of Veterans Affairs (to Y. H.). NR 40 TC 10 Z9 13 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD MAR PY 2012 VL 39 IS 3 BP 249 EP 255 DI 10.1111/j.1600-051X.2011.01788.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 883LM UT WOS:000299635500005 PM 22092744 ER PT J AU Oliveira, APD de Faveri, M Gursky, LC Mestnik, MJ Feres, M Haffajee, AD Socransky, SS Teles, RP AF de Lima Oliveira, Ana Paula de Faveri, Marcelo Gursky, Lauren Christine Mestnik, Maria Josefa Feres, Magda Haffajee, Anne D. Socransky, Sigmund S. Teles, Ricardo Palmier TI Effects of periodontal therapy on GCF cytokines in generalized aggressive periodontitis subjects SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE cytokines; gingival crevicular fluid; periodontal disease; periodontal therapy ID GINGIVAL CREVICULAR FLUID; TUMOR-NECROSIS-FACTOR; PORPHYROMONAS-GINGIVALIS; CLINICAL-PARAMETERS; PROGRESSIVE PERIODONTITIS; NONSURGICAL TREATMENT; ADULT PERIODONTITIS; BONE-RESORPTION; INTERLEUKIN-1-BETA; METRONIDAZOLE AB Aim: To examine changes in levels of gingival crevicular fluid (GCF) cytokines, after periodontal therapy of generalized aggressive periodontitis (GAgP). Materials and Methods: Twenty-five periodontally healthy and 24 GAgP subjects had periodontal clinical parameters measured and gingival crevicular fluid (GCF) samples collected from up to 14 sites/subject. GCF samples were analysed using multiplex bead immunoassay for: GM-CSF, IFN-gamma, IL-10, IL-1 beta, IL-2, IL-6 and TNF-alpha. Aggressive periodontitis subjects were randomly assigned to either scaling and root planing (SRP) alone or SRP plus systemic amoxicillin (500 mg) and metronidazole (400 mg) 3 times a day for 14 days. Clinical parameters and GCF cytokines were re-measured 6 months after treatment. Differences over time were analysed using the Wilcoxon test and between groups using the Mann-Whitney test. Results: Significant reductions in GCF GM-CSF, IL-1 beta and the ratio IL-1 beta/IL-10 and increases in GCF IL-6 were detected after therapy. The mean change in GCF cytokines did not differ significantly between groups. Conclusions: Periodontal therapy improved GCF cytokine profiles by lowering IL-1 beta and increasing IL-10 levels. The reduction in GCF GM-CSF after therapy implicates this cytokine in the pathogenesis of GAgP. There was no difference between therapies in changes of GCF cytokines. C1 [Teles, Ricardo Palmier] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [de Lima Oliveira, Ana Paula] Univ Fed Minas Gerais, Sch Dent, Dept Periodontol, Belo Horizonte, MG, Brazil. [de Faveri, Marcelo; Mestnik, Maria Josefa; Feres, Magda] Univ Guarulhos, Dept Periodontol, Dent Res Div, Guarulhos, SP, Brazil. [Gursky, Lauren Christine] Pontificia Univ Catolica Parana, Sch Dent, Curitiba, PR, Brazil. [Teles, Ricardo Palmier] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Teles, RP (reprint author), Forsyth Inst, Dept Periodontol, 245 1st St, Cambridge, MA 02142 USA. EM rteles@forsyth.org RI Faveri, Marcelo/C-4738-2012; Oliveira, Ana Paula/M-6700-2013; Feres, Magda/H-7964-2012 OI Oliveira, Ana Paula/0000-0001-6532-1700; FU NIDCR [U01 DE021127]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil) [2007/56413-0] FX This study was supported in part by NIDCR grant U01 DE021127 and by grant 2007/56413-0 from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Brazil). NR 41 TC 29 Z9 32 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD MAR PY 2012 VL 39 IS 3 BP 295 EP 302 DI 10.1111/j.1600-051X.2011.01817.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 883LM UT WOS:000299635500010 PM 22126282 ER PT J AU Poynter, JN Hooten, AJ Frazier, AL Ross, JA AF Poynter, Jenny N. Hooten, Anthony J. Frazier, A. Lindsay Ross, Julie A. TI Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors SO GENES CHROMOSOMES & CANCER LA English DT Article ID TESTIS DIFFERENTIATION; MAMMALIAN TESTIS; UNITED-STATES; CANCER; MOUSE; FETAL; SUSCEPTIBILITY; PROLIFERATION; MIGRATION; MIDLINE AB Recent genome wide association studies have identified susceptibility loci for adult testicular germ cell tumors (GCT) near KITLG, SPRY4, BAK1, and DMRT1. We evaluated variants in these four genes to determine whether these are also susceptibility loci for pediatric GCTs. DNA was isolated from 52 pediatric GCTs (ages 021 years) obtained from the Cooperative Human Tissue Network. Control DNA was isolated from de-identified dried blood spots from 141 white newborns. Genotyping was conducted using TaqMan assays (rs4474514) or by PCR and sequencing (rs4324715, rs210138, and rs755383). Associations between variants and GCT were evaluated using logistic regression with adjustment for sex. We also evaluated whether the associations differed by age at GCT diagnosis (09 years, 1021 years), sex, and tumor location (gonadal, non-gonadal). We observed a significant association for rs210138 (BAK1) and pediatric GCT overall (odds ratio (OR) = 1.80, 95% confidence interval (CI) 1.102.95, P = 0.02) with non-significant associations similar in magnitude in both the pediatric (P = 0.09) and adolescent (P = 0.06) age groups. The KITLG (rs4474514) and SPRY4 (rs4324715) variants were significantly associated with GCT only in the adolescent age group (rs4474514: OR = 2.28, 95% CI 1.094.79, P = 0.03 and rs4324715: OR = 2.40, 95% CI 1.194.83, P = 0.01). Associations were mostly similar when stratified by sex. This is the first study to suggest that these loci may also be important in susceptibility to GCTs in the adolescent (KITLG, SPRY4, and BAK1) and pediatric (BAK1) age groups. (c) 2011 Wiley Periodicals, Inc. C1 [Poynter, Jenny N.; Ross, Julie A.] Univ Minnesota, Div Pediat Epidemiol & Clin Res, Dept Pediat, Minneapolis, MN 55455 USA. [Poynter, Jenny N.; Hooten, Anthony J.; Ross, Julie A.] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN 55455 USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Poynter, JN (reprint author), Univ Minnesota, Div Pediat Epidemiol & Clin Res, Dept Pediat, 420 Delaware St SE,MMC 715, Minneapolis, MN 55455 USA. EM poynt006@umn.edu FU Children's Cancer Research Fund FX Supported by: Children's Cancer Research Fund. NR 28 TC 17 Z9 17 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAR PY 2012 VL 51 IS 3 BP 266 EP 271 DI 10.1002/gcc.20951 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 873JU UT WOS:000298880000007 PM 22072546 ER PT J AU Cianchetti, M Varvares, MA Deschler, DG Liebsch, NJ Wang, JJ Chan, ANW AF Cianchetti, Marco Varvares, Mark A. Deschler, Daniel G. Liebsch, Nobert J. Wang, Jing J. Chan, Annie W. TI Risk of sinonasal-cutaneous fistula after treatment for advanced sinonasal cancer SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) CY OCT 31-NOV 04, 2010 CL San Diego, CA SP Amer Soc Therapeut Radiol & Oncol (ASTRO) DE fistula; sinonasal malignancy; paranasal sinus cancer; craniofacial resection; radiation ID PARANASAL SINUSES; RADIATION-THERAPY; NECK-CANCER; CARCINOMA; HEAD; RECONSTRUCTION; RADIOTHERAPY; TUMORS; FLAP AB Background and Objectives To determine the rate and the risk factors for sinonasal-cutaneous fistula formation after treatment for sinonasal malignancy. Methods: Between 1991 and 2002, 99 patients with advanced sinonasal malignancy received radiation therapy +/- surgery. Primary site was maxillary sinus in 30, ethmoid sinus in 19, nasal cavity in 32, nasopharynx in 3, and sphenoid sinus in 15 patients. Eighty-two percent of patients had T4 disease. Sixty-eight percent of patients had undergone surgical resection. Median follow-up was 70.6 months. Results: Eight patients developed >= grade 3 sinonasal-cutaneous fistulas at a median time of 3.8 months after radiation. The overall rates of developing >= grade 3 fistulas in the entire group at 2 and 5 years were 6% and 10%, respectively. The fistulas were in the medial canthus in seven patients and in the infraorbital region in one patient. Fistulas developed exclusively along the transfacial incision scar and in patients whose tumors extended to the subcutaneous tissues. In univariate analysis, squamous cell carcinoma histology (P = 0.008), <= T4a primary tumor category (P = 0.02), and transfacial incision (P = 0.02) were associated with increased risk of fistula formation. Conclusions: Histologic subtype, T category, and quality of the skin and the underlying supporting tissues after transfacial incision are risk factors for sinonasal-cutaneous fistula formation. J. Surg. Oncol. 2012;105:261-265. (C) 2011 Wiley Periodicals, Inc. C1 [Cianchetti, Marco; Liebsch, Nobert J.; Wang, Jing J.; Chan, Annie W.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Varvares, Mark A.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Varvares, Mark A.; Deschler, Daniel G.; Liebsch, Nobert J.; Chan, Annie W.] Harvard Univ, Sch Med, Boston, MA USA. RP Chan, ANW (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St,Cox 337, Boston, MA 02114 USA. EM awchan@partners.org NR 14 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD MAR PY 2012 VL 105 IS 3 BP 261 EP 265 DI 10.1002/jso.22062 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 879ZV UT WOS:000299374300009 PM 22375288 ER PT J AU Ryu, KY Park, H Rossi, DJ Weissman, IL Kopito, RR AF Ryu, Kwon-Yul Park, Hyejin Rossi, Derrick J. Weissman, Irving L. Kopito, Ron R. TI Perturbation of the Hematopoietic System during Embryonic Liver Development Due to Disruption of Polyubiquitin Gene Ubc in Mice SO PLOS ONE LA English DT Article ID UBIQUITIN-PROTEASOME SYSTEM; STEM-CELLS; DEFICIENCIES; DEGRADATION; PROGRESSION; LACKING AB Disruption of the polyubiquitin gene Ubc leads to a defect in fetal liver development, which can be partially rescued by increasing the amount of ubiquitin. However, it is still not known why Ubc is required for fetal liver development and the nature of the defective cell types responsible for embryonic lethality have not been characterized. In this study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoietic system. We found that Ubc was highly expressed in the embryonic liver, and the proliferation capacity of fetal liver cells was reduced in Ubc(-/-) embryos. Specifically, Ubc was most highly expressed in hematopoietic cells, and the proliferation capacity of hematopoietic cells was significantly impaired in Ubc(-/-) embryos. While hematopoietic cell and hematopoietic stem cell (HSC) frequency was maintained in Ubc(-/-) embryos, the absolute number of these cells was diminished because of reduced total liver cell number in Ubc(-/-) embryos. Transplantations of fetal liver cells into lethally irradiated recipient mice by non-competitive and competitive reconstitution methods indicated that disruption of Ubc does not significantly impair the intrinsic function of fetal liver HSCs. These findings suggest that disruption of Ubc reduces the absolute number of HSCs in embryonic livers, but has no significant effect on the autonomous function of HSCs. Thus, the lethality of Ubc(-/-) embryos is not the result of intrinsic HSC failure. C1 [Ryu, Kwon-Yul; Park, Hyejin] Univ Seoul, Dept Life Sci, Seoul, South Korea. [Rossi, Derrick J.] Harvard Univ, Sch Med, Immune Dis Inst, Harvard Stem Cell Inst, Boston, MA USA. [Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Weissman, Irving L.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Kopito, Ron R.] Stanford Univ, Dept Biol, Stanford, CA 94305 USA. RP Ryu, KY (reprint author), Univ Seoul, Dept Life Sci, Seoul, South Korea. EM kyryu@uos.ac.kr FU National Research Foundation of Korea; Ministry of Education, Science and Technology [20100009065, 20110004618] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (20100009065 & 20110004618, http://www.nrf.re.kr/html/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 29 PY 2012 VL 7 IS 2 AR e32956 DI 10.1371/journal.pone.0032956 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928SI UT WOS:000303003500114 PM 22393459 ER PT J AU Sinha, AU Armstrong, SA AF Sinha, Amit U. Armstrong, Scott A. TI iCanPlot: Visual Exploration of High-Throughput Omics Data Using Interactive Canvas Plotting SO PLOS ONE LA English DT Article AB Increasing use of high throughput genomic scale assays requires effective visualization and analysis techniques to facilitate data interpretation. Moreover, existing tools often require programming skills, which discourages bench scientists from examining their own data. We have created iCanPlot, a compelling platform for visual data exploration based on the latest technologies. Using the recently adopted HTML5 Canvas element, we have developed a highly interactive tool to visualize tabular data and identify interesting patterns in an intuitive fashion without the need of any specialized computing skills. A module for geneset overlap analysis has been implemented on the Google App Engine platform: when the user selects a region of interest in the plot, the genes in the region are analyzed on the fly. The visualization and analysis are amalgamated for a seamless experience. Further, users can easily upload their data for analysis-which also makes it simple to share the analysis with collaborators. We illustrate the power of iCanPlot by showing an example of how it can be used to interpret histone modifications in the context of gene expression. C1 [Sinha, Amit U.; Armstrong, Scott A.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Hematol Oncol, Boston, MA 02115 USA. [Sinha, Amit U.; Armstrong, Scott A.] Harvard Univ, Sch Med, Boston, MA USA. [Armstrong, Scott A.] Harvard Stem Cell Inst, Boston, MA USA. RP Sinha, AU (reprint author), Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Div Hematol Oncol, Boston, MA 02115 USA. EM amit.sinha@childrens.harvard.edu; scott.armstrong@childrens.harvard.edu FU Charles H. Hood Foundation; Leukemia and Lymphoma Society FX This work was supported in part by the Charles H. Hood Foundation and the Leukemia and Lymphoma Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. NR 10 TC 7 Z9 7 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 29 PY 2012 VL 7 IS 2 AR e31690 DI 10.1371/journal.pone.0031690 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928SI UT WOS:000303003500020 PM 22393367 ER PT J AU Zhang, N Zhang, SL Szostak, JW AF Zhang, Na Zhang, Shenglong Szostak, Jack W. TI Activated Ribonucleotides Undergo a Sugar Pucker Switch upon Binding to a Single-Stranded RNA Template SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PROTON-MAGNETIC-RESONANCE; DIRECTED SYNTHESIS; HAIRPIN OLIGONUCLEOTIDES; DNA; OLIGOMERIZATION; CONFORMATION; NUCLEOTIDES; GUANOSINE; RESIDUES; LIGANDS AB Template-directed polymerization of chemically activated ribonucleotide monomers, such as nucleotide 5'-phosphorimidazolides, has been studied as a model for nonenzymatic RNA replication during the origin of life. Kinetic studies of the polymerization of various nucleotide monomers on oligonucleotide templates have suggested that the A-form (C3'-endo sugar pucker) conformation is optimal for both monomers and templates for efficient copying. However, RNA monomers are predominantly in the C2'-endo conformation when free in solution, except for cytidine, which is approximately equally distributed between the C2'-endo and C3'-endo conformations. We hypothesized that ribonucleotides undergo a switch in sugar pucker upon binding to an A-type template and that this conformational switch allows or enhances subsequent polymerization. We used transferred nuclear Overhauser effect spectroscopy (TrNO-ESY), which can be used for specific detection of the bound conformation of small-molecule ligands with relatively weak affinity to receptors, to study the interactions between nucleotide 5'-phosphorimidazolides and single-stranded oligonucleotide templates. We found that the sugar pucker of activated ribonucleotides switches from C2'-endo in the free state to C3'-endo upon binding to an RNA template. This switch occurs only on RNA and not on DNA templates. Furthermore, activated 2'-deoxyribonucleotides maintain a C2'-endo sugar pucker in both the free and template-bound states. Our results provide a structural explanation for the observations that activated ribonucleotides are superior to activated deoxyribonucleotides and that RNA templates are superior to DNA templates in template-directed nonenzymatic primer-extension reactions. C1 [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU F [CHE-0809413] FX We are grateful to Itay Budin, Ting Zhu, and Aaron Engelhart for helpful discussions and comments on the manuscript. 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. NR 29 TC 20 Z9 20 U1 1 U2 28 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 FEB 29 PY 2012 VL 134 IS 8 BP 3691 EP 3694 DI 10.1021/ja212027q PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 903ZE UT WOS:000301161600020 PM 22296305 ER PT J AU Sabolek, HR Swiercz, WB Lillis, KP Cash, SS Huberfeld, G Zhao, G Ste Marie, L Clemenceau, S Barsh, G Miles, R Staley, KJ AF Sabolek, Helen R. Swiercz, Waldemar B. Lillis, Kyle P. Cash, Sydney S. Huberfeld, Gilles Zhao, Grace Ste Marie, Linda Clemenceau, Stephane Barsh, Greg Miles, Richard Staley, Kevin J. TI A Candidate Mechanism Underlying the Variance of Interictal Spike Propagation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TEMPORAL-LOBE EPILEPSY; SYNCHRONIZED HIPPOCAMPAL BURSTS; RECURRENT COLLATERAL SYNAPSES; CA3 NETWORK ACTIVITY; EPILEPTIFORM ACTIVITY; RAT HIPPOCAMPUS; IN-VITRO; GABAERGIC INHIBITION; SURROUND INHIBITION; ORGANOTYPIC CULTURE AB Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited. C1 [Sabolek, Helen R.; Swiercz, Waldemar B.; Lillis, Kyle P.; Cash, Sydney S.; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sabolek, Helen R.; Swiercz, Waldemar B.; Lillis, Kyle P.; Cash, Sydney S.; Staley, Kevin J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Huberfeld, Gilles; Clemenceau, Stephane; Miles, Richard] Univ Paris 06, Inst Cerveau Moelle, Cortex & Epilepsy Lab,CNRS,UMR7225, Inst Natl Sante & Rech Med,Ctr Rech,UMRS975, F-75654 Paris, France. [Huberfeld, Gilles; Clemenceau, Stephane; Miles, Richard] Hop La Pitie Salpetriere, AP HP, Epilepsy Unit, F-75013 Paris, France. [Huberfeld, Gilles; Clemenceau, Stephane; Miles, Richard] UPMC, F-75005 Paris, France. [Zhao, Grace] Stanford Univ, Dept Neurobiol, Palo Alto, CA 94304 USA. [Ste Marie, Linda; Barsh, Greg] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA. RP Staley, KJ (reprint author), Massachusetts Gen Hosp, 114 16th St,Room 2600, Boston, MA 02129 USA. EM kstaley@partners.org FU NIH [5R01NS034700, 1R01NS074772] FX This work was supported by NIH Grants 5R01NS034700 and 1R01NS074772. NR 75 TC 24 Z9 24 U1 1 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 29 PY 2012 VL 32 IS 9 BP 3009 EP 3021 DI 10.1523/JNEUROSCI.5853-11.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 901CA UT WOS:000300938100009 PM 22378874 ER PT J AU Hudry, E Wu, HY Arbel-Ornath, M Hashimoto, T Matsouaka, R Fan, ZY Spires-Jones, TL Betensky, RA Bacskai, BJ Hyman, BT AF Hudry, Eloise Wu, Hai-Yan Arbel-Ornath, Michal Hashimoto, Tadafumi Matsouaka, Roland Fan, Zhanyun Spires-Jones, Tara L. Betensky, Rebecca A. Bacskai, Brian J. Hyman, Bradley T. TI Inhibition of the NFAT Pathway Alleviates Amyloid Beta Neurotoxicity in a Mouse Model of Alzheimer's Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM DEPRESSION; IN-VIVO; DENDRITIC SPINES; TRANSGENIC MICE; SYNAPSE LOSS; MULTIPHOTON MICROSCOPY; NERVOUS-SYSTEM; AD BRAIN; CALCINEURIN; PROTEIN AB Amyloid beta (A beta) peptides, the main pathological species associated with Alzheimer's disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by A beta leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without A beta. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by A beta exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in A beta-related neurotoxicity. In vivo, when VIVIT or its nuclear counterpart were overexpressed in a transgenic model of Alzheimer's disease via a gene therapy approach, the spine loss and neuritic abnormalities observed in the vicinity of amyloid plaques were blocked. Overall, these results suggest that NFAT/calcineurin transcriptional cascades contribute to A beta synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies. C1 [Hudry, Eloise; Wu, Hai-Yan; Arbel-Ornath, Michal; Hashimoto, Tadafumi; Fan, Zhanyun; Spires-Jones, Tara L.; Bacskai, Brian J.; Hyman, Bradley T.] Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol, Charlestown, MA 02129 USA. [Matsouaka, Roland; Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Hyman, BT (reprint author), Massachusetts Gen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org RI Hashimoto, Tadafumi/A-7723-2013; OI Spires-Jones, Tara/0000-0003-2530-0598 FU National Institutes of Health [AG08487, EB000768, EY13399]; Harvard Medical School; French Bettencourt-Schueller award FX This work was supported by National Institutes of Health Grants AG08487, EB000768, and EY13399, the Lefler fellowship (Harvard Medical School), and the French Bettencourt-Schueller award for young scientists. We thank Dr. Norris (Sanders-Brown Center on Aging, Lexington, KY) for providing the VIVIT-GFP constructs and Dr. Ruthazer (Montreal Neurological Institute, McGill University, Montreal, QC, Canada) for providing the NLS-VIVIT-GFP plasmid. We thank Dr. Alberto Serrano-Pozo for helpful comments during manuscript preparation and Daniel Joyner for primary neuron preparation. NR 63 TC 32 Z9 33 U1 1 U2 10 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 FEB 29 PY 2012 VL 32 IS 9 BP 3176 EP 3192 DI 10.1523/JNEUROSCI.6439-11.2012 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 901CA UT WOS:000300938100025 PM 22378890 ER PT J AU Soghoian, DZ Jessen, H Flanders, M Sierra-Davidson, K Cutler, S Pertel, T Ranasinghe, S Lindqvist, M Davis, I Lane, K Rychert, J Rosenberg, ES Piechocka-Trocha, A Brass, AL Brenchley, JM Walker, BD Streeck, H AF Soghoian, Damien Z. Jessen, Heiko Flanders, Michael Sierra-Davidson, Kailan Cutler, Sam Pertel, Thomas Ranasinghe, Srinika Lindqvist, Madelene Davis, Isaiah Lane, Kimberly Rychert, Jenna Rosenberg, Eric S. Piechocka-Trocha, Alicja Brass, Abraham L. Brenchley, Jason M. Walker, Bruce D. Streeck, Hendrik TI HIV-Specific Cytolytic CD4 T Cell Responses During Acute HIV Infection Predict Disease Outcome SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VIRUS TYPE-1 INFECTION; IMMUNODEFICIENCY-VIRUS; EFFECTOR FUNCTIONS; VIREMIA; REPLICATION; MACROPHAGES; MACAQUES; NEF; GAG; ASSOCIATION AB Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells-besides their helper function-have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses-but not CD8 T cell responses-compared to subjects who progressed to a high viral set point (P = 0.038). Markedly, this expansion occurred before differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of granzyme A(+) HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/mu l was 575 versus 306, P = 0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of granzyme A(+) HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication. C1 [Soghoian, Damien Z.; Flanders, Michael; Sierra-Davidson, Kailan; Cutler, Sam; Pertel, Thomas; Ranasinghe, Srinika; Lindqvist, Madelene; Davis, Isaiah; Lane, Kimberly; Piechocka-Trocha, Alicja; Brass, Abraham L.; Walker, Bruce D.; Streeck, Hendrik] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. [Soghoian, Damien Z.; Flanders, Michael; Sierra-Davidson, Kailan; Cutler, Sam; Pertel, Thomas; Ranasinghe, Srinika; Lindqvist, Madelene; Davis, Isaiah; Lane, Kimberly; Piechocka-Trocha, Alicja; Brass, Abraham L.; Walker, Bruce D.; Streeck, Hendrik] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Jessen, Heiko] Practice Jessen Jessen Stein, D-10777 Berlin, Germany. [Rychert, Jenna; Rosenberg, Eric S.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Brenchley, Jason M.] NIH, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Streeck, H (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA 02129 USA. EM hstreeck@partners.org OI Pertel, Thomas/0000-0002-2286-6011 FU Charles H. Hood Foundation; Howard Hughes Medical Institute; intramural National Institute of Allergy and Infectious Diseases/NIH; [5P01AI074415-03]; [1R01AI091450-01]; [1R01AI094602-01] FX This study was funded by a supplement to 5P01AI074415-03. H. S. is funded by 1R01AI091450-01 and 1R01AI094602-01. A. L. B. and T. P. are funded by the Charles H. Hood Foundation. B. D. W. and A.P.-T. are supported by the Howard Hughes Medical Institute. J.M.B. is funded by the intramural National Institute of Allergy and Infectious Diseases/NIH program. NR 48 TC 79 Z9 81 U1 3 U2 16 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 29 PY 2012 VL 4 IS 123 AR 123ra25 DI 10.1126/scitranslmed.3003165 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 901GT UT WOS:000300952600004 PM 22378925 ER PT J AU Wood, DK Soriano, A Mahadevan, L Higgins, JM Bhatia, SN AF Wood, David K. Soriano, Alicia Mahadevan, L. Higgins, John M. Bhatia, Sangeeta N. TI A Biophysical Indicator of Vaso-occlusive Risk in Sickle Cell Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID BIOMARKER QUALIFICATION; HEMOGLOBIN; ANEMIA; SEVERITY; MEDICINE; STROKE; ULTRASONOGRAPHY; DEOXYGENATION; BIOMECHANICS; TRANSFUSIONS AB The search for predictive indicators of disease has largely focused on molecular markers. However, biophysical markers, which can integrate multiple pathways, may provide a more global picture of pathophysiology. Sickle cell disease affects millions of people worldwide and has been studied intensely at the molecular, cellular, tissue, and organismal level for a century, but there are still few, if any, markers quantifying the severity of this disease. Because the complications of sickle cell disease are largely due to vaso-occlusive events, we hypothesized that a physical metric characterizing the vaso-occlusive process could serve as an indicator of disease severity. Here, we use a microfluidic device to characterize the dynamics of "jamming," or vaso-occlusion, in physiologically relevant conditions, by measuring a biophysical parameter that quantifies the rate of change of the resistance to flow after a sudden deoxygenation event. Our studies show that this single biophysical parameter could be used to distinguish patients with poor outcomes from those with good outcomes, unlike existing laboratory tests. This biophysical indicator could therefore be used to guide the timing of clinical interventions, to monitor the progression of the disease, and to measure the efficacy of drugs, transfusion, and novel small molecules in an ex vivo setting. C1 [Mahadevan, L.] Harvard Univ, Dept Organism & Evolutionary Biol, Wyss Inst Biol Inspired Engn, Sch Engn & Appl Sci,Dept Phys, Cambridge, MA 02138 USA. [Mahadevan, L.] Harvard Univ, Kavli Inst Nanobio Sci & Technol, Cambridge, MA 02138 USA. [Wood, David K.; Bhatia, Sangeeta N.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Soriano, Alicia] Brigham & Womens Hosp, Special Hematol Lab, Boston, MA 02115 USA. [Mahadevan, L.; Higgins, John M.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Higgins, John M.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Higgins, John M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bhatia, Sangeeta N.] MIT, Howard Hughes Med Inst, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Bhatia, Sangeeta N.] Brigham & Womens Hosp, Div Med, Boston, MA 02115 USA. RP Mahadevan, L (reprint author), Harvard Univ, Dept Organism & Evolutionary Biol, Wyss Inst Biol Inspired Engn, Sch Engn & Appl Sci,Dept Phys, Cambridge, MA 02138 USA. EM lm@seas.harvard.edu; john_higgins@hms.harvard.edu RI Wood, David/P-1998-2015 OI Wood, David/0000-0001-5225-2144 FU Stanford Microfluidics foundry; Massachusetts Institute of Technology Microtechnology Laboratory; National Institute of Biomedical Imaging and Bioengineering National Research Service; Kavli Institute for Nanobio Science and Technology at Harvard; MacArthur Foundation; National Institute of Diabetes and Digestive and Kidney Diseases [DK083242]; Howard Hughes Investigator FX We thank the many patients who donated blood for this study. We thank E. Mandell, R. Jaromin, H. Patel, S. Patel, M. Hames, P. Guglietta, M. Huang, D. Ebb, L. Lampert, C. Markopoulos, and A. Griffin for help in acquiring and testing blood samples. We thank F. Bunn, C. Brugnara, and M. Okam for helpful discussions. All video processing was performed on the Harvard Medical School Orchestra Computing Cluster. We thank the Stanford Microfluidics foundry and the Massachusetts Institute of Technology Microtechnology Laboratory for fabrication support.; Funding: National Institute of Biomedical Imaging and Bioengineering National Research Service Award fellowship (D. K. W.); Kavli Institute for Nanobio Science and Technology at Harvard and MacArthur Foundation (L. M.); and National Institute of Diabetes and Digestive and Kidney Diseases grant DK083242 (J.M.H.). S.N.B. is a Howard Hughes Investigator. NR 58 TC 23 Z9 23 U1 2 U2 19 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 FEB 29 PY 2012 VL 4 IS 123 AR 123ra26 DI 10.1126/scitranslmed.3002738 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 901GT UT WOS:000300952600005 PM 22378926 ER PT J AU Rice, WL Zhang, Y Chen, Y Matsuzaki, T Brown, D Lu, HAJ AF Rice, William L. Zhang, Yan Chen, Ying Matsuzaki, Toshiyuki Brown, Dennis Lu, Hua A. Jenny TI Differential, Phosphorylation Dependent Trafficking of AQP2 in LLC-PK1 Cells SO PLOS ONE LA English DT Article ID WATER CHANNEL AQUAPORIN-2; RENAL EPITHELIAL-CELLS; NEPHROGENIC DIABETES-INSIPIDUS; COLLECTING DUCT CELLS; PLASMA-MEMBRANE; PRINCIPAL CELLS; ENDOPLASMIC-RETICULUM; SURFACE EXPRESSION; APICAL MEMBRANE; IN-VIVO AB The kidney maintains water homeostasis by modulating aquaporin 2 (AQP2) on the plasma membrane of collecting duct principal cells in response to vasopressin (VP). VP mediated phosphorylation of AQP2 at serine 256 is critical for this effect. However, the role of phosphorylation of other serine residues in the AQP2 C-terminus is less well understood. Here, we examined the effect of phosphorylation of S256, S261 and S269 on AQP2 trafficking and association with recycling pathway markers. We used LLC-PK1 cells expressing AQP2(S-D) or (S-A) phospho mutants and a 20 degrees C cold block, which allows endocytosis to continue, but prevents protein exit from the trans Golgi network (TGN), inducing formation of a perinuclear AQP2 patch. AQP2-S256D persists on the plasma membrane during cold block, while wild type AQP2, AQP2-S256A, S261A, S269A and S269D are internalized and accumulate in the patch. Development of this patch, a measure of AQP2 internalization, was most rapid with AQP2-S256A, and slowest with S261A and S269D. AQP2-S269D exhibited a biphasic internalization profile with a significant amount not internalized until 150 minutes of cold block. After rewarming to 37 degrees C, wt AQP2, AQP2-S261A and AQP2-S269D rapidly redistributed throughout the cytoplasm within 20 minutes, whereas AQP2-S256A dissipated more slowly. Colocalization of AQP2 mutants with several key vesicular markers including clathrin, HSP70/HSC70, EEA, GM130 and Rab11 revealed no major differences. Overall, our data provide evidence supporting the role of S256 and S269 in the maintenance of AQP2 at the cell surface and reveal the dynamics of internalization and recycling of differentially phosphorylated AQP2 in cell culture. C1 [Rice, William L.] Massachusetts Gen Hosp, Dept Med, Program Membrane Biol, Ctr Syst Biol,Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Rice, WL (reprint author), Massachusetts Gen Hosp, Dept Med, Program Membrane Biol, Ctr Syst Biol,Div Nephrol, Boston, MA 02114 USA. EM Halu@partners.org FU National Institutes of Health (NIH) [DK075940, DK38452, 5T32 DK007540-24]; American Society of Nephrology (ASN); Boston Area Diabetes and Endocrinology Research Center (NIH) [DK-57521]; Center for the Study of Inflammatory Bowel Disease (NIH) [DK-43351] FX Funding was provided by the National Institutes of Health (NIH), www.nih.gov. H. J. Lu is supported by an NIH KO8 grant DK075940 and a Gottschalk research grant from the American Society of Nephrology (ASN http://www.asn-online.org/grants_and_funding/career-development-details. aspx). Additional support was from NIH grant DK38452 (D. Brown). W. Rice is supported by an NIH training grant (NIH 5T32 DK007540-24). The Microscopy Core Facility of the Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (NIH DK-57521) and from the Center for the Study of Inflammatory Bowel Disease (NIH DK-43351). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 19 Z9 20 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 28 PY 2012 VL 7 IS 2 AR e32843 DI 10.1371/journal.pone.0032843 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928RC UT WOS:000302999600065 PM 22403603 ER PT J AU Cullen, KR Wallace, S Magnotta, VA Bockholt, J Ehrlich, S Gollub, RL Manoach, DS Ho, BC Clark, VP Lauriello, J Bustillo, JR Schulz, SC Andreasen, NC Calhoun, VD Lim, KO White, T AF Cullen, Kathryn R. Wallace, Stuart Magnotta, Vincent A. Bockholt, Jeremy Ehrlich, Stefan Gollub, Randy L. Manoach, Dara S. Ho, Beng C. Clark, Vincent P. Lauriello, John Bustillo, Juan R. Schulz, S. Charles Andreasen, Nancy C. Calhoun, Vince D. Lim, Kelvin O. White, Tonya TI Cigarette smoking and white matter microstructure in schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Diffusion tensor imaging; Nicotine; Fractional anisotropy ID DIFFUSION-TENSOR MRI; TRANSDERMAL NICOTINE; GRAY-MATTER; ARCHITECTURE; NONSMOKERS; DEPENDENCE; CORTEX; ADULTS; VOLUME; TRACTOGRAPHY AB The majority of patients with schizophrenia smoke cigarettes. Both nicotine use and schizophrenia have been associated with alterations in brain white matter microstructure as measured by diffusion tensor imaging (DTI). The purpose of this study was to examine fractional anisotropy (FA) in smoking and non-smoking patients with schizophrenia and in healthy volunteers. A total of 43 patients (28 smoking and 15 nonsmoking) with schizophrenia and 40 healthy, non-smoking participants underwent DTI. Mean FA was calculated in four global regions of interest (ROIs) (whole brain, cerebellum, brainstem, and total cortical) as well as in four regional ROIs (frontal, temporal, parietal and occipital lobes). The non-smoking patient group had a significantly higher intellectual quotient (IQ) compared with the patients who smoked, and our results varied according to whether IQ was included as a covariate. Without IQ correction, significant between-group effects for FA were found in four ROIs: total brain, total cortical, frontal lobe and the occipital lobe. In all cases the FA was lower among the smoking patient group, and highest in the control group. Smoking patients differed significantly from non-smoking patients in the frontal lobe ROI. However, these differences were no longer significant after IQ correction. FA differences between non-smoking patients and controls were not significant. Among smoking and non-smoking patients with schizophrenia but not healthy controls, FA was correlated with IQ. In conclusion, group effects of smoking on FA in schizophrenia might be mediated by IQ. Further, low FA in specific brain areas may be a neural marker for complex pathophysiology and risk for diverse problems such as schizophrenia, low IQ and nicotine addiction. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Cullen, Kathryn R.] Univ Minnesota, Div Child & Adolescent Psychiat F256 28, Fairview Univ Med Ctr, Dept Psychiat,Med Sch, Minneapolis, MN 55454 USA. [Cullen, Kathryn R.; Lim, Kelvin O.] Univ Minnesota, Ctr Neurobehav Dev, Minneapolis, MN 55454 USA. [Wallace, Stuart; Ehrlich, Stefan; Gollub, Randy L.; Manoach, Dara S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Magnotta, Vincent A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Bockholt, Jeremy; Clark, Vincent P.; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Clark, Vincent P.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Ehrlich, Stefan; Gollub, Randy L.; Manoach, Dara S.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ho, Beng C.; Andreasen, Nancy C.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Bustillo, Juan R.; Calhoun, Vince D.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Lauriello, John] Univ Missouri, Missouri Psychiat Ctr, Columbia, MO USA. [White, Tonya] Erasmus MC, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. RP Cullen, KR (reprint author), Univ Minnesota, Div Child & Adolescent Psychiat F256 28, Fairview Univ Med Ctr, Dept Psychiat,Med Sch, 2450 Riverside Ave, Minneapolis, MN 55454 USA. EM rega0026@umn.edu RI Ho, Beng-Choon/D-6959-2011; bustillo, juan/J-7067-2013; Cullen, Kathryn/G-9654-2013; Clark, Vincent/B-3343-2010; OI Ho, Beng-Choon/0000-0003-3976-1555; Gollub, Randy L./0000-0002-9434-4044; Cullen, Kathryn/0000-0001-9631-3770; Clark, Vincent/0000-0002-9151-2102; Ehrlich, Stefan/0000-0003-2132-4445 FU NIBIB NIH HHS [R01 EB006841-01A1, R01 EB006841, R01 EB006841-01A1S1, R01 EB006841-02, R01 EB006841-03, R01 EB006841-04, R01 EB006841-05, R01 EB006841-06] NR 49 TC 19 Z9 19 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD FEB 28 PY 2012 VL 201 IS 2 BP 152 EP 158 DI 10.1016/j.pscychresns.2011.08.010 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 929UA UT WOS:000303090000009 PM 22386966 ER PT J AU van de Ven, AL Kim, P Haley, O Fakhoury, JR Adriani, G Schmulen, J Moloney, P Hussain, F Ferrari, M Liu, XW Yun, SH Decuzzi, P AF van de Ven, Anne L. Kim, Pilhan Haley, O'Hara Fakhoury, Jean R. Adriani, Giulia Schmulen, Jeffrey Moloney, Padraig Hussain, Fazle Ferrari, Mauro Liu, Xuewu Yun, Seok-Hyun Decuzzi, Paolo TI Rapid tumoritropic accumulation of systemically injected plateloid particles and their biodistribution SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Nanoparticles; Size and shape; Biodistribution; Tumor accumulation; Rational design; Intravital microscopy ID POROUS SILICON MICROPARTICLES; HUMAN TUMOR XENOGRAFT; IN-VIVO; MACROMOLECULAR THERAPEUTICS; VASCULAR-PERMEABILITY; DELIVERY-SYSTEM; CANCER-THERAPY; DRUG-DELIVERY; SOLID TUMORS; BLOOD-FLOW AB Nanoparticles for cancer therapy and imaging are designed to accumulate in the diseased tissue by exploiting the Enhanced Permeability and Retention (EPR) effect. This limits their size to about 100 nm. Here, using intravital microscopy and elemental analysis, we compare the in vivo localization of particles with different geometries and demonstrate that plateloid particles preferentially accumulate within the tumor vasculature at unprecedented levels, independent of the EPR effect. In melanoma-bearing mice, 1000 x 400 nm plateloid particles adhered to the tumor vasculature at about 5% and 10% of the injected dose per gram organ (ID/g) for untargeted and RGD-targeted particles respectively, and exhibited the highest tumor-to-liver accumulation ratios (0.22 and 0.35). Smaller and larger plateloid particles, as well as cylindroid particles, were more extensively sequestered by the liver, spleen, and lungs. Plateloid particles appeared well-suited for taking advantage of hydrodynamic forces and interfacial interactions required for efficient tumoritropic accumulation, even without using specific targeting ligands. (c) 2011 Elsevier B.V. All rights reserved. C1 [van de Ven, Anne L.; Fakhoury, Jean R.; Adriani, Giulia; Schmulen, Jeffrey; Ferrari, Mauro; Liu, Xuewu; Decuzzi, Paolo] Methodist Hosp, Res Inst, Dept Translat Imaging, Houston, TX 77030 USA. [van de Ven, Anne L.; Fakhoury, Jean R.; Adriani, Giulia; Schmulen, Jeffrey; Ferrari, Mauro; Liu, Xuewu; Decuzzi, Paolo] Methodist Hosp, Res Inst, Dept Nanomed, Houston, TX 77030 USA. [Kim, Pilhan; Haley, O'Hara; Yun, Seok-Hyun] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kim, Pilhan; Haley, O'Hara; Yun, Seok-Hyun] Wellman Ctr Photomed, Boston, MA 02114 USA. [Adriani, Giulia] Politecn Bari, Dept Mech & Management Engn, I-70125 Bari, Italy. [Moloney, Padraig] Rice Univ, Dept Mech Engn & Mat Sci, Houston, TX 77005 USA. [Hussain, Fazle] Univ Houston, Dept Mech Engn, Houston, TX 77204 USA. [Decuzzi, Paolo] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy. [Yun, Seok-Hyun] Korea Adv Inst Sci & Technol, Grad Sch Nano Sci & Technol, Taejon, South Korea. RP van de Ven, AL (reprint author), Methodist Hosp, Res Inst, Dept Translat Imaging, 6670 Bertner Ave, Houston, TX 77030 USA. EM avandeven@tmhs.org; pdecuzzi@tmhs.org RI Kim, Pilhan/C-1836-2011; Decuzzi, Paolo/F-1899-2016 OI Kim, Pilhan/0000-0001-8388-1840; Decuzzi, Paolo/0000-0001-6050-4188 FU Telemedicine and Advanced Technology Research Center (TATRC)-United States Army Medical Research Acquisition Activity (USAMRAA) through Alliance for Nano Health [W81XWH09-2-0139]; National Institutes of Health (USA) (NIH) [U54CA143837, U54CA151668]; Department of Defense (DoD) [W81XWH-09-1-0212]; University of Magna Graecia-Italy FX This work was supported by Telemedicine and Advanced Technology Research Center (TATRC)-United States Army Medical Research Acquisition Activity (USAMRAA) through the pre-centre grant W81XWH09-2-0139 of the Alliance for Nano Health. This work was also partially supported through grants from the National Institutes of Health (USA) (NIH)U54CA143837 and U54CA151668, and the Department of Defense (DoD) grant W81XWH-09-1-0212. The authors would like to thank Mr. Matthew Landry for helping with the graphical work, Mr. Aaron Mack for advice on particle conjugation and ICP-AES protocols, as well as Dr. W.M. Steve Lee and Dr. Jinwoo Choi for helping with animal preparations. PD would like to thank the President and staff at the University of Magna Graecia-Italy for their support. NR 53 TC 78 Z9 78 U1 2 U2 39 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD FEB 28 PY 2012 VL 158 IS 1 BP 148 EP 155 DI 10.1016/j.jconrel.2011.10.021 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 923FW UT WOS:000302605900018 PM 22062689 ER PT J AU Nordenstedt, H Mattsson, F El-Serag, H Lagergren, J AF Nordenstedt, H. Mattsson, F. El-Serag, H. Lagergren, J. TI Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE bile duct cancer; biliary tumour; cohort study; gallstones; population-based ID PRIMARY SCLEROSING CHOLANGITIS; UNITED-STATES; BILE-DUCT; INTRAHEPATIC CHOLANGIOCARCINOMA; EPIDEMIOLOGY; CANCER; POPULATION; PANCREAS AB BACKGROUND: Cholangiocarcinomas are highly lethal tumours of the intrahepatic or extrahepatic biliary tract. The aetiology is largely unknown, and the potential roles of gallstones and gall bladder removal (cholecystectomy) need to be addressed in a large study with a long follow-up. METHODS: A population-based nationwide Swedish cohort study was carried out, in which patients hospitalised for gallstone diagnosis with or without gallbladder removal (cholecystectomy) between 1965 and 2008 were identified in the Swedish Patient Registry. The cohort was followed up for cancer in the Swedish Cancer Registry. The observed numbers of intra- and extrahepatic cholangiocarcinomas that developed after one year of follow-up were compared with the expected numbers, calculated from the corresponding background population, and the relative risks were estimated by standardised incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: Among the 192 960 non-cholecystectomised individuals with gallstones, there was a more than two-fold overall increased risk of both intra- and extra-hepatic cholangiocarcinomas, which remained stable over the follow-up period (SIR 2.77, 95% CI 2.17-3.49, and SIR 2.58, 95% CI 2.21-3.00, respectively). In the cholecystectomy cohort, including 345 251 people and 4 854 969 person-years, 325 incident cholangiocarcinomas were identified, of which 98 (30%) were intrahepatic and 227 (70%) were extrahepatic. Initially (1-4 years after surgery), the risk was increased for both intrahepatic cholangiocarcinoma (SIR 1.80, 95% CI 1.19-2.62) and extrahepatic cholangiocarcinoma (SIR 2.29, 95% CI 1.83-2.82), but no increase remained after 10 years of follow-up or more (SIR 1.10, 95% CI 0.79-1.48, and SIR 0.87, 95% CI 0.70-1.07, respectively). INTERPRETATION: Gallstones seem to increase the risk of both intra-and extrahepatic cholangiocarcinoma. However, this risk seems to decline to the level of the background population with time after cholecystectomy. British Journal of Cancer (2012) 106, 1011-1015. doi:10.1038/bjc.2011.607 www.bjcancer.com Published online 12 January 2012 (C) 2012 Cancer Research UK C1 [Nordenstedt, H.; Mattsson, F.; Lagergren, J.] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [El-Serag, H.] Houston Ctr Qual Care & Utilizat Studies, Michael E DeBakey Vet Adm Med Ctr, Houston, TX USA. [El-Serag, H.] Houston Ctr Qual Care & Utilizat Studies, Baylor Coll Med, Houston, TX USA. [Lagergren, J.] Kings Coll London, Div Canc Studies, London WC2R 2LS, England. RP Nordenstedt, H (reprint author), Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. EM helena.nordenstedt@ki.se OI Lagergren, Jesper/0000-0002-5143-5448 FU Swedish Research Council; Swedish Cancer Society FX The study was supported by project grants from the Swedish Research Council and the Swedish Cancer Society. NR 21 TC 24 Z9 25 U1 6 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 28 PY 2012 VL 106 IS 5 BP 1011 EP 1015 DI 10.1038/bjc.2011.607 PG 5 WC Oncology SC Oncology GA 900NO UT WOS:000300894300031 PM 22240785 ER PT J AU Alemani, D Pappalardo, F Pennisi, M Motta, S Brusic, V AF Alemani, Davide Pappalardo, Francesco Pennisi, Marzio Motta, Santo Brusic, Vladimir TI Combining cellular automata and lattice Boltzmann method to model multiscale avascular tumor growth coupled with nutrient diffusion and immune competition SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Immune system; Dosage optimization; Computational models; Cellular automata; Hybrid models; Lattice Boltzmann ID MATHEMATICAL-MODELS; SOLID TUMOR; INDUCED ANGIOGENESIS; OXYGEN-CONSUMPTION; CANCER; INVASION; SYSTEM; CHEMOTHERAPY; ENVIRONMENT; SIMULATION AB In the last decades the Lattice Boltzmann method (LB) has been successfully used to simulate a variety of processes. The LB model describes the microscopic processes occurring at the cellular level and the macroscopic processes occurring at the continuum level with a unique function, the probability distribution function. Recently, it has been tried to couple deterministic approaches with probabilistic cellular automata (probabilistic CA) methods with the aim to model temporal evolution of tumor growths and three dimensional spatial evolution, obtaining hybrid methodologies. Despite the good results attained by CA-PDE methods, there is one important issue which has not been completely solved: the intrinsic stochastic nature of the interactions at the interface between cellular (microscopic) and continuum (macroscopic) level. CA methods are able to cope with the stochastic phenomena because of their probabilistic nature, while PDE methods are fully deterministic. Even if the coupling is mathematically correct, there could be important statistical effects that could be missed by the PDE approach. For such a reason, to be able to develop and manage a model that takes into account all these three level of complexity (cellular, molecular and continuum), we believe that PDE should be replaced with a statistic and stochastic model based on the numerical discretization of the Boltzmann equation: The Lattice Boltzmann (LB) method. In this work we introduce a new hybrid method to simulate tumor growth and immune system, by applying Cellular Automata Lattice Boltzmann (CA-LB) approach. (c) 2011 Elsevier B.V. All rights reserved. C1 [Pappalardo, Francesco; Pennisi, Marzio; Motta, Santo] Univ Catania, Catania, Italy. [Alemani, Davide] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland. [Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr Bioinformat Core, Boston, MA 02115 USA. RP Pappalardo, F (reprint author), Univ Catania, Catania, Italy. EM davide.alemani@epfl.ch; fp@francescopappalardo.net; mpennisi@dmi.unict.it; motta@dmi.unict.it; Vladimir_Brusic@DFCI.HARVARD.EDU RI Motta, Santo/I-5177-2012; Pappalardo, Francesco/C-5832-2011; Pennisi, Marzio/G-4618-2015; OI Pappalardo, Francesco/0000-0003-1668-3320; Pennisi, Marzio/0000-0003-0231-7653; Motta, Santo/0000-0003-3533-2972 FU Swiss National Science Foundation FX DA thanks financial support from the Swiss National Science Foundation through the 'Bourse pour chercheur debutant' program fund. NR 60 TC 21 Z9 21 U1 3 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 28 PY 2012 VL 376 IS 1-2 BP 55 EP 68 DI 10.1016/j.jim.2011.11.009 PG 14 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 904OC UT WOS:000301206800006 PM 22154892 ER PT J AU Ackerman, ME Moldt, B Wyatt, RT Dugast, AS McAndrew, E Tsoukas, S Jost, S Berger, CT Sciaranghella, G Liu, QQ Irvine, DJ Burton, DR Alter, G AF Ackerman, Margaret E. Moldt, Brian Wyatt, Richard T. Dugast, Anne-Sophie McAndrew, Elizabeth Tsoukas, Stephen Jost, Stephanie Berger, Christoph T. Sciaranghella, Gaia Liu, Qingquan Irvine, Darrell J. Burton, Dennis R. Alter, Galit TI A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples (vol 376, pg 156, 2012) SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Correction C1 [Ackerman, Margaret E.; Dugast, Anne-Sophie; McAndrew, Elizabeth; Tsoukas, Stephen; Jost, Stephanie; Berger, Christoph T.; Sciaranghella, Gaia; Liu, Qingquan; Irvine, Darrell J.; Burton, Dennis R.; Alter, Galit] MIT & Harvard Univ, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Moldt, Brian; Wyatt, Richard T.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Wyatt, Richard T.; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Consortium, La Jolla, CA 92037 USA. [Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. RP Ackerman, ME (reprint author), 149 13th St,Room 6616, Charlestown, MA 02129 USA. EM meackerman@partners.org RI Dugast, AnneSophie/L-9541-2015 NR 1 TC 1 Z9 1 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD FEB 28 PY 2012 VL 376 IS 1-2 BP 156 EP 156 DI 10.1016/j.jim.2011.12.006 PG 1 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 904OC UT WOS:000301206800018 ER PT J AU Cornier, MA Melanson, EL Salzberg, AK Bechtell, JL Tregellas, JR AF Cornier, Marc-Andre Melanson, Edward L. Salzberg, Andrea K. Bechtell, Jamie L. Tregellas, Jason R. TI The effects of exercise on the neuronal response to food cues SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE fMRI; Neuroimaging; Physical activity; Food intake; Appetite ID POSITRON-EMISSION-TOMOGRAPHY; MODULATES BRAIN ACTIVITY; PHYSICAL-ACTIVITY; WEIGHT-LOSS; ENERGY-BALANCE; BODY-WEIGHT; INDUCED SUPPRESSION; NEURAL RESPONSES; FUNCTIONAL MRI; APPETITE AB Increased physical activity is associated with successful long-term weight loss maintenance due to mechanisms likely more complex than simply increased energy expenditure. The impact of physical activity on the central regulation of food intake may be an important mechanism of this effect. The objective of this study was to examine the effects of exercise training and acute exercise on the neuronal response to food cues as well as eating behaviors. fMRI was performed in the fasted state at baseline and again after a 6 month progressive exercise intervention (supervised, 5 days/wk) both with and without an acute exercise bout in 12 overweight/obese (5 women, 7 men; BMI 33 +/- 4 kg/m(2)) healthy adults. fMRI data were acquired while subjects were presented with visual stimuli of foods of high hedonic value as compared to neutral control objects. Questionnaires on eating behaviors, ratings of appeal and desire for foods, and ratings of appetite (hunger, satiety, prospective intake) using visual analog scales were also performed at baseline and again after the 6-month exercise intervention. While only a trend was observed for a reduction in body weight (102 +/- 5 to 99 +/- 6 kg, p=0.09), a significant reduction in fat mass was observed (36.4 +/- 2.8 to 33.7 +/- 3.2 kg, p = 0.04), although as expected changes in fat mass were variable (-10.0 to +3.7 kg). Chronic exercise was associated with a reduction in the neuronal response to food, primarily in the posterior attention network and insula. A significant positive correlation between the change in fat/body mass and the change in insula response to food cues with chronic exercise was observed. An acute exercise bout attenuated the effects of chronic exercise. The exercise intervention, however, did not impact any of the measures of appetitive behavior. In summary, despite no effects on behavioral measures of appetite, chronic exercise training was associated with attenuation in the response to visual food cues in brain regions known to be important in food intake regulation. The insula, in particular, appears to play an important role in the potential exercise-induced weight loss and weight loss maintenance. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cornier, Marc-Andre; Melanson, Edward L.; Salzberg, Andrea K.; Bechtell, Jamie L.] Univ Colorado, Div Endocrinol Metab & Diabet, Sch Med, Dept Med, Aurora, CO 80045 USA. [Tregellas, Jason R.] Univ Colorado, Sch Med, Dept Psychiat, Aurora, CO 80045 USA. [Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO 80220 USA. RP Cornier, MA (reprint author), Univ Colorado, Div Endocrinol Metab & Diabet, Sch Med, Dept Med, Anschutz Med Campus,Mail Stop 8106,12801 E 17th A, Aurora, CO 80045 USA. EM marc.cornier@ucdenver.edu RI Tregellas, Jason/J-3637-2015 FU NIH/NCRR Colorado CTSI [UL1 RR025780]; NIH/NIDDK Clinical Nutrition Research Unit [DK48520]; NIH/NIDDK [R01DK07708, R01DK089095, R01DK072174] FX We acknowledge and thank Debra Singel and Yiping Du for their assistance with the fMRI studies. We also thank the dietary services and metabolic kitchen of the University of Colorado Denver CTRC. This publication was supported by NIH/NCRR Colorado CTSI Grant Number UL1 RR025780, NIH/NIDDK Clinical Nutrition Research Unit Grant Number DK48520, and NIH/NIDDK Grant Numbers R01DK07708, R01DK089095 and R01DK072174. Its contents are the authors' sole responsibility and do not necessarily represent official NIH views. NR 58 TC 41 Z9 42 U1 4 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB 28 PY 2012 VL 105 IS 4 BP 1028 EP 1034 DI 10.1016/j.physbeh.2011.11.023 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 898MW UT WOS:000300747500017 PM 22155218 ER PT J AU Sampson, JH Schmittling, RJ Archer, GE Congdon, KL Nair, SK Reap, EA Desjardins, A Friedman, AH Friedman, HS Herndon, JE Coan, A McLendon, RE Reardon, DA Vredenburgh, JJ Bigner, DD Mitchell, DA AF Sampson, John H. Schmittling, Robert J. Archer, Gary E. Congdon, Kendra L. Nair, Smita K. Reap, Elizabeth A. Desjardins, Annick Friedman, Allan H. Friedman, Henry S. Herndon, James E., II Coan, April McLendon, Roger E. Reardon, David A. Vredenburgh, James J. Bigner, Darell D. Mitchell, Duane A. TI A Pilot Study of IL-2R alpha Blockade during Lymphopenia Depletes Regulatory T-cells and Correlates with Enhanced Immunity in Patients with Glioblastoma SO PLOS ONE LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; GROWTH-FACTOR-BETA; MONOCLONAL-ANTIBODY; METASTATIC MELANOMA; PERIPHERAL-BLOOD; AUTOIMMUNE-DISEASE; HUMAN CYTOMEGALOVIRUS; CANCER-PATIENTS; SELF-TOLERANCE; IN-VIVO AB Background: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T-Regs) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2R alpha/CD25) can enhance antitumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2R alpha expressing anti-tumor effector T-cells. Objective: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2R alpha monoclonal antibody (MAbs) to selectively deplete T-Regs while permitting vaccine-stimulated immune responses. Methodology: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2R alpha MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T-Regs in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). Results and Conclusions: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p < 0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. Trial Registration: C1 [Sampson, John H.; Schmittling, Robert J.; Archer, Gary E.; Congdon, Kendra L.; Reap, Elizabeth A.; Desjardins, Annick; Friedman, Allan H.; Friedman, Henry S.; Vredenburgh, James J.; Bigner, Darell D.; Mitchell, Duane A.] Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. [Sampson, John H.; Friedman, Henry S.; McLendon, Roger E.; Bigner, Darell D.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Nair, Smita K.] Duke Univ, Med Ctr, Dept Surg, Div Surg Sci, Durham, NC 27710 USA. [Herndon, James E., II; Coan, April] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Reardon, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. EM john.sampson@duke.edu OI Sykes, April/0000-0002-7667-8155 FU National Institutes of Health (NIH) [RO1-CA097222, R21-NS067980, R21-CA132891]; NIH/National Institute of Neurological Disorders and Stroke SRC on Primary and Metastatic Tumors of the Central Nervous System [P50-NS020023]; Specialized Program of Research Excellence in Brain Cancer [P50-CA108786]; Duke University from National Center for Research Resources/NIH [1UL2-RR024128] FX This work was supported in part by National Institutes of Health (NIH) grants RO1-CA097222 (JHS), R21-NS067980 (JHS) and R21-CA132891 (JHS), grants from the NIH/National Institute of Neurological Disorders and Stroke SRC on Primary and Metastatic Tumors of the Central Nervous System P50-NS020023 (DAR, JHS and DDB) and Specialized Program of Research Excellence in Brain Cancer P50-CA108786 (DDB and JHS) and by Duke University's CTSA grant 1UL2-RR024128 from National Center for Research Resources/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Consultant or Advisory Role: JHS, Celldex Therapeutics (C); DDB, Celldex Therapeutics (C) Honoraria: JHS, Celldex Therapeutics; DDB, Celldex Therapeutics Research Funding: JHS. The designation (C) indicates a compensated position. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. CDX-110 is a Celldex product. There are no patents, products in development or other marketed products to declare. NR 76 TC 41 Z9 43 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 27 PY 2012 VL 7 IS 2 AR e31046 DI 10.1371/journal.pone.0031046 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 927OV UT WOS:000302918500017 PM 22383993 ER PT J AU Studenshi, SA AF Studenshi, Stephanie A. TI Gait Speed in Hospitalized Older People SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID ELDERLY-PATIENTS; DISABILITY; PREDICTOR; OUTCOMES; MOBILITY C1 [Studenshi, Stephanie A.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Dept Internal Med, Pittsburgh, PA 15090 USA. [Studenshi, Stephanie A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15090 USA. RP Studenshi, SA (reprint author), Univ Pittsburgh, Sch Med, Div Geriatr Med, Dept Internal Med, 3471 5th Ave,Ste 500, Pittsburgh, PA 15090 USA. EM studenskiS@dom.pitt.edu FU NIA NIH HHS [AG024827, P30 AG024827] NR 10 TC 6 Z9 6 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 FEB 27 PY 2012 VL 172 IS 4 BP 358 EP 359 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 898JU UT WOS:000300739500012 PM 22371923 ER PT J AU Raldow, AC Presley, CJ Yu, JB Sharma, R Cramer, LD Soulos, PR Long, JB Makarov, DV Gross, CP AF Raldow, Ann C. Presley, Carolyn J. Yu, James B. Sharma, Richa Cramer, Laura D. Soulos, Pamela R. Long, Jessica B. Makarov, Danil V. Gross, Cary P. TI The Relationship Between Clinical Benefit and Receipt of Curative Therapy for Prostate Cancer SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID RADIATION; OUTCOMES; QUALITY C1 [Presley, Carolyn J.; Soulos, Pamela R.; Long, Jessica B.; Gross, Cary P.] Yale Univ, Sch Med, Gen Internal Med Sect, New Haven, CT 06510 USA. [Raldow, Ann C.; Presley, Carolyn J.; Yu, James B.; Sharma, Richa; Cramer, Laura D.; Soulos, Pamela R.; Long, Jessica B.; Makarov, Danil V.; Gross, Cary P.] Yale Univ, Sch Med, Canc Outcomes Publ Policy & Effectiveness Res COP, Yale Comprehens Canc Ctr, New Haven, CT 06510 USA. [Presley, Carolyn J.; Soulos, Pamela R.; Long, Jessica B.; Gross, Cary P.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Yu, James B.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA. [Raldow, Ann C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Makarov, Danil V.] NYU, Sch Med, Dept Urol, New York, NY 10003 USA. [Makarov, Danil V.] US Dept Vet Affairs, Washington, DC USA. RP Gross, CP (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, 333 Cedar St,POB 208025, New Haven, CT 06510 USA. EM cary.gross@yale.edu FU NCI NIH HHS [5R01CA149045, R01 CA149045] NR 8 TC 6 Z9 6 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 FEB 27 PY 2012 VL 172 IS 4 BP 362 EP 363 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 898JU UT WOS:000300739500015 PM 22371925 ER PT J AU Myaskovsky, L Doebler, DA Posluszny, DM Dew, MA Unruh, M Fried, LF Switzer, GE Kim, S Chang, CCH Ramkumar, M Shapiro, R AF Myaskovsky, Larissa Doebler, Donna Almario Posluszny, Donna M. Dew, Mary Amanda Unruh, Mark Fried, Linda F. Switzer, Galen E. Kim, Sunghee Chang, Chung-Chou H. Ramkumar, Mohan Shapiro, Ron TI Perceived Discrimination Predicts Longer Time to Be Accepted for Kidney Transplant SO TRANSPLANTATION LA English DT Article DE Kidney transplantation; Disparities; Discrimination ID RENAL-TRANSPLANTATION; AFRICAN-AMERICANS; RACIAL-DIFFERENCES; ORGAN DONATION; DONOR; DISPARITIES; HEALTH; SURVIVAL; ACCESS; RACE AB Background. Although end-stage kidney disease in African Americans (AAs) is four times greater than in whites, AAs are less than one half as likely to undergo kidney transplantation (KT). This racial disparity has been found even after controlling for clinical factors such as comorbid conditions, dialysis vintage and type, and availability of potential living donors. Therefore, studying nonmedical factors is critical to understanding disparities in KT. Methods. We conducted a longitudinal cohort study with 127 AA and white patients with end-stage kidney disease undergoing evaluation for KT (December 2006 to July 2007) to determine whether, after controlling for medical factors, differences in time to acceptance for transplant is explained by patients' cultural factors (e. g., perceived racism and discrimination, medical mistrust, religious objections to living donor KT), psychosocial characteristics (e. g., social support, anxiety, depression), or transplant knowledge. Participants completed two telephone interviews (shortly after initiation of transplant evaluation and after being accepted or found ineligible for transplant). Results. Results indicated that AA patients reported higher levels of the cultural factors than did whites. We found no differences in comorbidity or availability of potential living donors. AAs took significantly longer to get accepted for transplant than did whites (hazard ratio = 1.49, P = 0.005). After adjustment for demographic, psychosocial, and cultural factors, the association of race with longer time for listing was no longer significant. Conclusions. We suggest that interventions to address racial disparities in KT incorporate key nonmedical risk factors in patients. C1 [Myaskovsky, Larissa; Fried, Linda F.; Switzer, Galen E.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Myaskovsky, Larissa; Posluszny, Donna M.; Unruh, Mark; Fried, Linda F.; Switzer, Galen E.; Chang, Chung-Chou H.; Ramkumar, Mohan] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Myaskovsky, Larissa; Dew, Mary Amanda; Switzer, Galen E.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Doebler, Donna Almario; Dew, Mary Amanda; Chang, Chung-Chou H.] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Dew, Mary Amanda] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Fried, Linda F.; Ramkumar, Mohan] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15206 USA. [Kim, Sunghee] Duke Univ, Med Ctr, Duke Clin Res Inst, Pittsburgh, PA USA. [Shapiro, Ron] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. RP Myaskovsky, L (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM larissa.myaskovsky@va.gov FU Veterans Administration (VA) Health Services Research and Development Department (HSRD) [04-409]; VA HSRD Merit Award [IIR 06-220]; VA Center for Health Equity Research and Promotion (CHERP) [LIP 72-023]; VA Veterans Integrated Service Network (VISN) [XVA 72-034]; National Institutes of Diabetes, Digestive, and Kidney Diseases (NIDDK) [R01DK081325]; University of Pittsburgh Center for Social and Urban Research [XNV 72-085] FX This work was supported by the Veterans Administration (VA) Health Services Research and Development Department (HSR&D) Merit Review Entry Program 04-409, VA HSR&D Merit Award IIR 06-220, VA Center for Health Equity Research and Promotion (CHERP) Pilot Fund LIP 72-023, VA Veterans Integrated Service Network (VISN) 4 Competitive Pilot Project Funds XVA 72-034, National Institutes of Diabetes, Digestive, and Kidney Diseases (NIDDK) R01DK081325, and the University of Pittsburgh Center for Social and Urban Research Manners Faculty Development Award XNV 72-085. NR 55 TC 8 Z9 8 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 27 PY 2012 VL 93 IS 4 BP 423 EP 429 DI 10.1097/TP.0b013e318241d0cd PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 894GT UT WOS:000300415800018 PM 22228417 ER PT J AU Roberts, DJ Wilson, ML Nelson, AM Adesina, AM Fleming, KA Milner, D Guarner, J Rebbeck, TR Castle, P Lucas, S AF Roberts, Drucilla Jane Wilson, Michael L. Nelson, Ann Marie Adesina, Adekunle M. Fleming, Kenneth A. Milner, Dan Guarner, Jeannette Rebbeck, Timothy R. Castle, Philip Lucas, Sebastian TI The good news about cancer in developing countries-pathology answers the call SO LANCET LA English DT Letter C1 [Roberts, Drucilla Jane] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilson, Michael L.] Univ Colorado, Sch Med, Denver, CO USA. [Nelson, Ann Marie] Int Pathol & Lab Med Initiat, Denver, CO USA. [Adesina, Adekunle M.] Texas Childrens Hosp, Hoston, TX USA. [Fleming, Kenneth A.] Univ Oxford, Clin Acad, Grad Sch, Oxford, England. [Milner, Dan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Guarner, Jeannette] Emory Univ, Atlanta, GA 30322 USA. [Rebbeck, Timothy R.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Castle, Philip] Amer Soc Clin Pathologists, Amer Soc Clin Pathol Inst, Chicago, IL USA. [Lucas, Sebastian] Kings Coll London, Sch Med, London WC2R 2LS, England. RP Roberts, DJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM djroberts@partners.org RI Guarner, Jeannette/B-8273-2013 NR 4 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD FEB 25 PY 2012 VL 379 IS 9817 BP 712 EP 712 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 899CU UT WOS:000300792600024 PM 22364759 ER PT J AU Meissner, TB Li, A Liu, YJ Gagnon, E Kobayashi, KS AF Meissner, Torsten B. Li, Amy Liu, Yuen-Joyce Gagnon, Etienne Kobayashi, Koichi S. TI The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE MHC class I; NLR proteins; CITA ID CLASS-II TRANSACTIVATOR; MHC CLASS-I; BARE LYMPHOCYTE SYNDROME; MICE LACKING; GTP-BINDING; CIITA; EXPRESSION; COMPLEX; GENES; TRANSCRIPTION AB Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. A member of the NLR (nucleotide-binding domain, leucine-rich repeat) protein family, NLRC5, has recently been identified as a transcriptional regulator of MHC class land related genes. While a 'master regulator' of MHC class II genes, CIITA, has long been known, NLRC5 specifically associates with and transactivates the proximal promoters of MHC class I genes. In this study, we analyzed the molecular requirements of NLRC5 nuclear import and transactivation activity. We show that NLRC5-mediated MHC class I gene induction requires an intact nuclear localization signal and nuclear distribution of NLRC5. In addition, we find that the nucleotide-binding domain (NBD) of NLRC5 is critical not only for nuclear translocation but also for the transactivation of MHC class I genes. Changing the cellular localization of NLRC5 is likely to immediately impact MHC class I expression as well as MHC class I-mediated antigen presentation. NLRC5 may thus provide a promising target for the modulation of MHC class I antigen presentation, especially in the setting of transplant medicine. (C) 2012 Elsevier Inc. All rights reserved. C1 [Meissner, Torsten B.; Li, Amy; Liu, Yuen-Joyce; Gagnon, Etienne; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Meissner, Torsten B.; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02215 USA. [Gagnon, Etienne] Univ Montreal, Dept Microbiol & Immunol, Inst Rech Immunol & Cancerol, Montreal, PQ H3T 1J4, Canada. RP Kobayashi, KS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Dana 1420A,450 Brookline Ave, Boston, MA 02215 USA. EM Koichi_Kobayashi@dfci.harvard.edu FU NIH [R01DK074738]; Crohn's and Colitis Foundation of America; Cancer Research Institute; Claudia Adams Barr Award; EMBO FX The authors thank Peter Cresswell, Peter van den Eisen, and Marja C.J.A. van Eggermond for providing reagents: Lisa Cameron for assistance with confocal microscopy. This work was supported by Grants from the NIH (R01DK074738) and the Crohn's and Colitis Foundation of America. K.S.K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award and T.B.M. is a recipient of the EMBO Long Term fellowship. The authors have no conflicting financial interests. NR 27 TC 19 Z9 19 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 24 PY 2012 VL 418 IS 4 BP 786 EP 791 DI 10.1016/j.bbrc.2012.01.104 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 906GE UT WOS:000301332100035 PM 22310711 ER PT J AU Vijayanand, P Seumois, G Simpson, LJ Abdul-Wajid, S Baumjohann, D Panduro, M Huang, XZ Interlandi, J Djuretic, VM Brown, DR Sharpe, AH Rao, A Ansel, KM AF Vijayanand, Pandurangan Seumois, Gregory Simpson, Laura J. Abdul-Wajid, Sarah Baumjohann, Dirk Panduro, Marisella Huang, Xiaozhu Interlandi, Jeneen Djuretic, Vane M. Brown, Daniel R. Sharpe, Arlene H. Rao, Anjana Ansel, K. Mark TI Interleukin-4 Production by Follicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V SO IMMUNITY LA English DT Article ID TYPE-2 IMMUNITY; GENE-EXPRESSION; IL-4 PRODUCTION; COORDINATE REGULATOR; CYTOKINE PRODUCTION; HELMINTH INFECTION; ALLERGIC DISEASES; GATA3 EXPRESSION; MAST-CELLS; TH2 CELLS AB Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3' enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases. C1 [Simpson, Laura J.; Abdul-Wajid, Sarah; Baumjohann, Dirk; Panduro, Marisella; Ansel, K. Mark] Univ Calif San Francisco, Dept Microbiol & Immunol, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care, San Francisco, CA 94143 USA. [Vijayanand, Pandurangan; Seumois, Gregory; Rao, Anjana] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA. [Vijayanand, Pandurangan; Seumois, Gregory] Southampton Gen Hosp, Sir Henry Wellcome Labs, Southampton NIHR Resp Biomed Res Unit, Div Infect Inflammat & Immun,Sch Med, Southampton SO16 6YD, Hants, England. [Vijayanand, Pandurangan; Seumois, Gregory] Univ Southampton, Southampton SO16 6YD, Hants, England. [Interlandi, Jeneen; Djuretic, Vane M.; Rao, Anjana] Harvard Univ, Sch Med, Immune Dis Inst, Dept Pathol, Boston, MA 02115 USA. [Interlandi, Jeneen; Djuretic, Vane M.; Rao, Anjana] Harvard Univ, Sch Med, Program Cellular & Mol Med, Boston, MA 02115 USA. [Brown, Daniel R.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Brown, Daniel R.; Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Ansel, KM (reprint author), Univ Calif San Francisco, Dept Microbiol & Immunol, Sandler Asthma Basic Res Ctr, San Francisco, CA 94143 USA. EM mark.ansel@ucsf.edu RI Baumjohann, Dirk/C-9047-2009; OI Baumjohann, Dirk/0000-0001-8385-8288; Abdul-Wajid, Sarah/0000-0002-6000-7226 FU Burroughs Wellcome Fund; GSK National Clinician Scientist Fellowship Award; Peel Travel Fellowship Award in United Kingdom; NIH [AI40127, AI44432]; American Asthma Foundation; National Science Foundation; Swiss National Science Foundation FX The authors thank L. Du, L. Smith, E. Yanni, Z. Yang, Y. Soo Choi, and J. Yang for expert technical assistance and M. Kubo and S. Crotty for advice and critical reading of the manuscript. This project was funded by the Burroughs Wellcome Fund (to K.M.A.), GSK National Clinician Scientist Fellowship Award and Peel Travel Fellowship Award in United Kingdom (to P.V.), NIH grants AI40127 and AI44432, and an award from the American Asthma Foundation (to A.R.). L.J.S. is a National Science Foundation Graduate Research Fellow. D.B. is the recipient of a Swiss National Science Foundation Postdoctoral Fellowship. P.V., G.S., K.M.A., and A.R. conceived the work, designed, performed and analyzed experiments, and wrote the paper; L.J.S., S.A.-W., J.I., I.M.D., and D.R.B. assisted in some of the experiments under the supervision of P.V., G.S., K.M.A., A.R., and A.H.S.; and X.H. performed some of the experiments with the model of allergic airway disease. NR 56 TC 51 Z9 51 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 24 PY 2012 VL 36 IS 2 BP 175 EP 187 DI 10.1016/j.immuni.2011.12.014 PG 13 WC Immunology SC Immunology GA 899JO UT WOS:000300812400007 PM 22326582 ER PT J AU Yang, XH Qiao, DH Meyer, K Pier, T Keles, S Friedl, A AF Yang, Xinhai Qiao, Dianhua Meyer, Kristy Pier, Thomas Keles, Sunduz Friedl, Andreas TI Angiogenesis Induced by Signal Transducer and Activator of Transcription 5A (STAT5A) Is Dependent on Autocrine Activity of Proliferin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MAMMARY EPITHELIAL-CELLS; GENE-EXPRESSION; ENDOTHELIAL-CELLS; MESSENGER-RNA; GROWTH; PROLACTIN; RECEPTOR; PROTEIN; FAMILY; FIBROSARCOMA AB Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that STAT5 plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of STAT5, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in mouse brain endothelial cells (EC). We found that the conditioned medium from CA-STAT5A but not from dominant-negative STAT5A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. Conversely, CA-STAT5A-induced conditioned medium had no effect on EC proliferation. Using a comparative genome-wide transcription array screen, we identified the prolactin family member proliferin (PLF1 and PLF4) as a candidate autocrine factor. The CA-STAT5A-dependent transcription and secretion of PLF by EC was confirmed by quantitative RT-PCR and Western blotting, respectively. CA-STAT5A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by shRNA or by blocking of PLF activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA-STAT5A transfected EC to induce angiogenesis in Matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a FGF/STAT5/PLF signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation. C1 [Yang, Xinhai; Qiao, Dianhua; Meyer, Kristy; Pier, Thomas; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53792 USA. [Keles, Sunduz] Univ Wisconsin, Dept Stat & Biostat & Med Informat, Madison, WI 53792 USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, Madison, WI 53705 USA. RP Friedl, A (reprint author), WIMR Rm 6051,1111 Highland Ave, Madison, WI 53705 USA. EM afriedl@wisc.edu FU National Institutes of Health [RO1NS048921-01]; Biomedical Laboratory Research and Development Service of the VA Office of Research and Development [I01BX000137] FX This work was supported, in whole or in part, by National Institutes of Health Grant RO1NS048921-01. This work was also based upon work supported in part by Award I01BX000137 from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development. NR 33 TC 7 Z9 7 U1 1 U2 2 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 FEB 24 PY 2012 VL 287 IS 9 BP 6490 EP 6502 DI 10.1074/jbc.M111.254631 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 899CQ UT WOS:000300791800038 PM 22199350 ER PT J AU Kakkar, R Hei, H Dobner, S Lee, RT AF Kakkar, Rahul Hei, Hillary Dobner, Stephan Lee, Richard T. TI Interleukin 33 as a Mechanically Responsive Cytokine Secreted by Living Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRESSURE-OVERLOAD; IN-VIVO; CARDIAC-HYPERTROPHY; IL-33; RECEPTOR; ST2; TRANSPORT; ALARMIN AB Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells. C1 [Kakkar, Rahul; Hei, Hillary; Dobner, Stephan; Lee, Richard T.] Brigham & Womens Hosp, Harvard Stem Cell Inst, Dept Med, Cambridge, MA 02139 USA. [Kakkar, Rahul; Hei, Hillary; Dobner, Stephan; Lee, Richard T.] Brigham & Womens Hosp, Div Cardiovasc, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Kakkar, Rahul] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Lee, RT (reprint author), Partners Res Facil, 65 Landsdowne St, Cambridge, MA 02139 USA. EM RLee@partners.org FU NHLBI, National Institutes of Health [HL092930, T32HL007208]; Massachusetts General Hospital Division of Cardiology; Austrian Science Fund (FWF) [J3004-B18] FX This work was supported, in whole or in part, by Grants HL092930 (to R.T.L.) and T32HL007208 (to R.K.) from the NHLBI, National Institutes of Health. This work was also supported by the Massachusetts General Hospital Division of Cardiology (to R.K.) and the Austrian Science Fund (FWF Grant J3004-B18) (to S.D.). NR 20 TC 114 Z9 122 U1 2 U2 15 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 FEB 24 PY 2012 VL 287 IS 9 BP 6941 EP 6948 DI 10.1074/jbc.M111.298703 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 899CQ UT WOS:000300791800078 PM 22215666 ER PT J AU Paraskar, A Soni, S Roy, B Papa, AL Sengupta, S AF Paraskar, Abhimanyu Soni, Shivani Roy, Bhaskar Papa, Anne-Laure Sengupta, Shiladitya TI Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy SO NANOTECHNOLOGY LA English DT Article ID DRUG-DELIVERY; LIPOSOMAL OXALIPLATIN; TUMOR-XENOGRAFT; CELLULAR-DNA; IN-VIVO; CISPLATIN; CANCER; CHEMOTHERAPY; PHARMACOKINETICS; DERIVATIVES AB Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O -> Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg(-1) platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy. C1 [Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya] Brigham & Womens Hosp, Div Biomed Engn, Dept Med, Cambridge, MA 02139 USA. [Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya] Brigham & Womens Hosp, Ctr Regenerat Therapeut, Cambridge, MA 02139 USA. [Sengupta, Shiladitya] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Sengupta, Shiladitya] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Paraskar, A (reprint author), Brigham & Womens Hosp, Div Biomed Engn, Dept Med, Cambridge, MA 02139 USA. EM ssengupta2@partners.org FU Department of Defense BCRP [W81XWH-07-1-0482, W81XWH-09-1-0728]; BCRP; NIH [1R01CA135242-01A2] FX This work is funded by a Department of Defense BCRP Era of Hope Scholar Award (W81XWH-07-1-0482), a BCRP Innovator Collaborative Award and an NIH RO1 (1R01CA135242-01A2) to SS. AP is supported by a DOD BCRP postdoctoral fellowship award (W81XWH-09-1-0728). NR 36 TC 10 Z9 10 U1 3 U2 30 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD FEB 24 PY 2012 VL 23 IS 7 AR 075103 DI 10.1088/0957-4484/23/7/075103 PG 9 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 888MF UT WOS:000300007000003 PM 22275055 ER PT J AU Demidova-Rice, TN Wolf, L Deckenback, J Hamblin, MR Herman, IM AF Demidova-Rice, Tatiana N. Wolf, Lindsey Deckenback, Jeffry Hamblin, Michael R. Herman, Ira M. TI Human Platelet-Rich Plasma- and Extracellular Matrix-Derived Peptides Promote Impaired Cutaneous Wound Healing In Vivo SO PLOS ONE LA English DT Article ID GROWTH-FACTORS; CELLS; MICE; ANGIOGENESIS; CYTOKINES; INJURY; VITRO AB Previous work in our laboratory has described several pro-angiogenic short peptides derived from endothelial extracellular matrices degraded by bacterial collagenase. Here we tested whether these peptides could stimulate wound healing in vivo. Our experiments demonstrated that a peptide created as combination of fragments of tenascin X and fibrillin 1 (comb1) applied into cranial dermal wounds created in mice treated with cyclophosphamide to impair wound healing, can improve the rate of wound closure. Furthermore, we identify and characterize a novel peptide (UN3) created and modified from two naturally-occurring peptides, which are present in human platelet-rich plasma. In vitro testing of UN3 demonstrates that it causes a 50% increase in endothelial proliferation, 250% increase in angiogenic response and a tripling of epithelial cell migration in response to injury. Results of in vivo experiments where comb1 and UN3 peptides were added together to cranial wounds in cyclophosphamide-treated mice leads to improvement of wound vascularization as shown by an increase of the number of blood vessels present in the wound beds. Application of the peptides markedly promotes cellular responses to injury and essentially restores wound healing dynamics to those of normal, acute wounds in the absence of cyclophosphamide impairment. Our current work is aimed at understanding the mechanisms underlying the stimulatory effects of these peptides as well as identification of the cellular receptors mediating these effects. C1 [Demidova-Rice, Tatiana N.; Wolf, Lindsey; Deckenback, Jeffry; Herman, Ira M.] Tufts Univ, Sch Med, Ctr Innovat Wound Healing Res, Grad Program Cellular & Mol Physiol,Sackler Sch G, Boston, MA 02111 USA. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Demidova-Rice, TN (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. EM ira.herman@tufts.edu OI Hamblin, Michael/0000-0001-6431-4605 FU National Institutes of Heatlh [EY15125, EY19533]; Wound Care Partners, LLC FX This work was supported in part by National Institutes of Heatlh EY15125, EY19533, and Wound Care Partners, LLC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 25 Z9 26 U1 1 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2012 VL 7 IS 2 AR e32146 DI 10.1371/journal.pone.0032146 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 927NZ UT WOS:000302916100054 PM 22384158 ER PT J AU Ramanadhan, S Salhi, C Achille, E Baril, N D'Entremont, K Grullon, M Judge, C Oppenheimer, S Reeves, C Savage, C Viswanath, K AF Ramanadhan, Shoba Salhi, Carmel Achille, Erline Baril, Nashira D'Entremont, Kerrie Grullon, Milagro Judge, Christine Oppenheimer, Sarah Reeves, Chrasandra Savage, Clara Viswanath, Kasisomayajula TI Addressing Cancer Disparities via Community Network Mobilization and Intersectoral Partnerships: A Social Network Analysis SO PLOS ONE LA English DT Article ID HEALTH-PROMOTION PROGRAMS; COLLABORATIVE ADVANTAGE; CAPACITY; STRATEGY; PREVENTION; COALITIONS; FRAMEWORK AB Community mobilization and collaboration among diverse partners are vital components of the effort to reduce and eliminate cancer disparities in the United States. We studied the development and impact of intersectoral connections among the members of the Massachusetts Community Network for Cancer Education, Research, and Training (MassCONECT). As one of the Community Network Program sites funded by the National Cancer Institute, this infrastructure-building initiative utilized principles of Community-based Participatory Research (CBPR) to unite community coalitions, researchers, policymakers, and other important stakeholders to address cancer disparities in three Massachusetts communities: Boston, Lawrence, and Worcester. We conducted a cross-sectional, sociometric network analysis four years after the network was formed. A total of 38 of 55 members participated in the study (69% response rate). Over four years of collaboration, the number of intersectoral connections reported by members (intersectoral out-degree) increased, as did the extent to which such connections were reported reciprocally (intersectoral reciprocity). We assessed relationships between these markers of intersectoral collaboration and three intermediate outcomes in the effort to reduce and eliminate cancer disparities: delivery of community activities, policy engagement, and grants/publications. We found a positive and statistically significant relationship between intersectoral out-degree and community activities and policy engagement (the relationship was borderline significant for grants/publications). We found a positive and statistically significant relationship between intersectoral reciprocity and community activities and grants/publications (the relationship was borderline significant for policy engagement). The study suggests that intersectoral connections may be important drivers of diverse intermediate outcomes in the effort to reduce and eliminate cancer disparities. The findings support investment in infrastructure-building and intersectoral mobilization in addressing disparities and highlight the benefits of using CBPR approaches for such work. C1 [Ramanadhan, Shoba; Viswanath, Kasisomayajula] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Salhi, Carmel] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Achille, Erline; Baril, Nashira] Boston Publ Hlth Commiss, New England Ctr Excellence Eliminat Dispar, Boston, MA USA. [D'Entremont, Kerrie; Grullon, Milagro] City Lawrence, Mayors Hlth Task Force, Lawrence, MA USA. [Judge, Christine; Oppenheimer, Sarah] Harvard Univ, Sch Publ Hlth, Div Publ Hlth Practice, Boston, MA 02115 USA. [Reeves, Chrasandra] Boston Alliance Community Hlth, Boston, MA USA. [Savage, Clara] Common Pathways, Worcester, MA USA. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Ramanadhan, S (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. EM shoba_ramanadhan@dfci.harvard.edu FU National Cancer Institute [5 U01 CA114644] FX This work was funded by the National Cancer Institute (Grant#: 5 U01 CA114644, Viswanath, PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. One co-author, Milagro Grullon, currently works for a commercial enterprise, but was employed by the City of Lawrence Mayor's Health Task Force at the time this work was conducted and the work was not funded or impacted by Lawrence Community Connections. NR 55 TC 7 Z9 7 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 23 PY 2012 VL 7 IS 2 AR e32130 DI 10.1371/journal.pone.0032130 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 927NZ UT WOS:000302916100053 PM 22384156 ER PT J AU de Calignon, A Polydoro, M Suarez-Calvet, M William, C Adamowicz, DH Kopeikina, KJ Pitstick, R Sahara, N Ashe, KH Carlson, GA Spires-Jones, TL Hyman, BT AF de Calignon, Alix Polydoro, Manuela Suarez-Calvet, Marc William, Christopher Adamowicz, David H. Kopeikina, Kathy J. Pitstick, Rose Sahara, Naruhiko Ashe, Karen H. Carlson, George A. Spires-Jones, Tara L. Hyman, Bradley T. TI Propagation of Tau Pathology in a Model of Early Alzheimer's Disease SO NEURON LA English DT Article ID ENTORHINAL CORTEX; DENTATE GYRUS; SYNAPSE LOSS; PATHOGENETIC IMPLICATIONS; PROTEIN IMMUNOREACTIVITY; HIPPOCAMPAL-FORMATION; ELECTRON-MICROSCOPY; CEREBROSPINAL-FLUID; PERFORANT PATH; NEURONAL LOSS AB Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration. C1 [de Calignon, Alix; Polydoro, Manuela; Suarez-Calvet, Marc; William, Christopher; Adamowicz, David H.; Kopeikina, Kathy J.; Spires-Jones, Tara L.; Hyman, Bradley T.] Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Massachusetts Gen Hosp,Alzheimers Dis Res Lab, Charlestown, MA 02129 USA. [de Calignon, Alix] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Suarez-Calvet, Marc] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain. [Kopeikina, Kathy J.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Pitstick, Rose; Carlson, George A.] McLaughlin Res Inst, Great Falls, MT 59405 USA. [Sahara, Naruhiko] Univ Florida, Dept Neurosci, Ctr Translat Res Neurodegenerat Dis, Gainesville, FL 32610 USA. [Carlson, George A.] Univ Minnesota, Dept Neurol, Sch Med, Minneapolis, MN 55455 USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, MassGen Inst Neurodegenerat Dis,Dept Neurol, Massachusetts Gen Hosp,Alzheimers Dis Res Lab, Charlestown, MA 02129 USA. EM bhyman@partners.org OI Suarez-Calvet, Marc/0000-0002-2993-569X; Spires-Jones, Tara/0000-0003-2530-0598 FU Alzheimer's Association; National Institutes of Health [AG08487, AG026249, K08NS069811, K99AG33670, R21AG038835-01A1, R21 NS067127]; American Health Assistance Foundation [A2011086] FX This work was supported by an Alzheimer's Association Zenith award; National Institutes of Health grants AG08487, AG026249, K08NS069811, K99AG33670, R21AG038835-01A1, and R21 NS067127; and American Health Assistance Foundation grant A2011086. We thank Mark Mayford for providing neuropsin-tTA mice, Peter Davies for providing tau antibodies, and Zhanyun Fan, Taylor Friedman, Charles Vanderburg, Ozge Cagsal-Getkin, and Meredith Banigan for technical assistance. NR 50 TC 448 Z9 451 U1 8 U2 119 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 23 PY 2012 VL 73 IS 4 BP 685 EP 697 DI 10.1016/j.neuron.2011.11.033 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 899KS UT WOS:000300815400009 PM 22365544 ER PT J AU Sosman, JA Kim, KB Schuchter, L Gonzalez, R Pavlick, AC Weber, JS McArthur, GA Hutson, TE Moschos, SJ Flaherty, KT Hersey, P Kefford, R Lawrence, D Puzanov, I Lewis, KD Amaravadi, RK Chmielowski, B Lawrence, HJ Shyr, Y Ye, F Li, J Nolop, KB Lee, RJ Joe, AK Ribas, A AF Sosman, Jeffrey A. Kim, Kevin B. Schuchter, Lynn Gonzalez, Rene Pavlick, Anna C. Weber, Jeffrey S. McArthur, Grant A. Hutson, Thomas E. Moschos, Stergios J. Flaherty, Keith T. Hersey, Peter Kefford, Richard Lawrence, Donald Puzanov, Igor Lewis, Karl D. Amaravadi, Ravi K. Chmielowski, Bartosz Lawrence, H. Jeffrey Shyr, Yu Ye, Fei Li, Jiang Nolop, Keith B. Lee, Richard J. Joe, Andrew K. Ribas, Antoni TI Survival in BRAF V600-Mutant Advanced Melanoma Treated with Vemurafenib SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID METASTATIC MALIGNANT-MELANOMA; COOPERATIVE-ONCOLOGY-GROUP; RAF INHIBITOR PLX4032; PHASE-III TRIAL; DACARBAZINE; RESISTANCE; KINASE; BRAF(V600E); MUTATION; INTERFERON-ALPHA-2B AB BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serinethreonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600-mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600-mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00949702.) C1 [Sosman, Jeffrey A.; Puzanov, Igor] Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Shyr, Yu; Ye, Fei] Vanderbilt Univ, Med Ctr, Ctr Quantitat Sci, Nashville, TN USA. [Kim, Kevin B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Schuchter, Lynn; Amaravadi, Ravi K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Gonzalez, Rene; Lewis, Karl D.] Univ Colorado, Denver, CO 80202 USA. [Pavlick, Anna C.] NYU, Med Ctr, New York, NY 10016 USA. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [McArthur, Grant A.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Hersey, Peter] Univ Newcastle, Newcastle, NSW 2300, Australia. [Kefford, Richard] Westmead Inst Canc Res, Westmead, NSW, Australia. [Kefford, Richard] Melanoma Inst Australia, Westmead, NSW, Australia. [Hutson, Thomas E.] Texas Oncol Baylor Sammons Canc Ctr, Dallas, TX USA. [Moschos, Stergios J.] Univ Pittsburgh, Pittsburgh, PA USA. [Flaherty, Keith T.; Lawrence, Donald] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Chmielowski, Bartosz; Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Lawrence, H. Jeffrey] Roche Mol Syst, Pleasanton, CA USA. [Nolop, Keith B.] Plexxikon, Berkeley, CA USA. [Li, Jiang; Lee, Richard J.; Joe, Andrew K.] Hoffmann La Roche, Nutley, NJ USA. RP Sosman, JA (reprint author), Vanderbilt Ingram Canc Ctr, 777 Preston Res Bldg, Nashville, TN 37232 USA. EM jeff.sosman@vanderbilt.edu FU Hoffmann-La Roche FX Supported by Hoffmann-La Roche. NR 39 TC 1015 Z9 1037 U1 7 U2 92 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 FEB 23 PY 2012 VL 366 IS 8 BP 707 EP 714 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 896FS UT WOS:000300551500008 PM 22356324 ER PT J AU Cho, TA Larvie, M Tian, D Mino-Kenudson, M AF Cho, Tracey A. Larvie, Mykol Tian, Di Mino-Kenudson, Mari TI Case 6-2012: A 45-Year-Old Man with a History of Alcohol Abuse and Rapid Cognitive Decline Alcoholic liver disease with fibrosis. Brain abscess due to toxoplasma. Advanced HIV infection SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIRETROVIRAL THERAPY; COST-EFFECTIVENESS; AIDS; ENCEPHALITIS; DIAGNOSIS; HEPATITIS; CRITERIA C1 [Cho, Tracey A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Larvie, Mykol] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Tian, Di; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cho, Tracey A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Tian, Di; Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cho, TA (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 19 TC 1 Z9 1 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 FEB 23 PY 2012 VL 366 IS 8 BP 745 EP 755 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 896FS UT WOS:000300551500013 PM 22356328 ER PT J AU Cash, SS Batchelor, TT Dalmau, J AF Cash, Sydney S. Batchelor, Tracy T. Dalmau, Josep TI Case 34-2011: A Man with Memory Loss and Partial Seizures REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ENCEPHALITIS C1 [Cash, Sydney S.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dalmau, Josep] Univ Penn, Philadelphia, PA 19104 USA. RP Cash, SS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. OI Dalmau, Josep/0000-0001-5856-2813 NR 3 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 FEB 23 PY 2012 VL 366 IS 8 BP 769 EP 769 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 896FS UT WOS:000300551500027 ER PT J AU Blood, AJ Kuster, JK Woodman, SC Kirlic, N Makhlouf, ML Multhaupt-Buell, TJ Makris, N Parent, M Sudarsky, LR Sjalander, G Breiter, H Breiter, HC Sharma, N AF Blood, Anne J. Kuster, John K. Woodman, Sandra C. Kirlic, Namik Makhlouf, Miriam L. Multhaupt-Buell, Trisha J. Makris, Nikos Parent, Martin Sudarsky, Lewis R. Sjalander, Greta Breiter, Henry Breiter, Hans C. Sharma, Nutan TI Evidence for Altered Basal Ganglia-Brainstem Connections in Cervical Dystonia SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TOXIN TYPE-A; FOCAL DYSTONIA; DYT1 DYSTONIA; PSYCHIATRIC COMORBIDITY; SPASMODIC TORTICOLLIS; ABNORMAL PLASTICITY; CEREBELLUM; CARRIERS; LESIONS AB Background: There has been increasing interest in the interaction of the basal ganglia with the cerebellum and the brainstem in motor control and movement disorders. In addition, it has been suggested that these subcortical connections with the basal ganglia may help to coordinate a network of regions involved in mediating posture and stabilization. While studies in animal models support a role for this circuitry in the pathophysiology of the movement disorder dystonia, thus far, there is only indirect evidence for this in humans with dystonia. Methodology/Principal Findings: In the current study we investigated probabilistic diffusion tractography in DYT1-negative patients with cervical dystonia and matched healthy control subjects, with the goal of showing that patients exhibit altered microstructure in the connectivity between the pallidum and brainstem. The brainstem regions investigated included nuclei that are known to exhibit strong connections with the cerebellum. We observed large clusters of tractography differences in patients relative to healthy controls, between the pallidum and the brainstem. Tractography was decreased in the left hemisphere and increased in the right hemisphere in patients, suggesting a potential basis for the left/right white matter asymmetry we previously observed in focal dystonia patients. Conclusions/Significance: These findings support the hypothesis that connections between the basal ganglia and brainstem play a role in the pathophysiology of dystonia. C1 [Blood, Anne J.; Kuster, John K.; Woodman, Sandra C.; Kirlic, Namik; Makhlouf, Miriam L.; Sjalander, Greta; Breiter, Henry; Breiter, Hans C.] Massachusetts Gen Hosp, Mood & Motor Control Lab, Charlestown, MA 02129 USA. [Blood, Anne J.; Kuster, John K.; Kirlic, Namik; Breiter, Hans C.] Massachusetts Gen Hosp, Lab Neuroimaging & Genet, Charlestown, MA USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Charlestown, MA USA. [Blood, Anne J.; Kuster, John K.; Woodman, Sandra C.; Kirlic, Namik; Makhlouf, Miriam L.; Makris, Nikos; Sjalander, Greta; Breiter, Henry; Breiter, Hans C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Blood, Anne J.; Kuster, John K.; Woodman, Sandra C.; Kirlic, Namik; Makris, Nikos; Breiter, Henry; Breiter, Hans C.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Blood, Anne J.; Kuster, John K.; Multhaupt-Buell, Trisha J.; Sjalander, Greta; Sharma, Nutan] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Breiter, Hans C.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Sudarsky, Lewis R.; Sharma, Nutan] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Blood, Anne J.; Makris, Nikos; Sudarsky, Lewis R.; Breiter, Hans C.; Sharma, Nutan] Harvard Univ, Sch Med, Boston, MA USA. [Kuster, John K.] Boston Univ, Sch Med, Div Grad Med Sci, Boston, MA 02118 USA. [Makhlouf, Miriam L.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Parent, Martin] Univ Laval, Fac Med, Ctr Rech Univ Laval Robert Giffard, Dept Psychiat & Neurosci, Quebec City, PQ G1K 7P4, Canada. [Breiter, Hans C.] NW Univ Feinberg, Warren Wright Adolescent Ctr, Sch Med, Dept Psychiat & Behav Sci, Chicago, IL USA. [Breiter, Hans C.] NW Univ Feinberg, Ctr Self Regulat, Chicago, IL USA. RP Blood, AJ (reprint author), Massachusetts Gen Hosp, Mood & Motor Control Lab, Charlestown, MA 02129 USA. EM ablood@nmr.mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke [R01NS052368, NINP50NS037409]; Dystonia Medical Research Foundation; National Center for Research Resources [P41 RR14075, UL1 RR025758-01]; Mental Illness and Neuroscience Discovery (MIND) Institute FX This work was supported by grants from the National Institute of Neurological Disorders and Stroke (grant number R01NS052368 to Dr. Blood, and grant number NINP50NS037409 to Dr. Breakefield with Dr. Sharma as PI of the clinical core), and a grant from the Dystonia Medical Research Foundation to Dr. Blood. The general infrastructure of the Martinos Center for Biomedical Imaging in which research on these grants was conducted, was supported by National Center for Research Resources (grant number P41 RR14075 to Dr. Rosen), and the Mental Illness and Neuroscience Discovery (MIND) Institute (Dr. Rosen). Prescreening and exams were conducted in the General Clinical Research Center, funded by National Center for Research Resources (grant number UL1 RR025758-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 22 Z9 23 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 22 PY 2012 VL 7 IS 2 AR e31654 DI 10.1371/journal.pone.0031654 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926ZZ UT WOS:000302875500028 PM 22384048 ER PT J AU Shapiro, RL Souda, S Parekh, N Binda, K Kayembe, M Lockman, S Svab, P Babitseng, O Powis, K Jimbo, W Creek, T Makhema, J Essex, M Roberts, DJ AF Shapiro, Roger L. Souda, Sajini Parekh, Natasha Binda, Kelebogile Kayembe, Mukendi Lockman, Shahin Svab, Petr Babitseng, Orphinah Powis, Kathleen Jimbo, William Creek, Tracy Makhema, Joseph Essex, Max Roberts, Drucilla J. TI High Prevalence of Hypertension and Placental Insufficiency, but No In Utero HIV Transmission, among Women on HAART with Stillbirths in Botswana SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; GESTATIONAL HYPERTENSION; PREGNANCY OUTCOMES; INCREASED RISK; INFECTION; PREECLAMPSIA; DELIVERY AB Background: Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth. Methods: HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed. Results: Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART). Conclusions: In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting. C1 [Shapiro, Roger L.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Shapiro, Roger L.; Lockman, Shahin; Powis, Kathleen; Makhema, Joseph; Essex, Max] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Roger L.; Souda, Sajini; Parekh, Natasha; Binda, Kelebogile; Lockman, Shahin; Powis, Kathleen; Makhema, Joseph; Essex, Max] Botswana Harvard Sch Publ Hlth, AIDS Inst Partnership HIV Res & Educ, Boston, MA 02115 USA. [Kayembe, Mukendi] Minist Hlth, Botswana Natl Hlth Lab, Gaborone, Botswana. [Lockman, Shahin] Brigham & Womens Hosp, Infect Dis Unit, Boston, MA 02115 USA. [Svab, Petr; Babitseng, Orphinah] Princess Marina Hosp, Minist Hlth, Gaborone, Botswana. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Jimbo, William; Creek, Tracy] Ctr Dis Control & Prevent, Atlanta, GA USA. [Roberts, Drucilla J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Shapiro, RL (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. EM rshapiro@hsph.harvard.edu FU Centers for Disease Control and Prevention [U2GPS000941]; Doris Duke Charitable Research Foundation FX This work was supported by a grant from the Centers for Disease Control and Prevention (U2GPS000941), and by a Research Fellowship from the Doris Duke Charitable Research Foundation (N.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 9 Z9 9 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 FEB 22 PY 2012 VL 7 IS 2 AR e31580 DI 10.1371/journal.pone.0031580 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926ZZ UT WOS:000302875500026 PM 22384039 ER PT J AU Wey, MCY Fernandez, E Martinez, PA Sullivan, P Goldstein, DS Strong, R AF Wey, Margaret Chia-Ying Fernandez, Elizabeth Martinez, Paul Anthony Sullivan, Patricia Goldstein, David S. Strong, Randy TI Neurodegeneration and Motor Dysfunction in Mice Lacking Cytosolic and Mitochondrial Aldehyde Dehydrogenases: Implications for Parkinson's Disease SO PLOS ONE LA English DT Article ID HUMAN ALPHA-SYNUCLEIN; ENDOGENOUS DOPAMINERGIC NEUROTOXIN; AMYOTROPHIC-LATERAL-SCLEROSIS; ONSET ALZHEIMERS-DISEASE; STRIDE LENGTH REGULATION; TREADMILL GAIT ANALYSIS; L-DOPA; HYDROGEN-PEROXIDE; 3,4-DIHYDROXYPHENYLACETALDEHYDE; SEROTONIN AB Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD(+) co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1(-/-) xAldh2(-/-) mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1(-/-) xAldh2(-/-) mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1(-/-) xAldh2(-/-) mice may be a useful animal model of PD. C1 [Wey, Margaret Chia-Ying; Fernandez, Elizabeth; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Wey, Margaret Chia-Ying; Fernandez, Elizabeth; Martinez, Paul Anthony; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Fernandez, Elizabeth; Strong, Randy] S Texas Vet Hlth Care Network, Ctr Geriatr Res Educ & Clin, San Antonio, TX USA. [Sullivan, Patricia; Goldstein, David S.] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Clin Neurosci Program, Div Intramural Res, Bethesda, MD USA. RP Wey, MCY (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM FernandezE@uthscsa.edu; Strong@uthscsa.edu FU Veteran Affairs Office of Research Development; National Institute of Aging [T32 AG021890-08] FX This work was supported by grants from the Veteran Affairs Office of Research & Development (to E.F. and R.S.) and the National Institute of Aging predoctoral training grant T32 AG021890-08 (to M.C.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 48 Z9 48 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 22 PY 2012 VL 7 IS 2 AR e31522 DI 10.1371/journal.pone.0031522 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926ZZ UT WOS:000302875500023 PM 22384032 ER PT J AU Rice, TW Wheeler, AP Thompson, BT Steingrub, J Hite, RD Moss, M Morris, A Dong, N Rock, P AF Rice, Todd W. Wheeler, Arthur P. Thompson, B. Taylor Steingrub, Jay Hite, R. Duncan Moss, Marc Morris, Alan Dong, Ning Rock, Peter CA National Heart Lung & Blood Inst A TI ONLINE FIRST Initial Trophic vs Full Enteral Feeding in Patients With Acute Lung Injury The EDEN Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MECHANICALLY VENTILATED PATIENTS; CRITICALLY-ILL PATIENTS; CLINICAL-PRACTICE GUIDELINES; INTENSIVE-CARE-UNIT; NUTRITION SUPPORT; PARENTERAL-NUTRITION; CALORIC-INTAKE; ADULT PATIENTS; OUTCOMES; MORTALITY AB Context The amount of enteral nutrition patients with acute lung injury need is unknown. Objective To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding. Design, Setting, and Participants The EDEN study, a randomized, open-label, multicenter trial conducted from January 2, 2008, through April 12, 2011. Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Interventions Participants were randomized to receive either trophic or full enteral feeding for the first 6 days. After day 6, the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol. Main Outcome Measures Ventilator-free days to study day 28. Results Baseline characteristics were similar between the trophic-feeding (n=508) and full-feeding (n=492) groups. The full-feeding group received more enteral calories for the first 6 days, about 1300 kcal/d compared with 400 kcal/d (P<.001). Initial trophic feeding did not increase the number of ventilator-free days (14.9 [95% CI, 13.9 to 15.8] vs 15.0 [95% CI, 14.1 to 15.9]; difference, -0.1 [95% CI, -1.4 to 1.2]; P=.89) or reduce 60-day mortality (23.2% [95% CI, 19.6% to 26.9%] vs 22.2% [95% CI, 18.5% to 25.8%]; difference, 1.0% [95% CI, -4.1% to 6.3%]; P=.77) compared with full feeding. There were no differences in infectious complications between the groups. Despite receiving more prokinetic agents, the full-feeding group experienced more vomiting (2.2% vs 1.7% of patient feeding days; P=.05), elevated gastric residual volumes (4.9% vs 2.2% of feeding days; P<.001), and constipation (3.1% vs 2.1% of feeding days; P=.003). Mean plasma glucose values and average hourly insulin administration were both higher in the full-feeding group over the first 6 days. Conclusion In patients with acute lung injury, compared with full enteral feeding, a strategy of initial trophic enteral feeding for up to 6 days did not improve ventilator-free days, 60-day mortality, or infectious complications but was associated with less gastrointestinal intolerance. C1 [Rice, Todd W.; Wheeler, Arthur P.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Thompson, B. Taylor; Dong, Ning] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Steingrub, Jay] Baystate Med Ctr, Springfield, MA USA. [Hite, R. Duncan] Wake Forest Sch Med, Winston Salem, NC USA. [Moss, Marc] Univ Colorado, Sch Med, Denver, CO USA. [Morris, Alan] Univ Utah, Sch Med, Salt Lake City, UT USA. [Rock, Peter] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Rice, TW (reprint author), Vanderbilt Univ Sch Med, T-1218 MCN, Nashville, TN 37232 USA. EM todd.rice@vanderbilt.edu FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268200536165C, HHSN268200536179C] FX This study was funded by National Heart, Lung, and Blood Institute (NHLBI) contracts HHSN268200536165C and HHSN268200536179C. NR 29 TC 219 Z9 225 U1 0 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 22 PY 2012 VL 307 IS 8 BP 795 EP 803 DI 10.1001/jama.2012.137 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 896FQ UT WOS:000300551300022 ER PT J AU Udell, JA Wang, CS Tinmouth, J FitzGerald, JM Ayas, NT Simel, DL Schulzer, M Mak, E Yoshida, EM AF Udell, Jacob A. Wang, Charlie S. Tinmouth, Jill FitzGerald, J. Mark Ayas, Najib T. Simel, David L. Schulzer, Michael Mak, Edwin Yoshida, Eric M. TI Does This Patient With Liver Disease Have Cirrhosis? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CHRONIC HEPATITIS-C; ALANINE AMINOTRANSFERASE RATIO; SIMPLE NONINVASIVE INDEXES; STANDARD LABORATORY TESTS; VIRUS-COINFECTED PATIENTS; CHRONIC VIRAL-HEPATITIS; ASPARTATE-AMINOTRANSFERASE; PREDICTING CIRRHOSIS; AST/ALT RATIO; INFECTED PATIENTS AB Context Among adult patients with liver disease, the ability to identify those most likely to have cirrhosis noninvasively is challenging. Objective To identify simple clinical indicators that can exclude or detect cirrhosis in adults with known or suspected liver disease. Data Sources We searched MEDLINE and EMBASE(1966 to December 2011) and reference lists from retrieved articles, previous reviews, and physical examination textbooks. Study Selection We retained 86 studies of adequate quality that evaluated the accuracy of clinical findings for identifying histologically proven cirrhosis. Data Extraction Two authors independently abstracted data (sensitivity, specificity, and likelihood ratios [LRs]) and assessed methodological quality. Random-effects meta-analyses were used to calculate summary LRs across studies. Results Among the 86 studies, 19 533 patients were included in this meta-analysis, among whom 4725 had biopsy-proven cirrhosis (prevalence rate, 24%; 95% CI, 20%-28%). Many physical examination and simple laboratory tests increase the likelihood of cirrhosis, though the presence of ascites (LR, 7.2; 95% CI, 2.9-12), a platelet count <160 x 10(3)/mu L (LR, 6.3; 95% CI, 4.3-8.3), spider nevi (LR, 4.3; 95% CI 2.4-6.2), or a combination of simple laboratory tests with the Bonacini cirrhosis discriminant score >7 (LR, 9.4; 95% CI, 2.6-37) are the most frequently studied, reliable, and informative results. For lowering the likelihood of cirrhosis, the most useful findings are a Lok index <0.2 (a score created from the platelet count, serum aspartate aminotransferase and alanine aminotransferase, and prothrombin international normalized ratio; LR, 0.09; 95% CI, 0.03-0.31); a platelet count >= 160 x 10(3)/mu L (LR, 0.29; 95% CI, 0.20-0.39); or the absence of hepatomegaly (LR, 0.37; 95% CI, 0.24-0.51). The overall impression of the clinician was not as informative as the individual findings or laboratory combinations. Conclusions For identifying cirrhosis, the presence of a variety of clinical findings or abnormalities in a combination of simple laboratory tests that reflect the underlying pathophysiology increase its likelihood. To exclude cirrhosis, combinations of normal laboratory findings are most useful. JAMA. 2012;307(8):832-842 C1 [Udell, Jacob A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Udell, Jacob A.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Charlie S.; Tinmouth, Jill] Sunnybrook Hlth Sci Ctr, Dept Med, Div Gastroenterol, Toronto, ON M4N 3M5, Canada. [Wang, Charlie S.; Tinmouth, Jill] Univ Toronto, Toronto, ON, Canada. [Wang, Charlie S.] Brantford Gen Hosp, Dept Med, Div Gastroenterol, Brantford, ON, Canada. [FitzGerald, J. Mark; Ayas, Najib T.] Vancouver Gen Hosp, Div Respirol, Dept Med, Vancouver, BC, Canada. [Mak, Edwin] Univ British Columbia, Pacific Parkinson Res Ctr, Vancouver, BC V5Z 1M9, Canada. [FitzGerald, J. Mark; Ayas, Najib T.; Schulzer, Michael] Vancouver Coastal Hlth Res Inst, Ctr Clin Epidemiol & Evaluat, Vancouver, BC, Canada. [Simel, David L.] Duke Univ, Dept Med, Durham Vet Affairs Med Ctr, Durham, NC USA. [Yoshida, Eric M.] Vancouver Gen Hosp, Dept Med, Div Gastroenterol, Vancouver, BC, Canada. RP Udell, JA (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM judell@partners.org FU Canadian Association of Gastroenterology-Axcan Pharma Inc; Canadian Institutes for Health Research (CIHR); Canadian Foundation for Women's Health; CHEST Foundation-Respiratory Association of Metropolitan Chicago; Canadian Institutes for Health Research Industry-Partnered (Astra-Zeneca); BC Lung Association; Michael Smith Foundation; VCHRI FX This study was funded by a Canadian Association of Gastroenterology-Axcan Pharma Inc Resident Research Grant awarded to Dr Wang. Dr Udell is a recipient of a Postdoctoral Research Fellowship from the Canadian Institutes for Health Research (CIHR) and Canadian Foundation for Women's Health, and a CHEST Foundation-Respiratory Association of Metropolitan Chicago Clinical Research Award in Women's Health. Dr Tinmouth holds a Canadian Institutes for Health Research Industry-Partnered (Astra-Zeneca) New Investigator Award. Dr FitzGerald is a recipient of a Canadian Institute for Health Research and BC Lung Association Scientist award, and a Michael Smith Foundation Distinguished Scholar Award. Dr Ayas is supported by an Established Clinician Scientist Award from the VCHRI. Dr Yoshida has no competing funding or support interests associated with this work. NR 147 TC 43 Z9 44 U1 0 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 22 PY 2012 VL 307 IS 8 BP 832 EP 842 DI 10.1001/jama.2012.186 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 896FQ UT WOS:000300551300026 PM 22357834 ER PT J AU Mittal, S Wong, IY Deen, WM Toner, M AF Mittal, Sukant Wong, Ian Y. Deen, William M. Toner, Mehmet TI Antibody-Functionalized Fluid-Permeable Surfaces for Rolling Cell Capture at High Flow Rates SO BIOPHYSICAL JOURNAL LA English DT Article ID CIRCULATING TUMOR-CELLS; ON-A-CHIP; MICROFLUIDIC SYSTEMS; CANCER-CELLS; ADHESION; IMMOBILIZATION; PARALLEL; SEPARATION; DIFFUSION; APTAMERS AB Adhesion-based cell capture on surfaces in microfluidic devices forms the basis of numerous biomedical diagnostics and in vitro assays. However, the performance of these platforms is partly limited by interfacial phenomena that occur at low Reynolds numbers. In contrast, cell homing to porous vasculature is highly effective in vivo during inflammation, stem cell trafficking, and cancer metastasis. Here, we show that a porous, fluid-permeable surface functionalized with cell-specific antibodies promotes efficient and selective cell capture in vitro. This architecture is advantageous due to enhanced transport as streamlines are diverted toward the surface. Moreover, specific cell-surface interactions are promoted due to reduced shear, allowing gentle cell rolling and arrest. Together, these synergistic effects enable highly effective cell capture at flow rates more than an order of magnitude larger than those provided by existing devices with solid surfaces. C1 [Mittal, Sukant; Wong, Ian Y.; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA 02114 USA. [Mittal, Sukant; Wong, Ian Y.; Toner, Mehmet] Harvard Univ, Sch Med, Boston, MA USA. [Mittal, Sukant; Toner, Mehmet] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Deen, William M.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA 02114 USA. EM mehmet_toner@hms.harvard.edu RI Wong, Ian/G-1611-2012 OI Wong, Ian/0000-0002-9439-2548 FU National Institute of Biomedical Imaging and Bioengineering [P41-EB002503] FX This work was supported by the National Institute of Biomedical Imaging and Bioengineering under grant P41-EB002503 (BioMEMS Resource Center). I.Y.W. is the Merck Fellow of the Damon Runyon Cancer Research Foundation (DRG-2065-10). NR 54 TC 24 Z9 24 U1 1 U2 42 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 22 PY 2012 VL 102 IS 4 BP 721 EP 730 DI 10.1016/j.bpj.2011.12.044 PG 10 WC Biophysics SC Biophysics GA 900WE UT WOS:000300921600002 PM 22385842 ER PT J AU Stetler, RA Gao, YQ Zhang, LL Weng, ZF Zhang, F Hu, XM Wang, SP Vosler, P Cao, GD Sun, DD Graham, SH Chen, J AF Stetler, R. Anne Gao, Yanqin Zhang, Lili Weng, Zhongfang Zhang, Feng Hu, Xiaoming Wang, Suping Vosler, Peter Cao, Guodong Sun, Dandan Graham, Steven H. Chen, Jun TI Phosphorylation of HSP27 by Protein Kinase D Is Essential for Mediating Neuroprotection against Ischemic Neuronal Injury SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HEAT-SHOCK-PROTEIN; CEREBRAL-ISCHEMIA; BRAIN-INJURY; CELL-DEATH; SERINE-82 PHOSPHORYLATION; UP-REGULATION; CYTOCHROME-C; APOPTOSIS; HEAT-SHOCK-PROTEIN-27; ACTIVATION AB Heat shock protein 27 (HSP27) (or HSPB1) exerts cytoprotection against many cellular insults, including cerebral ischemia. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical downstream target of HSP27 conferring the neuroprotective effects of HSP27 against neuronal ischemia. However, the function of HSP27 is highly influenced by posttranslational modification, with differential cellular effects based on phosphorylation at specific serine residues. The role of phosphorylation in neuronal ischemic neuroprotection is currently unknown. We have created transgenic mice and viral vectors containing HSP27 mutated at three critical serine residues (Ser15, Ser78, and Ser82) to either alanine (HSP27-A, nonphosphorylatable) or aspartate (HSP27-D, phosphomimetic) residues. Under both in vitro and in vivo neuronal ischemic settings, overexpression of wild-type HSP27 (HSP27) and HSP27-D, but not HSP27-A, was neuroprotective and inhibited downstream ASK1 signaling pathways. Consistently, overexpressed HSP27 was phosphorylated by endogenous mechanisms when neurons were under ischemic stress, and single-point mutations identified Ser15 and Ser82 as critical for neuroprotection. Using a panel of inhibitors and gene knockdown approaches, we identified the upstream kinase protein kinase D (PKD) as the primary kinase targeting HSP27 directly for phosphorylation. PKD and HSP27 coimmunoprecipitated, and inhibition or knockdown of PKD abrogated the neuroprotective effects of HSP27 as well as the interaction with and inhibition of ASK1 signaling. Together, these data demonstrate that HSP27 requires PKD-mediated phosphorylation for its suppression of ASK1 cell death signaling and neuroprotection against ischemic injury. C1 [Stetler, R. Anne; Gao, Yanqin; Zhang, Lili; Weng, Zhongfang; Zhang, Feng; Hu, Xiaoming; Wang, Suping; Vosler, Peter; Cao, Guodong; Sun, Dandan; Graham, Steven H.; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Gao, Yanqin; Zhang, Lili; Weng, Zhongfang; Zhang, Feng; Hu, Xiaoming; Wang, Suping; Vosler, Peter; Cao, Guodong; Sun, Dandan; Graham, Steven H.; Chen, Jun] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Zhang, Lili; Weng, Zhongfang; Zhang, Feng; Hu, Xiaoming; Wang, Suping; Vosler, Peter; Cao, Guodong; Sun, Dandan; Graham, Steven H.; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. [Stetler, R. Anne; Gao, Yanqin; Cao, Guodong; Chen, Jun] Fudan Univ, Sch Med, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Gao, Yanqin; Cao, Guodong; Chen, Jun] Fudan Univ, Sch Med, Inst Brain Sci, Shanghai 200032, Peoples R China. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. EM yqgao@shmu.edu.cn; chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016 OI Gao, Yanqin/0000-0002-4915-9819 FU NIH-NINDS [NS43802, NS45048, NS36736, NS56118]; Veterans Affairs Merit Review grant; Chinese Natural Science Foundation [30670642, 30870794, 81020108021]; American Heart Association [10SDG2560122, 10POST4150028]; NIH [1F30NS057886] FX This work was supported by NIH-NINDS Grants NS43802, NS45048, NS36736, and NS56118, and Veterans Affairs Merit Review grant (J.C.); and Chinese Natural Science Foundation Grants 30670642, 30870794, and 81020108021 (Y.G.). F.Z. and X. H. were supported American Heart Association Grants 10SDG2560122 and 10POST4150028, respectively. P. V. was supported by NIH National Research Service Award Fellowship 1F30NS057886. We thank Dr. Qiming Wang (University of Pittsburgh, Pittsburgh, PA) for providing the PKD inhibitor and the anti-PKD3 antibody. We thank Carol Culver for editorial assistance and Pat Strickler for secretarial support. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government. NR 38 TC 29 Z9 31 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 22 PY 2012 VL 32 IS 8 BP 2667 EP 2682 DI 10.1523/JNEUROSCI.5169-11.2012 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 898DT UT WOS:000300716600011 PM 22357851 ER PT J AU Chu, CJ Kramer, MA Pathmanathan, J Bianchi, MT Westover, MB Wizon, L Cash, SS AF Chu, Catherine J. Kramer, Mark A. Pathmanathan, Jay Bianchi, Matt T. Westover, M. Brandon Wizon, Lauren Cash, Sydney S. TI Emergence of Stable Functional Networks in Long-Term Human Electroencephalography SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GRAPH-THEORETICAL ANALYSIS; HUMAN SLEEP ELECTROENCEPHALOGRAM; DEFAULT MODE NETWORK; RESTING HUMAN BRAIN; CORTICAL NETWORKS; PHASE SYNCHRONIZATION; ALZHEIMERS-DISEASE; COHERENCE ANALYSIS; EVOKED-POTENTIALS; MEMORY PROCESSES AB Functional connectivity networks have become a central focus in neuroscience because they reveal key higher-dimensional features of normal and abnormal nervous system physiology. Functional networks reflect activity-based coupling between brain regions that may be constrained by relatively static anatomical connections, yet these networks appear to support tremendously dynamic behaviors. Within this growing field, the stability and temporal characteristics of functional connectivity brain networks have not been well characterized. We evaluated the temporal stability of spontaneous functional connectivity networks derived from multi-day scalp encephalogram (EEG) recordings in five healthy human subjects. Topological stability and graph characteristics of networks derived from averaged data epochs ranging from 1 s to multiple hours across different states of consciousness were compared. We show that, although functional networks are highly variable on the order of seconds, stable network templates emerge after as little as similar to 100 s of recording and persist across different states and frequency bands (albeit with slightly different characteristics in different states and frequencies). Within these network templates, the most common edges are markedly consistent, constituting a network "core." Although average network topologies persist across time, measures of global network connectivity, density and clustering coefficient, are state and frequency specific, with sparsest but most highly clustered networks seen during sleep and in the gamma frequency band. These findings support the notion that a core functional organization underlies spontaneous cortical processing and may provide a reference template on which unstable, transient, and rapidly adaptive long-range assemblies are overlaid in a frequency-dependent manner. C1 [Chu, Catherine J.; Pathmanathan, Jay; Bianchi, Matt T.; Westover, M. Brandon; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chu, Catherine J.; Pathmanathan, Jay; Bianchi, Matt T.; Westover, M. Brandon; Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kramer, Mark A.; Wizon, Lauren] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. RP Chu, CJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM cchushore@partners.org RI Kramer, Mark/A-1291-2014 FU National Institutes of Health/National Institute of Neurological Disorders and Stroke [NS062092]; Child Neurology Foundation; American Academy of Neurology; Harvard/Massachusetts Institute of Technology Health Sciences and Technology, Beth Israel Deaconess Medical Center; Pfizer; Merck; Burroughs Wellcome Fund FX S.S.C. and M. B. W. are supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant NS062092. C.J.C. is supported by the Child Neurology Foundation, the American Academy of Neurology, and the Clinical Investigator Training Program: Harvard/Massachusetts Institute of Technology Health Sciences and Technology, Beth Israel Deaconess Medical Center, in collaboration with Pfizer and Merck. M. A. K. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. NR 73 TC 39 Z9 39 U1 1 U2 12 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 FEB 22 PY 2012 VL 32 IS 8 BP 2703 EP 2713 DI 10.1523/JNEUROSCI.5669-11.2012 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 898DT UT WOS:000300716600014 PM 22357854 ER PT J AU Farra, R Sheppard, NF McCabe, L Neer, RM Anderson, JM Santini, JT Cima, MJ Langer, R AF Farra, Robert Sheppard, Norman F., Jr. McCabe, Laura Neer, Robert M. Anderson, James M. Santini, John T., Jr. Cima, Michael J. Langer, Robert TI First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PARATHYROID-HORMONE 1-34; MULTI-RESERVOIR ARRAY; IN-VITRO RELEASE; BONE; OSTEOPOROSIS; FRACTURES; DEVICE AB The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life. C1 [Farra, Robert; Sheppard, Norman F., Jr.; McCabe, Laura] MicroCHIPS Inc, Waltham, MA 02451 USA. [Neer, Robert M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA 02114 USA. [Anderson, James M.] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Santini, John T., Jr.] Demand Therapeut Inc, Tyngsboro, MA 01879 USA. [Cima, Michael J.] MIT, Dept Mat Sci & Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Langer, Robert] MIT, Dept Chem Engn, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Farra, R (reprint author), MicroCHIPS Inc, Waltham, MA 02451 USA. EM rfarra@mchips.com FU MicroCHIPS, Inc. FX This study was sponsored by MicroCHIPS, Inc. NR 27 TC 69 Z9 69 U1 6 U2 78 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 FEB 22 PY 2012 VL 4 IS 122 AR 122ra21 DI 10.1126/scitranslmed.3003276 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 901GQ UT WOS:000300952100003 PM 22344516 ER PT J AU Rana, S Powe, CE Salahuddin, S Verlohren, S Perschel, FH Levine, RJ Lim, KH Wenger, JB Thadhani, R Karumanchi, SA AF Rana, Sarosh Powe, Camille E. Salahuddin, Saira Verlohren, Stefan Perschel, Frank H. Levine, Richard J. Lim, Kee-Hak Wenger, Julia B. Thadhani, Ravi Karumanchi, S. Ananth TI Angiogenic Factors and the Risk of Adverse Outcomes in Women With Suspected Preeclampsia SO CIRCULATION LA English DT Article DE adverse maternal and perinatal outcomes; hypertension; pre-eclampsia; proteinuria; triage; vascular endothelial growth factors ID RANDOMIZED CONTROLLED-TRIAL; GROWTH-FACTOR; GESTATIONAL HYPERTENSION; DEVELOP PREECLAMPSIA; EXPECTANT MANAGEMENT; SOLUBLE ENDOGLIN; PREGNANCY; COMPLICATIONS; IDENTIFICATION; PREDICT AB Background-An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia. Methods and Results-We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation and examined for an association between the sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks. The median sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared with those who did not (47.0 [25th-75th percentile, 15.5-112.2] versus 10.8 [25th-75th percentile, 4.1-28.6]; P<0.0001). Among those presenting at <34 weeks (n = 167), the results were more striking (226.6 [25th-75th percentile, 50.4-547.3] versus 4.5 [25th-75th percentile, 2.0-13.5]; P<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared with the lowest (odds ratio, 47.8; 95% confidence interval, 14.6-156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the curve, 0.93 for hypertension, proteinuria, and sFlt1/PlGF versus 0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio >= 85 compared with 15.8% of women with an sFlt1/PlGF ratio <85 (hazard ratio, 15.2; 95% confidence interval, 8.0-28.7). Conclusions-In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within 2 weeks. The accuracy of this test is substantially better than that of current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings. (Circulation. 2012; 125:911-919.) C1 [Rana, Sarosh; Salahuddin, Saira; Lim, Kee-Hak; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Powe, Camille E.; Wenger, Julia B.; Thadhani, Ravi] Harvard Univ, Sch Med, Boston, MA USA. [Powe, Camille E.; Wenger, Julia B.; Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Verlohren, Stefan] Campus Virchow Clin, Dept Obstet, Berlin, Germany. [Perschel, Frank H.] Charite, Dept Lab Med Clin Chem & Pathobiochem, D-13353 Berlin, Germany. [Levine, Richard J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Rana, S (reprint author), Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Dept Obstet & Gynecol, 330 Brookline Ave,Kirstein 382, Boston, MA 02215 USA. EM srana1@bidmc.harvard.edu OI Verlohren, Stefan/0000-0003-3507-8636 FU Harvard Diversity and Community Partnership Faculty; Howard Hughes Medical Institute; Medical Research Council [G0601295] FX Dr Rana is supported by a Harvard Diversity and Community Partnership Faculty Fellowship Award. Dr Powe was supported by Howard Hughes Medical Institute Medical Research Training Fellowship (2009-2010). Dr Karumanchi is an investigator for the Howard Hughes Medical Institute. The study was also partially supported by the Medical Research Council (Grant no: G0601295). NR 33 TC 170 Z9 178 U1 4 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 21 PY 2012 VL 125 IS 7 BP 911 EP U199 DI 10.1161/CIRCULATIONAHA.111.054361 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 901GC UT WOS:000300949800017 PM 22261192 ER PT J AU Jarosiewicz, B Schummers, J Malik, WQ Brown, EN Sur, M AF Jarosiewicz, Beata Schummers, James Malik, Wasim Q. Brown, Emery N. Sur, Mriganka TI Functional Biases in Visual Cortex Neurons with Identified Projections to Higher Cortical Targets SO CURRENT BIOLOGY LA English DT Article ID FERRET MUSTELA-PUTORIUS; LATERAL GENICULATE-NUCLEUS; ORIENTATION SELECTIVITY; CORTICOCORTICAL CONNECTIONS; SUPRASYLVIAN CORTEX; RESPONSE PROPERTIES; MOTION PERCEPTION; AREA MT; CAT; CELLS AB Background: Visual perception involves information flow from lower- to higher-order cortical areas, which are known to process different kinds of information. How does this functional specialization arise? As a step toward addressing this question, we combined fluorescent retrograde tracing with in vivo two-photon calcium imaging to simultaneously compare the tuning properties of neighboring neurons in areas 17 and 18 of ferret visual cortex that have different higher cortical projection targets. Results: Neurons projecting to the posterior suprasylvian sulcus (PSS) were more direction selective and preferred shorter stimuli, higher spatial frequencies, and higher temporal frequencies than neurons projecting to area 21, anticipating key differences between the functional properties of the target areas themselves. These differences could not be explained by a correspondence between anatomical and functional clustering within early visual cortex, and the largest differences were in properties generated within early visual cortex (direction selectivity and length preference) rather than in properties present in its retinogeniculate inputs. Conclusions: These projection cell groups, and hence the higher-order visual areas to which they project, likely obtain their functional properties not from biased retinogeniculate inputs but from highly specific circuitry within the cortex. C1 [Jarosiewicz, Beata; Schummers, James; Sur, Mriganka] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Malik, Wasim Q.; Brown, Emery N.; Sur, Mriganka] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Malik, Wasim Q.; Brown, Emery N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Jarosiewicz, B (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. EM jarosiew@gmail.com; msur@mit.edu FU Ruth L. Kirschstein National Research Service Award [5F32NS054390]; NIH [EY018648, EY07023, DP1 OD003646, EB006385] FX The authors would like to thank Amanda Mower, Beau Cronin, Ian Wicker-sham, Ethan Meyers, Paul Manger, Nicolas Masse, Hongbo Yu, Brandon Farley, Caroline Runyan, and Travis Emery for their contributions. This work was supported by Ruth L. Kirschstein National Research Service Award 5F32NS054390 (B.J.), NIH grants EY018648 and EY07023 (M.S.), and NIH grants DP1 OD003646 and EB006385 (E.N.B.). NR 51 TC 17 Z9 17 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 21 PY 2012 VL 22 IS 4 BP 269 EP 277 DI 10.1016/j.cub.2012.01.011 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 896TW UT WOS:000300595300018 PM 22305753 ER PT J AU Moriguchi, H Zhang, Y Mihara, M Sato, C AF Moriguchi, Hisashi Zhang, Yue Mihara, Makoto Sato, Chifumi TI A therapeutic method for the direct reprogramming of human liver cancer cells with only chemicals (Retracted article. See vol. 2, 839, 2012) SO SCIENTIFIC REPORTS LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; AKR1B10; RETINOIDS; SMOKERS; MARKER AB Various methods for the direct reprogramming of human somatic cells have been developed. However, a therapeutic method to reprogram and eliminate human solid tumor cells has not been developed. Here we show a novel therapeutic method to reprogram and eliminate human solid tumor cells with chemicals. This therapeutic method may be applicable to various human solid tumor cells that express aldo-keto reductase family 1 member B10 (AKR1B10) and retinoid X receptors (RXRs). C1 [Moriguchi, Hisashi; Mihara, Makoto] Univ Tokyo, Sch Med, Dept Plast & Reconstruct Surg, Div iPS Cell Res & Applicat, Tokyo 113, Japan. [Moriguchi, Hisashi] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moriguchi, Hisashi; Zhang, Yue] Harvard Univ, Sch Med, Boston, MA USA. [Zhang, Yue] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Sato, Chifumi] Tokyo Med & Dent Univ, Grad Sch Hlth Sci, Dept Analyt Hlth Sci, Tokyo, Japan. RP Moriguchi, H (reprint author), Univ Tokyo, Sch Med, Dept Plast & Reconstruct Surg, Div iPS Cell Res & Applicat, Tokyo 113, Japan. EM moriguchi-tky@umin.ac.jp NR 15 TC 4 Z9 4 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD FEB 21 PY 2012 VL 2 AR 280 DI 10.1038/srep00280 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 896RB UT WOS:000300586700001 PM 22355790 ER PT J AU Polyak, K Vogt, PK AF Polyak, Kornelia Vogt, Peter K. TI Progress in breast cancer research SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID HETEROGENEITY C1 [Polyak, Kornelia] Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, Brigham & Womens Hosp,Med Sch, Boston, MA 02215 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Vogt, Peter K.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Polyak, K (reprint author), Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, Brigham & Womens Hosp,Med Sch, Boston, MA 02215 USA. EM kornelia_polyak@dfci.harvard.edu; pkvogt@scripps.edu FU NCI NIH HHS [R01 CA078230, R01 CA151574, R01 CA153124] NR 31 TC 8 Z9 9 U1 1 U2 10 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 FEB 21 PY 2012 VL 109 IS 8 BP 2715 EP 2717 DI 10.1073/pnas.1201091109 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100018 PM 22331869 ER PT J AU Jin, K Kong, XJ Shah, T Penet, MF Wildes, F Sgroi, DC Ma, XJ Huang, Y Kallioniemi, A Landberg, G Bieche, I Wu, XY Lobie, PE Davidson, NE Bhujwalla, ZM Zhu, T Sukumar, S AF Jin, Kideok Kong, Xiangjun Shah, Tariq Penet, Marie-France Wildes, Flonne Sgroi, Dennis C. Ma, Xiao-Jun Huang, Yi Kallioniemi, Anne Landberg, Goran Bieche, Ivan Wu, Xinyan Lobie, Peter E. Davidson, Nancy E. Bhujwalla, Zaver M. Zhu, Tao Sukumar, Saraswati TI The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR-RECEPTOR; ESTROGEN-RECEPTOR; ENDOCRINE THERAPY; RANDOMIZED-TRIAL; DOUBLE-BLIND; EXPRESSION; GENE; ALPHA; AMPLIFICATION; FULVESTRANT AB Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ER alpha-positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ER alpha signaling. HOXB7 is an ER alpha-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ER alpha-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance. C1 [Kong, Xiangjun; Zhu, Tao] Hefei Natl Lab Phys Sci, Hefei 230027, Anhui, Peoples R China. [Jin, Kideok; Huang, Yi; Wu, Xinyan; Davidson, Nancy E.; Bhujwalla, Zaver M.; Sukumar, Saraswati] Johns Hopkins Univ, Breast Canc Program, Dept Oncol, Sch Med, Baltimore, MD 21231 USA. [Shah, Tariq; Penet, Marie-France; Wildes, Flonne; Bhujwalla, Zaver M.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD 21231 USA. [Sgroi, Dennis C.] Harvard Univ, Dept Pathol, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ma, Xiao-Jun] AviaraDx, Carlsbad, CA 92010 USA. [Kallioniemi, Anne] Univ Tampere, Canc Genet Lab, FIN-33014 Tampere, Finland. [Landberg, Goran] Univ Manchester, Breakthrough Breast Canc Res Unit, Sch Canc & Enabling Sci, Paterson Inst Canc Res, Manchester M20 4BX, Lancs, England. [Bieche, Ivan] Hosp Rene Huguenin, Inst Curie, F-92210 St Cloud, France. [Lobie, Peter E.] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 119077, Singapore. [Lobie, Peter E.] Natl Univ Singapore, Dept Pharmacol, Singapore 119077, Singapore. RP Zhu, T (reprint author), Hefei Natl Lab Phys Sci, Hefei 230027, Anhui, Peoples R China. EM zhut@ustc.edu.cn; saras@jhmi.edu OI Kallioniemi, Anne/0000-0003-3552-8158 FU National Institutes of Health [P50-CA88843]; Susan G. Komen Postdoctoral Fellowships; National Key Scientific Program of China [2010CB912804, 2007CB914801, 2011CBA01103]; National Natural Science Foundation of China [30971492, 30725015] FX We thank Dr. Ben H. Park for generously providing the ERIN cell line, Drs. Richard Santen (University of Virginia, Charlottesville, VA) and V. Craig Jordan (Georgetown University, Washington, DC) for the LTED and TAMLT cell lysates, and Dr. Cynthia Zahnow and Hexin Chen for reviewing the manuscript. This work was supported by Specialized Programs Of Research Excellence (SPORE) in Breast Cancer: National Institutes of Health Grant P50-CA88843 (to S.S.), Susan G. Komen Postdoctoral Fellowships (to T.Z. and K.J.), the National Key Scientific Program of China (2010CB912804, 2007CB914801, and 2011CBA01103), and the National Natural Science Foundation of China (30971492 and 30725015) (to T.Z.). NR 36 TC 37 Z9 40 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 2736 EP 2741 DI 10.1073/pnas.1018859108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100022 PM 21690342 ER PT J AU Chiba, N Comaills, V Shiotani, B Takahashi, F Shimada, T Tajima, K Winokur, D Hayashida, T Willers, H Brachtel, E Vivanco, MD Haber, DA Zou, L Maheswaran, S AF Chiba, Naokazu Comaills, Valentine Shiotani, Bunsyo Takahashi, Fumiyuki Shimada, Toshiyuki Tajima, Ken Winokur, Daniel Hayashida, Tetsu Willers, Henning Brachtel, Elena Vivanco, Maria d. M. Haber, Daniel A. Zou, Lee Maheswaran, Shyamala TI Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GROWTH-FACTOR-BETA; BREAST-CANCER; MAMMALIAN-CELLS; ATM; RADIATION; TUMORIGENESIS; CHECKPOINT; EMT; MICROENVIRONMENT; BARRIER AB Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the double-stranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-beta, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9-TGF-beta-ATMaxis on checkpoint activation and DNA repair, suggesting that TGF-beta may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors. C1 [Chiba, Naokazu; Shiotani, Bunsyo; Takahashi, Fumiyuki; Shimada, Toshiyuki; Tajima, Ken; Winokur, Daniel; Hayashida, Tetsu; Haber, Daniel A.; Zou, Lee; Maheswaran, Shyamala] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Chiba, Naokazu; Takahashi, Fumiyuki; Shimada, Toshiyuki; Tajima, Ken; Hayashida, Tetsu; Maheswaran, Shyamala] Massachusetts Gen Hosp, Dept Surg, Charlestown, MA 02129 USA. [Willers, Henning] Massachusetts Gen Hosp, Dept Radiat Oncol, Charlestown, MA 02129 USA. [Brachtel, Elena] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Comaills, Valentine; Vivanco, Maria d. M.] Ctr Cooperat Res Biosci, Cell Biol & Stem Cell Unit, Derio Bizkaia 48160, Spain. RP Zou, L (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM zou.lee@mgh.harvard.edu; maheswaran@helix.mgh.harvard.edu RI cancer, biogune/H-7276-2012; Vivanco, Maria/G-2393-2011 OI Vivanco, Maria/0000-0002-9540-247X FU National Institutes of Health/National Cancer Institute [CA89138]; National Cancer Institute; [PDF0600282]; [KG090412]; [GM076388] FX We thank Drs. Isselbacher and Ellisen for critical reading of the manuscript. This work was supported by National Institutes of Health/National Cancer Institute Grant CA89138, National Cancer Institute Federal Share Program and Income (L.Z. and S.M.), and by Susan G. Komen for the Cure Grants PDF0600282 and KG090412 (to S.M.) and GM076388 (to L.Z.). NR 26 TC 33 Z9 36 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 FEB 21 PY 2012 VL 109 IS 8 BP 2760 EP 2765 DI 10.1073/pnas.1018867108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100026 PM 21930940 ER PT J AU Maruyama, R Shipitsin, M Choudhury, S Wu, ZH Protopopov, A Yao, J Lo, PK Bessarabova, M Ishkin, A Nikolsky, Y Liu, XS Sukumar, S Polyak, K AF Maruyama, Reo Shipitsin, Michail Choudhury, Sibgat Wu, Zhenhua Protopopov, Alexei Yao, Jun Lo, Pang-Kuo Bessarabova, Marina Ishkin, Alex Nikolsky, Yuri Liu, X. Shirley Sukumar, Saraswati Polyak, Kornelia TI Altered antisense-to-sense transcript ratios in breast cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NONCODING RNAS; GENOME; EXPRESSION; CELLS AB Transcriptome profiling studies suggest that a large fraction of the genome is transcribed and many transcripts function independent of their protein coding potential. The relevance of noncoding RNAs (ncRNAs) in normal physiological processes and in tumorigenesis is increasingly recognized. Here, we describe consistent and significant differences in the distribution of sense and antisense transcripts between normal and neoplastic breast tissues. Many of the differentially expressed antisense transcripts likely represent long ncRNAs. A subset of genes that mainly generate antisense transcripts in normal but not cancer cells is involved in essential metabolic processes. These findings suggest fundamental differences in global RNA regulation between normal and cancer cells that might play a role in tumorigenesis. C1 [Maruyama, Reo; Shipitsin, Michail; Choudhury, Sibgat; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wu, Zhenhua; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Protopopov, Alexei] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Maruyama, Reo; Shipitsin, Michail; Choudhury, Sibgat; Polyak, Kornelia] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Maruyama, Reo; Shipitsin, Michail; Choudhury, Sibgat; Polyak, Kornelia] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Wu, Zhenhua; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Yao, Jun] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Lo, Pang-Kuo; Sukumar, Saraswati] Johns Hopkins Oncol Ctr, Baltimore, MD 21231 USA. [Bessarabova, Marina; Ishkin, Alex] Russian Acad Sci, Vavilov Inst Gen Genet, Moscow 119331, Russia. [Nikolsky, Yuri] GeneGo Inc, St Joseph, MI 49085 USA. [Polyak, Kornelia] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM kornelia_polyak@dfci.harvard.edu FU Novartis Pharmaceuticals, Inc.; National Cancer Institute [CA89393]; Department of Defense [W81XWH-07-1-0294]; Avon Foundation; Breast Cancer Research Foundation; Susan G. Komen Foundation; Terri Brodeur Breast Cancer Foundation FX Conflict of interest statement: K.P. receives research support from and is a consultant to Novartis Pharmaceuticals, Inc. K.P. is also on the Scientific Advisory Board of Metamark Genetics, Inc. and Theracrine, Inc. Y.N. is a founder and employee of GeneGo, Inc.; We thank members of our laboratories for their critical reading of this manuscript and useful discussions. We greatly appreciate the help of Dr. Andrea Richardson (Brigham and Women's Hospital) in the acquisition of tissue samples and the Arthur and Rochelle Belfer Center for Cancer Genomics for array hybridization. This study was supported by the National Cancer Institute Specialized Program in Research Excellence in Breast Cancer at the Dana-Farber/Harvard University Cancer Center (Grant CA89393), the Department of Defense (Grant W81XWH-07-1-0294), and the Avon Foundation as well as by Breast Cancer Research Foundation grants (to K. P.), Susan G. Komen Foundation fellowships (to M. S. and R. M.), and a Terri Brodeur Breast Cancer Foundation Fellowship (to S.C.). NR 23 TC 23 Z9 23 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 2820 EP 2824 DI 10.1073/pnas.1010559107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100036 PM 21098291 ER PT J AU Luo, TP Masson, K Jaffe, JD Silkworth, W Ross, NT Scherer, CA Scholl, C Frohling, S Carr, SA Stern, AM Schreiber, SL Golub, TR AF Luo, Tuoping Masson, Kristina Jaffe, Jacob D. Silkworth, Whitney Ross, Nathan T. Scherer, Christina A. Scholl, Claudia Froehling, Stefan Carr, Steven A. Stern, Andrew M. Schreiber, Stuart L. Golub, Todd R. TI STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ONCOGENE ADDICTION; THERAPY; RAS; SELECTIVITY; DISCOVERY; TARGET; DRUG AB Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest in KRAS as a therapeutic target, direct blockade of KRAS function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels of protein kinases, KRAS-dependent cancer cells were proposed to have a unique requirement for the serine/threonine kinase STK33. Thus, it was suggested that small-molecule inhibitors of STK33 might have therapeutic benefit in these cancers. Here, we describe the development of selective, low nanomolar inhibitors of STK33's kinase activity. The most potent and selective of these, BRD8899, failed to kill KRAS-dependent cells. While several explanations for this result exist, our data are most consistent with the view that inhibition of STK33's kinase activity does not represent a promising anti-KRAS therapeutic strategy. C1 [Luo, Tuoping; Masson, Kristina; Jaffe, Jacob D.; Silkworth, Whitney; Ross, Nathan T.; Scherer, Christina A.; Carr, Steven A.; Stern, Andrew M.; Schreiber, Stuart L.; Golub, Todd R.] Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Luo, Tuoping; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Scholl, Claudia; Froehling, Stefan] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany. [Schreiber, Stuart L.; Golub, Todd R.] Howard Hughes Med Inst, Bethesda, MD 20817 USA. [Golub, Todd R.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Schreiber, SL (reprint author), Broad Inst Harvard & MIT, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM stuart_schreiber@harvard.edu; golub@broadinstitute.org FU Starr Cancer Consortium; National Institute of General Medical Sciences [GM38627]; Swedish Research Council (Vetenskapsradet); German Research Foundation; National Institutes of Health (NIH) [RL1-GM084437, RL1-CA133834, RL1-HG004671, UL1-DE019585] FX We thank members of the Broad Institute Chemical Biology Platform for high throughput screening assistance. We also thank D. Gary Gilliland at Merck Research Laboratories and Robert J. Gould at Epizyme for helpful advice. This study was supported by a Starr Cancer Consortium grant. In addition, T. L. was supported by a grant from the National Institute of General Medical Sciences (GM38627 awarded to S. L. S.), K. M. was supported by the Swedish Research Council (Vetenskapsradet), and C. S. was supported by an Emmy Noether Fellowship from the German Research Foundation. Support for these studies was also provided by the National Institutes of Health (NIH) Genomics Based Drug Discovery-Driving Medical Projects Grant RL1-GM084437 and RL1-CA133834, administratively linked to NIH grants RL1-HG004671 and UL1-DE019585. NR 24 TC 28 Z9 29 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 FEB 21 PY 2012 VL 109 IS 8 BP 2860 EP 2865 DI 10.1073/pnas.1120589109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100043 PM 22323609 ER PT J AU Russell, MK Longoni, M Wells, J Maalouf, FI Tracy, AA Loscertales, M Ackerman, KG Pober, BR Lage, K Bult, CJ Donahoe, PK AF Russell, Meaghan K. Longoni, Mauro Wells, Julie Maalouf, Faouzi I. Tracy, Adam A. Loscertales, Maria Ackerman, Kate G. Pober, Barbara R. Lage, Kasper Bult, Carol J. Donahoe, Patricia K. TI Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pleuroperitoneal folds; expression profiling; diaphragm development ID SET ENRICHMENT ANALYSIS; MAMMALIAN DIAPHRAGM; MOUSE DEVELOPMENT; SCALE ANALYSIS; HUMAN CANCERS; EXPRESSION; PROTEINS; DEFECTS; HOX; PBX AB Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies. C1 [Russell, Meaghan K.; Longoni, Mauro; Maalouf, Faouzi I.; Tracy, Adam A.; Loscertales, Maria; Pober, Barbara R.; Lage, Kasper; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Wells, Julie; Bult, Carol J.] Jackson Lab, Bar Harbor, ME 04609 USA. [Ackerman, Kate G.] Univ Rochester, Dept Pediat, Sch Med & Dent, Rochester, NY 14642 USA. [Ackerman, Kate G.] Univ Rochester, Sch Med & Dent, Dept Biomed Genet, Rochester, NY 14642 USA. [Pober, Barbara R.] Childrens Hosp Boston, Boston, MA 02115 USA. [Pober, Barbara R.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Lage, Kasper; Donahoe, Patricia K.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Lage, Kasper; Donahoe, Patricia K.] Broad Inst, Cambridge, MA 02142 USA. [Lage, Kasper] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Lage, Kasper] Univ Copenhagen, Ctr Prot Res, DK-2200 Copenhagen, Denmark. RP Donahoe, PK (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. EM pdonahoe@partners.org RI Congregado, Miguel/B-9062-2009; Longoni, Mauro/I-2526-2013 OI Congregado, Miguel/0000-0002-2404-0176; FU NHLBI NIH HHS [K08 HL076286, R01 HL085459]; NICHD NIH HHS [P01 HD068250] NR 69 TC 24 Z9 25 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 2978 EP 2983 DI 10.1073/pnas.1121621109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100063 PM 22315423 ER PT J AU Pillai, SK Abdel-Mohsen, M Guatelli, J Skasko, M Monto, A Fujimoto, K Yukl, S Greene, WC Kovari, H Rauch, A Fellay, J Battegay, M Hirschel, B Witteck, A Bernasconi, E Ledergerber, B Gunthard, HF Wong, JK AF Pillai, Satish K. Abdel-Mohsen, Mohamed Guatelli, John Skasko, Mark Monto, Alexander Fujimoto, Katsuya Yukl, Steven Greene, Warner C. Kovari, Helen Rauch, Andri Fellay, Jacques Battegay, Manuel Hirschel, Bernard Witteck, Andrea Bernasconi, Enos Ledergerber, Bruno Guenthard, Huldrych F. Wong, Joseph K. CA Swiss HIV Cohort Study TI Role of retroviral restriction factors in the interferon-alpha-mediated suppression of HIV-1 in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL ACTIVITY; REVERSE TRANSCRIPTION; CYTIDINE DEAMINATION; ANTIVIRAL PROTEIN; VIF PROTEIN; T-CELLS; C VIRUS; APOBEC3G; HYPERMUTATION AB The antiviral potency of the cytokine IFN-alpha has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-alpha-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-alpha treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naive individuals before, during, and after pegylated IFN-alpha/ribavirin (IFN-alpha/riba) combination therapy. IFN-alpha/riba therapy decreased HIV-1 viral load by -0.921 (+/- 0.858) log(10) copies/mL in HIV/HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-alpha/riba treatment in patient-derived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's rho), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-alpha/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-alpha in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals. C1 [Pillai, Satish K.; Abdel-Mohsen, Mohamed; Monto, Alexander; Yukl, Steven; Greene, Warner C.; Wong, Joseph K.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Pillai, Satish K.; Monto, Alexander; Fujimoto, Katsuya; Yukl, Steven; Wong, Joseph K.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Guatelli, John; Skasko, Mark] Univ Calif San Diego, Vet Affairs San Diego Healthcare Syst, Dept Med, La Jolla, CA 92093 USA. [Greene, Warner C.] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Kovari, Helen; Ledergerber, Bruno; Guenthard, Huldrych F.] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland. [Rauch, Andri] Univ Bern, Univ Hosp Berne, Div Infect Dis, CH-3010 Bern, Switzerland. [Fellay, Jacques] Univ Lausanne Hosp, Div Infect Dis, CH-1011 Lausanne, Switzerland. [Fellay, Jacques] Univ Lausanne Hosp, Inst Microbiol, CH-1011 Lausanne, Switzerland. [Battegay, Manuel] Univ Basel Hosp, Div Infect Dis, CH-4031 Basel, Switzerland. [Hirschel, Bernard] Univ Hosp Geneva, Div Infect Dis, CH-1211 Geneva, Switzerland. [Witteck, Andrea] Cantonal Hosp St Gallen, Div Infect Dis, CH-9007 St Gallen, Switzerland. [Bernasconi, Enos] Reg Hosp Lugano, Div Infect Dis, CH-6903 Lugano, Switzerland. RP Pillai, SK (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM satish.pillai@ucsf.edu RI Infektiologie, USZ/A-6921-2011; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; gunthard, huldrych/F-1724-2011; Fellay, Jacques/A-6681-2009; Ledergerber, Bruno/B-5656-2009; Fujimoto, Katsuya/G-2835-2012 OI gunthard, huldrych/0000-0002-1142-6723; Fellay, Jacques/0000-0002-8240-939X; Ledergerber, Bruno/0000-0002-6881-4401; FU National Institutes of Health [1K01DA024654, AI081668]; American Recovery and Reinvestment Act (ARRA); Swiss HIV Cohort Study Project [594]; Swiss National Science Foundation [324730-130865, R01NS051132, R21MH083573, R56AI91573, 33CSC0-108787]; Swiss HIV Cohort Study Research Foundation FX We thank the patients who participate in the Swiss HIV Cohort Study and the physicians and study nurses for excellent patient care. This study was supported by National Institutes of Health Grant 1K01DA024654 (to S. K. P.), Grant AI081668, and an American Recovery and Reinvestment Act (ARRA) supplement (to J.G.). Additional support was provided by Swiss HIV Cohort Study Project 594; the Veterans Affairs Merit Review (K. F., S.Y., and J.K.W.); and Swiss National Science Foundation Grants 324730-130865 (to H. F. G.), R01NS051132, R21MH083573, and R56AI91573. The Swiss HIV Cohort Study is supported by Swiss National Science Foundation Grant 33CSC0-108787 and the Swiss HIV Cohort Study Research Foundation. NR 56 TC 63 Z9 64 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 3035 EP 3040 DI 10.1073/pnas.1111573109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100073 PM 22315404 ER PT J AU Grad, YH Lipsitch, M Feldgarden, M Arachchi, HM Cerqueira, GC FitzGerald, M Godfrey, P Haas, BJ Murphy, CI Russ, C Sykes, S Walker, BJ Wortman, JR Young, S Zeng, QD Abouelleil, A Bochicchio, J Chauvin, S DeSmet, T Gujja, S McCowan, C Montmayeur, A Steelman, S Frimodt-Moller, J Petersen, AM Struve, C Krogfelt, KA Bingen, E Weill, FX Lander, ES Nusbaum, C Birren, BW Hung, DT Hanage, WP AF Grad, Yonatan H. Lipsitch, Marc Feldgarden, Michael Arachchi, Harindra M. Cerqueira, Gustavo C. FitzGerald, Michael Godfrey, Paul Haas, Brian J. Murphy, Cheryl I. Russ, Carsten Sykes, Sean Walker, Bruce J. Wortman, Jennifer R. Young, Sarah Zeng, Qiandong Abouelleil, Amr Bochicchio, James Chauvin, Sara DeSmet, Timothy Gujja, Sharvari McCowan, Caryn Montmayeur, Anna Steelman, Scott Frimodt-Moller, Jakob Petersen, Andreas M. Struve, Carsten Krogfelt, Karen A. Bingen, Edouard Weill, Francois-Xavier Lander, Eric S. Nusbaum, Chad Birren, Bruce W. Hung, Deborah T. Hanage, William P. TI Genomic epidemiology of the Escherichia coli O104:H4 outbreaks in Europe, 2011 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE food-borne outbreak; Shiga toxin; enteroaggregative E. coli; enterohemorrhagic E. coli ID HEMOLYTIC-UREMIC SYNDROME; DNA-SEQUENCING DATA; FRAMEWORK; GERMANY; FRANCE AB The degree to which molecular epidemiology reveals information about the sources and transmission patterns of an outbreak depends on the resolution of the technology used and the samples studied. Isolates of Escherichia coli O104:H4 from the outbreak centered in Germany in May-July 2011, and the much smaller outbreak in southwest France in June 2011, were indistinguishable by standard tests. We report a molecular epidemiological analysis using multiplatform whole-genome sequencing and analysis of multiple isolates from the German and French outbreaks. Isolates from the German outbreak showed remarkably little diversity, with only two single nucleotide polymorphisms (SNPs) found in isolates from four individuals. Surprisingly, we found much greater diversity (19 SNPs) in isolates from seven individuals infected in the French outbreak. The German isolates form a clade within the more diverse French outbreak strains. Moreover, five isolates derived from a single infected individual from the French outbreak had extremely limited diversity. The striking difference in diversity between the German and French outbreak samples is consistent with several hypotheses, including a bottleneck that purged diversity in the German isolates, variation in mutation rates in the two E. coli outbreak populations, or uneven distribution of diversity in the seed populations that led to each outbreak. C1 [Feldgarden, Michael; Arachchi, Harindra M.; Cerqueira, Gustavo C.; FitzGerald, Michael; Godfrey, Paul; Haas, Brian J.; Murphy, Cheryl I.; Russ, Carsten; Sykes, Sean; Walker, Bruce J.; Wortman, Jennifer R.; Young, Sarah; Zeng, Qiandong; Abouelleil, Amr; Bochicchio, James; Chauvin, Sara; DeSmet, Timothy; Gujja, Sharvari; McCowan, Caryn; Montmayeur, Anna; Steelman, Scott; Lander, Eric S.; Nusbaum, Chad; Birren, Bruce W.; Hung, Deborah T.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Grad, Yonatan H.; Hung, Deborah T.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Grad, Yonatan H.; Lipsitch, Marc; Hanage, William P.] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Dept Epidemiol, Boston, MA 02115 USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Feldgarden, Michael; Arachchi, Harindra M.; Cerqueira, Gustavo C.; FitzGerald, Michael; Godfrey, Paul; Haas, Brian J.; Murphy, Cheryl I.; Russ, Carsten; Sykes, Sean; Walker, Bruce J.; Wortman, Jennifer R.; Young, Sarah; Zeng, Qiandong; Abouelleil, Amr; Bochicchio, James; Chauvin, Sara; DeSmet, Timothy; Gujja, Sharvari; McCowan, Caryn; Montmayeur, Anna; Steelman, Scott; Lander, Eric S.; Nusbaum, Chad; Birren, Bruce W.; Hung, Deborah T.] MIT, Cambridge, MA 02142 USA. [Frimodt-Moller, Jakob] Hillerod Sygehus, Dept Clin Microbiol, DK-3400 Hillerod, Denmark. [Frimodt-Moller, Jakob; Petersen, Andreas M.; Struve, Carsten; Krogfelt, Karen A.] Statens Serum Inst, Dept Microbial Surveillance & Res, DK-2300 Copenhagen, Denmark. [Petersen, Andreas M.] Hvidovre Univ Hosp, Dept Gastroenterol, DK-2650 Hvidovre, Denmark. [Bingen, Edouard] Hop Robert Debre, AP HP, Microbiol Serv, Lab Associe,Ctr Natl Reference Escherichia Coli &, F-75019 Paris, France. [Bingen, Edouard] Univ Paris Diderot, EA3105, F-75505 Paris, France. [Weill, Francois-Xavier] Inst Pasteur, Ctr Natl Reference Escherichia Coli & Shigella, Unite Bacteries Pathogenes Enter, F-75015 Paris, France. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Hung, Deborah T.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Hung, Deborah T.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. RP Lander, ES (reprint author), Broad Inst Harvard, Cambridge, MA 02142 USA. EM lander@broadinstitute.org; whanage@hsph.harvard.edu RI Krogfelt , Karen Angeliki/O-8145-2016; OI Krogfelt , Karen Angeliki/0000-0001-7536-3453; Wortman, Jennifer/0000-0002-8713-1227; Weill, Francois-Xavier/0000-0001-9941-5799; Montmayeur, Anna/0000-0002-8132-1716; Petersen, Andreas Munk/0000-0003-0531-0553; Frimodt-Moller, Jakob/0000-0002-7585-636X; Lipsitch, Marc/0000-0003-1504-9213 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272200900018C]; Broad Institute; National Institute of General Medical Sciences [U54GM088558]; National Institutes of Allergy and Infectious Disease [AI007061]; Danish Council for Strategic Research [09-063070]; Institut de Veille Sanitaire FX We thank Flemming Scheutz from the World Health Organization Collaborating Centre for Reference and Research on Escherichia coli and Klebsiella, Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark for the valuable contribution of strains and discussion; R. T. Chandler for his insights; all members of the Broad Biological Samples Platform and the Genome Sequencing Platform; Lynne Aftuck, Scott Anderson, Patrick Cahill, Marc Chevrette, Julio Diaz, Danielle Dionne, Sheli Dookran, Rachel Erlich, Stephanie Grandbois, Lisa Green, Andrew Hollinger, Laurie Holmes, Andrew Hoss, Edward Kelliher, Sharon Kim, Purnima Kompella, Tony LaCasse, Matthew Lee, Niall J. Lennon, Dana Robbins, Alyssa Rosenthal, Elizabeth Ryan, Brian Sogoloff, Todd Sparrow, Alvin Tam, Austin Tzou, Cole Walsh, and Emily Wheeler for sequencing and technical support; and Lucia Alvarado-Balderrama, Aaron Berlin, Gary Gearin, Sante Gnerre, Giles Hall, Alma Imavovic, David B. Jaffe, Annie Lui, Iain MacCallum, J. Pendexter Macdonald, Matthew Pearson, Margaret Priest, Dariusz Przbylski, Andrew Roberts, Filipe J. Ribeiro, Sakina Saif, Ted Sharpe, Terry Shea, Narmada Shenoy, and Shuangye Yin for computational and analysis support. This project has been funded in part with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract HHSN272200900018C (to B. W. B.), and the Infectious Disease Program of the Broad Institute; National Institute of General Medical Sciences Award U54GM088558 (to M. L. and W. P. H.); National Institutes of Allergy and Infectious Disease T32 Grant AI007061 (to Y.H.G.); Danish Council for Strategic Research Grant 09-063070 (to K. A. K.); and the Institut de Veille Sanitaire (F.-X.W. and E.B.). NR 23 TC 107 Z9 113 U1 2 U2 27 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 FEB 21 PY 2012 VL 109 IS 8 BP 3065 EP 3070 DI 10.1073/pnas.1121491109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100078 PM 22315421 ER PT J AU Ching, SN Purdon, PL Vijayan, S Kopell, NJ Brown, EN AF Ching, ShiNung Purdon, Patrick L. Vijayan, Sujith Kopell, Nancy J. Brown, Emery N. TI A neurophysiological-metabolic model for burst suppression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CEREBRAL-BLOOD-FLOW; GENERAL-ANESTHESIA; MITOCHONDRIAL OSCILLATIONS; HEMORRHAGIC-SHOCK; OHTAHARA-SYNDROME; BRAIN PROTECTION; ALTERED STATES; EEG; HYPOTHERMIA; PHYSIOLOGY AB Burst suppression is an electroencepholagram (EEG) pattern in which high-voltage activity alternates with isoelectric quiescence. It is characteristic of an inactivated brain and is commonly observed at deep levels of general anesthesia, hypothermia, and in pathological conditions such as coma and early infantile encephalopathy. We propose a unifying mechanism for burst suppression that accounts for all of these conditions. By constructing a biophysical computational model, we show how the prevailing features of burst suppression may arise through the interaction between neuronal dynamics and brain metabolism. In each condition, the model suggests that a decrease in cerebral metabolic rate, coupled with the stabilizing properties of ATP-gated potassium channels, leads to the characteristic epochs of suppression. Consequently, the model makes a number of specific predictions of experimental and clinical relevance. C1 [Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Ching, ShiNung; Purdon, Patrick L.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Div Hlth Sci & Technol, Harvard Massachusetts Inst Technol, Cambridge, MA 02139 USA. [Vijayan, Sujith; Kopell, Nancy J.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Purdon, Patrick L.; Brown, Emery N.] Harvard Univ, Sch Med, Cambridge, MA 02115 USA. RP Ching, SN (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM shinung@neurostat.mit.edu; nk@bu.edu FU National Institutes of Health [DP1-OD003646, K25-NS057580, DP2-OD006454]; National Science Foundation [DMS-1042134, DMS-0717670] FX This study was supported by National Institutes of Health Grants DP1-OD003646, K25-NS057580, and DP2-OD006454 and National Science Foundation Grants DMS-1042134 and DMS-0717670. NR 49 TC 67 Z9 67 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 21 PY 2012 VL 109 IS 8 BP 3095 EP 3100 DI 10.1073/pnas.1121461109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KM UT WOS:000300495100083 PM 22323592 ER PT J AU Larson, JL Yuan, GC AF Larson, Jessica L. Yuan, Guo-Cheng TI Chromatin States Accurately Classify Cell Differentiation Stages SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; HUMAN GENOME; HISTONE MODIFICATIONS; GENE-EXPRESSION; PLURIPOTENT; EPIGENOMICS; DISTINCT; IDENTIFICATION; SIGNATURE; ENHANCERS AB Gene expression is controlled by the concerted interactions between transcription factors and chromatin regulators. While recent studies have identified global chromatin state changes across cell-types, it remains unclear to what extent these changes are co-regulated during cell-differentiation. Here we present a comprehensive computational analysis by assembling a large dataset containing genome-wide occupancy information of 5 histone modifications in 27 human cell lines (including 24 normal and 3 cancer cell lines) obtained from the public domain, followed by independent analysis at three different representations. We classified the differentiation stage of a cell-type based on its genome-wide pattern of chromatin states, and found that our method was able to identify normal cell lines with nearly 100% accuracy. We then applied our model to classify the cancer cell lines and found that each can be unequivocally classified as differentiated cells. The differences can be in part explained by the differential activities of three regulatory modules associated with embryonic stem cells. We also found that the "hotspot'' genes, whose chromatin states change dynamically in accordance to the differentiation stage, are not randomly distributed across the genome but tend to be embedded in multi-gene chromatin domains, and that specialized gene clusters tend to be embedded in stably occupied domains. C1 [Larson, Jessica L.; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Larson, JL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA. EM gcyuan@jimmy.harvard.edu FU HSPH; United States National Institutes of Health [HG005085]; NIH [GM074897] FX This work was supported by an HSPH Career Incubator Award and the United States National Institutes of Health grant HG005085 to GCY, and by a NIH training grant (GM074897) to JLL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 5 Z9 5 U1 0 U2 4 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 FEB 20 PY 2012 VL 7 IS 2 AR e31414 DI 10.1371/journal.pone.0031414 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926YY UT WOS:000302871500042 PM 22363642 ER PT J AU Meyerhardt, JA Li, L Sanoff, HK Carpenter, W Schrag, D AF Meyerhardt, Jeffrey A. Li, Ling Sanoff, Hanna K. Carpenter, William Schrag, Deborah TI Effectiveness of Bevacizumab With First-Line Combination Chemotherapy for Medicare Patients With Stage IV Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED-TRIAL; PHASE-III; PLUS FLUOROURACIL; IRINOTECAN; LEUCOVORIN; OXALIPLATIN; FOLFIRI; BOLUS; FLUOROPYRIMIDINES; MULTICENTER AB Purpose Clinical trials have shown that adding bevacizumab to cytotoxic chemotherapy improves survival for patients with colorectal cancer, although its effectiveness in the Medicare population is uncertain. Patients and Methods Using the Surveillance, Epidemiology, and End Results (SEER) -Medicare linked database, we identified 2,526 patients with stage IV colorectal cancer diagnosed between 2002 and 2007 who received first-line combination chemotherapy with a fluoropyrimidine and either irinotecan (33%) or oxaliplatin (67%). Thirty-six percent of patients received bevacizumab with first-line therapy. The primary outcome was overall survival. Secondary outcomes were bevacizumab-associated toxicities, including the incidence of stroke, myocardial infarction, and GI perforation. Results In the primary cohort inclusive of patients diagnosed between 2002 and 2007, bevacizumab with combination chemotherapy was associated with improved overall survival (adjusted hazard ratio [HR], 0.85; 95% CI, 0.78 to 0.93), although the effect was more modest when restricted to years 2004 to 2007 (HR, 0.93; 95% CI, 0.84 to 1.02). The observed survival advantage of bevacizumab was more apparent with irinotecan-based chemotherapy (HR, 0.80; 95% CI, 0.66 to 0.97) than with oxaliplatin-based chemotherapy (HR, 0.96; 95% CI, 0.86 to 1.07). Combination chemotherapy with bevacizumab, versus combination chemotherapy without bevacizumab, was associated with increased risk of stroke (4.9% v 2.5%, respectively; P < .01) and GI perforation (2.3% v 1.0%, respectively; P < .01). Cardiac events and venous thrombosis were not increased with bevacizumab. Conclusion The addition of bevacizumab to cytotoxic combination chemotherapy was associated with small improvement in overall survival as well as increased risk of stroke and perforation, but not cardiac events, among Medicare beneficiaries with stage IV colorectal cancer. J Clin Oncol 30:608-615. (c) 2012 by American Society of Clinical Oncology C1 [Meyerhardt, Jeffrey A.; Li, Ling; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02215 USA. [Sanoff, Hanna K.] Univ Virginia, Charlottesville, VA USA. [Carpenter, William] Univ N Carolina, Chapel Hill, NC USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM jmeyerhardt@partners.org RI Carpenter, William/E-5125-2013 FU Agency for Healthcare Research and Quality, US Department of Health and Human Services [HHSA290-2005-0016-I-TO7-WA4, 36-BWH-1] FX Supported by Contract No. HHSA290-2005-0016-I-TO7-WA4, 36-BWH-1 from the Agency for Healthcare Research and Quality, US Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions About Effectiveness program. NR 25 TC 56 Z9 57 U1 1 U2 6 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 FEB 20 PY 2012 VL 30 IS 6 BP 608 EP 615 DI 10.1200/JCO.2011.38.9650 PG 8 WC Oncology SC Oncology GA 923MQ UT WOS:000302623800018 PM 22253466 ER PT J AU Hoang, T Dahlberg, SE Schiller, JH Mehta, MP Fitzgerald, TJ Belinsky, SA Johnson, DH AF Hoang, Tien Dahlberg, Suzanne E. Schiller, Joan H. Mehta, Minesh P. Fitzgerald, Thomas J. Belinsky, Steven A. Johnson, David H. TI Randomized Phase III Study of Thoracic Radiation in Combination With Paclitaxel and Carboplatin With or Without Thalidomide in Patients With Stage III Non-Small-Cell Lung Cancer: The ECOG 3598 Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; SEQUENTIAL CHEMORADIOTHERAPY; DOUBLE-BLIND; TRIAL; CONCURRENT; CHEMOTHERAPY; CISPLATIN; THERAPY; SURVIVAL AB Purpose The primary objective of this study was to compare the survival of patients with unresectable stage III non-small-cell lung cancer (NSCLC) treated with combined chemoradiotherapy with or without thalidomide. Patients and Methods Patients were randomly assigned to the control arm (PC) involving two cycles of induction paclitaxel 225 mg/m(2) and carboplatin area under the curve (AUC) 6 followed by 60 Gy thoracic radiation administered concurrently with weekly paclitaxel 45 mg/m(2) and carboplatin AUC 2, or to the experimental arm (TPC), receiving the same treatment in combination with thalidomide at a starting dose of 200 mg daily. The protocol allowed an increase in thalidomide dose up to 1,000 mg daily based on patient tolerability. Results A total of 546 patients were eligible, including 275 in the PC arm and 271 in the TPC arm. Median overall survival, progression-free survival, and overall response rate were 15.3 months, 7.4 months, and 35.0%, respectively, for patients in the PC arm, in comparison with 16.0 months (P = .99), 7.8 months (P = .96), and 38.2% (P = .47), respectively, for patients in the TPC arm. Overall, there was higher incidence of grade 3 toxicities in patients treated with thalidomide. Several grade 3 or higher events were observed more often in the TPC arm, including thromboembolism, fatigue, depressed consciousness, dizziness, sensory neuropathy, tremor, constipation, dyspnea, hypoxia, hypokalemia, rash, and edema. Low-dose aspirin did not reduce the thromboembolic rate. Conclusion The addition of thalidomide to chemoradiotherapy increased toxicities but did not improve survival in patients with locally advanced NSCLC. J Clin Oncol 30:616-622. (c) 2012 by American Society of Clinical Oncology C1 [Hoang, Tien; Schiller, Joan H.; Mehta, Minesh P.] Univ Wisconsin, Madison, WI USA. [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fitzgerald, Thomas J.] Qual Assurance Review Ctr, Lincoln, RI USA. [Belinsky, Steven A.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Johnson, David H.] Vanderbilt Univ, Nashville, TN USA. RP Hoang, T (reprint author), Wisconsin Inst Med Res, 1111 Highland Ave, Madison, WI 53705 USA. EM txh@medicine.wisc.edu OI mehta, minesh/0000-0002-4812-5713 FU Public Health Service [CA23318, CA66636, CA21115, CA21076, CA49957, CA029511]; National Cancer Institute, National Institutes of Health, and Department of Health and Human Services FX Coordinated by the Eastern Cooperative Oncology Group and supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA21076, CA49957, and CA029511 and grants from the National Cancer Institute, National Institutes of Health, and Department of Health and Human Services. NR 20 TC 24 Z9 26 U1 0 U2 4 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 FEB 20 PY 2012 VL 30 IS 6 BP 616 EP 622 DI 10.1200/JCO.2011.36.9116 PG 7 WC Oncology SC Oncology GA 923MQ UT WOS:000302623800019 PM 22271472 ER PT J AU Mullins, CD Montgomery, R Abernethy, AP Hussain, A Pearson, SD Tunis, S AF Mullins, C. Daniel Montgomery, Russ Abernethy, Amy P. Hussain, Arif Pearson, Steven D. Tunis, Sean TI Recommendations for Clinical Trials of Off-Label Drugs Used to Treat Advanced-Stage Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PARTICIPATION AB Purpose To provide recommendations to trialists and sponsors that guide the design and implementation of prospective postapproval clinical trials for oncology drugs used outside US Food and Drug Administration-labeled indications for treatment of late-stage cancers. Methods A meeting was hosted by the Center for Medical Technology Policy in Baltimore, MD, on November 12, 2009. Discussions during the meeting and key informant interviews were conducted before and after this stakeholder meeting. Peer review by multidisciplinary stakeholders was followed by a public comment period. Input was received from patient advocacy groups, medical oncologists, pharmaceutical companies, the US Food and Drug Administration, Centers for Medicare and Medicaid Services, the National Cancer Institute, foreign government agencies involved in health technology assessment, public and private payers, drug compendia, clinical research entities, statisticians, academics, and the American Society of Clinical Oncology. Results To address the needs of patients and their clinical providers, compendia, payers, and policy makers, recommendations are proposed to guide the design of future prospective trials for off-label use of oncology drugs across four areas: trial design and data analysis, patient and site recruitment, comparators, and outcomes. Conclusion The US Food and Drug Administration provides guidance to the pharmaceutical industry and others designing randomized clinical trials for regulatory approval. However, a gap exists for postregulatory decision makers, including patients, prescribers, and payers, because regulatory trials do not answer the questions most relevant to them. Therefore, guidance is needed for trials performed in the postapproval environment for these postapproval decision makers. J Clin Oncol 30:661-666. (c) 2012 by American Society of Clinical Oncology C1 [Mullins, C. Daniel] Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. [Hussain, Arif] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Hussain, Arif] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. [Montgomery, Russ] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Mullins, C. Daniel; Montgomery, Russ; Tunis, Sean] Ctr Med Technol Policy, Baltimore, MD USA. [Abernethy, Amy P.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Durham, NC 27710 USA. [Abernethy, Amy P.] Duke Univ, Sch Med, Durham, NC USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pearson, Steven D.] Harvard Univ, Sch Med, Boston, MA USA. RP Mullins, CD (reprint author), Univ Maryland, Sch Pharm, 220 Arch St,12th Floor, Baltimore, MD 21201 USA. EM dmullins@rx.umaryland.edu FU Amgen; Bayer Pharmaceuticals; Genentech; sanofi-aventis FX Supported by unrestricted contributions from Amgen, Bayer Pharmaceuticals, Genentech, and sanofi-aventis. NR 15 TC 12 Z9 12 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 FEB 20 PY 2012 VL 30 IS 6 BP 661 EP 666 DI 10.1200/JCO.2011.35.5198 PG 6 WC Oncology SC Oncology GA 923MQ UT WOS:000302623800025 PM 22253467 ER PT J AU Cauley, S Balakrishnan, V Klimeck, G Koh, CK AF Cauley, Stephen Balakrishnan, Venkataramanan Klimeck, Gerhard Koh, Cheng-Kok TI A two-dimensional domain decomposition technique for the simulation of quantum-scale devices SO JOURNAL OF COMPUTATIONAL PHYSICS LA English DT Article DE NEGF; Parallel; Density of states; Atomistic ID ALGORITHM; MATRICES; INVERSE AB The simulation of realistically sized devices under the Non-Equilibrium Greens Function (NEGF) formalism typically requires prohibitive amounts of memory and computation time. In order to meet the rising computational challenges associated with quantum-scale device simulation we offer a 2-D domain decomposition technique. This technique is applicable to a large class of atomistic and spatial simulation problems. Considering a decomposition along both the cross section and length of the device, the framework presented in this work ensures efficient distribution of both memory and computation based upon the underlying device structure. As an illustration we stably generate the density of states and transmission, under the NEGF formalism, for the atomistic-based simulation of square 5 nm cross section silicon nanowires consisting of over one million atomic orbitals. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cauley, Stephen] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Balakrishnan, Venkataramanan; Klimeck, Gerhard; Koh, Cheng-Kok] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. RP Cauley, S (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM stcauley@nmr.mgh.harvard.edu; ragu@ecn.purdue.edu; gekco@purdue.edu; chengkok@ecn.purdue.edu RI Cauley, Stephen/P-1386-2014; Klimeck, Gerhard/A-1414-2012 OI Klimeck, Gerhard/0000-0001-7128-773X FU NSF [CCF-1065318] FX This work was partially supported by NSF grant CCF-1065318. NR 19 TC 5 Z9 5 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0021-9991 J9 J COMPUT PHYS JI J. Comput. Phys. PD FEB 20 PY 2012 VL 231 IS 4 BP 1293 EP 1313 DI 10.1016/j.jcp.2011.10.006 PG 21 WC Computer Science, Interdisciplinary Applications; Physics, Mathematical SC Computer Science; Physics GA 894XZ UT WOS:000300462100012 ER PT J AU Van Gulck, E Vlieghe, E Vekemans, M Van Tendeloo, VFI Van De Velde, A Smits, E Anguille, S Cools, N Goossens, H Mertens, L De Haes, W Wong, J Florence, E Vanham, G Berneman, ZN AF Van Gulck, Ellen Vlieghe, Erika Vekemans, Marc Van Tendeloo, Viggo F. I. Van De Velde, Ann Smits, Evelien Anguille, Sebastien Cools, Nathalie Goossens, Herman Mertens, Liesbet De Haes, Winni Wong, Johnsson Florence, Eric Vanham, Guido Berneman, Zwi N. TI mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients SO AIDS LA English DT Article DE dendritic cells; HIV-1; immunotherapy; mRNA electroporation; therapeutic vaccination ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHRONIC HIV-1 INFECTION; VIRAL LOAD; AUTOLOGOUS HIV-1; PROTEINS; INDUCTION; VACCINES; ASSAY; GAG; NONPROGRESSORS AB Background: In an effort to raise protective antiviral immunity, dendritic cell immunotherapy was evaluated in six adults infected with human immunodeficiency virus (HIV)-1 and stable under highly active antiretroviral therapy (HAART). Design and methods: Autologous monocyte-derived dendritic cells electroporated with mRNA encoding Gag and a chimeric Tat-Rev-Nef protein were administered, whereas patients remained on HAART. Feasibility, safety, immunogenicity and antiviral responses were investigated. Results: Dendritic cell vaccine preparation and administration were successful in all patients and only mild adverse events were seen. There was a significant increase postdendritic cell as compared to pre-dendritic cell vaccination in magnitude and breadth of HIV-1-specific interferon (IFN)-gamma response, in particular to Gag, and in T-cell proliferation. Breadth of IFN-gamma response and T-cell proliferation were both correlated with CD4(+) and CD8(+) polyfunctional T-cell responses. Importantly, dendritic cell vaccination induced or increased the capacity of autologous CD8(+) T cells to inhibit superinfection of CD4(+) T cells with the vaccine-related IIIB virus and some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-gamma response. Conclusions: Therapeutic immunization with dendritic cells was safe and successful in raising antiviral cellular immune responses, including effector CD8(+) T cells with virus inhibitory activity. The stimulation of those potent immunological and antiviral effects, which have been associated with control of HIV-1, underscores the potential of dendritic cell vaccination in the treatment of HIV-1. The incomplete nature of the response in some patients helped to identify potential targets for future improvement, that is increasing antigenic spectrum and enhancing T-cell response. (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Van Tendeloo, Viggo F. I.; Van De Velde, Ann; Smits, Evelien; Anguille, Sebastien; Cools, Nathalie; Berneman, Zwi N.] Antwerp Univ Hosp UZA, Ctr Cell Therapy & Regenerat Med CCRG, B-2650 Edegem, Belgium. [Van Tendeloo, Viggo F. I.; Van De Velde, Ann; Smits, Evelien; Anguille, Sebastien; Cools, Nathalie; Berneman, Zwi N.] Antwerp Univ Hosp UZA, Div Hematol, B-2650 Edegem, Belgium. [Van Gulck, Ellen; De Haes, Winni; Vanham, Guido] Inst Trop Med, Virol Unit, Div Microbiol, Dept Biomed Sci, B-2000 Antwerp, Belgium. [Vlieghe, Erika; Vekemans, Marc; Mertens, Liesbet; Florence, Eric] Inst Trop Med, Dept Clin Sci, Med Serv, HIV & STD Unit, B-2000 Antwerp, Belgium. [Van Tendeloo, Viggo F. I.; Van De Velde, Ann; Smits, Evelien; Anguille, Sebastien; Cools, Nathalie; Goossens, Herman; Berneman, Zwi N.] Univ Antwerp, Fac Med & Hlth Sci, Vaccine & Infect Dis Inst, B-2020 Antwerp, Belgium. [Wong, Johnsson] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Vanham, Guido] Univ Antwerp, Fac Pharmaceut Biomed & Vet Sci, B-2020 Antwerp, Belgium. [Vanham, Guido] Free Univ Brussels VUB, Fac Med & Pharm, Brussels, Belgium. RP Berneman, ZN (reprint author), Antwerp Univ Hosp UZA, Ctr Cell Therapy & Regenerat Med CCRG, Wilrijkstr 10, B-2650 Edegem, Belgium. EM Zwi.Berneman@uza.be RI Smits, Evelien/E-9654-2012; Cools, Nathalie/A-1211-2010; Smits, Evelien/A-3520-2014 OI Cools, Nathalie/0000-0002-0459-901X; Smits, Evelien/0000-0001-9255-3435 FU Interuniversity Attraction Poles (IAP) of Belgian Science Policy [P6/41]; Agency for Innovation by Science and Technology (IWT) [60511]; Antwerp University Hospital; Flemish Government FX The work was supported by the Interuniversity Attraction Poles (IAP grant no. P6/41) of Belgian Science Policy; by grant no. 60511 of the Agency for Innovation by Science and Technology (IWT); by the Fund for Cell Therapy of the Antwerp University Hospital and by a grant of the Methusalem program of the Flemish Government to the University of Antwerp and to H.G. E.S. and N.C. hold a postdoctoral fellowship and S.A. a PhD fellowship of the Research Foundation Flanders (FWO-Vlaanderen). W.D.H. holds a PhD fellowship of the IWT. The technical assistance of Barbara Stein, Griet Nijs, Celine Merlin and Derek Atkinson is gratefully acknowledged. NR 38 TC 33 Z9 34 U1 3 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD FEB 20 PY 2012 VL 26 IS 4 BP F1 EP F12 DI 10.1097/QAD.0b013e32834f33e8 PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 894FC UT WOS:000300411500001 PM 22156965 ER PT J AU Buxbaum, JD Betancur, C Bozdagi, O Dorr, NP Elder, GA Hof, PR AF Buxbaum, Joseph D. Betancur, Catalina Bozdagi, Ozlem Dorr, Nate P. Elder, Gregory A. Hof, Patrick R. TI Optimizing the phenotyping of rodent ASD models: enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features SO MOLECULAR AUTISM LA English DT Article DE Systems biology; mouse behavior; autism; autism spectrum disorders; genetically modified mice; forward genetics; reverse genetics ID COMPONENTS; PROTEOME AB Background: There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitutes useful phenotypes in ASD models. Methods: To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings: We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1) Changes in brain and neuronal morphology; (2) electrophysiological changes; (3) neurological changes; and (4) higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms. Conclusions: The results indicated that mutations in ASD genes result in defined groups of changes in mouse models and support a broad neurobiological approach to phenotyping rodent models for ASD, with a focus on biochemistry and molecular biology, brain and neuronal morphology, and electrophysiology, as well as both neurological and additional behavioral analyses. Analysis of human phenotypes associated with these genes reinforced these conclusions, supporting face validity for these approaches to phenotyping of ASD models. Such phenotyping is consistent with the successes in Fmr1 knockout mice, in which morphological changes recapitulated human findings and electrophysiological deficits resulted in molecular insights that have since led to clinical trials. We propose both broad domains and, based on expert review of more than 50 publications in each of the four neurobiological domains, specific tests to be applied to rodent models of ASD. C1 [Buxbaum, Joseph D.; Bozdagi, Ozlem] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [Buxbaum, Joseph D.; Bozdagi, Ozlem; Dorr, Nate P.; Elder, Gregory A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Buxbaum, Joseph D.; Hof, Patrick R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Buxbaum, Joseph D.; Elder, Gregory A.; Hof, Patrick R.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Elder, Gregory A.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Betancur, Catalina] INSERM, U952, F-75005 Paris, France. [Betancur, Catalina] CNRS, UMR 7224, F-75005 Paris, France. [Betancur, Catalina] Univ Paris 06, F-75005 Paris, France. [Elder, Gregory A.] James J Peters VA Med Ctr, Neurol Serv, Bronx, NY 10468 USA. RP Buxbaum, JD (reprint author), Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM joseph.buxbaum@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313; Betancur, Catalina/0000-0002-3327-4804 FU Seaver Foundation; Simons Foundation; NIMH [MH093725]; INSERM FX This work was supported by the Seaver Foundation (JDB, OB, PRH), the Simons Foundation (JDB, OB, PRH), the NIMH (MH093725; JDB, OB, PRH), and INSERM (CB). OB is a Seaver Fellow. JDB is the G Harold and Leila Y Mathers Professor at Mount Sinai. NR 9 TC 14 Z9 14 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2040-2392 J9 MOL AUTISM JI Mol. Autism PD FEB 20 PY 2012 VL 3 AR 1 DI 10.1186/2040-2392-3-1 PG 8 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 254RH UT WOS:000327184000001 PM 22348382 ER PT J AU Baselga, J Bradbury, I Eidtmann, H Di Cosimo, S de Azambuja, E Aura, C Gomez, H Dinh, P Fauria, K Van Dooren, V Aktan, G Goldhirsch, A Chang, TW Horvath, Z Coccia-Portugal, M Domont, J Tseng, LM Kunz, G Sohn, JH Semiglazov, V Lerzo, G Palacova, M Probachai, V Pusztai, L Untch, M Gelber, RD Piccart-Gebhart, M AF Baselga, Jose Bradbury, Ian Eidtmann, Holger Di Cosimo, Serena de Azambuja, Evandro Aura, Claudia Gomez, Henry Dinh, Phuong Fauria, Karine Van Dooren, Veerle Aktan, Gursel Goldhirsch, Aron Chang, Tsai-Wang Horvath, Zsolt Coccia-Portugal, Maria Domont, Julien Tseng, Ling-Min Kunz, Georg Sohn, Joo Hyuk Semiglazov, Vladimir Lerzo, Guillermo Palacova, Marketa Probachai, Volodymyr Pusztai, Lajos Untch, Michael Gelber, Richard D. Piccart-Gebhart, Martine CA NeoALTTO Study Team TI Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial SO LANCET LA English DT Article ID ADJUVANT CHEMOTHERAPY; INHIBITOR; PLUS; APOPTOSIS; GW572016; CELLS; WOMEN; ERBB2 AB Background The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy. Methods In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/kg, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m(2)) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358. Findings 154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51.3%; 95% CI 43.1-59.5]) than in the group given trastuzumab alone (44 of 149 patients [29.5%; 22.4-37.5]; difference 21.1%, 9.1-34.2, p=0.0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24.7%, 18.1-32.3]) and the trastuzumab (difference -4.8%, -17.6 to 8.2, p=0.34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23.4%]) and lapatinib plus trastuzumab (32 [21.1%]) than with trastuzumab (three [2.0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17.5%]) and lapatinib plus trastuzumab (15 [9.9%]) than with trastuzumab (11 [7.4%]). Interpretation Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting. C1 [Baselga, Jose] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Baselga, Jose; Di Cosimo, Serena; Fauria, Karine] SOLTI Breast Canc Res Grp, Barcelona, Spain. [Bradbury, Ian] Frontier Sci Scotland, Kincraig, Scotland. [Bradbury, Ian] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Eidtmann, Holger] Univ Hosp Kiel, Kiel, Germany. [Di Cosimo, Serena] Vall dHebron Univ Hosp, Breast Canc Ctr, Barcelona, Spain. [Aura, Claudia] Vall dHebron Univ Hosp, Vall dHebron Inst Oncol, Barcelona, Spain. [de Azambuja, Evandro; Van Dooren, Veerle] Inst Jules Bordet, Breast European Adjuvant Study Team, B-1000 Brussels, Belgium. [Dinh, Phuong] Inst Jules Bordet, Breast Int Grp, B-1000 Brussels, Belgium. [Piccart-Gebhart, Martine] Inst Jules Bordet, Dept Med, B-1000 Brussels, Belgium. [Gomez, Henry] Inst Nacl Enfermedades Neoplas, Lima, Peru. [Aktan, Gursel] GlaxoSmithKline, Collegeville, PA USA. [Goldhirsch, Aron] European Inst Oncol, Milan, Italy. [Goldhirsch, Aron] St Anna Clin, Swiss Ctr Breast Hlth, Lugano, Switzerland. [Chang, Tsai-Wang] Natl Cheng Kung Univ Hosp, Tainan 70428, Taiwan. [Horvath, Zsolt] Natl Inst Oncol, Budapest, Hungary. [Coccia-Portugal, Maria] Eastleigh Breast Care Ctr, Pretoria, South Africa. [Domont, Julien] Inst Gustave Roussy, Villejuif, France. [Tseng, Ling-Min] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Taipei 112, Taiwan. [Kunz, Georg] St Johannes Hosp, Dortmund, Germany. [Sohn, Joo Hyuk] Yonsei Univ, Coll Med, Seoul, South Korea. [Semiglazov, Vladimir] Petrov Res Inst Oncol, St Petersburg, Russia. [Lerzo, Guillermo] Invest Clin Ciudad Autonoma Buenos Aires, Buenos Aires, DF, Argentina. [Palacova, Marketa] Masarykuv Onkol Ustav, Brno, Czech Republic. [Probachai, Volodymyr] City Clin Hosp, Dnepropetrovsk, Ukraine. [Pusztai, Lajos] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Untch, Michael] Charite, Clin Gynaecol Gynaecol Oncol & Obstet, Breast Canc Ctr, D-13353 Berlin, Germany. [Gelber, Richard D.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Gelber, Richard D.] Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. RP Baselga, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Lawrence House 108, Boston, MA 02114 USA. EM jbaselga@partners.org RI Kwong, Ava/D-8005-2013; Horvath, Zsolt/B-9524-2012; Serena, Di Cosimo/E-9418-2017; OI Kwong, Ava/0000-0002-6968-9489; Serena, Di Cosimo/0000-0002-4666-8052; Semiglazov, Vladimir/0000-0003-0077-9619; Gomez, Henry/0000-0003-2660-1843; Ciruelos, Eva /0000-0002-2796-1042 FU GlaxoSmithKline; Roche; Novartis; Amgen; Abbott; AstraZeneca; Pfizer; Sanofi; Bristol-Myers Squibb FX JB has received honoraria from Roche. IB's institution has received funding from GlaxoSmithKline and Roche. HE has been a speaker and received travel grants from GlaxoSmithKline. SDC has been a speaker for GlaxoSmithKline. EdA has served on an advisory board and received a travelling grant from GlaxoSmithKline, and has been a speaker for Roche. KF's institution has received travelling grants from GlaxoSmithKline. VVD's and T-WC's institutions have received research funding from GlaxoSmithKline. AG has received honoraria from GlaxoSmithKline and Roche. T-WC has been a speaker for GlaxoSmithKline, Roche, Novartis, and Amgen; and has received consultancy funding from GlaxoSmithKline, Roche, Abbott, AstraZeneca, Novartis, and Amgen. LP has received consultancy fees from Pfizer, Sanofi, and Bristol-Myers Squibb; and research grants from Bristol-Myers Squibb and AstraZeneca. RDG's institution has received research funding from GlaxoSmithKline and Roche. MP-G has received honoraria from GlaxoSmithKline and Roche, and her institution has received research funding from GlaxoSmithKline. GA is a salaried employee of GlaxoSmithKline and retains stock and stock options at the company. The other authors declare that they have no conflicts of interest. NR 30 TC 499 Z9 529 U1 8 U2 77 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD FEB 18 PY 2012 VL 379 IS 9816 BP 633 EP 640 DI 10.1016/S0140-6736(11)61847-3 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 897ES UT WOS:000300629000034 PM 22257673 ER PT J AU Graewe, B De Weerd, P Farivar, R Castelo-Branco, M AF Graewe, Britta De Weerd, Peter Farivar, Reza Castelo-Branco, Miguel TI Stimulus Dependency of Object-Evoked Responses in Human Visual Cortex: An Inverse Problem for Category Specificity SO PLOS ONE LA English DT Article ID EVENT-RELATED POTENTIALS; FACE PERCEPTION; ELECTROMAGNETIC TOMOGRAPHY; UNFAMILIAR FACES; MOTION-ONSET; N170; RECOGNITION; BRAIN; ERPS; TEXTURE AB Many studies have linked the processing of different object categories to specific event-related potentials (ERPs) such as the face-specific N170. Despite reports showing that object-related ERPs are influenced by visual stimulus features, there is consensus that these components primarily reflect categorical aspects of the stimuli. Here, we re-investigated this idea by systematically measuring the effects of visual feature manipulations on ERP responses elicited by both structure-from-motion (SFM)-defined and luminance-defined object stimuli. SFM objects elicited a novel component at 200-250 ms (N250) over parietal and posterior temporal sites. We found, however, that the N250 amplitude was unaffected by restructuring SFM stimuli into meaningless objects based on identical visual cues. This suggests that this N250 peak was not uniquely linked to categorical aspects of the objects, but is strongly determined by visual stimulus features. We provide strong support for this hypothesis by parametrically manipulating the depth range of both SFM- and luminance-defined object stimuli and showing that the N250 evoked by SFM stimuli as well as the well-known N170 to static faces were sensitive to this manipulation. Importantly, this effect could not be attributed to compromised object categorization in low depth stimuli, confirming a strong impact of visual stimulus features on object-related ERP signals. As ERP components linked with visual categorical object perception are likely determined by multiple stimulus features, this creates an interesting inverse problem when deriving specific perceptual processes from variations in ERP components. C1 [Graewe, Britta; De Weerd, Peter] Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht, Netherlands. [Graewe, Britta] Univ Coimbra, Inst Biomeed Res Light & Image, Visual Neurosci Lab, Coimbra, Portugal. [De Weerd, Peter] Radboud Univ Nijmegen, Donders Inst Brain Behav & Cognit, NL-6525 ED Nijmegen, Netherlands. [Farivar, Reza] Harvard Univ, Sch Med, Charlestown, MA USA. [Farivar, Reza] Massachusetts Gen Hosp, A Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Castelo-Branco, Miguel] Univ Coimbra, IBILI, Visual Neurosci Lab, Coimbra, Portugal. RP Graewe, B (reprint author), Maastricht Univ, Fac Psychol & Neurosci, Dept Cognit Neurosci, Maastricht, Netherlands. EM britta.graewe@maastrichtuniversity.nl RI Castelo-Branco, Miguel/E-5689-2010; OI Castelo-Branco, Miguel/0000-0003-4364-6373 FU Foundation for Science and Technology Portugal [SFRH/BD/37385/2007, PTDC/SAU/NEU/68483/2006, PIC/IC/82986/2007]; Bial Foundation [94/06]; BIN (Brain Imaging Network of Portugal) FX This work was supported by a grant to BG, MC-B and PDW (SFRH/BD/37385/2007), Grants PTDC/SAU/NEU/68483/2006 and PIC/IC/82986/2007 from the Foundation for Science and Technology Portugal (http://www.fct.pt/) and the Bial Foundation 94/06 (http://www.bial.com/en/bial_foundation.11/grants.18/grants.a38.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors acknowledge the support of the BIN (Brain Imaging Network of Portugal). We would like to thank Jose Rebola for his help with creating the luminance-defined stimuli and Valerie Goffaux for valuable comments during manuscript revision. NR 59 TC 4 Z9 4 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2012 VL 7 IS 2 AR e30727 DI 10.1371/journal.pone.0030727 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926TC UT WOS:000302853600062 PM 22363479 ER PT J AU Kamat, A Misra, V Cassol, E Ancuta, P Yan, ZY Li, C Morgello, S Gabuzda, D AF Kamat, Anupa Misra, Vikas Cassol, Edana Ancuta, Petronela Yan, Zhenyu Li, Cheng Morgello, Susan Gabuzda, Dana TI A Plasma Biomarker Signature of Immune Activation in HIV Patients on Antiretroviral Therapy SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; HEPATITIS-C-VIRUS; T-CELL-ACTIVATION; NATURAL-KILLER-CELLS; DISEASE PROGRESSION; INTERFERON-GAMMA; MICROBIAL TRANSLOCATION; SIGMA-1 RECEPTORS; DENDRITIC CELLS; CRACK-COCAINE AB Background: Immune activation is a strong predictor of disease progression in HIV infection. Combinatorial plasma biomarker signatures that represent surrogate markers of immune activation in both viremic and aviremic HIV patients on combination antiretroviral therapy (cART) have not been defined. Here, we identify a plasma inflammatory biomarker signature that distinguishes between both viremic and aviremic HIV patients on cART and healthy controls and examine relationships of this signature to markers of disease progression. Methods: Multiplex profiling and ELISA were used to detect 15 cytokines/chemokines, soluble IL-2R (sIL-2R), and soluble CD14 (sCD14) in plasma from 57 HIV patients with CD4 nadir <300 cells/mu l and 29 healthy controls. Supervised and unsupervised analyses were used to identify biomarkers explaining variance between groups defined by HIV status or drug abuse. Relationships between biomarkers and disease markers were examined by Spearman correlation. Results: The majority (91%) of HIV subjects were on cART, with 38% having undetectable viral loads (VL). Hierarchical clustering identified a biomarker cluster in plasma consisting of two interferon-stimulated gene products (CXCL9 and CXCL10), T cell activation marker (sIL-2R), and monocyte activation marker (sCD14) that distinguished both viremic and aviremic HIV patients on cART from controls (p<0.0001) and were top-ranked in variables important in projection plots. IL-12 and CCL4 were also elevated in viremic and aviremic patients compared to controls (p<0.05). IL-12 correlated with IFN alpha, IFN gamma, CXCL9, and sIL-2R (p<0.05). CXCL10 correlated positively with plasma VL and percentage of CD16+ monocytes, and inversely with CD4 count (p = 0.001, <0.0001, and 0.04, respectively). Conclusion: A plasma inflammatory biomarker signature consisting of CXCL9, CXCL10, sIL-2R, and sCD14 may be useful as a surrogate marker to monitor immune activation in both viremic and aviremic HIV patients on cART during disease progression and therapeutic responses. C1 [Kamat, Anupa; Misra, Vikas; Cassol, Edana; Gabuzda, Dana] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Kamat, Anupa; Cassol, Edana; Gabuzda, Dana] Harvard Univ, Sch Med, Boston, MA USA. [Ancuta, Petronela] Univ Montreal, Dept Microbiol & Immunol, Fac Med, CHUM Res Ctr, Montreal, PQ H3C 3J7, Canada. [Yan, Zhenyu; Li, Cheng] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Morgello, Susan] Mt Sinai Med Ctr, New York, NY 10029 USA. RP Kamat, A (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu FU National Institutes of Health [DA30985, DA28994, U01MH083501, R24MH59724, U01MH083506, R24MH59745, U01MH083507, R24 NS45491, 5U01MH083500, NS38841, U01MH083545, N01MH32002]; Canadian Institutes of Health Research (CIHR); Fonds de la Recherche en Sante Quebec (FRSQ); CNS HIV Antiretroviral Therapy Effects Research (CHARTER) [N01MH22005]; Harvard Center for AIDS Research and Dana-Farber Cancer Institute/Harvard Center for Cancer Research FX This work was supported by National Institutes of Health Grants DA30985 and DA28994 to Dr. Gabuzda. Dr. Cassol was supported by a fellowship award from Canadian Institutes of Health Research (CIHR). Dr. Ancuta was supported by a Salary Award from Fonds de la Recherche en Sante Quebec (FRSQ). National NeuroAIDS Tissue Consortium (NNTC) sites were supported by National Institutes of Health Grants U01MH083501, R24MH59724, U01MH083506, R24MH59745, U01MH083507, R24 NS45491, 5U01MH083500, NS38841, U01MH083545, and N01MH32002. CNS HIV Antiretroviral Therapy Effects Research (CHARTER) was supported by N01MH22005. Core facilities were supported by the Harvard Center for AIDS Research and Dana-Farber Cancer Institute/Harvard Center for Cancer Research grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 44 Z9 44 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2012 VL 7 IS 2 AR e30881 DI 10.1371/journal.pone.0030881 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 926TC UT WOS:000302853600080 PM 22363505 ER PT J AU Singh, A Sweeney, MF Yu, M Burger, A Greninger, P Benes, C Haber, DA Settleman, J AF Singh, Anurag Sweeney, Michael F. Yu, Min Burger, Alexa Greninger, Patricia Benes, Cyril Haber, Daniel A. Settleman, Jeff TI TAK1 Inhibition Promotes Apoptosis in KRAS-Dependent Colon Cancers SO CELL LA English DT Article ID ONCOGENIC KRAS; BETA-CATENIN; C-ELEGANS; CELLS; RAS; PROTEIN; PROGRESSION; EXPRESSION; PATHWAY; ADDICTION AB Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived "TAK1 dependency signature'' is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation. C1 [Singh, Anurag; Sweeney, Michael F.; Yu, Min; Burger, Alexa; Greninger, Patricia; Benes, Cyril; Haber, Daniel A.; Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Singh, Anurag; Sweeney, Michael F.; Yu, Min; Burger, Alexa; Greninger, Patricia; Benes, Cyril; Haber, Daniel A.; Settleman, Jeff] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Haber, Daniel A.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM haber@helix.mgh.harvard.edu; settleman.jeffrey@gene.com RI Singh, Anurag/C-7347-2014 OI Singh, Anurag/0000-0003-4705-8683 FU NIH [K99 CA149169, R01 CA109447, R01 CA129933]; Lustgarten Foundation FX This work was supported by NIH K99 CA149169 to A.S. as well as NIH R01 CA109447 and a Lustgarten Foundation grant to J.S. and NIH R01 CA129933 to D.A.H. We are grateful to Randall Peterson, David Ting, and Andre Bernards for critical evaluation and comments on the manuscript. We thank Laura Libby and Brian Brannigan for technical assistance with mouse xenograft experiments and KRAS/BRAF sequencing analyses, respectively. We thank Vijay Yajnik for providing TOP-FLASH reporter plasmids. Finally, we also thank Kevin Haigis, Moon Yee Hang, Miguel Rivera, Jianmin Zhang, Mingzhu Liu, and Matt Zubrowski for intellectual and technical advice. NR 36 TC 95 Z9 100 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 17 PY 2012 VL 148 IS 4 BP 639 EP 650 DI 10.1016/j.cell.2011.12.033 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897DH UT WOS:000300622400007 PM 22341439 ER PT J AU Hu, J Hwang, SS Liesa, M Gan, BY Sahin, E Jaskelioff, M Ding, ZH Ying, HQ Boutin, AT Zhang, HL Johnson, S Ivanova, E Kost-Alimova, M Protopopov, A Wang, YA Shirihai, OS Chin, L DePinho, RA AF Hu, Jian Hwang, Soyoon Sarah Liesa, Marc Gan, Boyi Sahin, Ergun Jaskelioff, Mariela Ding, Zhihu Ying, Haoqiang Boutin, Adam T. Zhang, Hailei Johnson, Shawn Ivanova, Elena Kost-Alimova, Maria Protopopov, Alexei Wang, Yaoqi Alan Shirihai, Orian S. Chin, Lynda DePinho, Ronald A. TI Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer SO CELL LA English DT Article ID OXIDATIVE DNA-DAMAGE; TELOMERE DYSFUNCTION; MRE11/RAD50/NBS1 COMPLEX; DEPENDENT APOPTOSIS; STEM-CELLS; DEFICIENCY; MICE; SUPPRESSION; METABOLISM; GLUTAMINE AB To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/)-mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1 beta, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1 beta or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy. C1 [Hu, Jian; Hwang, Soyoon Sarah; Ying, Haoqiang; Boutin, Adam T.; Kost-Alimova, Maria; Protopopov, Alexei; Wang, Yaoqi Alan; DePinho, Ronald A.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Chin, Lynda] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA. [Gan, Boyi] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [Hu, Jian; Hwang, Soyoon Sarah; Gan, Boyi; Sahin, Ergun; Jaskelioff, Mariela; Ding, Zhihu; Ying, Haoqiang; Boutin, Adam T.; Zhang, Hailei; Ivanova, Elena; Kost-Alimova, Maria; Protopopov, Alexei; Wang, Yaoqi Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Hu, Jian; Hwang, Soyoon Sarah; Gan, Boyi; Sahin, Ergun; Jaskelioff, Mariela; Ding, Zhihu; Ying, Haoqiang; Boutin, Adam T.; Zhang, Hailei; Johnson, Shawn; Ivanova, Elena; Kost-Alimova, Maria; Protopopov, Alexei; Wang, Yaoqi Alan; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hu, Jian; Gan, Boyi; Sahin, Ergun; Jaskelioff, Mariela; Ding, Zhihu; Ying, Haoqiang; Boutin, Adam T.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet & Med, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Liesa, Marc; Shirihai, Orian S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. RP DePinho, RA (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. EM rdepinho@mdanderson.org OI Liesa Roig, Marc/0000-0002-5909-8570 FU leukemia and lymphoma society; Helen Hay Whitney fellowship; Fundacion Ramon Areces; NIH [R01-DK074778, R01-DK56690, R01CA84628, U01CA141508] FX We thank S. Jiang, R. Narurkar, and E. Fletcher-Sananikone for excellent mouse husbandry and care, and all members of DePinho and Chin labs for helpful discussion. We also thank Yingchui Liu for the Cox model analysis. J.H. and B.G. were supported by the leukemia and lymphoma society fellowship. A.T.B. is supported by the Helen Hay Whitney fellowship. M. L. is supported by the Fundacion Ramon Areces fellowship. O.S.S. is supported by R01 (R01-DK074778 and R01-DK56690) grants from NIH. L.C. and R.A.D. are supported by R01 (R01CA84628) and U01 (U01CA141508) grants from NIH. R.A.D. is an Ellison Foundation for Medical Research Senior Scholar and an American Cancer Society Research Professor. NR 50 TC 96 Z9 99 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 FEB 17 PY 2012 VL 148 IS 4 BP 651 EP 663 DI 10.1016/j.cell.2011.12.028 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897DH UT WOS:000300622400008 PM 22341440 ER PT J AU Zhang, BC Kracker, S Yasuda, T Casola, S Vanneman, M Homig-Holzel, C Wang, Z Derudder, E Li, S Chakraborty, T Cotter, SE Koyama, S Currie, T Freeman, GJ Kutok, JL Rodig, SJ Dranoff, G Rajewsky, K AF Zhang, Baochun Kracker, Sven Yasuda, Tomoharu Casola, Stefano Vanneman, Matthew Homig-Holzel, Cornelia Wang, Zhe Derudder, Emmanuel Li, Shuang Chakraborty, Tirtha Cotter, Shane E. Koyama, Shohei Currie, Treeve Freeman, Gordon J. Kutok, Jeffery L. Rodig, Scott J. Dranoff, Glenn Rajewsky, Klaus TI Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model SO CELL LA English DT Article ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS; NF-KAPPA-B; CYTOTOXIC T-LYMPHOCYTES; CELL-DEVELOPMENT; RECEPTOR SIGNALS; TRANSGENIC MICE; IFN-GAMMA; IN-VITRO; RESPONSES; EXPRESSION AB B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1(+) B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, andcould betargetedby anNKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach. C1 [Zhang, Baochun; Kracker, Sven; Yasuda, Tomoharu; Casola, Stefano; Wang, Zhe; Derudder, Emmanuel; Li, Shuang; Chakraborty, Tirtha; Rajewsky, Klaus] Harvard Univ, Program Cellular & Mol Med, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Zhang, Baochun; Kracker, Sven; Yasuda, Tomoharu; Casola, Stefano; Wang, Zhe; Derudder, Emmanuel; Li, Shuang; Chakraborty, Tirtha; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Casola, Stefano; Homig-Holzel, Cornelia; Rajewsky, Klaus] Univ Cologne, Inst Genet, D-50674 Cologne, Germany. [Vanneman, Matthew; Koyama, Shohei; Freeman, Gordon J.; Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Vanneman, Matthew; Koyama, Shohei; Freeman, Gordon J.; Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [Vanneman, Matthew; Koyama, Shohei; Freeman, Gordon J.; Dranoff, Glenn] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Cotter, Shane E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. [Cotter, Shane E.] Harvard Univ, Brigham & Womens Hosp, Dept Radiat Oncol, Sch Med, Boston, MA 02115 USA. [Currie, Treeve; Kutok, Jeffery L.; Rodig, Scott J.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Rajewsky, K (reprint author), Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. EM klaus.rajewsky@mdc-berlin.de OI Zhang, Baochun/0000-0003-1759-1161; Koyama, Shohei/0000-0002-6897-9417 FU NIH [CA098285, CA078378, AI56299]; Leukemia and Lymphoma SCOR; Leukemia and Lymphoma Society; JSPS; Astellas Foundation for Research on Metabolic Disorders FX We thank Dr. S. Cobbold for the anti-CD4, -CD8, and -Thy1 hybridomas; Dr. L. Lanier for the CX5 hybridoma; Dr. R. Schreiber for anti-TNF alpha (TN3-19.12) and anti-IFN gamma (H22) antibodies; Drs. E. Cahir-McFarland and E. Kieff for MSCV-IRES-GFP- and MSCV-LMP1-IRES-GFP-expressing vectors; Dr. D. Raulet for NKG2D-/- mice; Mr. P. Sage and Dr. A. Sharpe for CIITA-/- mice; Drs. U. Basu, F. Meng, and F. Alt for the anti-AID antibody; and Dr. M. Schmidt-Supprian for the JH probe. We thank the NIH Tetramer Facility at Emory University for the PE-conjugated mCD1d-PBS57 tetramer. We are grateful to M. Bamberg, J. Xia, D. Ghitza, C. Grosse, X. Chen, A. Pellerin, J. Grundy, and J. Wang for technical assistance; M. Ottaviano for administrative assistance; S. Koralov for help with sequence analysis and intracellular cytokine staining; S. Peng for HPRT primers; K. Kochert for advice on statistics; and D. Calado, M. Janz, K. Wucherpfennig, and all Rajewsky lab members for critical comments and suggestions. This work was supported by NIH grants CA098285, CA078378, and AI56299 and a Leukemia and Lymphoma SCOR. B.Z. is supported by a postdoctoral fellowship of the Leukemia and Lymphoma Society. T.Y is supported by a JSPS Postdoctoral Fellowship for Research Abroad and by the Astellas Foundation for Research on Metabolic Disorders. NR 50 TC 53 Z9 55 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 FEB 17 PY 2012 VL 148 IS 4 BP 739 EP 751 DI 10.1016/j.cell.2011.12.031 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897DH UT WOS:000300622400015 PM 22341446 ER PT J AU Qiao, DH Meyer, K Friedl, A AF Qiao, Dianhua Meyer, Kristy Friedl, Andreas TI Glypican-1 Stimulates Skp2 Autoinduction Loop and G(1)/S Transition in Endothelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANAPHASE PROMOTING COMPLEX/CYCLOSOME; RESTRICTION POINT CONTROL; TGF-BETA; CANCER-CELLS; CYCLIN D1; C-MYC; CDK INHIBITORS; S-PHASE; GROWTH; DEGRADATION AB The heparan sulfate proteoglycan glypican-1 (GPC1) is involved in tumorigenesis and angiogenesis and is overexpressed frequently in tumor and endothelial cells (ECs) in human gliomas. We demonstrated previously that in brain EC, GPC1 regulates mitotic cyclins and securin as well as mitosis and that GPC1 is required for progression through the cell cycle. To characterize the molecular mechanism underlying cell cycle regulation by GPC1, we systematically investigated its effects on key G(1)/S checkpoint regulators and on major signaling pathways reportedly activated by Dally (Division abnormally delayed) the Drosophila GPC1 homologue. We found that elevated GPC1 affected a wide range of G(1)/S checkpoint regulators, leading to inactivation of the G(1)/S checkpoint and increased S phase entry, apparently by activating the mitogen-independent Skp2 autoinduction loop. Specifically, GPC1 suppressed CDK inhibitors (CKIs), including p21, p27, p16, and p19, and the D cyclins, and induced CDK2 and Skp2. GPC1 may trigger the Skp2 autoinduction loop at least partially by suppressing p21 transcription as knockdown of p21 by RNAi can mimic the effect of GPC1 on the cell cycle regulators related to the loop. Moreover, multiple mitogenic signaling pathways, including ERK MAPK, Wnt and BMP signaling, were significantly stimulated by GPC1 as has been reported for Dally in Drosophila. Notably, the c-Myc oncoprotein, which is frequently up-regulated by both ERK and Wnt signaling and functions as a potent transcription repressor for CKIs as well as D cyclins, was also significantly induced by GPC1. These findings provide mechanistic insights into how GPC1 regulates the cell cycle and proliferation. C1 [Qiao, Dianhua; Meyer, Kristy; Friedl, Andreas] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. [Friedl, Andreas] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Dept Vet Affairs Med Ctr, Madison, WI 53705 USA. RP Friedl, A (reprint author), WIMR Room 6051,1111 Highland Ave, Madison, WI 53705 USA. EM afriedl@wisc.edu NR 51 TC 15 Z9 16 U1 1 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 FEB 17 PY 2012 VL 287 IS 8 BP 5898 EP 5909 DI 10.1074/jbc.M111.325282 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897HE UT WOS:000300638000064 PM 22203671 ER PT J AU Bergwitz, C Rasmussen, MD DeRobertis, C Wee, MJ Sinha, S Chen, HH Huang, J Perrimon, N AF Bergwitz, Clemens Rasmussen, Matthew D. DeRobertis, Charles Wee, Mark J. Sinha, Sumi Chen, Hway H. Huang, Joanne Perrimon, Norbert TI Roles of Major Facilitator Superfamily Transporters in Phosphate Response in Drosophila SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; INORGANIC-PHOSPHATE; SACCHAROMYCES-CEREVISIAE; VASCULAR CALCIFICATION; KINASE; CELLS; MELANOGASTER; CALCIUM; DIETARY; FAMILY AB The major facilitator superfamily (MFS) transporter Pho84 and the type III transporter Pho89 are responsible for metabolic effects of inorganic phosphate in yeast. While the Pho89 ortholog Pit1 was also shown to be involved in phosphate-activated MAPK in mammalian cells, it is currently unknown, whether orthologs of Pho84 have a role in phosphate-sensing in metazoan species. We show here that the activation of MAPK by phosphate observed in mammals is conserved in Drosophila cells, and used this assay to characterize the roles of putative phosphate transporters. Surprisingly, while we found that RNAi-mediated knockdown of the fly Pho89 ortholog dPit had little effect on the activation of MAPK in Drosophila S2R+ cells by phosphate, two Pho84/SLC17A1-9 MFS orthologs (MFS10 and MFS13) specifically inhibited this response. Further, using a Xenopus oocyte assay, we show that MSF13 mediates uptake of [P-33]-orthophosphate in a sodium-dependent fashion. Consistent with a role in phosphate physiology, MSF13 is expressed highest in the Drosophila crop, midgut, Malpighian tubule, and hindgut. Altogether, our findings provide the first evidence that Pho84 orthologs mediate cellular effects of phosphate in metazoan cells. Finally, while phosphate is essential for Drosophila larval development, loss of MFS13 activity is compatible with viability indicating redundancy at the levels of the transporters. C1 [Bergwitz, Clemens; DeRobertis, Charles; Wee, Mark J.; Sinha, Sumi; Chen, Hway H.; Huang, Joanne] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Genet, Boston, MA 02115 USA. [Rasmussen, Matthew D.] MIT, Comp Sci & Artificial Intelligence Lab, Boston, MA USA. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM cbergwitz@partners.org FU Harvard Catalyst; National institutes of Health, NIDDK [5K08DK078361] FX Funding was provided by Harvard Catalyst, http://catalyst.harvard.edu/ and http://www.google.com/url?sa=t&rct=j&rct=j&q=&q=&esrc=s&esrc=s&source=we b&source=web&cd=3&cd=3&ved=0CC0QFjAC&url=http%3A%2F%2Fcatalyst.harvard.e du%2Fservices%2Fpilotfunding%2Fdoc%2FHarvardCatalystyr2pilotawardees.pdf &ei=Q7LoTsvbA4Hs0gGX_bX-CQ&usg=AFQjCNH5urQAzoFgECvnBx7291P3xQFYyQ&sig2=2 txR0jw1srrB3xu-3HwW4A, and the National institutes of Health, NIDDK 5K08DK078361. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 9 Z9 10 U1 0 U2 19 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 FEB 16 PY 2012 VL 7 IS 2 AR e31730 DI 10.1371/journal.pone.0031730 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925XS UT WOS:000302796200093 PM 22359624 ER PT J AU Corey, KE Zheng, H Mendez-Navarro, J Delgado-Borrego, A Dienstag, JL Chung, RT AF Corey, Kathleen E. Zheng, Hui Mendez-Navarro, Jorge Delgado-Borrego, Aymin Dienstag, Jules L. Chung, Raymond T. CA HALT-C Trial Grp TI Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis SO PLOS ONE LA English DT Article ID METABOLIC BONE-DISEASE; GROWTH-FACTOR-I; PARATHYROID-HORMONE; MINERAL DENSITY; PROLIFERATION; CIRRHOSIS; INSULIN; MECHANISMS; EXPRESSION AB In animal models and human cross-sectional studies, vitamin D deficiency has been associated with liver disease progression. Vitamin D supplementation has been suggested as a treatment to prevent disease progression. We sought to evaluate the role of vitamin D levels in predicting chronic liver disease development. We conducted a nested case-control study of vitamin D levels in subjects with (cases) and without (controls) liver histologic progression or clinical decompensation over the course of the HALT-C Trial. Vitamin D levels were measured at 4 points over 45 months. 129 cases and 129 aged-matched controls were included. No difference in baseline vitamin D levels were found between cases and controls. (44.8 ng/mL vs. 44.0 ng/mL, P = 0.74). Vitamin D levels declined in cases and controls over time (P = 0.0005), however, there was no difference in the level of decline (P = 0.37). Among study subjects with diabetes mellitius, baseline vitamin D levels were higher in cases, 49.9 ng/mL, than controls, 36.3 ng/mL. (P = 0.03) In addition, baseline vitamin D levels were higher in black case subjects, 32.7 ng/mL, than in black control subjects, 25.2 ng/mL (P = 0.08) No difference in vitamin D levels was found between patients with and without progression of hepatitis C-associated liver disease over 4 years. Our data do not suggest any role for vitamin D supplementation in patients with advanced chronic hepatitis C and raise the possibility that higher vitamin D levels may be associated with disease progression. C1 [Corey, Kathleen E.; Mendez-Navarro, Jorge; Dienstag, Jules L.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Delgado-Borrego, Aymin] Univ Miami, Div Pediat Gastroenterol, Miami, FL USA. [Corey, Kathleen E.; Dienstag, Jules L.; Chung, Raymond T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Corey, KE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. EM rtchung@partners.org FU American College of Gastroenterology; National Institute of Diabetes & Digestive & Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Center for Minority Health and Health Disparities; General Clinical Research Center from the National Center for Research Resources, National Institutes of Health; Clinical and Translational Science Center from the National Center for Research Resources, National Institutes of Health; Hoffmann-La Roche, Inc.; National Institutes of Health; University of Massachusetts Medical Center, Worcester, MA [N01-DK-9-2326]; University of Connecticut Health Center, Farmington, CT [M01RR-06192]; Saint Louis University School of Medicine, St Louis, MO [N01-DK-9-2324]; Massachusetts General Hospital, Boston, MA [N01-DK-9-2319, M01RR-01066, 1 UL1 RR025758-01]; University of Colorado Denver, School of Medicine, Aurora, CO [N01-DK-9-2327, M01RR-00051, 1 UL1 RR 025780-01]; University of California - Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; University of Texas Southwestern Medical Center, Dallas, TX [N01-DK-9-2321, M01RR-00633, 1 UL1 RR024982-01]; University of Southern California, Los Angeles, CA [N01-DK-9-2325, M01RR-00043]; University of Michigan Medical Center, Ann Arbor, MI [N01-DK-9-2323, M01RR-00042, 1 UL1 RR024986]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; University of Washington, Seattle, WA [N01-DK-9-2318]; New England Research Institutes, Watertown, MA [N01-DK-9-2328] FX This work was principally supported by a grant from the American College of Gastroenterology. Additional support was provided by the National Institute of Diabetes & Digestive & Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement with the National Institutes of Health. Additional grants and contracts supporting the HALT-C Study are listed in the Acknowledgement section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN; University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP; Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN; Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark; University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01), Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN; University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN; University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH; University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN; University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Anna S. Lok, MD, Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS; Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN; University of Washington, Seattle, WA: (Contract N01-DK-9-2318) Chihiro Morishima, MD, David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed.; New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, May Yang, MPH NR 28 TC 16 Z9 16 U1 0 U2 4 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 FEB 16 PY 2012 VL 7 IS 2 AR e27144 DI 10.1371/journal.pone.0027144 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925XS UT WOS:000302796200001 PM 22359532 ER PT J AU He, DG Li, H Yusuf, N Elmets, CA Athar, M Katiyar, SK Xu, H AF He, Donggou Li, Hui Yusuf, Nabiha Elmets, Craig A. Athar, Mohammad Katiyar, Santosh K. Xu, Hui TI IL-17 Mediated Inflammation Promotes Tumor Growth and Progression in the Skin SO PLOS ONE LA English DT Article ID CD8(+) T-CELLS; INTERLEUKIN-17 FAMILY-MEMBERS; MYELOID SUPPRESSOR-CELLS; CHEMICAL CARCINOGENESIS; IMMUNE SUPPRESSION; MOUSE SKIN; CANCER; METASTASIS; MICROENVIRONMENT; TUMORIGENESIS AB The mechanism for inflammation associated tumor development is a central issue for tumor biology and immunology and remains to be fully elucidated. Although IL-17 is implicated in association with inflammation mediated carcinogenesis, mechanisms are largely elusive. In the current studies, we showed that IL-17 receptor-A gene deficient (IL-17R-/-) mice were resistant to chemical carcinogen-induced cutaneous carcinogenesis, a well-established inflammation associated tumor model in the skin. The deficiency in IL-17R increased the infiltration of CD8+ T cells whereas it inhibited the infiltration of CD11b+ myeloid cells and development of myeloid derived suppressor cells. Inflammation induced skin hyperplasia and production of pro-tumor inflammatory molecules were inhibited in IL-17R-/- mice. We found that pre-existing inflammation in the skin increased the susceptibility to tumor growth, which was associated with increased development of tumor specific IL-17 producing T cells. This inflammation induced susceptibility to tumor growth was abrogated in IL-17R-/- mice. Finally, neutralizing IL-17 in mice that had already developed chemical carcinogen induced skin tumors could inhibit inflammation mediated tumor progression at late stages. These results demonstrate that IL-17 mediated inflammation is an important mechanism for inflammation mediated promotion of tumor development. The study has major implications for targeting IL-17 in prevention and treatment of tumors. C1 [He, Donggou; Li, Hui; Yusuf, Nabiha; Elmets, Craig A.; Athar, Mohammad; Katiyar, Santosh K.; Xu, Hui] Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. [Yusuf, Nabiha; Elmets, Craig A.; Athar, Mohammad; Katiyar, Santosh K.; Xu, Hui] Univ Alabama Birmingham, Skin Dis Res Ctr, Birmingham, AL USA. [Yusuf, Nabiha; Elmets, Craig A.; Katiyar, Santosh K.; Xu, Hui] Birmingham VA Med Ctr, Birmingham, AL USA. RP He, DG (reprint author), Univ Alabama Birmingham, Dept Dermatol, Birmingham, AL 35294 USA. EM xuhui@uab.edu FU United States National Institutes of Health [ES017494, CA138998, AI071041, AR46256] FX This publication was made possible by grants (AI071041 and AR46256 [HX] and ES017494 and CA138998 [MA]) from the United States 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 63 TC 34 Z9 35 U1 0 U2 4 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 FEB 16 PY 2012 VL 7 IS 2 AR e32126 DI 10.1371/journal.pone.0032126 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925XS UT WOS:000302796200131 PM 22359662 ER PT J AU Zhang, LL Hong, Z Lin, WY Shao, RX Goto, K Hsu, VW Chung, RT AF Zhang, Leiliang Hong, Zhi Lin, Wenyu Shao, Run-Xuan Goto, Kaku Hsu, Victor W. Chung, Raymond T. TI ARF1 and GBF1 Generate a PI4P-Enriched Environment Supportive of Hepatitis C Virus Replication SO PLOS ONE LA English DT Article ID GENOTYPE 1 INFECTION; 4-KINASE III ALPHA; TELAPREVIR; PEGINTERFERON; REGULATORS; RIBAVIRIN; LIPIDS; TRAFFICKING; RECRUITMENT; PHOSPHATASE AB Cellular levels of phosphatidylinositol 4-phosphate (PI4P) have been shown to be upregulated during RNA replication of several viruses, including the HCV replicon model. However, whether PI4P is required in an infectious HCV model remains unknown. Moreover, it is not established whether the host transport machinery is sequestered by the generation of PI4P during HCV infection. Here we found that PI4P was enriched in HCV replication complexes when Huh7.5.1 cells were infected with JFH1. HCV replication was inhibited upon overexpression of the PI4P phosphatase Sac1. The PI4P kinase PI4KIII beta was also found to be required for HCV replication. Moreover, the vesicular transport proteins ARF1 and GBF1 colocalized with PI4KIII beta and were both required for HCV replication. During authentic HCV infection, PI4P plays an integral role in virus replication. C1 [Zhang, Leiliang; Hong, Zhi] Chinese Acad Med Sci, Inst Pathogen Biol, Beijing 100730, Peoples R China. [Zhang, Leiliang; Hong, Zhi] Peking Union Med Coll, Beijing 100021, Peoples R China. [Zhang, Leiliang; Lin, Wenyu; Shao, Run-Xuan; Goto, Kaku; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit,Dept Med, Boston, MA USA. [Hsu, Victor W.] Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Sch Med, Boston, MA 02115 USA. [Hsu, Victor W.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Zhang, LL (reprint author), Chinese Acad Med Sci, Inst Pathogen Biol, Beijing 100730, Peoples R China. EM rtchung@partners.org FU National Institutes of Health (NIH) [AI069939, AI082630, DK078772]; Institute of Pathogen Biology, Chinese Academy of Medical Sciences [2011IPB108]; NIH-MGH Center for Human Immunology FX This work was supported by grants AI069939, AI082630 and DK078772 (to RTC) from the National Institutes of Health (NIH), 2011IPB108 from Intramural Research Program of the Institute of Pathogen Biology, Chinese Academy of Medical Sciences (to LZ), and NIH-MGH Center for Human Immunology Pilot/Feasibility Study Grant (to WL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 30 Z9 30 U1 0 U2 4 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 FEB 16 PY 2012 VL 7 IS 2 AR e32135 DI 10.1371/journal.pone.0032135 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925XS UT WOS:000302796200132 PM 22359663 ER PT J AU Freudenreich, O Basgoz, N Fernandez-Robles, C Larvie, M Misdraji, J AF Freudenreich, Oliver Basgoz, Nesli Fernandez-Robles, Carlos Larvie, Mykol Misdraji, Joseph TI Case 5-2012: A 39-Year-Old Man with a Recent Diagnosis of HIV Infection and Acute Psychosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIRETROVIRAL THERAPY; 1ST-EPISODE SCHIZOPHRENIA; EXTRAPYRAMIDAL SYMPTOMS; AIDS; TUBERCULOSIS; PHENOMENOLOGY; MANAGEMENT; DEMENTIA C1 [Freudenreich, Oliver; Fernandez-Robles, Carlos] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Larvie, Mykol] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Basgoz, Nesli] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Freudenreich, Oliver; Fernandez-Robles, Carlos] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Basgoz, Nesli] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Larvie, Mykol] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Misdraji, Joseph] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Freudenreich, O (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 32 TC 1 Z9 1 U1 1 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 FEB 16 PY 2012 VL 366 IS 7 BP 648 EP 657 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 892IL UT WOS:000300279800012 PM 22335743 ER PT J AU Moran, CJ Forcione, D Katz, A AF Moran, Christopher J. Forcione, David Katz, Aubrey TI Case 32-2011: A Man with Recurrent Pancreatitis REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID ERCP; GUIDELINE C1 [Moran, Christopher J.; Forcione, David; Katz, Aubrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Moran, CJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. 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 FEB 16 PY 2012 VL 366 IS 7 BP 670 EP 670 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 892IL UT WOS:000300279800028 ER PT J AU Emmendorfer, T Glassman, PA Moore, V Leadholm, TC Good, CB Cunningham, F AF Emmendorfer, Thomas Glassman, Peter A. Moore, Von Leadholm, Thomas C. Good, Chester B. Cunningham, Francesca TI Monitoring adverse drug reactions across a nationwide health care system using information technology SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE Databases; Department of Veterans Affairs; Drugs, adverse reactions; Information; Quality assurance; Records; Technology ID AMBULATORY-CARE; EVENTS; VETERANS AB Purpose. The improvement and linkage of two Department of Veterans Affairs (VA) databases for monitoring adverse drug reactions (ADRs) are described, with a discussion of the potential implications for improved medication safety within the VA health care system. Summary. Before 2007, VA had limited capability to track and evaluate ADRs across its nationwide network of health care facilities. Since then, VA has established a standardized monitoring system that has improved the reporting, analysis, and trending of ADRs reported by providers and pharmacists at individual VA facilities. The enhanced system has two components with distinct but complementary functions: the Adverse Reaction Tracking database, which is derived by extracting text-based, patient-specific information entered into the VA electronic medical record system by clinicians at the point of care; and the VA Adverse Drug Event Reporting System (VA ADERS), an external web-based portal that contains aggregated data from 146 VA facilities, with standardized coding of reported events. Both databases allow for ADR reporting at the local, regional, and national levels. The VA ADERS database permits rapid electronic reporting of certain ADRs to the federal MedWatch program. The two databases can be used in tandem for more comprehensive assessments of ADR patterns and reporting rates and to generate a wide range of benchmarking data. Conclusion. In recent years, the refinement of two databases for ADR reporting has increased VA's capability to systematically monitor, track, and report ADRs across its national network of health care facilities. Linking the two databases has further strengthened those capabilities, enhancing medication safety practices and aiding in pharmacovigilance. C1 [Emmendorfer, Thomas; Glassman, Peter A.] VA Pharm Benefits Management Serv, VA Ctr Medicat Safety, Hines, IL 60141 USA. [Glassman, Peter A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Leadholm, Thomas C.] VA PBM Serv, VA ADERS, Tucson, AZ USA. [Leadholm, Thomas C.] Consolidated Mail Outpatient Pharm, Tucson, AZ USA. [Good, Chester B.] VA Pittsburgh Healthcare Syst, Sect Gen Med, Pittsburgh, PA USA. RP Emmendorfer, T (reprint author), VA Pharm Benefits Management Serv, VA Ctr Medicat Safety, 1st Ave,1 Block,N Cermak Rd,Bldg 37,Room 139, Hines, IL 60141 USA. EM thomas.emmendorfer@va.gov NR 13 TC 6 Z9 6 U1 0 U2 7 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 15 PY 2012 VL 69 IS 4 BP 321 EP 328 DI 10.2146/ajhp110026 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 943LM UT WOS:000304123500011 PM 22302257 ER PT J AU Engler, DA Gupta, S Growdon, WB Drapkin, RI Nitta, M Sergent, PA Allred, SF Gross, J Deavers, MT Kuo, WL Karlan, BY Rueda, BR Orsulic, S Gershenson, DM Birrer, MJ Gray, JW Mohapatra, G AF Engler, David A. Gupta, Sumeet Growdon, Whitfield B. Drapkin, Ronny I. Nitta, Mai Sergent, Petra A. Allred, Serena F. Gross, Jenny Deavers, Michael T. Kuo, Wen-Lin Karlan, Beth Y. Rueda, Bo R. Orsulic, Sandra Gershenson, David M. Birrer, Michael J. Gray, Joe W. Mohapatra, Gayatry TI Genome Wide DNA Copy Number Analysis of Serous Type Ovarian Carcinomas Identifies Genetic Markers Predictive of Clinical Outcome SO PLOS ONE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; HIGH-RESOLUTION ANALYSIS; TUMOR-SUPPRESSOR; LOW-GRADE; EXPRESSION PROFILES; BREAST-CANCER; CYCLIN-E; C-MYC; COLORECTAL-CANCER; SIGNALING PATHWAY AB Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups. C1 [Engler, David A.; Allred, Serena F.] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Nitta, Mai; Mohapatra, Gayatry] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Gupta, Sumeet] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Growdon, Whitfield B.; Sergent, Petra A.; Rueda, Bo R.] Massachusetts Gen Hosp, Dept Vincent Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Drapkin, Ronny I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kuo, Wen-Lin; Gray, Joe W.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. [Gross, Jenny; Karlan, Beth Y.; Orsulic, Sandra] Cedars Sinai Med Ctr, Womens Canc Res Inst, Los Angeles, CA 90048 USA. [Deavers, Michael T.; Gershenson, David M.] Univ Texas MD Anderson Canc Ctr, Dept Pathol & Gynecol Oncol, Houston, TX 77030 USA. [Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. RP Engler, DA (reprint author), Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. EM gmohapatra@partners.org RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 FU Office of Science, Office of Biological & Environmental Research, of the U. S. Department of Energy [DE-AC02-05CH11231]; National Cancer Institute [P50 CA 83639, RC4 CA 156551]; Dana Farber/Harvard Cancer Center Ovarian SPORE [P50 CA105009]; Ovarian Cancer Research Fund; Michael Wall Gynecologic Oncology Research Fund FX This work was supported by the Director, Office of Science, Office of Biological & Environmental Research, of the U. S. Department of Energy under Contract No. DE-AC02-05CH11231, the National Cancer Institute grant P50 CA 83639 (JWG), the National Cancer Institute grant RC4 CA 156551 (MJB), Dana Farber/Harvard Cancer Center Ovarian SPORE P50 CA105009 (SO and BRR), Ovarian Cancer Research Fund (SO and BRR), and by the Michael Wall Gynecologic Oncology Research Fund (GM). The GOG component was supported by the National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (Philip DiSaia U10 CA027469), GOG Tissue Bank (Philip DiSaia U10CA027469 and U24 CA011479), and the GOG Statistical Data Center (John Blessing U10 CA037517). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 106 TC 18 Z9 18 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 FEB 15 PY 2012 VL 7 IS 2 AR e30996 DI 10.1371/journal.pone.0030996 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925DP UT WOS:000302741300033 PM 22355333 ER PT J AU Wurster, AL Precht, P Becker, KG Wood, WH Zhang, YQ Wang, Z Pazin, MJ AF Wurster, Andrea L. Precht, Patricia Becker, Kevin G. Wood, William H., III Zhang, Yongqing Wang, Zhong Pazin, Michael J. TI IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme SO BMC IMMUNOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; HELPER-CELL DIFFERENTIATION; DISEASE SUSCEPTIBILITY LOCI; EMBRYONIC STEM-CELLS; GENE-EXPRESSION; T-CELLS; THYMOCYTE DEVELOPMENT; FACTOR GATA-3; CYCLE CONTROL; CHIP-SEQ AB Background: SWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported. Results: Here we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus. Conclusions: These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription. C1 [Becker, Kevin G.; Wood, William H., III; Zhang, Yongqing] NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Wang, Zhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Wurster, Andrea L.; Precht, Patricia; Pazin, Michael J.] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Pazin, MJ (reprint author), NHGRI, NIH, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM pazinm@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656; Pazin, Michael/0000-0002-7561-3640 FU NIH, National Institute on Aging [1 Z01 AG000524] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, 1 Z01 AG000524. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 87 TC 6 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD FEB 15 PY 2012 VL 13 AR 9 DI 10.1186/1471-2172-13-9 PG 19 WC Immunology SC Immunology GA 919JX UT WOS:000302322300001 PM 22336179 ER PT J AU Wong, JS Iorns, E Rheault, MN Ward, TM Rashmi, P Weber, U Lippman, ME Faul, C Mlodzik, M Mundel, P AF Wong, Jenny S. Iorns, Elizabeth Rheault, Michelle N. Ward, Toby M. Rashmi, Priyanka Weber, Ursula Lippman, Marc E. Faul, Christian Mlodzik, Marek Mundel, Peter TI Rescue of tropomyosin deficiency in Drosophila and human cancer cells by synaptopodin reveals a role of tropomyosin alpha in RhoA stabilization SO EMBO JOURNAL LA English DT Article DE actin filaments; cell migration; oskar mRNA; RhoA; Smurf1 ID OSKAR MESSENGER-RNA; ACTIN CYTOSKELETON; POSTERIOR LOCALIZATION; KIDNEY PODOCYTES; EPITHELIAL-CELLS; BINDING PROTEIN; EXPRESSION; OOCYTE; ORGANIZATION; POLARITY AB Tropomyosins are widespread actin-binding proteins that influence numerous cellular functions including actin dynamics, cell migration, tumour suppression, and Drosophila oocyte development. Synaptopodin is another actin-binding protein with a more restricted expression pattern in highly dynamic cell compartments such as kidney podocyte foot processes, where it promotes RhoA signalling by blocking the Smurf1-mediated ubiquitination of RhoA. Here, we show that synaptopodin has a shorter half-life but shares functional properties with the highly stable tropomyosin. Transgenic expression of synaptopodin restores oskar mRNA localization in Drosophila oocytes mutant for TmII, thereby rescuing germline differentiation and fertility. Synaptopodin restores stress fibres in tropomyosin-deficient human MDA-MB 231 breast cancer cells and TPM alpha-depleted fibroblasts. Gene silencing of TPM alpha but not TPM beta causes loss of stress fibres by promoting Smurf1-mediated ubiquitination and proteasomal degradation of RhoA. Functionally, overexpression of synaptopodin or RhoA(K6,7R) significantly reduces MDA-MB 231 cell migration. Our findings elucidate RhoA stabilization by structurally unrelated actin-binding proteins as a conserved mechanism for regulation of stress fibre dynamics and cell motility in a cell type-specific fashion. The EMBO Journal (2012) 31, 1028-1040. doi: 10.1038/emboj.2011.464; Published online 13 December 2011 C1 [Wong, Jenny S.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Iorns, Elizabeth; Ward, Toby M.; Lippman, Marc E.; Faul, Christian] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Rheault, Michelle N.] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Rashmi, Priyanka; Mundel, Peter] Harvard Univ, Sch Med, Boston, MA USA. [Rashmi, Priyanka; Mundel, Peter] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Weber, Ursula; Mlodzik, Marek] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY USA. RP Mundel, P (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Nephrol,Dept Med, 149 13th St,Room 8-203, Charlestown, MA 02129 USA. EM mundel.peter@mgh.harvard.edu OI Rheault, Michelle/0000-0003-2494-3970; Iorns, Elizabeth/0000-0002-5515-1258 FU Child Health Research Center [HD052890]; NIH [DK57683, DK062472, EY14597] FX We thank Miklos Erdelyi, Szeged, Hungary for providing oskar plasmid and TmII mutant flies; the Drosophila stock center, Bloomington, IN, USA for fly strains; and Sophy Okello, New York, NY, USA for transgenic injections. We thank Anna Greka, Boston, MA, USA for help with confocal microscopy. We also thank Peter Gunning Westmead, Australia for Tm1 cDNA; Tadaomi Takenawa, Tokyo, Japan for GST-RhoA(T19N) cDNA; Jeffrey Wrana, Toronto, Canada for RhoA(K6,7R) cDNA; Keiji Tanaka, Tokyo, Japan for HA-ubiquitin cDNA; and Takeshi Imamura (The JFCR Cancer Institute, Tokyo, Japan) for wild-type Smurf1 and catalytically inactive Smurf1(C710A) cDNAs. MNR was supported by a Child Health Research Center grant HD052890. This work was supported by NIH grants DK57683 and DK062472 to PM and EY14597 to MM. This manuscript has been used by JSW to fulfil the requirements for obtaining a PhD degree from the Graduate School at the Mount Sinai School of Medicine, New York, NY, USA. NR 54 TC 12 Z9 12 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 15 PY 2012 VL 31 IS 4 BP 1028 EP 1040 DI 10.1038/emboj.2011.464 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 900FN UT WOS:000300872100022 PM 22157816 ER PT J AU Cooper, RJ Gagnon, L Goldenholz, DM Boas, DA Greve, DN AF Cooper, R. J. Gagnon, Louis Goldenholz, Daniel M. Boas, David A. Greve, Douglas N. TI The utility of near-infrared spectroscopy in the regression of low-frequency physiological noise from functional magnetic resonance imaging data SO NEUROIMAGE LA English DT Article DE Near-infrared spectroscopy; Functional magnetic resonance imaging; Low-frequency oscillations; Resting state ID EVENT-RELATED FMRI; SURFACE-BASED ANALYSIS; HUMAN BRAIN; BOLD SIGNAL; RESPONSE FUNCTION; NEURONAL-ACTIVITY; CONCURRENT FMRI; BALLOON MODEL; ACTIVATION; NIRS AB Near-infrared spectroscopy (NIRS) signals have been shown to correlate with resting-state BOLD-fMRI data across the whole brain volume, particularly at frequencies below 0.1 Hz. While the physiological origins of this correlation remain unclear, its existence may have a practical application in minimizing the background physiological noise present in BOLD-fMRI recordings. We performed simultaneous, resting-state fMRI and 28-channel NIRS in seven adult subjects in order to assess the utility of NIRS signals in the regression of physiological noise from fMRI data. We calculated the variance of the residual error in a general linear model of the baseline fMRI signal, and the reduction of this variance achieved by including NIRS signals in the model. In addition, we introduced a sequence of simulated hemodynamic response functions (HRFs) into the resting-state fMRI data of each subject in order to quantify the effectiveness of NIRS signals in optimizing the recovery of that HRF. For comparison, these calculations were also performed using a pulse and respiration RETROICOR model. Our results show that the use of 10 or more NIRS channels can reduce variance in the residual error by as much as 36% on average across the whole cortex. However the same number of low-pass filtered white noise regressors is shown to produce a reduction of 19%. The RETROICOR model obtained a variance reduction of 6.4%. Our HRF simulation showed that the mean-squared error (MSE) between the recovered and true HRFs is reduced by 21% on average when 10 NIRS channels are applied and by introducing an optimized time lag between the NIRS and fMRI time series, a single NIRS channel can provide an average MSE reduction of 14%. The RETROICOR model did not provide a significant change in MSE. By each of the metrics calculated, NIRS recording is shown to be of significant benefit to the regression of low-frequency physiological noise from fMRI data. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cooper, R. J.; Gagnon, Louis; Goldenholz, Daniel M.; Boas, David A.; Greve, Douglas N.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA USA. [Gagnon, Louis] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Gagnon, Louis] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Cooper, RJ (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA USA. EM rcooper@nmr.mgh.harvard.edu OI Goldenholz, Daniel/0000-0002-8370-2758 FU NIH [P41-RR14075, R01-EB006385]; Fond Quebecois de Recherche sur la Nature et les Technologies FX This work was supported by NIH grants P41-RR14075 and R01-EB006385. L Gagnon is supported by the Fond Quebecois de Recherche sur la Nature et les Technologies. NR 42 TC 17 Z9 17 U1 0 U2 8 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 FEB 15 PY 2012 VL 59 IS 4 BP 3128 EP 3138 DI 10.1016/j.neuroimage.2011.11.028 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100007 PM 22119653 ER PT J AU Gutchess, AH Schacter, DL AF Gutchess, Angela H. Schacter, Daniel L. TI The neural correlates of gist-based true and false recognition SO NEUROIMAGE LA English DT Article DE Memory; False recognition; Gist; fMRI; Hippocampus ID CONSTRUCTIVE EPISODIC SIMULATION; FUZZY-TRACE THEORY; EVENT-RELATED FMRI; COGNITIVE NEUROSCIENCE; FUTURE EVENTS; SOURCE MEMORY; OLDER-ADULTS; PATTERN SEPARATION; LOBE CONTRIBUTIONS; YOUNGER ADULTS AB When information is thematically related to previously studied information, gist-based processes contribute to false recognition. Using functional MRI, we examined the neural correlates of gist-based recognition as a function of increasing numbers of studied exemplars. Sixteen participants incidentally encoded small, medium, and large sets of pictures, and we compared the neural response at recognition using parametric modulation analyses. For hits, regions in middle occipital, middle temporal, and posterior parietal cortex linearly modulated their activity according to the number of related encoded items. For false alarms, visual, parietal, and hippocampal regions were modulated as a function of the encoded set size. The present results are consistent with prior work in that the neural regions supporting veridical memory also contribute to false memory for related information. The results also reveal that these regions respond to the degree of relatedness among similar items, and implicate perceptual and constructive processes in gist-based false memory. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gutchess, Angela H.] Brandeis Univ, Dept Psychol, Waltham, MA 02454 USA. [Gutchess, Angela H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schacter, Daniel L.] Harvard Univ, Cambridge, MA 02138 USA. RP Gutchess, AH (reprint author), Brandeis Univ, Dept Psychol, MS 062,POB 549110, Waltham, MA 02454 USA. EM gutchess@brandeis.edu OI Schacter, Daniel/0000-0002-2460-6061 FU National Institutes of Health [NIMH R01 MH60941, NIA F32 AG026920]; National Center for Research Resources [P41 RR14075]; MIND Institute FX The authors gratefully acknowledge support from the National Institutes of Health, grants NIMH R01 MH60941 (to DLS) and NIA F32 AG026920 (to AHG). Portions of this research were conducted when A.H.G. was a fellow of the American Federation for Aging Research. The Athinoula A. Martinos Center for Biomedical Imaging is supported by the National Center for Research Resources (grant P41 RR14075) and by the MIND Institute. We thank Elizabeth Kensinger and Rachel Garoff Eaton for helpful discussions, and Donna Rose Addis for generously sharing her expertise and insights. NR 68 TC 22 Z9 23 U1 2 U2 30 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 FEB 15 PY 2012 VL 59 IS 4 BP 3418 EP 3426 DI 10.1016/j.neuroimage.2011.11.078 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100038 PM 22155331 ER PT J AU Dykstra, AR Chan, AM Quinn, BT Zepeda, R Keller, CJ Cormier, J Madsen, JR Eskandar, EN Cash, SS AF Dykstra, Andrew R. Chan, Alexander M. Quinn, Brian T. Zepeda, Rodrigo Keller, Corey J. Cormier, Justine Madsen, Joseph R. Eskandar, Emad N. Cash, Sydney S. TI Individualized localization and cortical surface-based registration of intracranial electrodes SO NEUROIMAGE LA English DT Article DE Electrocorticography; Image registration; Epilepsy; CT; MRI ID BRAIN-COMPUTER-INTERFACE; SUBDURAL ELECTRODES; EPILEPSY SURGERY; FUNCTIONAL ARCHITECTURE; DIGITAL PHOTOGRAPHY; COORDINATE SYSTEM; CORTEX; MRI; COREGISTRATION; RECONSTRUCTION AB In addition to its widespread clinical use, the intracranial electroencephalogram (iEEG) is increasingly being employed as a tool to map the neural correlates of normal cognitive function as well as for developing neuroprosthetics. Despite recent advances, and unlike other established brain-mapping modalities (e.g. functional MRI, magneto- and electroencephalography), registering the iEEG with respect to neuroanatomy in individuals and coregistering functional results across subjects remains a significant challenge. Here we describe a method which coregisters high-resolution preoperative MRI with postoperative computerized tomography (CT) for the purpose of individualized functional mapping of both normal and pathological (e.g., interictal discharges and seizures) brain activity. Our method accurately (within 3 mm, on average) localizes electrodes with respect to an individual's neuroanatomy. Furthermore, we outline a principled procedure for either volumetric or surface-based group analyses. We demonstrate our method in five patients with medically-intractable epilepsy undergoing invasive monitoring of the seizure focus prior to its surgical removal. The straight-forward application of this procedure to all types of intracranial electrodes, robustness to deformations in both skull and brain, and the ability to compare electrode locations across groups of patients makes this procedure an important tool for basic scientists as well as clinicians. (C) 2011 Elsevier Inc. All rights reserved. C1 [Dykstra, Andrew R.] MIT, Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. [Chan, Alexander M.] MIT, Harvard Mit Div Hlth Sci & Technol, Program Med Engn & Med Phys, Cambridge, MA 02139 USA. [Dykstra, Andrew R.; Chan, Alexander M.; Zepeda, Rodrigo; Keller, Corey J.; Cormier, Justine; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Cort Physiol Lab, Boston, MA 02114 USA. [Dykstra, Andrew R.; Chan, Alexander M.; Zepeda, Rodrigo; Keller, Corey J.; Cormier, Justine; Madsen, Joseph R.; Eskandar, Emad N.; Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA USA. [Quinn, Brian T.] NYU, Sch Med, New York, NY USA. [Madsen, Joseph R.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Dykstra, AR (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. EM adykstra@mit.edu OI Keller, Corey/0000-0003-0529-3490 FU NIBIB NIH HHS [T32 EB001680, T32 EB001680-06A2]; NIDCD NIH HHS [T32 DC000038, T32 DC000038-15, T32 DC000038-15S1, T32 DC000038-16, T32 DC000038-17, T32 DC000038-18, T32 DC000038-19, T32 DC000038-20]; NINDS NIH HHS [R01 NS062092, R01 NS062092-01A2, R01 NS062092-02, R01 NS062092-03] NR 42 TC 47 Z9 47 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 FEB 15 PY 2012 VL 59 IS 4 BP 3563 EP 3570 DI 10.1016/j.neuroimage.2011.11.046 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100052 PM 22155045 ER PT J AU Gagnon, L Yucel, MA Dehaes, M Cooper, RJ Perdue, KL Selb, J Huppert, TJ Hoge, RD Boas, DA AF Gagnon, Louis Yuecel, Meryem A. Dehaes, Mathieu Cooper, Robert J. Perdue, Katherine L. Selb, Juliette Huppert, Theodore J. Hoge, Richard D. Boas, David A. TI Quantification of the cortical contribution to the NIRS signal over the motor cortex using concurrent NIRS-fMRI measurements SO NEUROIMAGE LA English DT Article DE NIRS-fMRI; Pial vasculature; Balloon Model; Monte Carlo simulations ID NEAR-INFRARED SPECTROSCOPY; CEREBRAL OXYGEN-METABOLISM; BRAIN ACTIVATION; BALLOON MODEL; BLOOD-VOLUME; RESPONSES; DYNAMICS; BOLD; FLOW; RESOLUTION AB Near-Infrared Spectroscopy (NIRS) measures the functional hemodynamic response occurring at the surface of the cortex. Large pial veins are located above the surface of the cerebral cortex. Following activation, these veins exhibit oxygenation changes but their volume likely stays constant. The back-reflection geometry of the NIRS measurement renders the signal very sensitive to these superficial pial veins. As such, the measured NIRS signal contains contributions from both the cortical region as well as the pial vasculature. In this work, the cortical contribution to the NIRS signal was investigated using (1) Monte Carlo simulations over a realistic geometry constructed from anatomical and vascular MRI and (2) multimodal NIRS-BOLD recordings during motor stimulation. A good agreement was found between the simulations and the modeling analysis of in vivo measurements. Our results suggest that the cortical contribution to the deoxyhemoglobin signal change (Delta HbR) is equal to 16-22% of the cortical contribution to the total hemoglobin signal change (Delta HbT). Similarly, the cortical contribution of the oxyhemoglobin signal change (,Delta HbO) is equal to 73-79% of the cortical contribution to the Delta HbT signal. These results suggest that Delta HbT is far less sensitive to pial vein contamination and therefore, it is likely that the Delta HbT signal provides better spatial specificity and should be used instead of Delta HbO or Delta HbR to map cerebral activity with NIRS. While different stimuli will result in different pial vein contributions, our finger tapping results do reveal the importance of considering the pial contribution. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gagnon, Louis; Yuecel, Meryem A.; Cooper, Robert J.; Selb, Juliette; Boas, David A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Gagnon, Louis; Boas, David A.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Gagnon, Louis] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Dehaes, Mathieu] Harvard Univ, Sch Med, Boston, MA USA. [Dehaes, Mathieu] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Perdue, Katherine L.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Huppert, Theodore J.] Univ Pittsburgh, Dept Radiol & Bioengn, Pittsburgh, PA USA. [Hoge, Richard D.] Univ Montreal, Dept Physiol & Biomed Engn, Montreal, PQ, Canada. [Hoge, Richard D.] Univ Montreal, CRIUGM, Montreal, PQ, Canada. RP Gagnon, L (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. EM lgagnon@nmr.mgh.harvard.edu RI Perdue, Katherine/D-4306-2013; OI Perdue, Katherine/0000-0003-2846-3149; Cooper, Robert/0000-0001-6696-8020 FU NIH [P41-RR14075, R01-EB006385]; Fonds Quebecois sur la Nature et les Technologies FX We want to thank Qianqian Fang for providing the Monte Carlo code used in this study as well as providing useful advice. The authors are also grateful to Sungho Tak, Yunjie Tong, Blaise deB. Frederick and Evgeniya Kirilina for fruitful discussions. This work was supported by NIH grants P41-RR14075 and R01-EB006385. L. Gagnon was supported by the Fonds Quebecois sur la Nature et les Technologies. NR 32 TC 73 Z9 73 U1 2 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2012 VL 59 IS 4 BP 3933 EP 3940 DI 10.1016/j.neuroimage.2011.10.054 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 903BG UT WOS:000301090100086 PM 22036999 ER PT J AU Tobin, MJ AF Tobin, Martin J. TI Extubation and the Myth of "Minimal Ventilator Settings" SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID PRESSURE SUPPORT VENTILATION; MECHANICAL VENTILATION; WEANING PATIENTS; FAILURE; AIRWAY C1 [Tobin, Martin J.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Hines, IL 60141 USA. [Tobin, Martin J.] Loyola Univ Chicago, Stritch Sch Med, Hines, IL USA. RP Tobin, MJ (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Div Pulm & Crit Care Med, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. NR 13 TC 22 Z9 22 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2012 VL 185 IS 4 BP 349 EP 350 DI 10.1164/rccm.201201-0050ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 897EY UT WOS:000300629900003 PM 22336673 ER PT J AU Desmedt, C Majjaj, S Kheddoumi, N Singhal, SK Haibe-Kains, B El Ouriaghli, F Chaboteaux, C Michiels, S Lallemand, F Journe, F Duvillier, H Loi, S Quackenbush, J Dekoninck, S Blanpain, C Lagneaux, L Houhou, N Delorenzi, M Larsimont, D Piccart, M Sotiriou, C AF Desmedt, Christine Majjaj, Samira Kheddoumi, Naima Singhal, Sandeep K. Haibe-Kains, Benjamin El Ouriaghli, Frank Chaboteaux, Carole Michiels, Stefan Lallemand, Francoise Journe, Fabrice Duvillier, Hughes Loi, Sherene Quackenbush, John Dekoninck, Sophie Blanpain, Cedric Lagneaux, Laurence Houhou, Nawal Delorenzi, Mauro Larsimont, Denis Piccart, Martine Sotiriou, Christos TI Characterization and Clinical Evaluation of CD10(+) Stroma Cells in the Breast Cancer Microenvironment SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION SIGNATURES; IN-SITU; TUMOR MICROENVIRONMENT; METASTASIS; PROGRESSION; CARCINOMAS; TRANSITION; RESISTANCE; SURVIVAL; SUBTYPES AB Purpose: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance. Experimental Design: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets. Results: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients. Conclusions: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease. Clin Cancer Res; 18(4); 1004-14. (C)2012 AACR. C1 [Desmedt, Christine; Majjaj, Samira; Kheddoumi, Naima; Singhal, Sandeep K.; Haibe-Kains, Benjamin; El Ouriaghli, Frank; Chaboteaux, Carole; Michiels, Stefan; Lallemand, Francoise; Loi, Sherene; Sotiriou, Christos] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab JC Heuson, B-1000 Brussels, Belgium. [Journe, Fabrice] Univ Libre Bruxelles, Inst Jules Bordet, Lab Oncol & Expt Surg, B-1000 Brussels, Belgium. [Duvillier, Hughes] Univ Libre Bruxelles, Inst Jules Bordet, Dept Flow Cytometry, B-1000 Brussels, Belgium. [Dekoninck, Sophie; Blanpain, Cedric] Inst Jules Bordet, Interdisciplinary Res Inst IRIBHM, B-1000 Brussels, Belgium. [Lagneaux, Laurence] Inst Jules Bordet, Dept Expt Hematol, B-1000 Brussels, Belgium. [Larsimont, Denis] Inst Jules Bordet, Dept Pathol, B-1000 Brussels, Belgium. [Piccart, Martine; Sotiriou, Christos] Inst Jules Bordet, Dept Med Oncol, B-1000 Brussels, Belgium. [Haibe-Kains, Benjamin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Computat Biol & Funct Genom Lab,Ctr Canc Computat, Boston, MA 02115 USA. [Houhou, Nawal; Delorenzi, Mauro] CHU Vaudois, Dept Format & Rech, CH-1011 Lausanne, Switzerland. RP Desmedt, C (reprint author), Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab JC Heuson, 125 Bld Waterloo, B-1000 Brussels, Belgium. EM christine.desmedt@bordet.be RI Michiels, Stefan/L-1516-2013; Loi, Sherene/H-1979-2016; Haibe-Kains, Benjamin/D-3702-2011; OI Michiels, Stefan/0000-0002-6963-2968; Loi, Sherene/0000-0001-6137-9171; Haibe-Kains, Benjamin/0000-0002-7684-0079; Desmedt, Christine/0000-0002-5223-5579 FU MEDIC Foundation; Les Amis de l'Institut Bordet; Fonds National de la Recherche Scientifique; Brussels Region FX This project was supported by the MEDIC Foundation, Les Amis de l'Institut Bordet, the "Fonds National de la Recherche Scientifique," and the Brussels Region (Impulse Programme 2007). NR 36 TC 22 Z9 23 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2012 VL 18 IS 4 BP 1004 EP 1014 DI 10.1158/1078-0432.CCR-11-0383 PG 11 WC Oncology SC Oncology GA 897EO UT WOS:000300628100011 PM 22235100 ER PT J AU Chau, BN Xin, CY Hartner, J Ren, SY Castano, AP Linn, G Li, J Tran, PT Kaimal, V Huang, XQ Chang, AN Li, SY Kalra, A Grafals, M Portilla, D MacKenna, DA Orkin, SH Duffield, JS AF Chau, B. Nelson Xin, Cuiyan Hartner, Jochen Ren, Shuyu Castano, Ana P. Linn, Geoffrey Li, Jian Tran, Phong T. Kaimal, Vivek Huang, Xinqiang Chang, Aaron N. Li, Shenyang Kalra, Aarti Grafals, Monica Portilla, Didier MacKenna, Deidre A. Orkin, Stuart H. Duffield, Jeremy S. TI MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; MEMBRANE-PROTEIN; OXIDATIVE STRESS; PEROXISOME PROLIFERATORS; MPV17-LIKE PROTEIN; ENERGY-METABOLISM; EXPRESSION DATA; RENAL FIBROSIS; INJURY; MICE AB Scarring of the kidney is a major public health concern, directly promoting loss of kidney function. To understand the role of microRNA (miRNA) in the progression of kidney scarring in response to injury, we investigated changes in miRNA expression in two kidney fibrosis models and identified 24 commonly up-regulated miRNAs. Among them, miR-21 was highly elevated in both animal models and in human transplanted kidneys with nephropathy. Deletion of miR-21 in mice resulted in no overt abnormality. However, miR-21(-/-) mice suffered far less interstitial fibrosis in response to kidney injury, a phenotype duplicated in wild-type mice treated with anti-miR-21 oligonucleotides. Global derepression of miR-21 target mRNAs was readily detectable in miR-21(-/-) kidneys after injury. Analysis of gene expression profiles up-regulated in the absence of miR-21 identified groups of genes involved in metabolic pathways, including the lipid metabolism pathway regulated by peroxisome proliferator-activated receptor-alpha (Ppar alpha), a direct miR-21 target. Overexpression of Ppar alpha prevented ureteral obstruction-induced injury and fibrosis. Ppar alpha deficiency abrogated the antifibrotic effect of anti-miR-21 oligonucleotides. miR-21 also regulated the redox metabolic pathway. The mitochondrial inhibitor of reactive oxygen species generation Mpv17l was repressed by miR-21, correlating closely with enhanced oxidative kidney damage. These studies demonstrate that miR-21 contributes to fibrogenesis and epithelial injury in the kidney in two mouse models and is a candidate target for antifibrotic therapies. C1 [Chau, B. Nelson; Li, Jian; Tran, Phong T.; Kaimal, Vivek; Huang, Xinqiang; Chang, Aaron N.; MacKenna, Deidre A.] Regulus Therapeut, San Diego, CA 92121 USA. [Xin, Cuiyan; Ren, Shuyu; Linn, Geoffrey; Duffield, Jeremy S.] Univ Washington, Div Nephrol, Ctr Lung Biol, Dept Med, Seattle, WA 98109 USA. [Xin, Cuiyan; Ren, Shuyu; Linn, Geoffrey; Duffield, Jeremy S.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98109 USA. [Hartner, Jochen; Orkin, Stuart H.] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02215 USA. [Hartner, Jochen; Castano, Ana P.; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Li, Shenyang; Portilla, Didier] Univ Arkansas Med Sci, Div Nephrol, Little Rock, AR 72205 USA. [Kalra, Aarti] Lahey Clin Med Ctr, Div Pathol, Burlington, MA 01805 USA. [Grafals, Monica] Lahey Clin Med Ctr, Div Transplantat, Burlington, MA 01805 USA. [Grafals, Monica] Tufts Univ, Boston, MA 02110 USA. RP Chau, BN (reprint author), Regulus Therapeut, San Diego, CA 92121 USA. EM nchau@regulusrx.com; jeremysd@u.washington.edu FU NIH [DK73299, DK84077, DK87389, DK75976]; Genzyme GRIP; University of Washington; Regulus Therapeutics; Veterans Affairs Merit Award FX Funding: The Duffield Lab is funded by NIH grants DK73299, DK84077, and DK87389; Genzyme GRIP Award; University of Washington; and a research agreement from Regulus Therapeutics. D. P. is funded by NIH grant DK75976 and a Veterans Affairs Merit Award. NR 58 TC 85 Z9 92 U1 3 U2 26 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 FEB 15 PY 2012 VL 4 IS 121 AR 121ra18 DI 10.1126/scitranslmed.3003205 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 898HR UT WOS:000300732600002 PM 22344686 ER PT J AU Wang, Y Shi, M Chung, KA Zabetian, CP Leverenz, JB Berg, D Srulijes, K Trojanowski, JQ Lee, VMY Siderowf, AD Hurtig, H Litvan, I Schiess, MC Peskind, ER Masuda, M Hasegawa, M Lin, XM Pan, C Galasko, D Goldstein, DS Jensen, PH Yang, H Cain, KC Zhang, J AF Wang, Yu Shi, Min Chung, Kathryn A. Zabetian, Cyrus P. Leverenz, James B. Berg, Daniela Srulijes, Karin Trojanowski, John Q. Lee, Virginia M. -Y. Siderowf, Andrew D. Hurtig, Howard Litvan, Irene Schiess, Mya C. Peskind, Elaine R. Masuda, Masami Hasegawa, Masato Lin, Xiangmin Pan, Catherine Galasko, Douglas Goldstein, David S. Jensen, Poul Henning Yang, Hui Cain, Kevin C. Zhang, Jing TI Phosphorylated alpha-Synuclein in Parkinson's Disease SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; MULTIPLE-SYSTEM ATROPHY; HUMAN CEREBROSPINAL-FLUID; RICHARDSONS-SYNDROME; CONSENSUS STATEMENT; ALZHEIMERS-DISEASE; PSP-PARKINSONISM; LEWY BODIES; DIAGNOSIS; NEURODEGENERATION AB Phosphorylated alpha-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson's disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total alpha-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of similar to 600 samples). PS-129 CSF concentrations correlated weakly with PD severity and, when combined with total alpha-synuclein concentrations in CSF, contributed to distinguishing PD from MSA and PSP. Further rigorous validation in independent cohorts of patients, especially those where samples have been collected longitudinally, will determine whether the concentration of PS-129 in CSF will be useful for diagnosing PD and for monitoring PD severity and progression. C1 [Wang, Yu; Shi, Min; Lin, Xiangmin; Pan, Catherine; Yang, Hui; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Wang, Yu] Huazhong Univ Sci & Technol, Dept Neurosurg, Tongji Hosp, Tongji Med Coll, Wuhan 430030, Hubei, Peoples R China. [Chung, Kathryn A.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Zabetian, Cyrus P.] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. [Zabetian, Cyrus P.; Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98104 USA. [Leverenz, James B.; Peskind, Elaine R.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98105 USA. [Leverenz, James B.; Peskind, Elaine R.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Berg, Daniela; Srulijes, Karin] Univ Tubingen, Dept Neurodegenerat, Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany. [Berg, Daniela; Srulijes, Karin] Univ Tubingen, German Ctr Neurodegenerat Dis, D-72076 Tubingen, Germany. [Trojanowski, John Q.; Lee, Virginia M. -Y.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Inst Aging,Ctr Neurodegenerat Dis Res, Philadelphia, PA 19104 USA. [Siderowf, Andrew D.; Hurtig, Howard] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19107 USA. [Litvan, Irene] Univ Louisville, Sch Med, Div Movement Disorders, Louisville, KY 40202 USA. [Schiess, Mya C.] Univ Texas Hlth Sci Ctr, Dept Neurol, Houston, TX 77030 USA. [Masuda, Masami; Hasegawa, Masato] Tokyo Metropolitan Inst Med Sci, Dept Neuropathol & Cell Biol, Setagaya Ku, Tokyo 1568585, Japan. [Goldstein, David S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Goldstein, David S.] NINDS, Clin Neurocardiol Sect, Community Networks Program, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Jensen, Poul Henning] Aarhus Univ, Dept Med Chem, DK-8000 Aarhus C, Denmark. [Cain, Kevin C.] Univ Washington, Dept Biostat, Seattle, WA 98105 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. EM zhangj@uw.edu RI Shi, Min/G-6165-2012; OI Shi, Min/0000-0002-6901-2558; , xiangmin/0000-0001-9128-689X FU NIH [AG025327, AG033398, ES004696-5897, ES007033-6364, NS057567, NS060252, NS062684, NS065070, NS053488]; Lundbeck Foundation; European Community [241791]; Avid Radiopharmaceuticals FX Funding: The investigation was supported by the NIH (grants AG025327, AG033398, ES004696-5897, ES007033-6364, NS057567, and NS060252 to J.Z.; NS062684 to J.Z., C. P.Z., and J.B.L.; NS065070 to C. P.Z.; and NS053488 to J.Q.T., V.M.-Y.L., and A. D. S.), the Lundbeck Foundation, and the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 241791 (to P.H.J.).; Competing interests: A. D. S. serves as a consultant for Teva Neuroscience and has grant support from Avid Radiopharmaceuticals not related to this investigation. J.B.L. serves as a consultant for Bayer, Novartis, and Teva Neuroscience. The other authors declare that they have no competing interests. NR 32 TC 30 Z9 30 U1 2 U2 19 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 15 PY 2012 VL 4 IS 121 AR 121ra20 DI 10.1126/scitranslmed.3002566 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 898HR UT WOS:000300732600004 PM 22344688 ER PT J AU Yue, XM Biederman, I Mangini, MC von der Malsburg, C Amir, O AF Yue, Xiaomin Biederman, Irving Mangini, Michael C. von der Malsburg, Christoph Amir, Ori TI Predicting the psychophysical similarity of faces and non-face complex shapes by image-based measures SO VISION RESEARCH LA English DT Article DE Scaling shape similarity; Face discrimination; Gabor filtering; Shape discriminability ID LATERAL OCCIPITAL COMPLEX; HUMAN EXTRASTRIATE CORTEX; INFERIOR TEMPORAL CORTEX; OBJECT RECOGNITION; VISUAL AWARENESS; VIEWPOINT INVARIANCE; FEATURES; AREA; ARCHITECTURE; RESPONSES AB Shape representation is accomplished by a series of cortical stages in which cells in the first stage (V1) have local receptive fields tuned to contrast at a particular scale and orientation, each well modeled as a Gabor filter. In succeeding stages, the representation becomes largely invariant to Gabor coding (Kobatake & Tanaka, 1994). Because of the non-Gabor tuning in these later stages, which must be engaged for a behavioral response (Tong, 2003; Tong et al., 1998), a V1-based measure of shape similarity based on Gabor filtering would not be expected to be highly correlated with human performance when discriminating complex shapes (faces and teeth-like blobs) that differ metrically on a two-choice, match-to-sample task. Here we show that human performance is highly correlated with Gabor-based image measures (Gabor simple and complex cells), with values often in the mid 0.90s, even without discounting the variability in the speed and accuracy of performance not associated with the similarity of the distractors. This high correlation is generally maintained through the stages of HMAX, a model that builds upon the Gabor metric and develops units for complex features and larger receptive fields. This is the first report of the psychophysical similarity of complex shapes being predictable from a biologically motivated, physical measure of similarity. As accurate as these measures were for accounting for metric variation, a simple demonstration showed that all were insensitive to viewpoint invariant (nonaccidental) differences in shape. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Yue, Xiaomin] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Biederman, Irving; Amir, Ori] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Biederman, Irving; Amir, Ori] Univ So Calif, Neurosci Program, Los Angeles, CA 90089 USA. [Mangini, Michael C.] Concordia Coll, Dept Psychol, Morehead, MN 56562 USA. [von der Malsburg, Christoph] Frankfurt Inst Adv Studies, D-60438 Frankfurt, Germany. RP Yue, XM (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM xiaomin@nmr.mgh.harvard.edu FU National Science Foundation [0531177, 0617699] FX This work was supported by the National Science Foundation Grant numbers 0531177 and 0617699 to I.B. We thank Bosco Tjan for helpful discussions. NR 31 TC 13 Z9 13 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD FEB 15 PY 2012 VL 55 BP 41 EP 46 DI 10.1016/j.visres.2011.12.012 PG 6 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 899GK UT WOS:000300804200006 PM 22248730 ER PT J AU Yeo, KK Li, S Amsterdam, EA Wang, TY Bhatt, DL Saucedo, JF Kontos, MC Roe, MT French, WJ AF Yeo, Khung Keong Li, Shuang Amsterdam, Ezra A. Wang, Tracy Y. Bhatt, Deepak L. Saucedo, Jorge F. Kontos, Michael C. Roe, Matthew T. French, William J. TI Comparison of Clinical Characteristics, Treatments and Outcomes of Patients With ST-Elevation Acute Myocardial Infarction With Versus Without New or Presumed New Left Bundle Branch Block (from NCDR (R)) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY DISEASE; ACUTE HEART-FAILURE; MORTALITY; TROPONIN; THERAPY AB Guidelines recommend urgent reperfusion for patients with new left bundle branch block (LBBB), similar to patients with ST-segment elevation myocardial infarction (STEMI). However, there are limited contemporary data comparing these 2 groups of patients. Patients presenting with acute STEMI or presumed new LBBB (nLBBB) enrolled in the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry Get With the Guidelines (GWTG) from January 2007 to March 2009 were evaluated for clinical characteristics, treatment patterns, and outcomes. Logistic generalized estimating equation modeling was used to examine associated risk-adjusted mortality. Of 46,006 patients with either STEMI or nLBBB, 44,405 (96.5%) had STEMI, and 1,601 (3.5%) had nLBBB. Overall, patients with nLBBB had more baseline co-morbidities compared to those with STEMI. Compared to patients with STEMI, those with nLBBB were less likely to receive acute reperfusion (93.9% vs 48.3% p < 0.0001) and were less likely to have door-to-balloon times <= 90 minutes (76.8% vs 34.5%, p < 0.0001). Mortality rates were higher for patients with nLBBB compared to those with STEMI (13.3% vs 5.6%, p < 0.0001). After multivariate adjustment, nLBBB was not associated with an increased risk for in-hospital mortality (odds ratio 0.91, 95% confidence interval 0.75 to 1.12, p = 0.38). In conclusion, patients with nLBBB were clinically different from those with STEMI, with significantly more co-morbidities, and were less likely to receive emergent reperfusion therapy. Despite these differences, adjusted mortality rates were similar between patients with nLBBB and those with STEMI. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:497-501) C1 [French, William J.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Yeo, Khung Keong; Amsterdam, Ezra A.] Univ Calif Davis, Davis Med Ctr, Sacramento, CA 95817 USA. [Li, Shuang; Wang, Tracy Y.; Roe, Matthew T.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Saucedo, Jorge F.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Kontos, Michael C.] Virginia Commonwealth Univ, Richmond, VA USA. RP French, WJ (reprint author), Harbor UCLA Med Ctr, Torrance, CA 90509 USA. EM wjfrench@ucla.edu FU Society of Chest Pain Centers, Dublin, Ohio; American College of Emergency Physicians, Irving, Texas; Society of Hospital Medicine, Philadelphia, Pennsylvania; Bristol-Myers Squibb/Sanofi Pharmaceuticals; American College of Cardiology Foundation's National Cardiovascular Data Registry; Bristol-Myers Squibb/Sanofi; Schering Plough, Kenilworth, New Jersey; Medicines Company, Parsippany, New Jersey; Heartscape Technologies, Bothell, Washington; Canyon Pharmaceuticals, Columbia, Maryland; Eli Lilly/Daiichi Sankyo Alliance; AstraZeneca, Wilmington, Delaware; Bristol-Myers Squibb, New York, New York; Eisai, Research Triangle Park, North Carolina; Ethicon, Blue Ash, Ohio; Medtronic, Minneapolis, Minnesota; Sanofi-Aventis, Paris, France; Medicines Company; AstraZeneca; Bristol-Myers Squibb; Sanofi-Aventis; Eli Lilly & Company, Indianapolis, Indiana; Merck/Schering-Plough, Whitehouse Station, New Jersey; Abbott Laboratories, Abbott Park, Illinois; Eli Lilly Company; Merck/Schering-Plough; GlaxoSmithKline, London, United Kingdom; Novartis AG, Basel, Switzerland FX ACTION Registry-GWTG is an initiative of the American College of Cardiology Foundation, Bethesda, Maryland, and the American Heart Association, Dallas, Texas, with partnering support from the Society of Chest Pain Centers, Dublin, Ohio, the American College of Emergency Physicians, Irving, Texas, and the Society of Hospital Medicine, Philadelphia, Pennsylvania. The registry is sponsored in part by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. This research was supported by the American College of Cardiology Foundation's National Cardiovascular Data Registry. The views expressed in this report represent those of the authors and do not necessarily represent the official views of the National Cardiovascular Data Registry or its associated professional societies, identified at http://www.ncdr.com.; Dr. Wang has received research support from Bristol-Myers Squibb/Sanofi Partnership; Schering Plough, Kenilworth, New Jersey; The Medicines Company, Parsippany, New Jersey; Heartscape Technologies, Bothell, Washington; Canyon Pharmaceuticals, Columbia, Maryland; and Eli Lilly/Daiichi Sankyo Alliance. Dr. Bhatt has received institutional research support from AstraZeneca, Wilmington, Delaware; Bristol-Myers Squibb, New York, New York; Eisai, Research Triangle Park, North Carolina; Ethicon, Blue Ash, Ohio; Medtronic, Minneapolis, Minnesota; Sanofi-Aventis, Paris, France; and The Medicines Company. Dr. Saucedo has received institutional research support from AstraZeneca; Bristol-Myers Squibb; Sanofi-Aventis; The Medicines Company; Eli Lilly & Company, Indianapolis, Indiana; Merck/Schering-Plough, Whitehouse Station, New Jersey; and Abbott Laboratories, Abbott Park, Illinois. Dr. Kontos is a member of the speakers bureaus of and is a consultant for Sanofi-Aventis and Astellas Pharma, Deerfield, Illinois. Dr. Roe has received research funding from Eli Lilly & Company, Bristol-Myers Squibb, Sanofi-Aventis, and Merck/Schering-Plough. Dr. Roe has received consulting fees or honoraria from GlaxoSmithKline, London, United Kingdom; Novartis AG, Basel, Switzerland; Eli Lilly & Company; Bristol-Myers Squibb; Sanofi-Aventis; Merck/Schering-Plough, and AstraZeneca. NR 11 TC 10 Z9 10 U1 0 U2 0 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 FEB 15 PY 2012 VL 109 IS 4 BP 497 EP 501 DI 10.1016/j.amjcard.2011.09.040 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896SO UT WOS:000300591900009 PM 22152973 ER PT J AU Rienstra, M Sun, JX Magnani, JW Sinner, MF Lubitz, SA Sullivan, LM Ellinor, PT Benjamin, EJ AF Rienstra, Michiel Sun, Jenny X. Magnani, Jared W. Sinner, Moritz F. Lubitz, Steven A. Sullivan, Lisa M. Ellinor, Patrick T. Benjamin, Emelia J. TI White Blood Cell Count and Risk of Incident Atrial Fibrillation (From the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; CARDIOTHORACIC SURGERY; LEUKOCYTE COUNT; STATIN THERAPY; MORTALITY; INFLAMMATION; ASSOCIATION; PREDICTOR; COHORT AB Several studies have reported that inflammatory markers are associated with atrial fibrillation (AF). The white blood cell (WBC) count is a widely available and broadly used marker of systemic inflammation. We sought to investigate the association between an increased WBC count and incident AF and whether this association is mediated by smoking, myocardial infarction, and heart failure. We examined the participants in the Framingham Heart Study original cohort. Cox proportional hazard regression analysis was used to examine the relation between the WBC count and incident AF during a 5-year follow-up period. We adjusted for standard AF risk factors, smoking, previous myocardial infarction, and interim myocardial infarction and heart failure before the incident AF. Our sample consisted of 936 participants (mean age 76 +/- 6 years and 61% women). The median WBC count was 6.4 x 10(9)/L (25th to 75th percentile 5.6 x 10(9)/L to 7.8 x 10(9)/L). During a median 5-year follow-up period, 82 participants (9%) developed new-onset AF. After adjusting for standard risk factors for AF, an increased WBC count was significantly associated with incident AF, with a hazard ratio per SD (0.26 x 10(9)/L) increase of 2.22 (95% confidence interval 1.10 to 4.48; p = 0.03). We found no substantive differences adjusting for smoking, previous myocardial infarction, interim myocardial infarction, or heart failure. In conclusion, in our community-based sample, an increased WBC count was associated with incident AF during 5 years of follow-up. Our findings provide additional evidence for the relation between systemic inflammation and AF. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:533-537) C1 [Rienstra, Michiel; Magnani, Jared W.; Sinner, Moritz F.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rienstra, Michiel; Magnani, Jared W.; Sinner, Moritz F.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Rienstra, Michiel; Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Rienstra, Michiel] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Sun, Jenny X.; Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Sinner, Moritz F.] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM emelia@bu.edu OI Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195]; Boston University School of Medicine, Boston, Massachusetts; Netherlands Organization for Scientific Research, The Hague, The Netherlands [825.09.020]; American Heart Association (Dallas, Texas) [09FTF2190028]; German Heart Foundation (Frankfurt, Germany); National Institutes of Health, Bethesda, Maryland [1R01 HL092577, 1RC1HL101056, 1R01HL102214, R01AG028321, 6R01-NS 17950, 5R21DA027021, 5RO1HL104156, 1K24HL105780]; Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative (Boston University, Boston, Massachusetts) FX The Framingham Heart Study is supported by grant N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland and by Boston University School of Medicine, Boston, Massachusetts. Dr. Rienstra is supported by Rubicon grant 825.09.020 from The Netherlands Organization for Scientific Research, The Hague, The Netherlands; Dr. Magnani is supported by American Heart Association Award 09FTF2190028 (Dallas, Texas). Dr. Sinner is supported by the German Heart Foundation (Frankfurt, Germany). This work was supported by grant 1R01 HL092577 from the National Institutes of Health, Bethesda, Maryland to Drs. Benjamin and Ellinor, grants 1RC1HL101056, 1R01HL102214, and R01AG028321 and support via grant 6R01-NS 17950 to Dr. Benjamin, and grants 5R21DA027021, 5RO1HL104156, 1K24HL105780 to Dr. Ellinor. This study was partially supported by the Evans Center for Interdisciplinary Biomedical Research ARC on Atrial Fibrillation Initiative (Boston University, Boston, Massachusetts). NR 32 TC 27 Z9 30 U1 0 U2 3 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 FEB 15 PY 2012 VL 109 IS 4 BP 533 EP 537 DI 10.1016/j.amjcard.2011.09.049 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 896SO UT WOS:000300591900016 PM 22100030 ER PT J AU Gore, JL Wright, JL Daratha, KB Roberts, KP Lin, DW Wessells, H Porter, M AF Gore, John L. Wright, Jonathan L. Daratha, Kenn B. Roberts, Kenneth P. Lin, Daniel W. Wessells, Hunter Porter, Michael TI Hospital-level variation in the quality of urologic cancer surgery SO CANCER LA English DT Article DE prostate carcinoma; kidney carcinoma; bladder carcinoma; quality of care ID OUTCOMES ASSESSMENT PROGRAM; RADICAL PROSTATECTOMY; BLADDER-CANCER; KIDNEY-CANCER; OPERATIVE MORTALITY; CYSTECTOMY; VOLUME; CARE; COMPLICATIONS AB BACKGROUND: Unexplained variation in outcomes after common surgeries raises concerns about the quality and appropriateness of surgical care. Understanding variation in surgical outcomes may identify processes that could affect the quality of surgical and postoperative care. The authors of this report examined hospital-level variation in outcomes after inpatient urologic oncology procedures. METHODS: Patients who underwent radical cystectomy, radical nephrectomy, and radical prostatectomy were identified from the Washington State Comprehensive Hospital Abstract Reporting System for the years 2003 through 2007. The postoperative length of stay (LOS) was measured, and LOS that exceeded the 75th percentile was classified as prolonged. The occurrence of Agency for Healthcare Quality patient safety indicators (PSIs), readmissions, and deaths also were measured. Analyses were adjusted for patient age and comorbidity in random effects, multilevel, multivariable models that assessed hospital-level outcomes. RESULTS: The authors identified 853 patients from 37 hospitals who underwent cystectomy, 3018 patients who underwent nephrectomy from 51 hospitals, and 8228 patients who underwent prostatectomy from 51 hospitals. Complications captured by PSIs were rare. Hospital-level variation was most profound for LOS outcomes after nephrectomy and prostatectomy (variance in prolonged LOS, 8.1% and 26.7%, respectively), thromboembolic events after nephrectomy (8% of variance), and mortality after cystectomy (7.1% of variance). CONCLUSIONS: Hospital-level variation confounds the care of urologic cancer patients in the state of Washington. The authors concluded that transparent reporting of surgical outcomes and local quality-improvement initiatives should be considered to ameliorate the observed variation and improve the quality of cystectomy, nephrectomy, and prostatectomy care. Cancer 2012;118:987-96. Published 2011 by the American Cancer Society*. C1 [Gore, John L.; Wright, Jonathan L.; Lin, Daniel W.; Wessells, Hunter; Porter, Michael] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Wright, Jonathan L.; Lin, Daniel W.; Porter, Michael] Vet Affairs Puget Sound Hlth Care Syst, Div Urol, Seattle, WA USA. [Daratha, Kenn B.] Washington State Univ, Coll Nursing, Spokane, WA USA. [Roberts, Kenneth P.] Washington State Univ, Washington Wyoming Alaska Montana Idaho WWAMI Med, Spokane, WA USA. RP Gore, JL (reprint author), Univ Washington, Sch Med, Dept Urol, 1959 NE Pacific St,Box 356510, Seattle, WA 98195 USA. EM jlgore@u.washington.edu RI Roberts, Ken/D-5701-2012; OI Gore, John/0000-0002-2847-5062 FU National Center for Research Resources, National Institutes of Health [UL1RR025014]; Veterans Affairs Puget Sound Health Care System, Seattle, Washington FX This work was supported by grant UL1RR025014 from the National Center for Research Resources, National Institutes of Health. This material also is the result of work supported in part by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. NR 32 TC 11 Z9 11 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2012 VL 118 IS 4 BP 987 EP 996 DI 10.1002/cncr.26373 PG 10 WC Oncology SC Oncology GA 886EF UT WOS:000299834300016 PM 21792864 ER PT J AU Patel, YR Carr, KA Magjuka, D Mohammadi, Y Dropcho, EF Reed, AD Moore, ML Waddell, MJ Shedd-Steele, R Sweeney, CJ Hahn, NM AF Patel, Yash R. Carr, Katherine A. Magjuka, David Mohammadi, Yousef Dropcho, Edward F. Reed, Angela D. Moore, Marietta L. Waddell, Mary Jane Shedd-Steele, Rivienne Sweeney, Christopher J. Hahn, Noah M. TI Successful recruitment of healthy African American men to genomic studies from high-volume community health fairs SO CANCER LA English DT Article DE African American; genomic research; healthy population; demographics; community health fairs ID PROSTATE-SPECIFIC ANTIGEN; DIGITAL RECTAL EXAMINATION; MARITAL STABILITY; RACIAL-DIFFERENCES; CANCER STATISTICS; CHURCH ATTENDANCE; CLINICAL-TRIALS; MARRIAGE; RACE; PARTICIPATION AB BACKGROUND: Study of genomic data obtained from patient biospecimens is frequent in research of subjects with prostate and other epithelial malignancies. Understanding of the characteristics of healthy men who participate in genomic research is limited. METHODS: Patients were identified through the Prostate Cancer Genetic Risk Evaluation of SNPs Study and the Indiana University Cancer Biomarker Study, 2 population-based biomarker and cohort studies. Between 2006 and 2010, healthy Caucasian (n = 774) and healthy African American (n 381) men were recruited and enrolled at high-volume free community health fairs. Each participant completed a demographic questionnaire and provided a blood sample for genomic research investigations. Frequency differences between demographic features of healthy African American and Caucasian men were compared and analyzed by 2-sample t test and multivariate logistic regression after adjusting potential confounding variables with significance at the P <. 05 level. Features examined included: age, body mass index (BMI), income, education, marital status, tobacco, alcohol, family history, prostate-specific antigen (PSA) level, and prior prostate cancer screening history. RESULTS: Significant differences between healthy Caucasian and African American men participating in genomic research included: marital status (married, 69% Caucasian vs 46% African American, P <<. 001), mean age (years, 58 Caucasian vs 54 African American, P <. 001), mean BMI (kg/m(2), 30.9 Caucasian vs 32.3 African American, P = .004), annual income (P = .038), education (P = .002), and mean PSA (ng/mL, 1.2 Caucasian vs 2.0 African American, P = .005). CONCLUSIONS: Significant demographic differences exist between healthy Caucasian and African American men choosing to participate in genomic research. These differences may be important in designing genomic research study recruitment strategies. Cancer 2012;118:1075-82. (C) 2011 American Cancer Society. C1 [Patel, Yash R.; Carr, Katherine A.; Magjuka, David; Mohammadi, Yousef; Dropcho, Edward F.; Reed, Angela D.; Moore, Marietta L.; Waddell, Mary Jane; Shedd-Steele, Rivienne; Sweeney, Christopher J.; Hahn, Noah M.] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46202 USA. [Sweeney, Christopher J.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hahn, NM (reprint author), Indiana Univ, Melvin & Bren Simon Canc Ctr, Indiana Canc Pavil Room RT445,535 Barnhill Dr, Indianapolis, IN 46202 USA. EM nhahn@iupui.edu FU Walther Cancer Research Institute; Clarian Health Partners; Indiana University School of Medicine FX Supported by grant funding from the Walther Cancer Research Institute and Clarian Health Partners, and institutional research support from the Indiana University School of Medicine. NR 49 TC 1 Z9 1 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD FEB 15 PY 2012 VL 118 IS 4 BP 1075 EP 1082 DI 10.1002/cncr.26328 PG 8 WC Oncology SC Oncology GA 886EF UT WOS:000299834300026 PM 21766294 ER PT J AU Friedl, P Hubbell, J Livingston, D Mihich, E AF Friedl, Peter Hubbell, Jeff Livingston, David Mihich, Enrico TI Twenty-Third Annual Pezcoller Symposium: Engineering Influences in Cancer Research SO CANCER RESEARCH LA English DT Editorial Material AB The cross-disciplinary focus of the meeting highlighted recent progress in physical and genetic analysis and engineering of cancer disease models. As the central theme, mechanical forces affecting cell signaling, growth, differentiation, and metastasis were discussed with emphasis on the tumor microenvironment and cellular immunity, taking into account novel nanotechnology, biosensing, and intravital microscopy tools to monitor animal cancer models and human cancer. Emerging themes were the role of extracellular matrix imposing mechanical mechanisms on tumor cell function, including microenvironmental cues controlling the movement of tumor and immune cells, advanced genetic animal models for cancer that better recapitulate human disease, and preclinical and clinical molecular imaging of tumor architecture and stiffness, as well as novel nanotechnologies for anticancer drug delivery. Cancer Res; 72(4); 841-4. (C) 2012 AACR. C1 [Livingston, David; Mihich, Enrico] Dana Farber Canc Inst, Boston, MA 02115 USA. [Friedl, Peter] NCMLS, Nijmegen, Netherlands. [Hubbell, Jeff] Ecole Polytech Fed Lausanne, CH-1015 Lausanne, Switzerland. RP Mihich, E (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM enrico_mihich@dfci.harvard.edu RI Hubbell, Jeffrey/A-9266-2008; Friedl, Peter/A-8961-2010 OI Hubbell, Jeffrey/0000-0003-0276-5456; NR 0 TC 1 Z9 1 U1 1 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 FEB 15 PY 2012 VL 72 IS 4 BP 841 EP 844 DI 10.1158/0008-5472.CAN-11-3080 PG 4 WC Oncology SC Oncology GA 897ET UT WOS:000300629100003 PM 22237623 ER PT J AU Flynn, RL Chang, S Zou, L AF Flynn, Rachel Litman Chang, Sandy Zou, Lee TI RPA and POT1 Friends or foes at telomeres? SO CELL CYCLE LA English DT Article DE RPA; POT1; telomere; ATR; checkpoint ID SINGLE-STRANDED-DNA; REPLICATION PROTEIN-A; ABERRANT HOMOLOGOUS RECOMBINATION; REPEAT-CONTAINING RNA; FISSION YEAST; MAMMALIAN TELOMERES; BINDING-PROTEIN; CHROMOSOME ENDS; BREAK REPAIR; CELL-CYCLE AB Telomere maintenance in cycling cells relies on both DNA replication and capping by the protein complex shelterin. Two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomere 1 (POT1) play critical roles in DNA replication and telomere capping, respectively. While RPA binds to ssDNA in a non-sequence-specific manner, POT1 specifically recognizes single-stranded TTAGGG telomeric repeats. Loss of POT1 leads to aberrant accumulation of RPA at telomeres and activation of the ataxia telangiectasia and Rad3-related kinase (ATR)-mediated checkpoint response, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. The requirement for both POT1 and RPA in telomere maintenance and the antagonism between the two proteins raises the important question of how they function in concert on telomeric ssDNA. Two interesting models were proposed by recent studies to explain the regulation of POT1 and RPA at telomeres. Here, we discuss how these models help unravel the coordination, and also the antagonism, between POT1 and RPA during the cell cycle. C1 [Flynn, Rachel Litman; Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Zou, Lee] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chang, Sandy] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. RP Zou, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM zou.lee@mgh.harvard.edu FU ACS [0902501]; NIH [CA129037, GM076388] FX R.L.F. is supported the ACS fellowship 0902501. S.C. is supported by the NIH grant CA129037. L.Z. is supported by the NIH grant GM076388. L.Z. is the Jim and Ann Orr MGH Research Scholar and a Scholar of the Ellison Medical Foundation. NR 50 TC 8 Z9 8 U1 0 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2012 VL 11 IS 4 BP 652 EP 657 DI 10.4161/cc.11.4.19061 PG 6 WC Cell Biology SC Cell Biology GA 897CY UT WOS:000300621400013 PM 22373525 ER PT J AU Coon, TA Glasser, JR Mallampalli, RK Chen, BB AF Coon, Tiffany A. Glasser, Jennifer R. Mallampalli, Rama K. Chen, Bill B. TI Novel E3 ligase component FBXL7 ubiquitinates and degrades Aurora A, causing mitotic arrest SO CELL CYCLE LA English DT Article DE F-box protein; centrosome; mitosis; Aurora A ID SPINDLE ASSEMBLY CHECKPOINT; F-BOX PROTEINS; HUMAN-CELLS; REGULATORY ENZYME; B DEGRADATION; IDENTIFICATION; MITOSIS; CANCER; CYTOKINESIS; ANEUPLOIDY AB Aurora family kinases play pivotal roles in several steps during mitosis. Specifically, Aurora A kinase is an important regulator of bipolar mitotic spindle formation and chromosome segregation. Like other members of the Aurora family, Aurora A kinase is also regulated by post-translational modifications. Here, we show that a previously undescribed E3 ligase component belonging to the SCF (Skp-Cullin1-F-box protein) E3 ligase family, SCFFBXL7, impairs cell proliferation by mediating Aurora A polyubiquitination and degradation. Both Aurora A and FBXL7 co-localize within the centrosome during spindle formation. FBXL7 ectopic expression led to G(2)/M phase arrest in transformed epithelia, resulting in the appearance of tetraploidy and mitotic arrest with circular monopolar spindles and multipolar spindle formation. Interestingly, FBXL7 specifically interacts with Aurora A during mitosis but not in interphase, suggesting a regulatory role for FBXL7 in controlling Aurora A abundance during mitosis. C1 [Coon, Tiffany A.; Glasser, Jennifer R.; Mallampalli, Rama K.; Chen, Bill B.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15260 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Chen, BB (reprint author), Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15260 USA. EM chenb@upmc.edu FU US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development; US Department of Veterans Affairs; National Institutes of Health [HL096376, HL097376, HL098174] FX This material is based upon work supported, in part, by the US Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. This work was supported by a Merit Review Award from the US Department of Veterans Affairs and National Institutes of Health R01 grants HL096376, HL097376 and HL098174 (to R.K.M.). The contents presented do not represent the views of the Department of Veterans Affairs or the United States Government. NR 40 TC 18 Z9 20 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2012 VL 11 IS 4 BP 721 EP 729 DI 10.4161/cc.11.4.19171 PG 9 WC Cell Biology SC Cell Biology GA 897CY UT WOS:000300621400022 PM 22306998 ER PT J AU Trowbridge, JJ Sinha, AU Zhu, N Li, MJ Armstrong, SA Orkin, SH AF Trowbridge, Jennifer J. Sinha, Amit U. Zhu, Nan Li, Mingjie Armstrong, Scott A. Orkin, Stuart H. TI Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains SO GENES & DEVELOPMENT LA English DT Article DE DNA methylation; leukemia stem cell; Dnmt1; bivalent chromatin ID ACUTE MYELOID-LEUKEMIA; HEMATOPOIETIC STEM; H3K79 METHYLATION; DNA; CANCER; METHYLTRANSFERASE; GENES; HYPOMETHYLATION; PROGENITOR; PROFILES AB Epigenetic mechanisms regulating leukemia stem cells (LSCs) are an attractive target for therapy of blood cancers. Here, we report that conditional knockout of the DNA methyltransferase Dnmt1 blocked development of leukemia, and haploinsufficiency of Dnmt1 was sufficient to delay progression of leukemogenesis and impair LSC self-renewal without altering normal hematopoiesis. Haploinsufficiency of Dnmt1 resulted in tumor suppressor gene derepression associated with reduced DNA methylation and bivalent chromatin marks. These results suggest that LSCs depend on not only active expression of leukemogenic programs, but also DNA methylation-mediated silencing of bivalent domains to enforce transcriptional repression. C1 [Trowbridge, Jennifer J.; Sinha, Amit U.; Zhu, Nan; Li, Mingjie; Armstrong, Scott A.; Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol,Div Hemat, Childrens Hosp Boston,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol,Div Hemat, Childrens Hosp Boston,Harvard Stem Cell Inst, 44 Binney St, Boston, MA 02115 USA. EM orkin@bloodgroup.tch.harvard.edu FU Leukemia and Lymphoma Society; Children's Leukemia Research Foundation; ASH; NIH [CA105423]; GO [CA148222]; HSCI FX We thank members of the Orkin and Armstrong laboratories for helpful discussion, and John Daley, Suzan Lazo-Kallanian, and Rob Smith of the DFCI HemNeo Flow Facility. J.J.T. was supported by a fellowship from the Leukemia and Lymphoma Society, the Children's Leukemia Research Foundation, and ASH Scholar award. This work was supported by NIH U01 grant CA105423 (to S.H.O.), GO grant RC2 CA148222 (to S.H.O. and S. A. A.), and the HSCI blood program (S.H.O. and S. A. A.). S.H.O. is an Investigator of the HHMI. NR 25 TC 61 Z9 63 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2012 VL 26 IS 4 BP 344 EP 349 DI 10.1101/gad.184341.111 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 897EH UT WOS:000300626800005 PM 22345515 ER PT J AU Miles, WO Tschop, K Herr, A Ji, JY Dyson, NJ AF Miles, Wayne O. Tschoep, Katrin Herr, Anabel Ji, Jun-Yuan Dyson, Nicholas J. TI Pumilio facilitates miRNA regulation of the E2F3 oncogene SO GENES & DEVELOPMENT LA English DT Article DE cancer; E2F3; Pumilio; miRNA ID HUNCHBACK MESSENGER-RNA; GERMLINE STEM-CELLS; DROSOPHILA-MELANOGASTER; BLADDER-CANCER; TRANSLATIONAL REPRESSION; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTOR; BINDING PROTEINS; PUM2 GENES; S-PHASE AB E2F transcription factors are important regulators of cell proliferation and are frequently dysregulated in human malignancies. To identify novel regulators of E2F function, we used Drosophila as a model system to screen for mutations that modify phenotypes caused by reduced levels of dE2F1. This screen identified components of the Pumilio translational repressor complex (Pumilio, Nanos, and Brain tumor) as suppressors of dE2F1-RNAi phenotypes. Subsequent experiments provided evidence that Pumilio complexes repress dE2F1 levels and that this mechanism of post-transcriptional regulation is conserved in human cells. The human Pumilio homologs Pum 1 and Pum 2 repress the translation of E2F3 by binding to the E2F3 39 untranslated region (UTR) and also enhance the activity of multiple E2F3 targeting microRNAs (miRNAs). E2F3 is an oncogene with strong proliferative potential and is regularly dysregulated or overexpressed in cancer. Interestingly, Pumilio/miRNA-mediated regulation of E2F3 is circumvented in cancer cells in several different ways. Bladder carcinomas selectively downregulate miRNAs that cooperate with Pumilio to target E2F3, and multiple tumor cell lines shorten the 39 end of the E2F3 mRNA, removing the Pumilio regulatory elements. These studies suggest that Pumilio-miRNA repression of E2F3 translation provides an important level of E2F regulation that is frequently abrogated in cancer cells. C1 [Miles, Wayne O.; Tschoep, Katrin; Herr, Anabel; Ji, Jun-Yuan; Dyson, Nicholas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr,Lab Mol Oncol, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr,Lab Mol Oncol, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU National Institutes of Health (NIH) [R01GM053203] FX We thank Dr. Spyros Artanavis-Tsakonas for providing fly stocks. We also thank A. Gladden, A. Walker, H. Najafi-Shoushtari, S. Vasudevan, A. Naar, and J. Walker for careful reading of the manuscript, and all members of the Naar and Dyson laboratories for helpful comments and discussions. This work was supported by National Institutes of Health (NIH) grant R01GM053203 to N.J.D. N.J.D. is the Saltonstall Scholar of the Massachusetts General Hospital Cancer Center. NR 57 TC 42 Z9 46 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2012 VL 26 IS 4 BP 356 EP 368 DI 10.1101/gad.182568.111 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 897EH UT WOS:000300626800007 PM 22345517 ER PT J AU Yaroslavsky, AN Patel, R Salomatina, E Li, CQ Lin, C Al-Arashi, M Neel, V AF Yaroslavsky, Anna N. Patel, Rakesh Salomatina, Elena Li, Chunqiang Lin, Charles Al-Arashi, Munir Neel, Victor TI High-contrast mapping of basal cell carcinomas SO OPTICS LETTERS LA English DT Article ID NONMELANOMA SKIN CANCERS; CONFOCAL MICROSCOPY; POLARIZED-LIGHT; EXCISIONS; SURGERY AB Because of low optical contrast in the visible spectral range, accurate detection of basal cell carcinomas (BCC) remains a challenging problem. In this letter, we experimentally demonstrate that reflectance confocal imaging in the vicinity of 1300 nm can be used for the detection of BCC without exogenous contrast agents. We present high- contrast reflectance confocal images of thick fresh skin tissues with clearly delineated cancer and discuss possible reasons for causing decreased scattering of BCC. Comparison with histopathology confirms that tumors scatter less and exhibit lower pixel values in the images, as compared to benign skin structures. The results demonstrate the feasibility of real- time noninvasive detection of BCC using intrinsic differences in scattering between tumors and normal skin. (C) 2012 Optical Society of America C1 [Yaroslavsky, Anna N.; Patel, Rakesh] Univ Massachusetts, Lowell, MA 01854 USA. [Yaroslavsky, Anna N.; Salomatina, Elena; Li, Chunqiang; Lin, Charles; Al-Arashi, Munir; Neel, Victor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Yaroslavsky, AN (reprint author), Univ Massachusetts, Lowell, MA 01854 USA. EM Anna_Yaroslavsky@uml.edu NR 21 TC 6 Z9 6 U1 1 U2 4 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD FEB 15 PY 2012 VL 37 IS 4 BP 644 EP 646 PG 3 WC Optics SC Optics GA 898AF UT WOS:000300706500067 PM 22344134 ER PT J AU Morrow, WR Frazier, EA Mahle, WT Harville, TO Pye, SE Knecht, KR Howard, EL Smith, RN Saylors, RL Garcia, X Jaquiss, RDB Woodle, ES AF Morrow, William Robert Frazier, Elizabeth A. Mahle, William T. Harville, Terry O. Pye, Sherry E. Knecht, Kenneth R. Howard, Emily L. Smith, R. Neal Saylors, Robert L. Garcia, Xiomara Jaquiss, Robert D. B. Woodle, E. Steve TI Rapid Reduction in Donor-Specific Anti-Human Leukocyte Antigen Antibodies and Reversal of Antibody-Mediated Rejection With Bortezomib in Pediatric Heart Transplant Patients SO TRANSPLANTATION LA English DT Article DE Antibody-mediated rejection; Pediatric heart transplant; Donor-specific antibodies ID PANEL-REACTIVE ANTIBODY; PROTEASOME INHIBITOR BORTEZOMIB; VENTRICULAR ASSIST DEVICE; CORONARY-ARTERY-DISEASE; CARDIAC TRANSPLANTATION; HUMORAL REJECTION; CROSS-MATCH; ALLOGRAFT-REJECTION; PLASMAPHERESIS; THERAPY AB Background. High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce antihuman leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. Methods. Patients received four intravenous dose of bortezomib (1.3 mg/m(2)) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. Results. AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. Conclusions. Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA. C1 [Morrow, William Robert; Frazier, Elizabeth A.; Harville, Terry O.; Pye, Sherry E.; Knecht, Kenneth R.; Howard, Emily L.; Saylors, Robert L.; Garcia, Xiomara] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Cardiol Sect, Little Rock, AR 72205 USA. [Mahle, William T.] Childrens Healthcare Atlanta, Sibley Heart Ctr, Atlanta, GA USA. [Smith, R. Neal] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Jaquiss, Robert D. B.] Duke Univ, Sch Med, Dept Surg, Durham, NC USA. [Woodle, E. Steve] Univ Cincinnati, Dept Surg, Div Transplantat, Cincinnati, OH 45267 USA. RP Knecht, KR (reprint author), 1 Childrens Way,Slot 512-3, Little Rock, AR 72202 USA. EM krknecht@uams.edu FU NIAID NIH HHS [U19 AI102405] NR 37 TC 45 Z9 46 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD FEB 15 PY 2012 VL 93 IS 3 BP 319 EP 324 DI 10.1097/TP.0b013e31823f7eea PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 891CF UT WOS:000300193200019 PM 22179403 ER PT J AU LaRocque, RC Rao, SR Lee, J Ansdell, V Yates, JA Schwartz, BS Knouse, M Cahill, J Hagmann, S Vinetz, J Connor, BA Goad, JA Oladele, A Alvarez, S Stauffer, W Walker, P Kozarsky, P Franco-Paredes, C Dismukes, R Rosen, J Hynes, NA Jacquerioz, F McLellan, S Hale, D Sofarelli, T Schoenfeld, D Marano, N Brunette, G Jentes, ES Yanni, E Sotir, MJ Ryan, ET AF LaRocque, Regina C. Rao, Sowmya R. Lee, Jennifer Ansdell, Vernon Yates, Johnnie A. Schwartz, Brian S. Knouse, Mark Cahill, John Hagmann, Stefan Vinetz, Joseph Connor, Bradley A. Goad, Jeffery A. Oladele, Alawode Alvarez, Salvador Stauffer, William Walker, Patricia Kozarsky, Phyllis Franco-Paredes, Carlos Dismukes, Roberta Rosen, Jessica Hynes, Noreen A. Jacquerioz, Frederique McLellan, Susan Hale, DeVon Sofarelli, Theresa Schoenfeld, David Marano, Nina Brunette, Gary Jentes, Emily S. Yanni, Emad Sotir, Mark J. Ryan, Edward T. CA Global TravEpiNet Consortium TI Global TravEpiNet: A National Consortium of Clinics Providing Care to International Travelers-Analysis of Demographic Characteristics, Travel Destinations, and Pretravel Healthcare of High-Risk US International Travelers, 2009-2011 SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; SURVEILLANCE; DISEASES AB Background. International travel poses a risk of destination-specific illness and may contribute to the global spread of infectious diseases. Despite this, little is known about the health characteristics and pretravel healthcare of US international travelers, particularly those at higher risk of travel-associated illness. Methods. We formed a national consortium (Global TravEpiNet) of 18 US clinics registered to administer yellow fever vaccination. We collected data regarding demographic and health characteristics, destinations, purpose of travel, and pretravel healthcare from 13 235 international travelers who sought pretravel consultation at these sites from January 2009 through January 2011. Results. The destinations and itineraries of Global TravEpiNet travelers differed from those of the overall population of US international travelers. The majority of Global TravEpiNet travelers were visiting low-or lower-middle-income countries, and Africa was the most frequently visited region. Seventy-five percent of travelers were visiting malaria-endemic countries, and 38% were visiting countries endemic for yellow fever. Fifty-nine percent of travelers reported >= 1 medical condition. Atovaquone/proguanil was the most commonly prescribed antimalarial drug, and most travelers received an antibiotic for self-treatment of travelers' diarrhea. Hepatitis A and typhoid were the most frequently administered vaccines. Conclusions. Data from Global TravEpiNet provide insight into the characteristics and pretravel healthcare of US international travelers who are at increased risk of travel-associated illness due to itinerary, purpose of travel, or existing medical conditions. Improved understanding of this epidemiologically significant population may help target risk-reduction strategies and interventions to limit the spread of infections related to global travel. C1 [LaRocque, Regina C.] Massachusetts Gen Hosp, Div Infect Dis, Travelers Advice & Immunizat Ctr, Boston, MA 02114 USA. [LaRocque, Regina C.; Ryan, Edward T.] Harvard Univ, Sch Med, Boston, MA USA. [Rao, Sowmya R.; Schoenfeld, David] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Lee, Jennifer] NW Mem Hosp, Travel & Immunizat Ctr, Chicago, IL 60611 USA. [Ansdell, Vernon; Yates, Johnnie A.] Kaiser Permanente Honolulu, Travel Med Clin, Honolulu, HI USA. [Schwartz, Brian S.] Univ Calif San Francisco, Travel Med & Immunizat Clin, San Francisco, CA 94143 USA. [Knouse, Mark] Lehigh Valley Hlth Network, Allentown, PA USA. [Cahill, John] St Lukes Roosevelt, Travel & Immunizat Ctr, New York, NY USA. [Hagmann, Stefan] Albert Einstein Coll Med, Bronx Ctr Travel & Int Hlth, New York, NY USA. [Vinetz, Joseph] Univ Calif San Diego, Dept Med, Div Infect Dis, Travel Clin, La Jolla, CA 92093 USA. [Connor, Bradley A.] Cornell Univ, New York Ctr Travel & Trop Med, New York, NY 10021 USA. [Goad, Jeffery A.] Univ So Calif, Int Travel Med Clin, Los Angeles, CA USA. [Oladele, Alawode] DeKalb Cty Board Hlth Travel Serv, Decatur, GA USA. [Alvarez, Salvador] Mayo Clin, Jacksonville, FL 32224 USA. [Stauffer, William; Walker, Patricia] HealthPartners Travel Med Clin, St Paul, MN USA. [Kozarsky, Phyllis; Franco-Paredes, Carlos; Dismukes, Roberta] Emory Univ, Atlanta, GA 30322 USA. [Rosen, Jessica] Georgetown Univ, Washington, DC USA. [Hynes, Noreen A.] Johns Hopkins Sch Med, Div Infect Dis, Baltimore, MD USA. [Jacquerioz, Frederique; McLellan, Susan] Tulane Univ, New Orleans, LA 70118 USA. [Hale, DeVon; Sofarelli, Theresa] Univ Utah, Int Travel Clin, Salt Lake City, UT USA. [Marano, Nina; Brunette, Gary; Jentes, Emily S.; Yanni, Emad; Sotir, Mark J.] Ctr Dis Control & Prevent, Div Global Migrat & Quarantine, Atlanta, GA USA. RP LaRocque, RC (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Travelers Advice & Immunizat Ctr, GRJ 504,55 Fruit St, Boston, MA 02114 USA. EM rclarocque@partners.org OI Vinetz, Joseph/0000-0001-8344-2004 FU US Centers for Disease Control and Prevention (CDC) [U19CI000514, U01CK000175]; Salix Pharmaceuticals; Elsevier Publishing; Novartis Vaccines; GlaxoSmithKline; Merck FX This work was supported by grants from the US Centers for Disease Control and Prevention (CDC; U19CI000514 and U01CK000175).; B. A. C. has received grant support from Salix Pharmaceuticals, royalties from Elsevier Publishing, and payment for lectures from Novartis Vaccines, GlaxoSmithKline, and Salix Pharmaceuticals. J. A. G. has received payment for lectures from Merck. P. K. has consulted for Crucell Biologics, has received payment for lectures from GlaxoSmithKline, has received royalties from Elsevier Publishing, and has received an honorarium for the development of educational materials from Sanofi. All other authors report no potential conflicts. NR 19 TC 49 Z9 49 U1 0 U2 4 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 FEB 15 PY 2012 VL 54 IS 4 BP 455 EP 462 DI 10.1093/cid/cir839 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888YM UT WOS:000300040600003 PM 22144534 ER PT J AU Godinez-Puig, V Frangos, J Hollmann, TJ Dryden-Peterson, S Matulonis, U Lipworth, AD AF Godinez-Puig, Victoria Frangos, Jason Hollmann, Travis J. Dryden-Peterson, Scott Matulonis, Ursula Lipworth, Adam D. TI Rash in a Patient With Ovarian Cancer SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID CARCINOMA-ERYSIPELOIDES; BREAST; SKIN; METASTASIS; PAX8 C1 [Frangos, Jason; Lipworth, Adam D.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Godinez-Puig, Victoria] Univ Nacl Autonoma Mexico, Sch Med, Mexico City 04510, DF, Mexico. [Hollmann, Travis J.] Brigham & Womens Hosp, Dept Pathol, Div Dermatopathol, Boston, MA 02115 USA. [Dryden-Peterson, Scott] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Matulonis, Ursula] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Lipworth, AD (reprint author), Brigham & Womens Hosp, Dept Dermatol, 221 Longwood Ave, Boston, MA 02115 USA. EM alipworth@partners.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2012 VL 54 IS 4 BP 538 EP + DI 10.1093/cid/cir775 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888YM UT WOS:000300040600014 PM 22294566 ER PT J AU Ji, GX Gu, AH Wang, YB Huang, C Hu, F Zhou, Y Song, L Wang, XR AF Ji, Guixiang Gu, Aihua Wang, Yubang Huang, Cong Hu, Fan Zhou, Yong Song, Ling Wang, Xinru TI Genetic variants in antioxidant genes are associated with sperm DNA damage and risk of male infertility in a Chinese population SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Oxidative stress; Antioxidant genes; Polymorphisms; Male infertility; DNA fragmentation; 8-Hydroxydeoxyguanosine; Free radicals ID MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; HUMAN SPERMATOZOA; PREGNANCY LOSS; IN-VITRO; MEN; FRAGMENTATION; FERTILIZATION; SEMEN; OVEREXPRESSION AB To test the hypothesis that polymorphisms in antioxidant genes are more susceptible to sperm DNA damage and male infertility, we examined 11 single-nucleotide polymorphism from six antioxidant genes (GPX1, CA) PON1, NQO1, SOD2/MnSOD, and SOD3) in 580 infertility cases and 580 controls from a Chinese population-based case-control study (NJMU Infertility Study). Genotypes were determined using the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8-hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio and 95% confidence interval (CI) were estimated using unconditional logistic regression. The results indicated that the PON1 Arg192Glu (rs662) and SOD2 Val16Ala (rs4880) variant genotypes were associated with a significantly higher risk of male infertility. In addition, subjects carrying variant genotypes of both loci had a twofold (95% CI, 1.42-2.90) increase in the risk of male infertility, indicating a significant gene-gene interaction between these two loci (P for multiplicative interaction = 0.045). Moreover, linear regression analysis showed that individuals carrying the PON1 Arg192Glu (rs662) or SOD2 Val16Ala (rs4880) variants have significantly higher levels of sperm DNA fragmentation and 8-OHdG. These data suggest that genetic variations in antioxidant genes may contribute to oxidative sperm DNA damage and male infertility. (C) 2011 Elsevier Inc. All rights reserved. C1 [Ji, Guixiang; Gu, Aihua; Huang, Cong; Song, Ling; Wang, Xinru] Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing 210029, Jiangsu, Peoples R China. [Ji, Guixiang; Gu, Aihua; Huang, Cong; Song, Ling; Wang, Xinru] Nanjing Med Univ, Inst Toxicol, State Key Lab Reprod Med, Nanjing 210029, Jiangsu, Peoples R China. [Ji, Guixiang] Minist Environm Protect, Key Lab Pesticide Environm Assessment & Pollut Co, Nanjing Inst Environm Sci, Nanjing 210042, Jiangsu, Peoples R China. [Wang, Yubang] Nanjing Med Univ, Sch Publ Hlth, Safety Assessment & Res Ctr Drugs Jiangsu Prov, Nanjing 210029, Jiangsu, Peoples R China. [Hu, Fan] Nanjing Med Univ, Anal Ctr, Nanjing 210029, Jiangsu, Peoples R China. [Zhou, Yong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Gu, AH (reprint author), Nanjing Med Univ, Sch Publ Hlth, Minist Educ, Key Lab Modern Toxicol, Nanjing 210029, Jiangsu, Peoples R China. EM aihuagu@njmu.edu.cn; xrwang@njmu.edu.cn FU National Basic Research Program of China (973 Program) [2009CB941703, 2011CB944304]; National Natural Science Foundation of China [30930079]; National Science Foundation of China [81172694, 30901210]; Priority Academic Program Development of Jiangsu Higher Education Institutions FX This study was supported in part by the National Basic Research Program of China (973 Program, 2009CB941703 and 2011CB944304), The Key Project of the National Natural Science Foundation of China (30930079), and the National Science Foundation of China (Grant No. 81172694 and 30901210). This project was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. We thank C. Chen for statistical analysis. NR 50 TC 20 Z9 22 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2012 VL 52 IS 4 BP 775 EP 780 DI 10.1016/j.freeradbiomed.2011.11.032 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 886OF UT WOS:000299863000007 PM 22206979 ER PT J AU Thadhani, R Appelbaum, E Pritchett, Y Chang, YC Wenger, J Tamez, H Bhan, I Agarwal, R Zoccali, C Wanner, C Lloyd-Jones, D Cannata, J Thompson, BT Andress, D Zhang, WY Packham, D Singh, B Zehnder, D Shah, A Pachika, A Manning, WJ Solomon, SD AF Thadhani, Ravi Appelbaum, Evan Pritchett, Yili Chang, Yuchiao Wenger, Julia Tamez, Hector Bhan, Ishir Agarwal, Rajiv Zoccali, Carmine Wanner, Christoph Lloyd-Jones, Donald Cannata, Jorge Thompson, B. Taylor Andress, Dennis Zhang, Wuyan Packham, David Singh, Bhupinder Zehnder, Daniel Shah, Amil Pachika, Ajay Manning, Warren J. Solomon, Scott D. TI Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease The PRIMO Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LEFT-VENTRICULAR MASS; GLOMERULAR-FILTRATION-RATE; D-RECEPTOR ACTIVATION; LEFT ATRIAL VOLUME; CARDIOVASCULAR MAGNETIC-RESONANCE; RENIN-ANGIOTENSIN SYSTEM; HEART-FAILURE; D DEFICIENCY; RENAL-FUNCTION; 1,25-DIHYDROXYVITAMIN D-3 AB Context Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. Objective To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). Design, Setting, and Participants Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. Intervention Participants were randomly assigned to receive oral paricalcitol, 2 mu g/d (n=115), or matching placebo (n=112). Main Outcome Measures Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echo-cardiographic changes in left ventricular diastolic function. Results Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. Conclusion Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. C1 [Thadhani, Ravi; Wenger, Julia; Tamez, Hector; Bhan, Ishir] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Appelbaum, Evan; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Perfuse Cardiovasc Magnet Resonance Core Lab, Boston, MA 02215 USA. [Appelbaum, Evan; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Shah, Amil; Pachika, Ajay; Solomon, Scott D.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Andress, Dennis; Zhang, Wuyan; Pachika, Ajay] Abbott Labs, Abbott Pk, IL 60064 USA. [Agarwal, Rajiv] Indiana Univ Sch Med, Dept Med, Indianapolis, IN USA. [Zoccali, Carmine] Inst Biomed & Immunol Mol Alberto Monroy Clin Epi, Nephrol Dialysis & Transplantat Unit, Reggio Di Calabria, Italy. [Zoccali, Carmine] Inst Biomed & Immunol Mol Alberto Monroy Clin Epi, CNR, Reggio Di Calabria, Italy. [Wanner, Christoph] Univ Wurzburg, Univ Hosp, Dept Med, Div Nephrol, Wurzburg, Germany. [Lloyd-Jones, Donald] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Cannata, Jorge] Hosp Univ Cent Asturias, Inst Reina Sofia Invest, Serv Metab Oseo & Mineral, Inst Carlos III, Oviedo, Spain. [Packham, David] Royal Melbourne Hosp, Dept Nephrol, Reservoir Private Hosp, Melbourne Renal Res Grp, Melbourne, Vic 3050, Australia. [Packham, David] Austin Hosp, Dept Nephrol, Melbourne, Vic 3084, Australia. [Singh, Bhupinder] SW Kidney Inst, Tempe, AZ USA. [Zehnder, Daniel] Univ Warwick, Warwick Med Sch, Clin Sci Res Inst, Coventry CV4 7AL, W Midlands, England. RP Thadhani, R (reprint author), Massachusetts Gen Hosp, Dept Med, Div Nephrol, 55 Fruit St,Bulfinch 127, Boston, MA 02114 USA. EM thadhani.r@mgh.harvard.edu RI Lloyd-Jones, Donald/C-5899-2009; Solomon, Scott/I-5789-2013; Cannata-Andia, Jorge/L-2260-2013; OI Zoccali, Carmine/0000-0002-6616-1996 FU Abbott Laboratories; Pfizer; Roche FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Thadhani reported receiving a coordinating grant from Abbott Laboratories to the Massachusetts General Hospital and speaker's fees and travel support from Abbott Laboratories. Drs Pritchett, Andress, and Zhang are employees of Abbott Laboratories and may own Abbott stock or options. Dr Agarwal reported receiving honoraria for serving on the speaker's bureau and steering committees of Abbott Laboratories. Dr Zoccali reported receiving consulting/honorarium fees and travel support from Abbott Laboratories, honoraria for lectures from Genzyme, Roche, Amgen, Abbott Laboratories, and Malesci and research grants from Pfizer, Roche, and Abbott Laboratories. Drs Wanner and Packham serve on an advisory board and have received travel support from Abbott Laboratories. Dr Wanner has received research support and speakers fees from Abbott Laboratories. Dr Zehnder reported receiving honoraria for serving on a steering committee and for lectures from Abbott Laboratories and receiving grants from Abbott Laboratories. Dr Manning received travel support for a CMR meeting from Abbott Laboratories. Dr Solomon is supported by a research grant from Abbott Laboratories to the Brigham and Women's Hospital. No other disclosures were reported. NR 62 TC 208 Z9 218 U1 2 U2 18 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 FEB 15 PY 2012 VL 307 IS 7 BP 674 EP 684 DI 10.1001/jama.2012.120 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 892HY UT WOS:000300278500024 PM 22337679 ER PT J AU Imataki, O Ansen, S Tanaka, M Butler, MO Berezovskaya, A Milstein, MI Kuzushima, K Nadler, LM Hirano, N AF Imataki, Osamu Ansen, Sascha Tanaka, Makito Butler, Marcus O. Berezovskaya, Alla Milstein, Matthew I. Kuzushima, Kiyotaka Nadler, Lee M. Hirano, Naoto TI IL-21 Can Supplement Suboptimal Lck-Independent MAPK Activation in a STAT-3-Dependent Manner in Human CD8(+) T Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; MHC CLASS-I; ALPHA-3 DOMAIN MUTANTS; BETA-CHAIN; EFFECTOR FUNCTION; CTL ACTIVATION; TUMOR-ANTIGENS; REACTIVE CTL; AVIDITY; CORECEPTOR AB Although both MHC class II/CD8 alpha double-knockout and CD8 beta null mice show a defect in the development of MHC class I-restricted CD8(+) T cells in the thymus, they possess low numbers of high-avidity peripheral CTL with limited clonality and are able to contain acute and chronic infections. These in vivo data suggest that the CD8 coreceptor is not absolutely necessary for the generation of Ag-specific CTL. Lack of CD8 association causes partial TCR signaling because of the absence of CD8/Lck recruitment to the proximity of the MHC/TCR complex, resulting in suboptimal MAPK activation. Therefore, there should exist a signaling mechanism that can supplement partial TCR activation caused by the lack of CD8 association. In this human study, we have shown that CD8-independent stimulation of Ag-specific CTL previously primed in the presence of CD8 coligation, either in vivo or in vitro, induced severely impaired in vitro proliferation. When naive CD8(+) T cells were primed in the absence of CD8 binding and subsequently restimulated in the presence of CD8 coligation, the proliferation of Ag-specific CTL was also severely hampered. However, when CD8-independent T cell priming and restimulation were supplemented with IL-21, Ag-specific CD8(+) CTL expanded in two of six individuals tested. We found that IL-21 rescued partial MAPK activation in a STAT3- but not STAT1-dependent manner. These results suggest that CD8 coligation is critical for the expansion of postthymic peripheral Ag-specific CTL in humans. However, STAT3-mediated IL-21 signaling can supplement partial TCR signaling caused by the lack of CD8 association. The Journal of Immunology, 2012, 188: 1609-1619. C1 [Hirano, Naoto] Ontario Canc Inst, Immune Therapy Program, Campbell Family Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada. [Imataki, Osamu; Ansen, Sascha; Tanaka, Makito; Butler, Marcus O.; Berezovskaya, Alla; Milstein, Matthew I.; Nadler, Lee M.; Hirano, Naoto] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Imataki, Osamu; Ansen, Sascha; Tanaka, Makito; Butler, Marcus O.; Nadler, Lee M.; Hirano, Naoto] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [Kuzushima, Kiyotaka] Aichi Canc Ctr, Res Inst, Aichi 4648681, Japan. [Imataki, Osamu; Ansen, Sascha; Tanaka, Makito; Butler, Marcus O.; Nadler, Lee M.; Hirano, Naoto] Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA. [Hirano, Naoto] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Hirano, N (reprint author), Ontario Canc Inst, Immune Therapy Program, Campbell Family Inst Breast Canc Res, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM nhirano@uhnres.utoronto.ca FU National Institutes of Health [K22CA129240, R01CA148673]; Cancer Research Institute; American Society of Hematology FX This work was supported by National Institutes of Health Grants K22CA129240 and R01CA148673 (to N.H.). M.T., M.O.B., and L.M.N. were supported by funds from the Cancer Research Institute. N.H. was supported by the American Society of Hematology Scholar Award. NR 68 TC 8 Z9 8 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2012 VL 188 IS 4 BP 1609 EP 1619 DI 10.4049/jimmunol.1003446 PG 11 WC Immunology SC Immunology GA 890IT UT WOS:000300139000006 PM 22238455 ER PT J AU Yui, N Lu, HJ Bouley, R Brown, D AF Yui, Naofumi Lu, Hua Jenny Bouley, Richard Brown, Dennis TI AQP2 is necessary for vasopressin- and forskolin-mediated filamentous actin depolymerization in renal epithelial cells SO BIOLOGY OPEN LA English DT Article DE AQP2; Vasopressin; Actin cytoskeleton AB Remodeling of the actin cytoskeleton is required for vasopressin (VP)-induced aquaporin 2 (AQP2) trafficking. Here, we asked whether VP and forskolin (FK)-mediated F-actin depolymerization depends on AQP2 expression. Using various MDCK and LLC-PK1 cell lines with different AQP2 expression levels, we performed F-actin quantification and immunofluorescence staining after VP/FK treatment. In MDCK cells, in which AQP2 is delivered apically, VP/FK mediated F-actin depolymerization was significantly correlated with AQP2 expression levels. A decrease of apical membrane associated F-actin was observed upon VP/FK treatment in AQP2 transfected, but not in untransfected cells. There was no change in basolateral actin staining under these conditions. In LLC-PK1 cells, which deliver AQP2 basolaterally, a significant VP/FK mediated decrease in F-actin was also detected only in AQP2 transfected cells. This depolymerization response to VP/FK was significantly reduced by siRNA knockdown of AQP2. By immunofluorescence, an inverse relationship between plasma membrane AQP2 and membrane-associated F-actin was observed after VP/FK treatment again only in AQP2 transfected cells. This is the first report showing that VP/FK mediated F-actin depolymerization is dependent on AQP2 protein expression in renal epithelial cells, and that this is not dependent on the polarity of AQP2 membrane insertion. (C) 2011. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0). C1 [Brown, Dennis] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Brown, D (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. EM brown.dennis@mgh.harvard.edu FU NIH [DK38452, DK75940]; Gottschalk research grant (American Society of Nephrology) FX This work was supported by NIH grant DK38452 (DB, RB), DK75940, and a Gottschalk research grant (American Society of Nephrology). We thank Dr S. Uchida and Dr S. Sasaki (Tokyo Medical and Dental University) for their providing us MDCK clones. We thank Dr M. Knepper (NIH) for providing the pS261 AQP2 polyclonal antibody. NR 43 TC 12 Z9 14 U1 1 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 2046-6390 J9 BIOL OPEN JI Biol. Open PD FEB 15 PY 2012 VL 1 IS 2 BP 101 EP 108 DI 10.1242/bio.2011042 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA V36HZ UT WOS:000209204700005 PM 23213402 ER PT J AU Julg, B Poole, D Ghebremichael, M Castilla, C Altfeld, M Sunpath, H Murphy, RA Walker, BD AF Julg, Boris Poole, Danielle Ghebremichael, Musie Castilla, Carmen Altfeld, Marcus Sunpath, Henry Murphy, Richard A. Walker, Bruce D. TI Factors Predicting Discordant Virological and Immunological Responses to Antiretroviral Therapy in HIV-1 Clade C Infected Zulu/Xhosa in South Africa SO PLOS ONE LA English DT Article ID CD4 CELL COUNT; 1-INFECTED PATIENTS; RECOVERY; COHORT; SUPPRESSION; INDIVIDUALS; COMMUNITY; OUTCOMES; SEX AB Factors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIV clade-C infected African populations. Multivariate analysis using logistic regression and longitudinal analyses using mixed models were employed to assess the impact of age, gender, baseline CD4 cell count, hemoglobin, body mass index (BMI), tuberculosis and other opportunistic co-infections, and frequencies of regimen change on CD4 cell recovery at 12 and 30 months and on overtime change in CD4 cells among 442 virologically suppressed South Africans. Despite adequate virological response 37% (95% CI:32%-42%) and 83% (95% CI:79%-86%) of patients on antiretroviral therapy failed to restore CD4 cell counts >= 200 cells/mm(3) after 12 and >= 500 cells/mm(3) after 30 months, respectively, in this South African cohort. Critical risk factors for inadequate recovery were older age (p = 0.001) and nadir CD4 cell count at ART initiation (p < 0.0001), while concurrent TB co-infection, BMI, baseline hemoglobin, gender and antiretroviral regimen were not significant risk factors. These data suggest that greater efforts are needed to identify and treat HAART-eligible patients prior to severe CD4 cell decline or achievement of advanced age. C1 [Julg, Boris; Poole, Danielle; Ghebremichael, Musie; Altfeld, Marcus; Walker, Bruce D.] MIT, Ragon Inst MGH, Boston, MA USA. [Julg, Boris; Poole, Danielle; Altfeld, Marcus; Walker, Bruce D.] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Durban, South Africa. [Julg, Boris; Poole, Danielle; Altfeld, Marcus; Walker, Bruce D.] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Ghebremichael, Musie] Harvard Univ, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ghebremichael, Musie] Dana Farber Canc Inst, Boston, MA 02115 USA. [Castilla, Carmen] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Sunpath, Henry] McCord Hosp, Durban, South Africa. [Murphy, Richard A.] Doctors Borders, Operat Support Unit, New York, NY USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Julg, B (reprint author), MIT, Ragon Inst MGH, Boston, MA USA. EM bjulg@partners.org FU Mark and Lisa Schwartz Foundation; Doris Duke Distinguished Clinical Scientist Award; Howard Hughes Medical Institute; National Institutes of Health [AI30914]; Ragon Institute of MGH, MIT and Harvard; McCord Hospital; CDC FX Financial support was provided by the Ragon Institute of MGH, MIT and Harvard, the Mark and Lisa Schwartz Foundation, a Doris Duke Distinguished Clinical Scientist Award to MA, and The Howard Hughes Medical Institute (to BDW). Further support was provided by National Institutes of Health grant AI30914 to BDW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We wish to thank Roma Maharaj, Ansuri Singh and Fiona Samed from Sinikithemba ARV clinic at McCord hospital for their assistance in the collection of data; we wish to furthermore thank Claire Kerry and the management of McCord Hospital for support of this study. The Sinikithemba ARV clinic at Mc Cord hospital is a PEPFAR and CDC funded programme. NR 22 TC 7 Z9 7 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 14 PY 2012 VL 7 IS 2 AR e31161 DI 10.1371/journal.pone.0031161 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925CF UT WOS:000302737400011 PM 22348047 ER PT J AU Monje, M Dietrich, J AF Monje, Michelle Dietrich, Joerg TI Cognitive side effects of cancer therapy demonstrate a functional role for adult neurogenesis SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE Hippocampal neurogenesis; Radiation; Chemotherapy; White matter; Late effects; "Chemobrain" ID CENTRAL-NERVOUS-SYSTEM; LONG-TERM SURVIVORS; HIPPOCAMPAL NEUROGENESIS; BREAST-CANCER; ADJUVANT CHEMOTHERAPY; DENTATE GYRUS; CRANIAL IRRADIATION; CELL-PROLIFERATION; RADIATION-THERAPY; BRAIN IRRADIATION AB Cancer therapies frequently result in a spectrum of neurocognitive deficits that include impaired learning, memory, attention and speed of information processing. Damage to dynamic neural progenitor cell populations in the brain are emerging as important etiologic factors. Radiation and chemotherapy-induced damage to neural progenitor populations responsible for adult hippocampal neurogenesis and for maintenance of subcortical white matter integrity are now believed to play major roles in the neurocognitive impairment many cancer survivors experience. (C) 2011 Elsevier B.V. All rights reserved. C1 [Monje, Michelle] Stanford Univ, Med Ctr, Dept Neurol, Div Child Neurol, Palo Alto, CA 94304 USA. [Dietrich, Joerg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Canc Ctr,Dept Neurol, Boston, MA 02114 USA. [Dietrich, Joerg] Harvard Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. RP Monje, M (reprint author), Stanford Univ, Med Ctr, Dept Neurol, Div Child Neurol, 750 Welch Rd,Suite 317, Palo Alto, CA 94304 USA. EM mmonje@stanford.edu; jdietrich1@partners.org FU National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS) [1K08NS070926 - 01]; Paul Calabresi Career Development Award for Clinical Oncology; Stephen E. and Catherine Pappas Foundation FX The authors gratefully acknowledge support from the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS) grant 1K08NS070926 - 01 (MM.), Paul Calabresi Career Development Award for Clinical Oncology (J.D.), and the Stephen E. and Catherine Pappas Foundation Award for Brain Tumor Research (J.D.). NR 60 TC 54 Z9 55 U1 0 U2 12 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 FEB 14 PY 2012 VL 227 IS 2 SI SI BP 376 EP 379 DI 10.1016/j.bbr.2011.05.012 PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 907FU UT WOS:000301404000010 PM 21621557 ER PT J AU Meirelles, K Benedict, LA Dombkowski, D Pepin, D Preffer, FI Teixeira, J Tanwar, PS Young, RH MacLaughlin, DT Donahoe, PK Wei, XL AF Meirelles, Katia Benedict, Leo Andrew Dombkowski, David Pepin, David Preffer, Frederic I. Teixeira, Jose Tanwar, Pradeep Singh Young, Robert H. MacLaughlin, David T. Donahoe, Patricia K. Wei, Xiaolong TI Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy with cisplatin; pluripotency factors ID STEM-CELLS; TGF-BETA; CHEMOTHERAPEUTIC-AGENTS; MESENCHYMAL TRANSITION; EPITHELIAL-CELLS; DUCT REGRESSION; MESSENGER-RNA; CYCLE ARREST; HUMAN TUMORS; II RECEPTOR AB Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad-) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+ Ecad- cells. Similarly, proliferation of the 3+ Ecad- cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3-Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+ Ecad- subpopulation through the induction of cyclin-dependent kinase inhibitors. 3+ Ecad- cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics. C1 [Meirelles, Katia; Benedict, Leo Andrew; Pepin, David; MacLaughlin, David T.; Donahoe, Patricia K.; Wei, Xiaolong] Massachusetts Gen Hosp, Dept Surg, Pediat Surg Res Labs, Boston, MA 02114 USA. [Dombkowski, David; Preffer, Frederic I.] Massachusetts Gen Hosp, Flow Cytometry Lab, Boston, MA 02114 USA. [Preffer, Frederic I.; Young, Robert H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Teixeira, Jose; Tanwar, Pradeep Singh] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Teixeira, Jose; Tanwar, Pradeep Singh] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Donahoe, PK (reprint author), Massachusetts Gen Hosp, Dept Surg, Pediat Surg Res Labs, Boston, MA 02114 USA. EM pdonahoe@partners.org; xwei2@partners.org OI Teixeira, Jose/0000-0002-6438-5064 FU National Research Service [T32 CA071345-13]; Tufts Medical Center; Massachusetts General Hospital Executive Committee on Research Award; Surdna-Gar Foundation; National Institute of Child Health and Human Development [R01HD052701]; National Center for Research Resources [1S10RR023440-01A1, 1S10RR020936-01]; National Institutes of Health [R01 CA17393]; Harvard Stem Cell Institute; Department of Defense; Julie Fund FX We thank Ms. Caroline Coletti for editorial support; Dr. George Daley for Let-7 primers; Dr. Samuel C. Mok for HOSE-4 and -6; Dr. Denise C. Connolly for MOVCAR-7 and -8 cell lines; Scott Monsma at Primorigen for conjugated LIN28 monoclonal antibody; and Dr. Peter R. Mueller (Department of Radiology, Massachusetts General Hospital and Harvard Medical School) for providing de-identified discarded specimens from ovarian cancer patients (MGH IRB 2007P001918/6 and Dana-Farber Cancer Institute IRB 02051). These studies were supported by National Research Service Award T32 CA071345-13 (to K.M.); a Kiwanis Award from Tufts Medical Center (to L.A.B.); a Massachusetts General Hospital Executive Committee on Research Award and the Surdna-Gar Foundation (X.W.); National Institute of Child Health and Human Development Grant R01HD052701 (to J.T.); National Center for Research Resources Grants 1S10RR023440-01A1 and 1S10RR020936-01 (to F.P.); National Institutes of Health Grant R01 CA17393 (to P.K.D. and D.T.M.); the Harvard Stem Cell Institute; the Department of Defense Ovarian Cancer Research Program; the Julie Fund (P.K.D.); and gifts from Commons Development, the McBride Family Foundation, and the Austen Foundation. NR 54 TC 45 Z9 46 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 FEB 14 PY 2012 VL 109 IS 7 BP 2358 EP 2363 DI 10.1073/pnas.1120733109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200044 PM 22308459 ER PT J AU Kebede, M Ferdaoussi, M Mancini, A Alquier, T Kulkarni, RN Walker, MD Poitout, V AF Kebede, Melkam Ferdaoussi, Mourad Mancini, Arturo Alquier, Thierry Kulkarni, Rohit N. Walker, Michael D. Poitout, Vincent TI Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STIMULATED INSULIN-SECRETION; LINKED N-ACETYLGLUCOSAMINE; BETA-CELLS; GLCNAC TRANSFERASE; POSTTRANSLATIONAL MODIFICATION; IN-VIVO; GPR40; EXPRESSION; NUCLEAR; GLYCOSYLATION AB The G protein-coupled free fatty acid receptor-1 (FFA1/GPR40) plays a major role in the regulation of insulin secretion by fatty acids. GPR40 is considered a potential therapeutic target to enhance insulin secretion in type 2 diabetes; however, its mode of regulation is essentially unknown. The aims of this study were to test the hypothesis that glucose regulates GPR40 gene expression in pancreatic beta-cells and to determine the mechanisms of this regulation. We observed that glucose stimulates GPR40 gene transcription in pancreatic beta-cells via increased binding of pancreas-duodenum homeobox-1 (Pdx-1) to the A-box in the HR2 region of the GPR40 promoter. Mutation of the Pdx-1 binding site within the HR2 abolishes glucose activation of GPR40 promoter activity. The stimulation of GPR40 expression and Pdx-1 binding to the HR2 in response to glucose are mimicked by N-acetyl glucosamine, an intermediate of the hexosamine biosynthesis pathway, and involve PI3K-dependent O-GlcNAcylation of Pdx-1 in the nucleus. We demonstrate that O-GlcNAc transferase (OGT) interacts with the product of the PI3K reaction, phosphatidylinositol 3,4,5-trisphosphate (PIP3), in the nucleus. This interaction enables OGT to catalyze O-GlcNAcylation of nuclear proteins, including Pdx-1. We conclude that glucose stimulates GPR40 gene expression at the transcriptional level through Pdx-1 binding to the HR2 region and via a signaling cascade that involves an interaction between OGT and PIP3 at the nuclear membrane. These observations reveal a unique mechanism by which glucose metabolism regulates the function of transcription factors in the nucleus to induce gene expression. C1 [Kebede, Melkam; Ferdaoussi, Mourad; Mancini, Arturo; Alquier, Thierry; Poitout, Vincent] Univ Montreal, CRCHUM, Montreal Diabet Res Ctr, Montreal, PQ H3T 1J4, Canada. [Kebede, Melkam; Ferdaoussi, Mourad; Mancini, Arturo; Alquier, Thierry; Poitout, Vincent] Univ Montreal, Dept Med, Montreal, PQ H3T 1J4, Canada. [Poitout, Vincent] Univ Montreal, Dept Nutr, Montreal, PQ H3T 1J4, Canada. [Poitout, Vincent] Univ Montreal, Dept Biochem, Montreal, PQ H3T 1J4, Canada. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Walker, Michael D.] Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RP Poitout, V (reprint author), Univ Montreal, CRCHUM, Montreal Diabet Res Ctr, Montreal, PQ H3T 1J4, Canada. EM vincent.poitout@umontreal.ca OI Alquier, Thierry/0000-0001-8171-802X; Poitout, Vincent/0000-0002-6555-5053 FU University of Alberta; Coordinating Center of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institutes of Health Research [MOP-86545]; National Institutes of Health [R01-DK67536]; Canadian Diabetes Association; Diabete Quebec; Centre de Recherche du Centre Hospitalier de l'Universite de Montreal FX We thank Drs. James Shapiro and Tatsuya Kin from the University of Alberta and the Coordinating Center of the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases-supported Integrated Islet Distribution Program for providing isolated human islets. This study was supported by the Canadian Institutes of Health Research Grant MOP-86545 (to V.P.) and National Institutes of Health Grant R01-DK67536 (to R.N.K.). M.K. is the recipient of a postdoctoral fellowship from the Canadian Diabetes Association. M.F. is the recipient of postdoctoral fellowships from Diabete Quebec and from the Centre de Recherche du Centre Hospitalier de l'Universite de Montreal. V.P. holds the Canada Research Chair in Diabetes and Pancreatic Beta-cell Function. NR 41 TC 23 Z9 23 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2376 EP 2381 DI 10.1073/pnas.1114350109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200047 PM 22308370 ER PT J AU Oksenych, V Alt, FW Kumar, V Schwer, B Wesemann, DR Hansen, E Patel, H Su, A Guo, CG AF Oksenych, Valentyn Alt, Frederick W. Kumar, Vipul Schwer, Bjoern Wesemann, Duane R. Hansen, Erica Patel, Harin Su, Arthur Guo, Chunguang TI Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ataxia telangiectasia-mutated; double-strand DNA break repair; NHEJ1; Cernunnos ID CLASS-SWITCH RECOMBINATION; END-JOINING PATHWAY; LIGASE IV DEFICIENCY; DOUBLE-STRAND BREAKS; CHROMOSOMAL TRANSLOCATIONS; HOMOLOGOUS RECOMBINATION; DEFECTIVE NEUROGENESIS; GENOMIC INSTABILITY; CELLS; SUPPRESSION AB The classical nonhomologous DNA end-joining (C-NHEJ) double-strand break (DSB) repair pathway in mammalian cells maintains genome stability and is required for V(D)J recombination and lymphocyte development. Mutations in the XLF C-NHEJ factor or ataxia telangiectasia-mutated (ATM) DSB response protein cause radiosensitivity and immunodeficiency in humans. Although potential roles for XLF in C-NHEJ are unknown, ATM activates a general DSB response by phosphorylating substrates, including histone H2AX and 53BP1, which are assembled into chromatin complexes around DSBs. In mice, C-NHEJ, V(D) J recombination, and lymphocyte development are, at most, modestly impaired in the absence of XLF or ATM, but are severely impaired in the absence of both. Redundant functions of XLF and ATM depend on ATM kinase activity; correspondingly, combined XLF and H2AX deficiency severely impairs V(D) J recombination, even though H2AX deficiency alone has little impact on this process. These and other findings suggest that XLF may provide functions that overlap more broadly with assembled DSB response factors on chromatin. As one test of this notion, we generated mice and cells with a combined deficiency for XLF and 53BP1. In this context, 53BP1 deficiency, although leading to genome instability, has only modest effects on V(D) J recombination or lymphocyte development. Strikingly, we find that combined XLF/53BP1 deficiency in mice severely impairs C-NHEJ, V(D) J recombination, and lymphocyte development while also leading to general genomic instability and growth defects. We conclude that XLF is functionally redundant with multiple members of the ATM-dependent DNA damage response in facilitating C-NHEJ and discuss implications of our findings for potential functions of these factors. C1 [Oksenych, Valentyn; Alt, Frederick W.; Kumar, Vipul; Schwer, Bjoern; Wesemann, Duane R.; Hansen, Erica; Patel, Harin; Su, Arthur; Guo, Chunguang] Harvard Univ, Sch Med, Dept Genet, Childrens Hosp,Immune Dis Inst,Howard Hughes Med, Boston, MA 02115 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Dept Med, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Childrens Hosp,Immune Dis Inst,Howard Hughes Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; cguo@idi.harvard.edu OI Oksenych, Valentyn/0000-0002-5088-3791 FU National Institutes of Health [AI076210, K08AI89972]; American Association of Allergy Asthma and Immunology; CSL Behring; Burroughs Wellcome Fund FX We thank Dr. B. Sleckman for providing 53BP1-/- mice with a Bcl2 transgene. This work is supported by National Institutes of Health Grant AI076210 (to F. W. A.). D. R. W. is supported by National Institutes of Health Grant K08AI89972 and by an award from the American Association of Allergy Asthma and 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. C. G. is a fellow of Cancer Research Institute. NR 28 TC 27 Z9 27 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2455 EP 2460 DI 10.1073/pnas.1121458109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200061 PM 22308489 ER PT J AU Gewurz, BE Towfic, F Mar, JC Shinners, NP Takasaki, K Zhao, B Cahir-McFarland, ED Quackenbush, J Xavier, RJ Kieff, E AF Gewurz, Benjamin E. Towfic, Fadi Mar, Jessica C. Shinners, Nicholas P. Takasaki, Kaoru Zhao, Bo Cahir-McFarland, Ellen D. Quackenbush, John Xavier, Ramnik J. Kieff, Elliott TI Genome-wide siRNA screen for mediators of NF-kappa B activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lymphoma; inflammation; signaling; oncogene; cytokine ID EPSTEIN-BARR-VIRUS; MEMBRANE-PROTEIN 1; CHAIN ASSEMBLY COMPLEX; SIGNAL-TRANSDUCTION; NEUROTROPHIN RECEPTOR; IMMUNE-SYSTEM; CELL LYMPHOMA; TNF-ALPHA; IKK-ALPHA; PATHWAY AB Although canonical NF kappa B is frequently critical for cell proliferation, survival, or differentiation, NF kappa B hyperactivation can cause malignant, inflammatory, or autoimmune disorders. Despite intensive study, mammalian NF kappa B pathway loss-of-function RNAi analyses have been limited to specific protein classes. We therefore undertook a human genome-wide siRNA screen for novel NF kappa B activation pathway components. Using an Epstein Barr virus latent membrane protein (LMP1) mutant, the transcriptional effects of which are canonical NF kappa B-dependent, we identified 155 proteins significantly and substantially important for NF kappa B activation in HEK293 cells. These proteins included many kinases, phosphatases, ubiquitin ligases, and deubiquinating enzymes not previously known to be important for NF kappa B activation. Relevance to other canonical NF kappa B pathways was extended by finding that 118 of the 155 LMP1 NF-kappa B activation pathway components were similarly important for IL-1 beta-, and 79 for TNF alpha-mediated NF kappa B activation in the same cells. MAP3K8, PIM3, and six other enzymes were uniquely relevant to LMP1-mediated NF kappa B activation. Most novel pathway components functioned upstream of I kappa B kinase complex (IKK) activation. Robust siRNA knockdown effects were confirmed for all mRNAs or proteins tested. Although multiple ZC3H-family proteins negatively regulate NF kappa B, ZC3H13 and ZC3H18 were activation pathway components. ZC3H13 was critical for LMP1, TNF alpha, and IL-1 beta NF kappa B-dependent transcription, but not for IKK activation, whereas ZC3H18 was critical for IKK activation. Down-modulators of LMP1 mediated NF kappa B activation were also identified. These experiments identify multiple targets to inhibit or stimulate LMP1-, IL-1 beta-, or TNF alpha-mediated canonical NF kappa B activation. C1 [Gewurz, Benjamin E.; Shinners, Nicholas P.; Takasaki, Kaoru; Zhao, Bo; Cahir-McFarland, Ellen D.; Kieff, Elliott] Brigham & Womens Hosp, Dept Med & Microbiol & Mol Genet, Channing Lab, Boston, MA 02115 USA. [Gewurz, Benjamin E.; Shinners, Nicholas P.; Takasaki, Kaoru; Zhao, Bo; Cahir-McFarland, Ellen D.; Kieff, Elliott] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Towfic, Fadi; Mar, Jessica C.; Xavier, Ramnik J.] Harvard Univ, Ctr Computat & Integrat Biol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Towfic, Fadi; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Mar, Jessica C.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Kieff, E (reprint author), Brigham & Womens Hosp, Dept Med & Microbiol & Mol Genet, Channing Lab, Boston, MA 02115 USA. EM ekieff@rics.bwh.harvard.edu RI Zhao, Bo/B-3852-2014 FU National Cancer Institute [K08CA140780, R01CA085180, R01CA47006, 5T32CA009031]; National Human Genome Research Institute [HGS5P50HG004233]; National Institute of Allergy and Infectious Diseases [U54AI057159]; National Institute of Diabetes, Digestive, and Kidney Diseases [R01043351, R0183756]; National Center for Research Resources [UL1RR025758]; [R01AI062773] FX We thank E. Davis (MD Anderson) for I kappa B alpha-Photinus and Renilla luciferase vectors and technical assistance; T. Yasui (Osaka University) for Tet-On DsRed; D. Hill and M. Vidal (Harvard Medical School) for split YFP expression vectors; W. Khan (University of Miami) for a GST-I kappa B alpha expression vector; D. Portal for help with figure preparation; D. Boehm for helpful discussions and technical assistance, and G. Hoffman, A. Brass, J. Smith, C. Shamu, D. Wrobel, S. Rudnicki, S. Johnston, M. Padi, E. Bennett, M. Sowa, and J. W. Harper for helpful discussions. B. E. G. is a fellow of the Leukemia and Lymphoma Society and the Karin Grunebaum Cancer Foundation. This research was supported by National Cancer Institute Grants K08CA140780 (to B. E. G.), R01CA085180 (to E. K.), R01CA47006 (to E. K.), and 5T32CA009031 (to N.S.), by National Human Genome Research Institute Grant HGS5P50HG004233 (to E. K. and J.Q.), by National Institute of Allergy and Infectious Diseases Grants U54AI057159 to the New England Regional Center of Excellence in Biodefense and Emerging Infectious Diseases and R01AI062773 (to R.J.X.), by National Institute of Diabetes, Digestive, and Kidney Diseases Grants R01043351 and R0183756 (to R.J.X.), and by National Center for Research Resources Harvard Catalyst Grant UL1RR025758 (to B.E.G.). NR 57 TC 29 Z9 29 U1 1 U2 10 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 FEB 14 PY 2012 VL 109 IS 7 BP 2467 EP 2472 DI 10.1073/pnas.1120542109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200063 PM 22308454 ER PT J AU Boboila, C Oksenych, V Gostissa, M Wang, JH Zha, S Zhang, Y Chai, H Lee, CS Jankovic, M Saez, LMA Nussenzweig, MC McKinnon, PJ Alt, FW Schwer, B AF Boboila, Cristian Oksenych, Valentyn Gostissa, Monica Wang, Jing H. Zha, Shan Zhang, Yu Chai, Hua Lee, Cheng-Sheng Jankovic, Mila Saez, Liz-Marie Albertorio Nussenzweig, Michel C. McKinnon, Peter J. Alt, Frederick W. Schwer, Bjoern TI Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CLASS-SWITCH RECOMBINATION; STRAND BREAK REPAIR; LIGASE-III; B-CELLS; V(D)J RECOMBINATION; SOMATIC HYPERMUTATION; MAMMALIAN-CELLS; TRANSLOCATIONS; PATHWAY; MECHANISMS AB Classical nonhomologous DNA end-joining (C-NHEJ), which is a major DNA double-strand break (DSB) repair pathway in mammalian cells, plays a dominant role in joining DSBs during Ig heavy chain (IgH) class switch recombination (CSR) in activated B lymphocytes. However, in B cells deficient for one or more requisite C-NHEJ factors, such as DNA ligase 4 (Lig4) or XRCC4, end-joining during CSR occurs by a distinct alternative end-joining (A-EJ) pathway. A-EJ also has been implicated in joining DSBs found in oncogenic chromosomal translocations. DNA ligase 3 (Lig3) and its cofactor XRCC1 are widely considered to be requisite A-EJ factors, based on biochemical studies or extrachromosomal substrate end-joining studies. However, potential roles for these factors in A-EJ of endogenous chromosomal DSBs have not been tested. Here, we report that Xrcc1 inactivation via conditional gene-targeted deletion in WT or XRCC4-deficient primary B cells does not have an impact on either CSR or IgH/c-myc translocations in activated B lymphocytes. Indeed, homozygous deletion of Xrcc1 does not impair A-EJ of I-SceI-induced DSBs in XRCC4-deficient pro-B-cell lines. Correspondingly, substantial depletion of Lig3 in Lig4-deficient primary B cells or B-cell lines does not impair A-EJ of CSR-mediated DSBs or formation of IgH/c-myc translocations. Our findings firmly demonstrate that XRCC1 is not a requisite factor for A-EJ of chromosomal DSBs and raise the possibility that DNA ligase 1 (Lig1) may contribute more to A-EJ than previously considered. C1 [Boboila, Cristian; Oksenych, Valentyn; Gostissa, Monica; Wang, Jing H.; Zha, Shan; Zhang, Yu; Chai, Hua; Lee, Cheng-Sheng; Alt, Frederick W.; Schwer, Bjoern] Harvard Univ, Program Cellular & Mol Med, Howard Hughes Med Inst, Childrens Hosp Boston,Med Sch, Boston, MA 02115 USA. [Boboila, Cristian; Oksenych, Valentyn; Gostissa, Monica; Wang, Jing H.; Zha, Shan; Zhang, Yu; Chai, Hua; Lee, Cheng-Sheng; Alt, Frederick W.; Schwer, Bjoern] Harvard Univ, Dept Genet, Immune Dis Inst, Sch Med, Boston, MA 02115 USA. [Jankovic, Mila; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, Howard Hughes Med Inst, New York, NY 10065 USA. [Saez, Liz-Marie Albertorio] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00680 USA. [McKinnon, Peter J.] St Jude Childrens Hosp, Dept Genet, Memphis, TN 38105 USA. RP Alt, FW (reprint author), Harvard Univ, Program Cellular & Mol Med, Howard Hughes Med Inst, Childrens Hosp Boston,Med Sch, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; schwer@idi.harvard.edu RI Wang, Jing/M-7813-2015; OI Wang, Jing/0000-0003-4343-2527; Oksenych, Valentyn/0000-0002-5088-3791 FU National Institutes of Health [AI031541, CA092625, NS-37956, CA-21765, AI037526, 5T32CA009382, 5T32CA009382-26]; Leukemia and Lymphoma Society of America; Cancer Research Institute FX We thank Maria-Vivienne Boboila for stimulating discussions and critical reading of the manuscript; Erica Hansen, Grace Yuen, and Duane Wesemann for help with experiments and suggestions; Ralph Scully for providing the I-SceI vectors; and Kefei Yu for providing the Lig4 null CH12F3 cells. This work was supported by National Institutes of Health Grants AI031541 and CA092625 (to F. W. A.), NS-37956 and CA-21765 (to P.J.M.), and AI037526 (to M.C.N.). B. S. was supported by National Institutes of Health Training Grant 5T32CA009382. J.H.W. was supported by a Leukemia and Lymphoma Society of America Special Fellowship and by National Institutes of Health Training Grant 5T32CA009382-26. C. B. was supported by a Cancer Research Institute training grant. Y.Z. was supported by a Cancer Research Institute postdoctoral fellowship. M. G. is a V Foundation Scholar. F. W. A. and M.C.N. are investigators of the Howard Hughes Medical Institute. NR 53 TC 50 Z9 51 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2473 EP 2478 DI 10.1073/pnas.1121470109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200064 PM 22308491 ER PT J AU Cortez-Retamozo, V Etzrodt, M Newton, A Rauch, PJ Chudnovskiy, A Berger, C Ryan, RJH Iwamoto, Y Marinelli, B Gorbatov, R Forghani, R Novobrantseva, TI Koteliansky, V Figueiredo, JL Chen, JW Anderson, DG Nahrendorf, M Swirski, FK Weissleder, R Pittet, MJ AF Cortez-Retamozo, Virna Etzrodt, Martin Newton, Andita Rauch, Philipp J. Chudnovskiy, Aleksey Berger, Cedric Ryan, Russell J. H. Iwamoto, Yoshiko Marinelli, Brett Gorbatov, Rostic Forghani, Reza Novobrantseva, Tatiana I. Koteliansky, Victor Figueiredo, Jose-Luiz Chen, John W. Anderson, Daniel G. Nahrendorf, Matthias Swirski, Filip K. Weissleder, Ralph Pittet, Mikael J. TI Origins of tumor-associated macrophages and neutrophils SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer immunity; tumor microenvironment ID DENDRITIC CELLS; PROGENITOR CELLS; INFLAMMATORY MONOCYTES; SUPPRESSOR-CELLS; IMMUNE-SYSTEM; CANCER; MICE; CHEMOTHERAPY; SPLENECTOMY; METASTASIS AB Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b(+) Ly-6C(hi) monocytic and CD11b(+) Ly-6G(hi) granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells. C1 [Cortez-Retamozo, Virna; Etzrodt, Martin; Newton, Andita; Rauch, Philipp J.; Chudnovskiy, Aleksey; Berger, Cedric; Iwamoto, Yoshiko; Marinelli, Brett; Gorbatov, Rostic; Forghani, Reza; Figueiredo, Jose-Luiz; Chen, John W.; Nahrendorf, Matthias; Swirski, Filip K.; Weissleder, Ralph; Pittet, Mikael J.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Cortez-Retamozo, Virna; Etzrodt, Martin; Newton, Andita; Rauch, Philipp J.; Chudnovskiy, Aleksey; Berger, Cedric; Iwamoto, Yoshiko; Marinelli, Brett; Gorbatov, Rostic; Forghani, Reza; Figueiredo, Jose-Luiz; Chen, John W.; Nahrendorf, Matthias; Swirski, Filip K.; Weissleder, Ralph; Pittet, Mikael J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ryan, Russell J. H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Novobrantseva, Tatiana I.; Koteliansky, Victor] Alnylam Pharmaceut, Cambridge, MA 02142 USA. [Anderson, Daniel G.] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Weissleder, Ralph] Harvard Univ, Dept Syst Biol, Sch Med, Boston, MA 02115 USA. RP Pittet, MJ (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM mpittet@mgh.harvard.edu RI Etzrodt, Martin/P-3325-2015 OI Etzrodt, Martin/0000-0003-1928-3904 FU Alnylam Pharmaceuticals; National Institutes of Health [P50-CA86355, R01-AI084880, R56-AI084880, U54-CA126515]; American Association for Cancer Research; Boehringer Ingelheim Fonds FX T.I.N. and V.K. are Alnylam Pharmaceuticals employees, and D.G.A. receives funding from, and is a consultant with, Alnylam Pharmaceuticals.; We thank T. Jacks (Massachusetts Institute of Technology), R. Weinberg (Whitehead Institute, Cambridge, MA), and E. Meylan and M. Winslow (Massachusetts Institute of Technology) for helpful discussions; K. Hassard, S. Holder, and the Massachusetts General Hospital surgical pathology accessioners for assistance with human tissue collection; J. Sullivan and R. Kohler (Massachusetts General Hospital) for imaging; M. Maier, H. Epstein-Barash, and W. Cantley for medium-scale siRNA synthesis and formulation (Alnylam); and M. Waring (Ragon Institute, Massachusetts General Hospital) for sorting cells. This work was supported, in part, by National Institutes of Health Grants P50-CA86355, R01-AI084880, and R56-AI084880 (to M. J. P.) and National Institutes of Health Grant U54-CA126515 (to R. W.). M. E. was supported by the American Association for Cancer Research Centennial Predoctoral Fellowship and the Boehringer Ingelheim Fonds. NR 43 TC 170 Z9 176 U1 11 U2 60 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 FEB 14 PY 2012 VL 109 IS 7 BP 2491 EP 2496 DI 10.1073/pnas.1113744109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200067 PM 22308361 ER PT J AU Tsuji-Takechi, K Negishi-Koga, T Sumiya, E Kukita, A Kato, S Maeda, T Pandolfi, PP Moriyama, K Takayanagi, H AF Tsuji-Takechi, Kaori Negishi-Koga, Takako Sumiya, Eriko Kukita, Akiko Kato, Shigeaki Maeda, Takahiro Pandolfi, Pier Paolo Moriyama, Keiji Takayanagi, Hiroshi TI Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BONE HOMEOSTASIS; GENE-EXPRESSION; POZ DOMAIN; DIFFERENTIATION; NFATC1; POKEMON; PROTEIN; CANCER; MICE; OVEREXPRESSION AB Cell fate determination is tightly regulated by transcriptional activators and repressors. Leukemia/lymphoma-related factor (LRF; encoded by Zbtb7a), known as a POK (POZ/BTB and Kruppel) family transcriptional repressor, is induced during the development of bone-resorbing osteoclasts, but the physiological significance of LRF in bone metabolism and the molecular mechanisms underlying the transcriptional regulation of osteoclastogenesis by LRF have not been elucidated. Here we show that LRF negatively regulates osteoclast differentiation by repressing nuclear factor of activated T cells c1 (NFATc1) induction in the early phase of osteoclast development, while positively regulating osteoclast-specific genes by functioning as a coactivator of NFATc1 in the bone resorption phase. The stage-specific distinct functions of LRF were demonstrated in two lines of conditional knockout mice in which LRF was deleted in the early or late phase of osteoclast development. Thus, this study shows that LRF plays stage-specific distinct roles in osteoclast differentiation, exemplifying the delicate transcriptional regulation at work in lineage commitment. C1 [Tsuji-Takechi, Kaori; Negishi-Koga, Takako; Sumiya, Eriko; Takayanagi, Hiroshi] Tokyo Med & Dent Univ, Dept Cell Signaling, Grad Sch Med & Dent Sci, Bunkyo Ku, Tokyo 1138549, Japan. [Tsuji-Takechi, Kaori; Negishi-Koga, Takako; Sumiya, Eriko; Moriyama, Keiji; Takayanagi, Hiroshi] Int Res Ctr Mol Sci Tooth & Bone Dis, Global Ctr Excellence Program, Bunkyo Ku, Tokyo 1138549, Japan. [Tsuji-Takechi, Kaori; Moriyama, Keiji] Tokyo Med & Dent Univ, Dept Maxillofacial Orthognath, Grad Sch Med & Dent Sci, Bunkyo Ku, Tokyo 1138549, Japan. [Negishi-Koga, Takako; Sumiya, Eriko; Takayanagi, Hiroshi] Japan Sci & Technol Agcy, Takayanagi Osteonetwork Project, Bunkyo Ku, Tokyo 1138549, Japan. [Kukita, Akiko] Saga Univ, Fac Med, Dept Microbiol, Saga 8498501, Japan. [Kato, Shigeaki] Univ Tokyo, Inst Mol & Cellular Biosci, Grad Sch Med, Bunkyo Ku, Tokyo 1130032, Japan. [Maeda, Takahiro; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Beth Israel Deaconess Canc Ctr,Canc Genet Program, Dept Med & Pathol,Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Takayanagi, Hiroshi] Univ Western Australia, Ctr Orthopaed Res, Sch Surg, Nedlands, WA 6009, Australia. RP Takayanagi, H (reprint author), Tokyo Med & Dent Univ, Dept Cell Signaling, Grad Sch Med & Dent Sci, Bunkyo Ku, Tokyo 1138549, Japan. EM taka.csi@tmd.ac.jp FU Japan Science and Technology; Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology of Japan FX We thank T. Kitamura and M. Matsumoto for kindly providing the retroviral vectors and Plat-E cells, and the reporter plasmid pCtsk-luc, respectively; and M. Shinohara, N. Komatsu, A. Terashima, T. Ando, Y. Kunisawa, Y. Ogihara, and A. Suematsu for discussion and technical assistance. This work was supported in part by a grant from Exploratory Research for Advanced Technology, Takayanagi Osteonetwork Project from Japan Science and Technology; a Grant-in-Aid for Scientific Research B; a Grant-in-Aid for Young Scientist A; a Grant-in-Aid for Challenging Exploratory Research from the Japan Society for the Promotion of Science; and a grant from the Global Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 36 TC 8 Z9 8 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 14 PY 2012 VL 109 IS 7 BP 2561 EP 2566 DI 10.1073/pnas.1116042109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895IH UT WOS:000300489200079 PM 22308398 ER PT J AU Dominy, JE Vazquez, F Puigserver, P AF Dominy, John E. Vazquez, Francisca Puigserver, Pere TI Glycine Decarboxylase Cleaves a "Malignant" Metabolic Path to Promote Tumor Initiation SO CANCER CELL LA English DT Editorial Material ID STEM-CELLS; CANCER AB Tumor-initiating cells (TICs) are thought to be critical for promoting tumorigenesis. In a recent Cell article, Zhang and colleagues found that non-small cell lung cancer TICs overexpress the metabolic enzyme glycine decarboxylase, which leads to increases in pyrimidine synthesis and is critical for proliferation and tumor initiation. C1 [Dominy, John E.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. [Vazquez, Francisca] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dominy, John E.; Puigserver, Pere] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Vazquez, Francisca] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Puigserver, P (reprint author), Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. EM pere_puigserver@dfci.harvard.edu NR 10 TC 3 Z9 3 U1 1 U2 8 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 FEB 14 PY 2012 VL 21 IS 2 BP 143 EP 145 DI 10.1016/j.ccr.2012.01.019 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 895DI UT WOS:000300476000004 PM 22340586 ER PT J AU Corrales-Medina, VF Musher, DM Wells, GA Chirinos, JA Chen, L Fine, MJ AF Corrales-Medina, Vicente F. Musher, Daniel M. Wells, George A. Chirinos, Julio A. Chen, Li Fine, Michael J. TI Cardiac Complications in Patients With Community-Acquired Pneumonia Incidence, Timing, Risk Factors, and Association With Short-Term Mortality SO CIRCULATION LA English DT Article DE pneumonia; complications; heart failure; arrhythmias, cardiac; myocardial infarction ID ACUTE CORONARY SYNDROMES; MYOCARDIAL-INFARCTION; HOSPITALIZED-PATIENTS; CLINICAL-OUTCOMES; ACUTE INFECTION; UNITED-STATES; IMPACT; HEART; SURVIVAL; EVENTS AB Background-Community-acquired pneumonia (CAP) affects > 5 million adults each year in the United States. Although incident cardiac complications occur in patients with community-acquired pneumonia, their incidence, timing, risk factors, and associations with short-term mortality are not well understood. Methods and Results-A total of 1343 inpatients and 944 outpatients with community-acquired pneumonia were followed up prospectively for 30 days after presentation. Incident cardiac complications (new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction) were diagnosed in 358 inpatients (26.7%) and 20 outpatients (2.1%). Although most events (89.1% in inpatients, 75% in outpatients) were diagnosed within the first week, more than half of them were recognized in the first 24 hours. Factors associated with their diagnosis included older age (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.02-1.04), nursing home residence (OR, 1.8; 95% CI, 1.2-2.9), history of heart failure (OR, 4.3; 95% CI, 3.0-6.3), prior cardiac arrhythmias (OR, 1.8; 95% CI, 1.2-2.7), previously diagnosed coronary artery disease (OR, 1.5; 95% CI, 1.04-2.0), arterial hypertension (OR, 1.5; 95% CI, 1.1-2.1), respiratory rate >= 30 breaths per minute (OR, 1.6; 95% CI, 1.1-2.3), blood pH < 7.35 (OR, 3.2; 95% CI, 1.8 -5.7), blood urea nitrogen >= 30 mg/dL (OR, 1.5; 95% CI, 1.1-2.2), serum sodium < 130 mmol/L (OR, 1.8; 95% CI, 1.02-3.1), hematocrit < 30% (OR, 2.0; 95% CI, 1.3-3.2), pleural effusion on presenting chest x-ray (OR, 1.6; 95% CI, 1.1-2.4), and inpatient care (OR, 4.8; 95% CI, 2.8-8.3). Incident cardiac complications were associated with increased risk of death at 30 days after adjustment for baseline Pneumonia Severity Index score (OR, 1.6; 95% CI, 1.04-2.5). Conclusions-Incident cardiac complications are common in patients with community-acquired pneumonia and are associated with increased short-term mortality. Older age, nursing home residence, preexisting cardiovascular disease, and pneumonia severity are associated with their occurrence. Further studies are required to test risk stratification and prevention and treatment strategies for cardiac complications in this population. (Circulation. 2012; 125: 773-781.) C1 [Wells, George A.] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Corrales-Medina, Vicente F.; Wells, George A.] Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Wells, George A.; Chen, Li] Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr, Ottawa, ON, Canada. [Musher, Daniel M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Dept Mol Virol, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Dept Microbiol, Houston, TX 77030 USA. [Musher, Daniel M.] Michael E DeBakey VA Med Ctr, Med Care Line Infect Dis Sect, Houston, TX USA. [Chirinos, Julio A.] Philadelphia VA Med Ctr, Div Cardiol, Philadelphia, PA USA. [Chirinos, Julio A.] Univ Penn, Philadelphia, PA 19104 USA. [Fine, Michael J.] Univ Pittsburgh, Ctr Hlth Equ Res & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Fine, Michael J.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. RP Corrales-Medina, VF (reprint author), 1053 Carling Ave,CPC 470, Ottawa, ON K1Y 4E9, Canada. EM vcorrales@toh.on.ca OI Corrales-Medina, Vicente/0000-0002-9691-491X FU Agency for Healthcare Research and Quality; Department of Medicine of the Ottawa Hospital; Ottawa Hospital Research Institute FX The PORT study was funded by the Agency for Healthcare Research and Quality. Dr Corrales-Medina is supported by a research priority grant from the Department of Medicine of the Ottawa Hospital and a Junior Investigator Award from the Ottawa Hospital Research Institute. NR 33 TC 103 Z9 108 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 14 PY 2012 VL 125 IS 6 BP 773 EP U92 DI 10.1161/CIRCULATIONAHA.111.040766 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 896XR UT WOS:000300605200015 PM 22219349 ER PT J AU Cella, D Bushmakin, AG Cappelleri, JC Charbonneau, C Michaelson, MD Motzer, RJ AF Cella, D. Bushmakin, A. G. Cappelleri, J. C. Charbonneau, C. Michaelson, M. D. Motzer, R. J. TI Baseline quality of life as a prognostic survival tool in patients receiving sunitinib for metastatic renal cell carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE metastatic renal cell carcinoma; quality of life; prognostic tool; sunitinib; survival; Weibull model ID INTERFERON-ALPHA; TARGETED THERAPY; KIDNEY CANCER; SYMPTOMS; THROMBOCYTOSIS; VALIDATION; SORAFENIB; TRIAL; SCALE AB BACKGROUND: In a randomized phase III trial of sunitinib vs interferon-alfa (IFN-alpha) in metastatic renal cell carcinoma (mRCC), better baseline quality of life (QoL) was predictive of longer survival. Using this dataset, we have developed a novel prognostic tool that establishes a relationship between baseline QoL scores and median survival time. METHODS: Baseline QoL was assessed using the FACT-Kidney Symptom Index-15 item (FKSI-15), its disease-related symptoms (FKSI-DRS) subscale, and the Functional Assessment of Cancer Therapy-General (FACT-G) scale. Weibull models estimated median progression-free survival (mPFS) and overall survival (mOS) as a function of baseline QoL. RESULTS: Longer PFS and OS were associated with higher baseline FKSI-15, FKSI-DRS, and FACT-G scores (P<0.05), and baseline FKSI-15 score was the best predictor of survival. For example, for a baseline FKSI-15 score of 60, the predicted mPFS was 67.9 weeks, and predicted mOS was 240.6 weeks. The magnitude of benefit was greater with sunitinib vs IFN-alpha for a given baseline QoL score. CONCLUSION: This novel tool indicates that baseline FKSI-15 scores were linked to mPFS and mOS in a clear and interpretable way. The results support evaluation of patient-reported QoL symptoms at baseline as a prognostic indicator of survival in clinical research and practice. C1 [Cella, D.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL USA. [Bushmakin, A. G.; Cappelleri, J. C.] Pfizer Oncol, Global Res & Dev, New London, CT USA. [Charbonneau, C.] Pfizer Oncol, Global Outcomes Res, New York, NY USA. [Michaelson, M. D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Cella, D (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL USA. EM d-cella@northwestern.edu OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer FX We would like to thank all of the participating patients and their families, as well as the investigators, research nurses, study coordinators, and operations staff. This study was sponsored by Pfizer. Medical writing support was provided by Rachel Mason at ACUMED (Tytherington, UK) and was funded by Pfizer. NR 24 TC 11 Z9 11 U1 3 U2 6 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 FEB 14 PY 2012 VL 106 IS 4 BP 646 EP 650 DI 10.1038/bjc.2011.589 PG 5 WC Oncology SC Oncology GA 892RL UT WOS:000300303200006 PM 22240794 ER PT J AU Tanizaki, J Okamoto, I Takezawa, K Sakai, K Azuma, K Kuwata, K Yamaguchi, H Hatashita, E Nishio, K Janne, PA Nakagawa, K AF Tanizaki, J. Okamoto, I. Takezawa, K. Sakai, K. Azuma, K. Kuwata, K. Yamaguchi, H. Hatashita, E. Nishio, K. Janne, P. A. Nakagawa, K. TI Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE EML4-ALK; non-small-cell lung cancer; apoptosis; BIM; survivin ID EML4-ALK FUSION GENE; ANAPLASTIC LYMPHOMA; KINASE; IDENTIFICATION AB BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective. C1 [Tanizaki, J.; Okamoto, I.; Takezawa, K.; Sakai, K.; Azuma, K.; Kuwata, K.; Yamaguchi, H.; Hatashita, E.; Nakagawa, K.] Kinki Univ, Dept Med Oncol, Fac Med, Osaka 5898511, Japan. [Nishio, K.] Kinki Univ, Dept Genome Biol, Fac Med, Osaka 5898511, Japan. [Janne, P. A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Janne, P. A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Okamoto, I (reprint author), Kinki Univ, Dept Med Oncol, Fac Med, 377-2 Ohno Higashi, Osaka 5898511, Japan. EM chi-okamoto@dotd.med.kindai.ac.jp NR 11 TC 17 Z9 22 U1 0 U2 6 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 FEB 14 PY 2012 VL 106 IS 4 BP 763 EP 767 DI 10.1038/bjc.2011.586 PG 5 WC Oncology SC Oncology GA 892RL UT WOS:000300303200022 PM 22240786 ER PT J AU Brennan, JM Dai, D Patel, MR Rao, SV Armstrong, EJ Messenger, JC Curtis, JP Shunk, KA Anstrom, KJ Eisenstein, EL Weintraub, WS Peterson, ED Douglas, PS Hillegass, WB AF Brennan, J. Matthew Dai, David Patel, Manesh R. Rao, Sunil V. Armstrong, Ehrin J. Messenger, John C. Curtis, Jeptha P. Shunk, Kendrick A. Anstrom, Kevin J. Eisenstein, Eric L. Weintraub, William S. Peterson, Eric D. Douglas, Pamela S. Hillegass, William B. TI Characteristics and Long-Term Outcomes of Percutaneous Revascularization of Unprotected Left Main Coronary Artery Stenosis in the United States SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE long-term outcomes; percutaneous revascularization; unprotected left main coronary artery stenosis ID DRUG-ELUTING STENTS; CARDIAC-SURGERY; DISEASE; REGISTRY; INTERVENTION; IMPACT; SAFETY AB Objectives This study sought to assess percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) stenosis in routine U. S. clinical practice. Background Percutaneous coronary intervention for ULMCA stenosis is controversial; however, current use and outcomes of ULMCA PCI in routine U. S. clinical practice have not been described. Methods We evaluated 5,627 patients undergoing ULMCA PCI at 693 centers within the National Cardiovascular Data Registry Catheterization Percutaneous Coronary Intervention Registry for temporal trends in PCI use (2004 to 2008), patient characteristics, and in-hospital mortality. Thirty-month mortality and composite major adverse events (death, myocardial infarction, and revascularization) with drug-eluting versus bare-metal stents were compared using inverse probability weighted (IPW) hazard ratios (HRs) in a nonrandomized Medicare-linked (age >= 65 years) patient cohort (n = 2,765). Results ULMCA PCI was performed in 4.3% of patients with ULMCA stenosis. Unadjusted in-hospital mortality rates ranged from 2.9% for elective cases to 45.1% for emergent/salvage cases. By 30 months, 57.9% of the elderly ULMCA PCI population experienced death, myocardial infarction, or revascularization, and 42.7% died. Patients receiving drug-eluting stents (versus bare-metal stents) had a lower 30-month mortality (IPW HR: 0.84, 95% confidence interval [CI]: 0.73 to 0.96), but the composite of major adverse events were similar (IPW HR: 0.95, 95% CI: 0.84 to 1.06). Conclusions In the United States, ULMCA PCI is performed in <5% of patients with ULMCA disease and is generally reserved for those at high procedural risk. Adverse events are common in elderly patients and are related to patient and procedural characteristics, including stent type. (J Am Coll Cardiol 2012;59:648-54) (C) 2012 by the American College of Cardiology Foundation C1 [Brennan, J. Matthew; Dai, David; Patel, Manesh R.; Rao, Sunil V.; Anstrom, Kevin J.; Eisenstein, Eric L.; Peterson, Eric D.; Douglas, Pamela S.] Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Med, Durham, NC 27705 USA. [Armstrong, Ehrin J.] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Shunk, Kendrick A.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Armstrong, Ehrin J.; Shunk, Kendrick A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Messenger, John C.] Univ Colorado Denver Sch Med, Dept Med, Aurora, CO USA. [Curtis, Jeptha P.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Weintraub, William S.] Christiana Care Hosp, Dept Med, Newark, DE USA. [Hillegass, William B.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Brennan, JM (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, Dept Med, 2400 Pratt St,Suite 800, Durham, NC 27705 USA. EM brenn009@mc.duke.edu FU Agency for Healthcare Research and Quality, United States Department of Health and Human Services, Rockville, Maryland [ID 24-DKE-3, HHSAA290-2005-0032-TO4-WA2]; Cordis Corporation; Medtronic, Inc.; ACC-NCDR; Abbott Vascular; Alexion; AstraZeneca; Bristol-Myers Squibb; Eli Lilly; Innocoll Pharmaceuticals; Medtronic; PfizerProctor Gamble; Bristol-Myers Squibb/Sanofi-Aventis; Merck; Lilly; Johnson Johnson; Society of Thoracic Surgeons; American College of Cardiology; National Cardiovascular Data Registry, American College of Cardiology, Washington, DC; Siemens Medical Systems; SurgiVision; Revascular Therapeutics FX This project was sponsored by the Agency for Healthcare Research and Quality, United States Department of Health and Human Services, Rockville, Maryland, as part of the Cardiovascular Consortium and funded under Project ID 24-DKE-3 and Work Assignment Number HHSAA290-2005-0032-TO4-WA2 as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. Dr. Patel is a consultant for Bayer Healthcare, Ortho-McNeil Jansen, and Genzyme. Dr. Rao has received research funding from Cordis Corporation. Dr. Messenger is the site principal investigator for the Resolute and EDUCATE studies; and has received funding from Medtronic, Inc. Dr. Curtis receives salary support from the ACC-NCDR; and has equity holding in Medtronic. Dr. Shunk has received research funding from Abbott Vascular and Siemens Medical Systems and consulting fees from SurgiVision and Revascular Therapeutics. Dr. Anstrom has received research funding and salary support from Alexion, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Innocoll Pharmaceuticals, Medtronic, Pfizer, and Proctor & Gamble; serves on the data safety monitoring boards of Pfizer and Vertex; and receives consulting fees from Abbott Vascular, Ikaria, Pacific Therapeutics, Bristol-Myers Squibb, and AstraZeneca. Mr. Eisenstein has received research funding from Medtronic and Eli Lilly. Dr. Peterson has received research funding from Bristol-Myers Squibb/Sanofi-Aventis, Merck, Lilly, Johnson & Johnson, Society of Thoracic Surgeons, and American College of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or by the United States Department of Health and Human Services. Additional support was obtained from the National Cardiovascular Data Registry, American College of Cardiology, Washington, DC. NR 18 TC 28 Z9 32 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 FEB 14 PY 2012 VL 59 IS 7 BP 648 EP 654 DI 10.1016/j.jacc.2011.10.883 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 893YN UT WOS:000300393900004 PM 22322080 ER PT J AU Greenspon, AJ Prutkin, JM Sohail, MR Vikram, HR Baddour, LM Danik, SB Peacock, J Falces, C Miro, JM Blank, E Naber, C Carrillo, RG Tseng, CH Uslan, DZ AF Greenspon, Arnold J. Prutkin, Jordan M. Sohail, Muhammad R. Vikram, Holenarasipur R. Baddour, Larry M. Danik, Stephan B. Peacock, James Falces, Carlos Miro, Jose M. Blank, Elisabeth Naber, Christoph Carrillo, Roger G. Tseng, Chi-Hong Uslan, Daniel Z. TI Timing of the Most Recent Device Procedure Influences the Clinical Outcome of Lead-Associated Endocarditis Results of the MEDIC (Multicenter Electrophysiologic Device Infection Cohort) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE endocarditis; implantable cardioverter-defibrillator; permanent pacemaker ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS; STAPHYLOCOCCUS-AUREUS BACTEREMIA; PERMANENT PACEMAKER; MYOCARDIAL-INFARCTION; TEMPORAL TRENDS; MANAGEMENT; COMPLICATIONS; BENEFICIARIES; RISK; EXTRACTION AB Objectives The purpose of this study was to determine whether the timing of the most recent cardiac implantable electronic device (CIED) procedure, either a permanent pacemaker or implantable cardioverter-defibrillator, influences the clinical presentation and outcome of lead-associated endocarditis (LAE). Background The CIED infection rate has increased at a time of increased device use. LAE is associated with significant morbidity and mortality. Methods The clinical presentation and course of LAE were evaluated by the MEDIC (Multicenter Electrophysiologic Device Cohort) registry, an international registry enrolling patients with CIED infection. Consecutive LAE patients enrolled in the Multicenter Electrophysiologic Device Cohort registry between January 2009 and May 2011 were analyzed. The clinical features and outcomes of 2 groups were compared based on the time from the most recent CIED procedure (early, <6 months; late, >6 months). Results The Multicenter Electrophysiologic Device Cohort registry entered 145 patients with LAE (early = 43, late = 102). Early LAE patients presented with signs and symptoms of local pocket infection, whereas a remote source of bacteremia was present in 38% of patients with late LAE but only 8% of early LAE (p < 0.01). Staphylococcal species were the most frequent pathogens in both early and late LAE. Treatment consisted of removal of all hardware and intravenous administration of antibiotics. In-hospital mortality was low (early = 7%, late = 6%). Conclusions The clinical presentation of LAE is influenced by the time from the most recent CIED procedure. Although clinical manifestations of pocket infection are present in the majority of patients with early LAE, late LAE should be considered in any CIED patient who presents with fever, bloodstream infection, or signs of sepsis, even if the device pocket appears uninfected. Prompt recognition and management may improve outcomes. (J Am Coll Cardiol 2012;59:681-7) (C) 2012 by the American College of Cardiology Foundation C1 [Greenspon, Arnold J.] Thomas Jefferson Univ Hosp, Cardiac Electrophysiol Lab, Jefferson Heart Inst, Philadelphia, PA 19107 USA. [Prutkin, Jordan M.] Univ Washington, Seattle, WA 98195 USA. [Sohail, Muhammad R.; Baddour, Larry M.] Mayo Clin, Coll Med, Rochester, MN USA. [Vikram, Holenarasipur R.] Mayo Clin, Phoenix, AZ USA. [Danik, Stephan B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peacock, James] Wake Forest Univ, Winston Salem, NC 27109 USA. [Falces, Carlos; Miro, Jose M.] Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain. [Blank, Elisabeth; Naber, Christoph] Elisabeth Hosp, Essen, Germany. [Carrillo, Roger G.] Univ Miami, Miami, FL USA. [Tseng, Chi-Hong; Uslan, Daniel Z.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Greenspon, AJ (reprint author), Thomas Jefferson Univ Hosp, Cardiac Electrophysiol Lab, Jefferson Heart Inst, 925 Chestnut St, Philadelphia, PA 19107 USA. EM arnold.greenspon@jefferson.edu RI Carrillo, Roger/C-2231-2015; Sohail, Muhammad/K-1803-2016; OI Carrillo, Roger/0000-0002-0443-8689; Sohail, Muhammad/0000-0001-6355-0526; Falces, Carlos/0000-0002-3483-3786 FU American Heart Association; St. Jude Medical FX This study was funded, in part, by a grant from the American Heart Association (Dr. Uslan, Primary Investigator). Dr. Greenspon has received speaker honoraria from Medtronic, Boston Scientific, and St. Jude Medical. Dr. Sohail is a consultant to TyRx. Dr. Carrillo is a consultant to Spectranetics; is on the Speaker's Bureau of St. Jude Medical and Boston Scientific; and is the recipient of a research grant from St. Jude Medical. Dr. Uslan is a consultant to Medtronic and TyRx; and has received honoraria from Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 36 Z9 37 U1 0 U2 2 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 FEB 14 PY 2012 VL 59 IS 7 BP 681 EP 687 DI 10.1016/j.jacc.2011.11.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 893YN UT WOS:000300393900009 PM 22322085 ER PT J AU DiGiovanna, J Carpaneto, J Micera, S Merfeld, DM AF DiGiovanna, Jack Carpaneto, Jacopo Micera, Silvestro Merfeld, Daniel M. TI Alignment of angular velocity sensors for a vestibular prosthesis SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Vestibular prosthetics; sensor alignment; neuro-prosthetics ID SEMICIRCULAR CANAL PROSTHESIS; ELECTRICAL-STIMULATION; ADAPTATION; SYSTEM AB Vestibular prosthetics transmit angular velocities to the nervous system via electrical stimulation. Head-fixed gyroscopes measure angular motion, but the gyroscope coordinate system will not be coincident with the sensory organs the prosthetic replaces. Here we show a simple calibration method to align gyroscope measurements with the anatomical coordinate system. We benchmarked the method with simulated movements and obtain proof-of-concept with one healthy subject. The method was robust to misalignment, required little data, and minimal processing. C1 [DiGiovanna, Jack; Micera, Silvestro] ETH, Automat Control Lab, Neuroprosthet Control Grp, CH-8092 Zurich, Switzerland. [Carpaneto, Jacopo; Micera, Silvestro] Scuola Super Sant Anna, BioRobot Inst, Pisa, Italy. [Merfeld, Daniel M.] Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. [Merfeld, Daniel M.] Harvard Univ, Sch Med, Boston, MA USA. RP DiGiovanna, J (reprint author), ETH, Automat Control Lab, Neuroprosthet Control Grp, Phys Str 3,ETL K24, CH-8092 Zurich, Switzerland. EM digiovanna@control.ee.ethz.ch FU EU [225929] FX We thank Vito Monaco for invaluable assistance in validating angular velocity calculations based on marker data. We also thank Dr. Andrea Gesi for donating the bite-bar apparatus used in this study. Financial support for the authors was provided in part by the EU Future & Emerging Technologies Open Scheme, Project 225929 (CLONS). NR 20 TC 5 Z9 5 U1 1 U2 4 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 FEB 13 PY 2012 VL 9 AR 14 DI 10.1186/1743-0003-9-14 PG 13 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 951YL UT WOS:000304756500001 PM 22329908 ER PT J AU Bentink, S Haibe-Kains, B Risch, T Fan, JB Hirsch, MS Holton, K Rubio, R April, C Chen, J Wickham-Garcia, E Liu, J Culhane, A Drapkin, R Quackenbush, J Matulonis, UA AF Bentink, Stefan Haibe-Kains, Benjamin Risch, Thomas Fan, Jian-Bing Hirsch, Michelle S. Holton, Kristina Rubio, Renee April, Craig Chen, Jing Wickham-Garcia, Eliza Liu, Joyce Culhane, Aedin Drapkin, Ronny Quackenbush, John Matulonis, Ursula A. TI Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer SO PLOS ONE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; ILLUMINA MICROARRAY; STAGE-III; PHASE-II; SURVIVAL; PACLITAXEL; PROFILES; CHEMOTHERAPY; BEVACIZUMAB; VALIDATION AB Ovarian cancer is the fifth leading cause of cancer death for women in the U.S. and the seventh most fatal worldwide. Although ovarian cancer is notable for its initial sensitivity to platinum-based therapies, the vast majority of patients eventually develop recurrent cancer and succumb to increasingly platinum-resistant disease. Modern, targeted cancer drugs intervene in cell signaling, and identifying key disease mechanisms and pathways would greatly advance our treatment abilities. In order to shed light on the molecular diversity of ovarian cancer, we performed comprehensive transcriptional profiling on 129 advanced stage, high grade serous ovarian cancers. We implemented a, re-sampling based version of the ISIS class discovery algorithm (rISIS: robust ISIS) and applied it to the entire set of ovarian cancer transcriptional profiles. rISIS identified a previously undescribed patient stratification, further supported by micro-RNA expression profiles, and gene set enrichment analysis found strong biological support for the stratification by extracellular matrix, cell adhesion, and angiogenesis genes. The corresponding "angiogenesis signature'' was validated in ten published independent ovarian cancer gene expression datasets and is significantly associated with overall survival. The subtypes we have defined are of potential translational interest as they may be relevant for identifying patients who may benefit from the addition of anti-angiogenic therapies that are now being tested in clinical trials. C1 [Bentink, Stefan; Haibe-Kains, Benjamin; Risch, Thomas; Holton, Kristina; Rubio, Renee; Culhane, Aedin; Quackenbush, John] Dana Farber Canc Inst, Dept Biostatist & Computat Biol, Boston, MA 02115 USA. [Liu, Joyce; Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Fan, Jian-Bing; April, Craig; Chen, Jing; Wickham-Garcia, Eliza] Illumina Inc, San Diego, CA USA. [Hirsch, Michelle S.; Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Div Womans & Perinatal Pathol, Boston, MA 02115 USA. [Drapkin, Ronny; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bentink, Stefan; Haibe-Kains, Benjamin; Culhane, Aedin; Quackenbush, John] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hirsch, Michelle S.; Liu, Joyce; Drapkin, Ronny; Matulonis, Ursula A.] Harvard Univ, Sch Med, Boston, MA USA. RP Bentink, S (reprint author), Dana Farber Canc Inst, Dept Biostatist & Computat Biol, Boston, MA 02115 USA. EM johnq@jimmy.harvard.edu RI Haibe-Kains, Benjamin/D-3702-2011; Drapkin, Ronny/E-9944-2016 OI Haibe-Kains, Benjamin/0000-0002-7684-0079; Drapkin, Ronny/0000-0002-6912-6977 FU Dana-Farber/Harvard Cancer Center; Claudia Adams Barr Foundation; Kittredge Foundation; Dana-Farber Cancer Institute; National Cancer Institute [3P50 CA105009-05S1] FX This work was supported by grants from the Dana-Farber/Harvard Cancer Center Women's Cancer Program, the Claudia Adams Barr Foundation, the Kittredge Foundation, and the Dana-Farber Cancer Institute High Tech Fund. Additional support was provided by a grant from the National Cancer Institute (3P50 CA105009-05S1). The DASL assays were provided by Illumina, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 39 Z9 41 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 13 PY 2012 VL 7 IS 2 AR e30269 DI 10.1371/journal.pone.0030269 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 925BB UT WOS:000302733900005 PM 22348002 ER PT J AU Weigert, O Lane, AA Bird, L Kopp, N Chapuy, B van Bodegom, D Toms, AV Marubayashi, S Christie, AL McKeown, M Paranal, RM Bradner, JE Yoda, A Gaul, C Vangrevelinghe, E Romanet, V Murakami, M Tiedt, R Ebel, N Evrot, E De Pover, A Regnier, CH Erdmann, D Hofmann, F Eck, MJ Sallan, SE Levine, RL Kung, AL Baffert, F Radimerski, T Weinstock, DM AF Weigert, Oliver Lane, Andrew A. Bird, Liat Kopp, Nadja Chapuy, Bjoern van Bodegom, Diederik Toms, Angela V. Marubayashi, Sachie Christie, Amanda L. McKeown, Michael Paranal, Ronald M. Bradner, James E. Yoda, Akinori Gaul, Christoph Vangrevelinghe, Eric Romanet, Vincent Murakami, Masato Tiedt, Ralph Ebel, Nicolas Evrot, Emeline De Pover, Alain Regnier, Catherine H. Erdmann, Dirk Hofmann, Francesco Eck, Michael J. Sallan, Stephen E. Levine, Ross L. Kung, Andrew L. Baffert, Fabienne Radimerski, Thomas Weinstock, David M. TI Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-CELL LYMPHOMAS; POLYCYTHEMIA-VERA; TYROSINE KINASE; ANTITUMOR-ACTIVITY; BCR-ABL; MYELOPROLIFERATIVE DISORDERS; ACTIVATING MUTATION; MYELOID METAPLASIA; CANCER AB Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor-like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100-1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors. C1 [Weigert, Oliver; Lane, Andrew A.; Bird, Liat; Kopp, Nadja; Chapuy, Bjoern; van Bodegom, Diederik; McKeown, Michael; Paranal, Ronald M.; Bradner, James E.; Yoda, Akinori; Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Toms, Angela V.; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Christie, Amanda L.; Sallan, Stephen E.; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Marubayashi, Sachie; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Human Oncol Pathogenesis Program, New York, NY 10065 USA. [Marubayashi, Sachie; Levine, Ross L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10065 USA. [Gaul, Christoph; Vangrevelinghe, Eric; Romanet, Vincent; Murakami, Masato; Tiedt, Ralph; Ebel, Nicolas; Evrot, Emeline; De Pover, Alain; Regnier, Catherine H.; Erdmann, Dirk; Hofmann, Francesco; Baffert, Fabienne; Radimerski, Thomas] Novartis Inst Biomed Res, CH-4057 Basel, Switzerland. [Toms, Angela V.; Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kung, Andrew L.; Weinstock, David M.] Harvard Univ, Sch Med, Dept Biol & Biomed Sci, Boston, MA 02115 USA. EM thomas.radimerski@novartis.com; dweinstock@partners.org OI Regnier, Catherine/0000-0002-4386-1324; Kung, Andrew/0000-0002-9091-488X FU Deutsche Forschungsgemeinschaft; NCI [1R01CA151898-01]; DFCI/Novartis; Novartis FX O. Weigert is supported by the Deutsche Forschungsgemeinschaft. This work was supported by NCI 1R01CA151898-01 (D.M. Weinstock) and the DFCI/Novartis Drug Discovery Program (D.M. Weinstock).; C. Gaul, E. Vangrevelinghe, V. Romanet, M. Murakami, R. Teidt, N. Ebel, E. Evrot, A. De Pover, C. H. Regnier, D. Erdmann, F. Hofmann, F. Baffert, and T. Radimerski are employed by the Novartis Institute for Biomedical Research. M.J. Eck, A. L. Kung, and D.M. Weinstock are paid consultants and receive research support from Novartis. NR 55 TC 81 Z9 83 U1 2 U2 13 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 FEB 13 PY 2012 VL 209 IS 2 BP 259 EP 273 DI 10.1084/jem.20111694 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 914IO UT WOS:000301943200008 PM 22271575 ER PT J AU Hur, KY So, JS Ruda, V Frank-Kamenetsky, M Fitzgerald, K Koteliansky, V Iwawaki, T Glimcher, LH Lee, AH AF Hur, Kyu Yeon So, Jae-Seon Ruda, Vera Frank-Kamenetsky, Maria Fitzgerald, Kevin Koteliansky, Victor Iwawaki, Takao Glimcher, Laurie H. Lee, Ann-Hwee TI IRE1 alpha activation protects mice against acetaminophen-induced hepatotoxicity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INDUCED LIVER-INJURY; TRANSCRIPTION FACTOR XBP-1; INDUCED HEPATIC-NECROSIS; ENDOPLASMIC-RETICULUM; MESSENGER-RNA; ER STRESS; TRANSMEMBRANE PROTEIN; TERMINAL KINASE; OXIDATIVE STRESS; IRE1 AB The mammalian stress sensor IRE1 alpha plays a central role in the unfolded protein, or endoplasmic reticulum (ER), stress response by activating its downstream transcription factor XBP1 via an unconventional splicing mechanism. IRE1 alpha can also induce the degradation of a subset of mRNAs in a process termed regulated IRE1-dependent decay (RIDD). Although diverse mRNA species can be degraded by IRE1 alpha in vitro, the pathophysiological functions of RIDD are only beginning to be explored. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in young adults in the United States and is primarily caused by CYP1A2-, CYP2E1-, and CYP3A4-driven conversion of APAP into hepatotoxic metabolites. We demonstrate here that genetic ablation of XBP1 results in constitutive IRE1 alpha activation in the liver, leading to RIDD of Cyp1a2 and Cyp2e1 mRNAs, reduced JNK activation, and protection of mice from APAP-induced hepatotoxicity. A pharmacological ER stress inducer that activated IRE1 alpha suppressed the expression of Cyp1a2 and Cyp2e1 in WT, but not IRE1 alpha-deficient mouse liver, indicating the essential role of IRE1 alpha in the down-regulation of these mRNAs upon ER stress. Our study reveals an unexpected function of RIDD in drug metabolism. C1 [Hur, Kyu Yeon; So, Jae-Seon; Glimcher, Laurie H.; Lee, Ann-Hwee] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Ruda, Vera] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ruda, Vera] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ruda, Vera] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Frank-Kamenetsky, Maria; Fitzgerald, Kevin; Koteliansky, Victor] Alnylam Pharmaceut, Cambridge, MA 02142 USA. [Iwawaki, Takao] Inst Phys & Chem Res, Iwawaki Initiat Res Unit, Wako, Saitama 3510198, Japan. [Iwawaki, Takao] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. [Iwawaki, Takao] Gunma Univ, Adv Sci Res Leaders Dev Unit, Gunma 3718511, Japan. [Glimcher, Laurie H.; Lee, Ann-Hwee] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Glimcher, Laurie H.] MIT, Ragon Inst MGH, Boston, MA 02115 USA. [Glimcher, Laurie H.] Harvard, Boston, MA 02115 USA. EM lglimche@hsph.harvard.edu; ahlee@hsph.harvard.edu FU National Institutes of Health [AI32412, DK082448, DK089211]; American Heart Association FX This study was supported by National Institutes of Health grants AI32412 (L.H. Glimcher), DK082448 (L.H. Glimcher), and DK089211 (A.-H. Lee), and a grant from the American Heart Association (A.-H. Lee). NR 60 TC 55 Z9 56 U1 1 U2 8 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 FEB 13 PY 2012 VL 209 IS 2 BP 307 EP 318 DI 10.1084/jem.20111298 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 914IO UT WOS:000301943200011 PM 22291093 ER PT J AU Schubert, DA Gordo, S Sabatino, JJ Vardhana, S Gagnon, E Sethi, DK Seth, NP Choudhuri, K Reijonen, H Nepom, GT Evavold, BD Dustin, ML Wucherpfennig, KW AF Schubert, David A. Gordo, Susana Sabatino, Joseph J., Jr. Vardhana, Santosh Gagnon, Etienne Sethi, Dhruv K. Seth, Nilufer P. Choudhuri, Kaushik Reijonen, Helena Nepom, Gerald T. Evavold, Brian D. Dustin, Michael L. Wucherpfennig, Kai W. TI Self-reactive human CD4 T cell clones form unusual immunological synapses SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SUPRAMOLECULAR ACTIVATION CLUSTER; THYMIC EPITHELIAL-CELLS; KINASE-C-THETA; PEPTIDE-MHC; RECEPTOR MICROCLUSTERS; ADHESION MOLECULES; NEGATIVE SELECTION; ACTIN CYTOSKELETON; IN-VITRO; HLA-DM AB Recognition of self-peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR-pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease. C1 [Schubert, David A.; Gordo, Susana; Gagnon, Etienne; Sethi, Dhruv K.; Seth, Nilufer P.; Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. [Sabatino, Joseph J., Jr.; Evavold, Brian D.] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Vardhana, Santosh; Choudhuri, Kaushik; Dustin, Michael L.] Helen L & Martin S Kimmel Ctr Biol & Med, Skirball Inst Biomol Med, Program Mol Pathogenesis, New York, NY 10016 USA. [Vardhana, Santosh; Choudhuri, Kaushik; Dustin, Michael L.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Reijonen, Helena; Nepom, Gerald T.] Benaroya Res Inst Virginia Mason, Seattle, WA 98101 USA. EM kai_wucherpfennig@dfci.harvard.edu OI Vardhana, Santosha/0000-0002-3100-1298; Nepom, Gerald/0000-0002-8063-1464; Dustin, Michael/0000-0003-4983-6389 FU National Institutes of Health [PO1 AI045757]; Cancer Research Institute; Ernst-Schering Foundation; Generalitat de Catalunya - AGAUR; National Multiple Sclerosis Society FX This work was supported by grants from the National Institutes of Health (PO1 AI045757 to K.W. Wucherpfennig and M. L. Dustin) and by postdoctoral fellowships from the Cancer Research Institute (to D. A. Schubert and E. Gagnon), the Ernst-Schering Foundation (to D. A. Schubert), the Generalitat de Catalunya - AGAUR (to S. Gordo), and the National Multiple Sclerosis Society (to D.K. Sethi). NR 64 TC 33 Z9 34 U1 1 U2 7 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 FEB 13 PY 2012 VL 209 IS 2 BP 335 EP 352 DI 10.1084/jem.20111485 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 914IO UT WOS:000301943200013 PM 22312112 ER PT J AU Partridge, AH AF Partridge, Ann H. TI Ovarian Suppression for Prevention of Premature Menopause and Infertility: Empty Promise or Effective Therapy? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PREMENOPAUSAL BREAST-CANCER; ADJUVANT CHEMOTHERAPY; PROGNOSTIC IMPACT; YOUNG-WOMEN; AMENORRHEA; FERTILITY; TRIAL C1 [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Partridge, Ann H.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 14 TC 10 Z9 11 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 FEB 10 PY 2012 VL 30 IS 5 BP 479 EP 481 DI 10.1200/JCO.2011.37.9883 PG 3 WC Oncology SC Oncology GA 923MH UT WOS:000302622900011 PM 22231046 ER PT J AU Roberts, AW Seymour, JF Brown, JR Wierda, WG Kipps, TJ Khaw, SL Carney, DA He, SZ Huang, DCS Xiong, H Cui, Y Busman, TA McKeegan, EM Krivoshik, AP Enschede, SH Humerickhouse, R AF Roberts, Andrew W. Seymour, John F. Brown, Jennifer R. Wierda, William G. Kipps, Thomas J. Khaw, Seong Lin Carney, Dennis A. He, Simon Z. Huang, David C. S. Xiong, Hao Cui, Yue Busman, Todd A. McKeegan, Evelyn M. Krivoshik, Andrew P. Enschede, Sari H. Humerickhouse, Rod TI Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BH3 MIMETIC ABT-737; CELL-DEATH; ANTAGONIST ABT-737; LYMPHOMA-CELLS; FAMILY; CANCER; APOPTOSIS; CHEMOTHERAPY; SENSITIVITY; RESISTANCE AB Purpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-x(L) and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and Methods Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. Results Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax >= 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to >= 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-x(L) inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM: BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. Conclusion BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease. J Clin Oncol 30: 488-496. (C) 2011 by American Society of Clinical Oncology C1 [Roberts, Andrew W.] Royal Melbourne Hosp, Dept Clin Haematol, Parkville, Vic 3050, Australia. [Roberts, Andrew W.; Khaw, Seong Lin; He, Simon Z.; Huang, David C. S.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Roberts, Andrew W.; Huang, David C. S.] Australian Canc Res Fdn Ctr Therapeut Target Disc, Parkville, Vic, Australia. [Roberts, Andrew W.; Seymour, John F.; Khaw, Seong Lin; Carney, Dennis A.; He, Simon Z.; Huang, David C. S.] Univ Melbourne, Parkville, Vic 3052, Australia. [Seymour, John F.; Carney, Dennis A.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wierda, William G.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kipps, Thomas J.] Moores Univ Calif, San Diego Canc Ctr, La Jolla, CA USA. [Xiong, Hao; Cui, Yue; Busman, Todd A.; McKeegan, Evelyn M.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod] Abbott Labs, Abbott Pk, IL 60064 USA. RP Roberts, AW (reprint author), Royal Melbourne Hosp, Dept Clin Haematol, 2 Ctr,Grattan St, Parkville, Vic 3050, Australia. EM roberts@wehi.edu.au RI Roberts, Andrew/C-6736-2012; Huang, David/C-7586-2013 OI Roberts, Andrew/0000-0002-7341-5720; FU Abbott Laboratories; Celgene; Genzyme; GlaxoSmithKline; Genentech; National Health and Medical Research Council of Australia; Victorian Cancer Agency; Leukaemia Foundation Australia; Australian Cancer Research Foundation; Leukemia and Lymphoma Society FX Research Funding: Andrew W. Roberts, Abbott Laboratories; Jennifer R. Brown, Celgene, Genzyme; William G. Wierda, GlaxoSmithKline, Abbott Laboratories; Thomas J. Kipps, Abbott Laboratories; Supported by Abbott Laboratories and Genentech. Additional support for correlative studies was provided by National Health and Medical Research Council of Australia, Victorian Cancer Agency, Leukaemia Foundation Australia, Australian Cancer Research Foundation, and the Leukemia and Lymphoma Society. NR 34 TC 300 Z9 302 U1 0 U2 29 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 FEB 10 PY 2012 VL 30 IS 5 BP 488 EP 496 DI 10.1200/JCO.2011.34.7898 PG 9 WC Oncology SC Oncology GA 923MH UT WOS:000302622900013 PM 22184378 ER PT J AU Choueiri, TK Ross, RW Jacobus, S Vaishampayan, U Yu, EY Quinn, DI Hahn, NM Hutson, TE Sonpavde, G Morrissey, SC Buckle, GC Kim, WY Petrylak, DP Ryan, CW Eisenberger, MA Mortazavi, A Bubley, GJ Taplin, ME Rosenberg, JE Kantoff, PW AF Choueiri, Toni K. Ross, Robert W. Jacobus, Susanna Vaishampayan, Ulka Yu, Evan Y. Quinn, David I. Hahn, Noah M. Hutson, Thomas E. Sonpavde, Guru Morrissey, Stephanie C. Buckle, Geoffrey C. Kim, William Y. Petrylak, Daniel P. Ryan, Christopher W. Eisenberger, Mario A. Mortazavi, Amir Bubley, Glenn J. Taplin, Mary-Ellen Rosenberg, Jonathan E. Kantoff, Philip W. TI Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; PHASE-II TRIAL; EPIDERMAL-GROWTH-FACTOR; ADVANCED BLADDER-CANCER; 2ND-LINE TREATMENT; PROGNOSTIC-FACTORS; ONCOLOGY-GROUP; LUNG-CANCER; PACLITAXEL; CHEMOTHERAPY AB Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Patients and Methods The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided alpha at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. Results In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. Conclusion In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal. J Clin Oncol 30: 507-512. (C) 2011 by American Society of Clinical Oncology C1 [Choueiri, Toni K.; Ross, Robert W.; Jacobus, Susanna; Morrissey, Stephanie C.; Buckle, Geoffrey C.; Taplin, Mary-Ellen; Rosenberg, Jonathan E.; Kantoff, Philip W.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Bubley, Glenn J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Vaishampayan, Ulka] Karmanos Canc Inst, Detroit, MI USA. [Yu, Evan Y.] Univ Washington, Seattle, WA 98195 USA. [Quinn, David I.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Hahn, Noah M.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Hutson, Thomas E.] Baylor Sammons Canc Ctr, Dallas, TX USA. [Sonpavde, Guru] Baylor Coll Med, Houston, TX 77030 USA. [Kim, William Y.] Univ N Carolina, Chapel Hill, NC USA. [Petrylak, Daniel P.] Columbia Univ, Med Ctr, New York, NY USA. [Ryan, Christopher W.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Eisenberger, Mario A.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Mortazavi, Amir] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Mortazavi, Amir] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Choueiri, TK (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,DANA 1230, Boston, MA 02215 USA. EM Toni_Choueiri@dfci.harvard.edu RI Quinn, David/F-4343-2015 OI Quinn, David/0000-0002-1411-0417 FU AstraZeneca; Dana-Farber Cancer Institute; sanofi-aventis; Bristol-Myers Squibb; Pfizer; Millennium Pharmaceuticals; Celgene; Genentech; Merck; Novartis FX Supported by AstraZeneca and Friends of Dana-Farber Cancer Institute.; Research Funding: Ulka Vaishampayan, sanofi-aventis; Evan Y. Yu, AstraZeneca; Noah M. Hahn, sanofi-aventis, Bristol-Myers Squibb, AstraZeneca, Pfizer, Millennium Pharmaceuticals, Celgene, Genentech, Merck, Novartis NR 28 TC 81 Z9 81 U1 1 U2 2 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 FEB 10 PY 2012 VL 30 IS 5 BP 507 EP 512 DI 10.1200/JCO.2011.37.7002 PG 6 WC Oncology SC Oncology GA 923MH UT WOS:000302622900015 PM 22184381 ER PT J AU Barry, MJ Gallagher, PM Skinner, JS Fowler, FJ AF Barry, Michael J. Gallagher, Patricia M. Skinner, Jonathan S. Fowler, Floyd J., Jr. TI Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; CANCER; OUTCOMES; SATISFACTION; SURGERY; UROLOGY; URINARY AB Purpose Robotic-assisted laparoscopic radical prostatectomy is eclipsing open radical prostatectomy among men with clinically localized prostate cancer. The objective of this study was to compare the risks of problems with continence and sexual function following these procedures among Medicare-age men. Patients and Methods A population-based random sample was drawn from the 20% Medicare claims files for August 1, 2008, through December 31, 2008. Participants had hospital and physician claims for radical prostatectomy and diagnostic codes for prostate cancer and reported undergoing either a robotic or open surgery. They received a mail survey that included self-ratings of problems with continence and sexual function a median of 14 months postoperatively. Results Completed surveys were obtained from 685 (86%) of 797 eligible participants, and 406 and 220 patients reported having had robotic or open surgery, respectively. Overall, 189 (31.1%; 95% CI, 27.5% to 34.8%) of 607 men reported having a moderate or big problem with continence, and 522 (88.0%; 95% CI, 85.4% to 90.6%) of 593 men reported having a moderate or big problem with sexual function. In logistic regression models predicting the log odds of a moderate or big problem with postoperative continence and adjusting for age and educational level, robotic prostatectomy was associated with a nonsignificant trend toward greater problems with continence (odds ratio [ OR] 1.41; 95% CI, 0.97 to 2.05). Robotic prostatectomy was not associated with greater problems with sexual function (OR, 0.87; 95% CI, 0.51 to 1.49). Conclusion Risks of problems with continence and sexual function are high after both procedures. Medicare-age men should not expect fewer adverse effects following robotic prostatectomy. J Clin Oncol 30:513-518. (C) 2012 by American Society of Clinical Oncology C1 [Barry, Michael J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gallagher, Patricia M.; Fowler, Floyd J., Jr.] Univ Massachusetts, Boston, MA 02125 USA. [Barry, Michael J.; Fowler, Floyd J., Jr.] Fdn Informed Med Decis Making, Boston, MA USA. [Skinner, Jonathan S.] Dartmouth Coll, Hanover, NH 03755 USA. [Skinner, Jonathan S.] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM mbarry@partners.org FU National Institute on Aging [2 P01 AG019783-08] FX Supported by Grant No. 2 P01 AG019783-08 from the National Institute on Aging. NR 28 TC 77 Z9 79 U1 0 U2 2 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 FEB 10 PY 2012 VL 30 IS 5 BP 513 EP 518 DI 10.1200/JCO.2011.36.8621 PG 6 WC Oncology SC Oncology GA 923MH UT WOS:000302622900016 PM 22215756 ER PT J AU Walensky, LD AF Walensky, Loren D. TI From Mitochondrial Biology to Magic Bullet: Navitoclax Disarms BCL-2 in Chronic Lymphocytic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BH3 MIMETIC ABT-737; CHROMOSOME-TRANSLOCATION; INHIBITOR; APOPTOSIS; PROTEINS; FAMILY; MCL-1; RESISTANCE; MUTAGENESIS; LIGANDS C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA050239] NR 26 TC 18 Z9 20 U1 1 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 FEB 10 PY 2012 VL 30 IS 5 BP 554 EP 557 DI 10.1200/JCO.2011.37.9339 PG 4 WC Oncology SC Oncology GA 923MH UT WOS:000302622900022 PM 22184389 ER PT J AU Wen, PY Schiff, D Cloughesy, TF Reardon, DA Batchelor, TT DeAngelis, LM AF Wen, Patrick Y. Schiff, David Cloughesy, Timothy F. Reardon, David A. Batchelor, Tracy T. DeAngelis, Lisa M. TI Toward a Better Dialogue Between Neuro-Oncologists and Phase I Investigators Response SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Wen, Patrick Y.; Reardon, David A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wen, Patrick Y.; Reardon, David A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schiff, David] Univ Virginia, Charlottesville, VA USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Los Angeles, CA USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [DeAngelis, Lisa M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Wen, PY (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 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 FEB 10 PY 2012 VL 30 IS 5 BP 563 EP 564 DI 10.1200/JCO.2011.40.1513 PG 3 WC Oncology SC Oncology GA 923MH UT WOS:000302622900027 ER PT J AU Lee, HJ Mariappan, MM Feliers, D Cavaglieri, RC Sataranatarajan, K Abboud, HE Choudhury, GG Kasinath, BS AF Lee, Hak Joo Mariappan, Meenalakshmi M. Feliers, Denis Cavaglieri, Rita C. Sataranatarajan, Kavithalakshmi Abboud, Hanna E. Choudhury, Goutam Ghosh Kasinath, Balakuntalam S. TI Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA TRANSLATION; CYSTATHIONINE-GAMMA-LYASE; DIABETIC-NEPHROPATHY; MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY; SULFANE SULFUR; KNOCKOUT MICE; HYPERTROPHY; GROWTH; RAT AB Hydrogen sulfide, a signaling gas, affects several cell functions. We hypothesized that hydrogen sulfide modulates high glucose (30 mM) stimulation of matrix protein synthesis in glomerular epithelial cells. High glucose stimulation of global protein synthesis, cellular hypertrophy, and matrix laminin and type IV collagen content was inhibited by sodium hydrosulfide (NaHS), an H2S donor. High glucose activation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1), shown by phosphorylation of p70S6 kinase and 4E-BP1, was inhibited by NaHS. High glucose stimulated mTORC1 to promote key events in the initiation and elongation phases of mRNA translation: binding of eIF4A to eIF4G, reduction in PDCD4 expression and inhibition of its binding to eIF4A, eEF2 kinase phosphorylation, and dephosphorylation of eEF2; these events were inhibited by NaHS. The role of AMP-activated protein kinase (AMPK), an inhibitor of protein synthesis, was examined. NaHS dose-dependently stimulated AMPK phosphorylation and restored AMPK phosphorylation reduced by high glucose. Compound C, an AMPK inhibitor, abolished NaHS modulation of high glucose effect on events in mRNA translation as well as global and matrix protein synthesis. NaHS induction of AMPK phosphorylation was inhibited by siRNA for calmodulin kinase kinase beta, but not LKB1, upstream kinases for AMPK; STO-609, a calmodulin kinase kinase beta inhibitor, had the same effect. Renal cortical content of cystathionine beta-synthase and cystathionine gamma-lyase, hydrogen sulfide-generating enzymes, was significantly reduced in mice with type 1 diabetes or type 2 diabetes, coinciding with renal hypertrophy and matrix accumulation. Hydrogen sulfide is a newly identified modulator of protein synthesis in the kidney, and reduction in its generation may contribute to kidney injury in diabetes. C1 [Lee, Hak Joo; Mariappan, Meenalakshmi M.; Feliers, Denis; Cavaglieri, Rita C.; Sataranatarajan, Kavithalakshmi; Abboud, Hanna E.; Choudhury, Goutam Ghosh; Kasinath, Balakuntalam S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Lee, Hak Joo; Mariappan, Meenalakshmi M.; Sataranatarajan, Kavithalakshmi; Abboud, Hanna E.; Choudhury, Goutam Ghosh; Kasinath, Balakuntalam S.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Kasinath, BS (reprint author), 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM kasinath@uthscsa.edu FU National Institutes of Health [DK077295, RC2AG036613, DK050190]; Veterans Affairs Medical Research Service; Juvenile Diabetes Research Foundation [1-2010-141, 1-2008-185]; Veterans Affairs Research Career Scientist Award FX This work was supported, in whole or in part, by National Institutes of Health Grants DK077295 and RC2AG036613 (to B. S. K.) and DK050190 (to G. G. C.). This work was also supported by a grant from the Veterans Affairs Medical Research Service (to B. S. K. and G. G. C.) and Juvenile Diabetes Research Foundation Grants 1-2010-141 (to D. F.) and 1-2008-185 (to G. G. C.).; Recipient of a Veterans Affairs Research Career Scientist Award. NR 65 TC 39 Z9 42 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 FEB 10 PY 2012 VL 287 IS 7 BP 4451 EP 4461 DI 10.1074/jbc.M111.278325 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500009 PM 22158625 ER PT J AU Maeno, Y Li, Q Park, K Rask-Madsen, C Gao, BB Matsumoto, M Liu, YJ Wu, IH White, MF Feener, EP King, GL AF Maeno, Yasuhiro Li, Qian Park, Kyoungmin Rask-Madsen, Christian Gao, Benbo Matsumoto, Motonobu Liu, Yingjie Wu, I-Hsien White, Morris F. Feener, Edward P. King, George L. TI Inhibition of Insulin Signaling in Endothelial Cells by Protein Kinase C-induced Phosphorylation of p85 Subunit of Phosphatidylinositol 3-Kinase (PI3K) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SUBSTRATE-1 TYROSINE PHOSPHORYLATION; RECEPTOR SUBSTRATE-1; NITRIC-OXIDE; DIABETIC COMPLICATIONS; GENE-EXPRESSION; PAI-1 GENE; IN-VIVO; ACTIVATION; GROWTH; RESISTANCE AB The regulation of endothelial function by insulin is consistently abnormal in insulin-resistant states and diabetes. Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders. C1 [Maeno, Yasuhiro; Li, Qian; Park, Kyoungmin; Rask-Madsen, Christian; Gao, Benbo; Matsumoto, Motonobu; Liu, Yingjie; Wu, I-Hsien; Feener, Edward P.; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Vasc Cell Biol, Boston, MA 02115 USA. [White, Morris F.] Childrens Hosp Boston, Boston, MA 02115 USA. RP King, GL (reprint author), Joslin Diabet Ctr, Sect Vasc Cell Biol & Complicat, Dianne Nunnally Hoppes Lab Diabet Complicat, 1 Joslin Pl, Boston, MA 02215 USA. EM George.king@joslin.harvard.edu FU National Institutes of Health from NIDDK [R01-DK53105]; National Institutes of Health from NIDDK (DERC) [P30-DK36836-21]; American Diabetes Association [1-08-RA-93] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01-DK53105 from NIDDK and P30-DK36836-21 from NIDDK (DERC). This work was also supported by American Diabetes Association Grant 1-08-RA-93. NR 37 TC 23 Z9 24 U1 1 U2 5 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 FEB 10 PY 2012 VL 287 IS 7 BP 4518 EP 4530 DI 10.1074/jbc.M111.286591 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500015 PM 22158866 ER PT J AU Hedrich, CM Rauen, T Kis-Toth, K Kyttaris, VC Tsokos, GC AF Hedrich, Christian M. Rauen, Thomas Kis-Toth, Katalin Kyttaris, Vasileios C. Tsokos, George C. TI cAMP-responsive Element Modulator alpha (CREM alpha) Suppresses IL-17F Protein Expression in T Lymphocytes from Patients with Systemic Lupus Erythematosus (SLE) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IL-2 PRODUCTION; HETERODIMERIC CYTOKINE; AUTOIMMUNE-DISEASES; HOST-DEFENSE; CELLS; GENE; BINDING; TRANSCRIPTION; PROMOTER; IDENTIFICATION AB The proinflammatory cytokines IL-17A and IL-17F are primarily produced by Th17 lymphocytes. Both are involved in host defense mechanisms against bacterial and fungal pathogens and contribute to the development of various autoimmune diseases. T lymphocytes from patients with systemic lupus erythematosus (SLE) display increased expression of transcription factor cAMP-responsive element modulator alpha (CREM alpha), which has been documented to account for aberrant T cell function and contributes to the pathogenesis of SLE. Here, we provide evidence that IL-17F expression is reduced in SLE T cells. We demonstrate that CREM alpha binds to a yet unidentified CRE site within the proximal promoter. This results in reduced IL-17F expression in SLE T lymphocytes and is independent of activating epigenetic patterns (increased histone H3 Lys-18 acetylation, reduced histone H3 Lys-27 trimethylation, and CpG-DNA demethylation). Forced CREM alpha expression in human T lymphocytes results in reduced IL-17F expression. Our findings demonstrate extended involvement of CREM alpha in cytokine dysregulation in SLE by contributing to a disrupted balance between IL-17A and IL-17F. An increased IL-17A/IL-17F ratio may aggravate the proinflammatory phenotype of SLE. C1 [Hedrich, Christian M.; Rauen, Thomas; Kis-Toth, Katalin; Kyttaris, Vasileios C.; Tsokos, George C.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Rheumatol,Dept Med, Boston, MA 02115 USA. [Rauen, Thomas] Rhein Westfal TH Aachen, Dept Nephrol & Clin Immunol, D-50062 Aachen, Germany. RP Tsokos, GC (reprint author), Beth Israel Deaconess Med Ctr CLS 937, Div Rheumatol, Dept Med, 330 Brookline Ave, Boston, MA 02115 USA. EM chedrich@bidmc.harvard.edu; gtsokos@bidmc.harvard.edu FU National Institutes of Health [K23 AR055672, R01 AI42269, R01 AI49954, R01 AI85567]; Deutsche Forschungsgemeinschaft [RA1927-1/1] FX This work was supported, in whole or in part, by National Institutes of Health Grants K23 AR055672 (to V. C. K.) and R01 AI42269, R01 AI49954, and R01 AI85567 (to G. C. T.). This work was also supported by Deutsche Forschungsgemeinschaft Grant RA1927-1/1 (to T. R.). NR 37 TC 26 Z9 26 U1 0 U2 0 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 FEB 10 PY 2012 VL 287 IS 7 BP 4715 EP 4725 DI 10.1074/jbc.M111.323261 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896YX UT WOS:000300608500033 PM 22184122 ER PT J AU Yu, M Mazor, T Huang, H Huang, HT Kathrein, KL Woo, AJ Chouinard, CR Labadorf, A Akie, TE Moran, TB Xie, HF Zacharek, S Taniuchi, I Roeder, RG Kim, CF Zon, LI Fraenkel, E Cantor, AB AF Yu, Ming Mazor, Tali Huang, Hui Huang, Hsuan-Ting Kathrein, Katie L. Woo, Andrew J. Chouinard, Candace R. Labadorf, Adam Akie, Thomas E. Moran, Tyler B. Xie, Huafeng Zacharek, Sima Taniuchi, Ichiro Roeder, Robert G. Kim, Carla F. Zon, Leonard I. Fraenkel, Ernest Cantor, Alan B. TI Direct Recruitment of Polycomb Repressive Complex 1 to Chromatin by Core Binding Transcription Factors SO MOLECULAR CELL LA English DT Article ID HEMATOPOIETIC STEM-CELLS; ADULT HEMATOPOIESIS; RUNX1; DIFFERENTIATION; CBFA2; MICE; HAPLOINSUFFICIENCY; TRANSFORMATION; MEGAKARYOCYTE; MAINTENANCE AB Polycomb repressive complexes (PRCs) play key roles in developmental epigenetic regulation. Yet the mechanisms that target PRCs to specific loci in mammalian cells remain incompletely understood. In this study we show that Bmi1, a core component of Polycomb Repressive Complex 1 (PRC1), binds directly to the Runx1/CBF beta transcription factor complex. Genome-wide studies in megakaryocytic cells demonstrate significant chromatin occupancy overlap between the PRC1 core component Ring1b and Runx1/CBF beta and functional regulation of a considerable fraction of commonly bound genes. Bmi1/Ring1b and Runx1/CBF beta deficiencies generate partial phenocopies of one another in vivo. We also show that Ring1b occupies key Runx1 binding sites in primary murine thymocytes and that this occurs via PRC2-independent mechanisms. Genetic depletion of Runx1 results in reduced Ring1b binding at these sites in vivo. These findings provide evidence for site-specific PRC1 chromatin recruitment by core binding transcription factors in mammalian cells. C1 [Mazor, Tali; Chouinard, Candace R.; Labadorf, Adam; Fraenkel, Ernest] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Mazor, Tali; Chouinard, Candace R.; Labadorf, Adam; Fraenkel, Ernest] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Yu, Ming; Huang, Hui; Huang, Hsuan-Ting; Kathrein, Katie L.; Woo, Andrew J.; Akie, Thomas E.; Moran, Tyler B.; Xie, Huafeng; Zacharek, Sima; Kim, Carla F.; Zon, Leonard I.; Cantor, Alan B.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Yu, Ming; Huang, Hui; Huang, Hsuan-Ting; Kathrein, Katie L.; Woo, Andrew J.; Akie, Thomas E.; Moran, Tyler B.; Xie, Huafeng; Zacharek, Sima; Kim, Carla F.; Zon, Leonard I.; Cantor, Alan B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Taniuchi, Ichiro] RIKEN, Res Ctr Allergy & Immunol, Lab Transcript Regulat, Yokohama, Kanagawa 2300045, Japan. [Roeder, Robert G.] Rockefeller Univ, Lab Biochem & Mol Biol, New York, NY 10065 USA. [Kim, Carla F.; Zon, Leonard I.; Cantor, Alan B.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Fraenkel, E (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM fraenkel-admin@mit.edu; alan.cantor@childrens.harvard.edu RI Taniuchi, Ichiro/N-6399-2015; OI Taniuchi, Ichiro/0000-0002-9853-9068; Fraenkel, Ernest/0000-0001-9249-8181 FU Wendy Will Case Cancer Fund; American Heart Association; NIH [R01-HL082952, U54-CA112967, R01-GM089903, P30-ES002109]; Eugene Bell Career Development Chair; National Science Foundation [DB1-0821391] FX M.Y. is supported by a grant from the Wendy Will Case Cancer Fund and an American Heart Association postdoctoral fellowship award. A.B.C. is supported by a grant from the NIH (R01-HL082952). E.F. is the recipient of the Eugene Bell Career Development Chair and is supported by NIH Grants U54-CA112967 and R01-GM089903. This work used computing resources funded by the National Science Foundation under Award No. DB1-0821391, and sequencing support from the NIH (P30-ES002109). The authors would like to thank D. Gary Gilliland, Stuart Orkin, and Maarten van Lohuizen for providing knockout mouse strains and Ross Tomaino and Steven Gygi at the Taplin Mass Spectrometry Facility for assistance with protein identification. NR 50 TC 91 Z9 93 U1 1 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 FEB 10 PY 2012 VL 45 IS 3 BP 330 EP 343 DI 10.1016/j.molcel.2011.11.032 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 895FH UT WOS:000300481100008 PM 22325351 ER PT J AU Agarwal, N Boucher, KM Maughan, B Hussain, SA Kaufman, DS Lorusso, V Moore, MJ Galsky, MD Sonpavde, G AF Agarwal, Neeraj Boucher, Kenneth M. Maughan, Benjamin Hussain, Syed A. Kaufman, Donald S. Lorusso, Vito Moore, Malcolm J. Galsky, Matt D. Sonpavde, Guru CA SWOG TI Pooled analysis of phase II trials evaluating weekly or conventional cisplatin as first-line therapy for advanced urothelial carcinoma (UC) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Huntsman Canc Inst, Salt Lake City, UT USA. Univ Utah, Salt Lake City, UT USA. Canc Res UK Inst Canc Studies, Birmingham, W Midlands, England. Massachusetts Gen Hosp, Boston, MA 02114 USA. Vito Fazzi Hosp, Med Oncol Unit, Lecce, Italy. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. US Oncol Res LLC, McKesson Specialty Hlth, The Woodlands, TX USA. Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. Deke Slayton Canc Ctr, Webster, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 308 PG 2 WC Oncology SC Oncology GA V31OH UT WOS:000208892400307 PM 28143134 ER PT J AU Aizer, A Paly, JJ Zietman, AL D'Amico, AV Nguyen, PL Beard, C Rao, SK Kaplan, ID Hirsch, MS Wu, CL Efstathiou, JA AF Aizer, Ayal Paly, Jonathan J. Zietman, Anthony L. D'Amico, Anthony Victor Nguyen, Paul Linh Beard, Clair Rao, Sandhya K. Kaplan, Irving D. Hirsch, Michelle S. Wu, Chin-Lee Efstathiou, Jason Alexander TI Multidisciplinary care and pursuit of active surveillance in low-risk prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 131 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400132 PM 28143227 ER PT J AU Bian, S Kuban, DA Levy, LB Oh, JH Castle, K Pugh, T Choi, S McGuire, SE Frank, SJ Nguyen, PL Lee, A Hoffman, KE AF Bian, Shelly Kuban, Deborah A. Levy, Lawrence B. Oh, Jeong Hoon Castle, Katherine Pugh, Thomas Choi, Seungtaek McGuire, Sean E. Frank, Steven J. Paul Linh Nguyen Lee, Andrew Hoffman, Karen Elizabeth TI Effect of adding short-term androgen deprivation therapy to dose-escalated radiation therapy on failure-free survival for select men with intermediate-risk prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Baylor Coll Med, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Univ Texas MD Anderson Canc Ctr, Dept Internal Med, Houston, TX 77030 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 176 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400177 PM 28143155 ER PT J AU Bosco, JLF Halpenny, B Berry, DL AF Bosco, Jaclyn Lee Fong Halpenny, Barbara Berry, Donna Lynn TI Personal preferences and treatment choice in an intervention trial of men newly diagnosed with localized prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 [Bosco, Jaclyn Lee Fong; Halpenny, Barbara; Berry, Donna Lynn] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 170 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400171 PM 28143171 ER PT J AU Cho, E Je, Y Choueiri, TK AF Cho, Eunyoung Je, Youjin Choueiri, Toni K. TI Analgesic use and the risk of renal cell carcinoma (RCC): Results from a large up-to-date meta-analysis. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 395 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400394 PM 28143284 ER PT J AU Cho, E Joh, HK Choueiri, TK AF Cho, Eunyoung Joh, Hee-Kyung Choueiri, Toni K. TI ABO blood group and risk of renal cell cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 371 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400370 PM 28143240 ER PT J AU Choueiri, TK Pal, SK McDermott, DF Ramies, DA Morrissey, S Lee, Y Miles, D Holland, JS Dutcher, JP AF Choueiri, Toni K. Pal, Sumanta Kumar McDermott, David F. Ramies, David A. Morrissey, Stephanie Lee, Yihua Miles, Dale Holland, Jaymes S. Dutcher, Janice P. TI Activity of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. City Hope Natl Med Ctr, Duarte, CA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Exelixis, San Francisco, CA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. St Lukes Roosevelt Hosp, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 364 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400363 ER PT J AU Choueiri, TK Xie, WL Harshman, LC Bjarnason, GA Knox, JJ MacKenzie, MJ Wood, L Vaishampayan, UN Tan, MH Rha, SY Donskov, F Agarwal, N Kollmannsberger, CK North, SA Rini, BI Heng, DYC AF Choueiri, Toni K. Xie, Wanling Harshman, Lauren Christine Bjarnason, Georg A. Knox, Jennifer J. MacKenzie, Mary J. Wood, Lori Vaishampayan, Ulka N. Tan, Min-Han Rha, Sun Young Donskov, Frede Agarwal, Neeraj Kollmannsberger, Christian K. North, Scott A. Rini, Brian I. Heng, Daniel Yick Chin TI Conditional survival (CS) for patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)-targeted therapy (TT): Results from the International mRCC Database Consortium. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. London Reg Canc Program, London, ON, Canada. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Natl Canc Ctr, Singapore, Singapore. Yonsei Univ, Coll Med, Severance Hosp, Seoul, South Korea. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 358 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400357 PM 28143033 ER PT J AU Choueiri, TK Vaishampayan, UN Rosenberg, JE Logan, T Harzstark, AL Rini, BI Srinivas, S Adams, LM Sherman, LJ Ottesen, LH McDermott, DF Bottaro, DP Linehan, WM Srinivasan, R AF Choueiri, Toni K. Vaishampayan, Ulka N. Rosenberg, Jonathan E. Logan, Theodore Harzstark, Andrea Lynne Rini, Brian I. Srinivas, Sandy Adams, Laurel M. Sherman, Laurie Jill Ottesen, Lone Harild McDermott, David F. Bottaro, Donald P. Linehan, W. Marston Srinivasan, Ramaprasad TI A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Stanford Med Ctr, Stanford, CA USA. GlaxoSmithKline, Res Triangle Pk, NC USA. GlaxoSmithKline, Philadelphia, PA USA. GlaxoSmithKline Oncol R&D, Uxbridge, Middx, England. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 355 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400354 ER PT J AU Drazer, MW Prasad, SM Huo, DZ Schonberg, MA Eggener, SE AF Drazer, Michael W. Prasad, Sandip M. Huo, Dezheng Schonberg, Mara A. Eggener, Scott E. TI Impact of US Preventive Services Task Force recommendation on screening for prostate cancer in men age 75 or older SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Chicago, Chicago, IL 60637 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 216 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400217 PM 28142963 ER PT J AU Duarte, C Sarkisian, N Nguyen, PL Garroutte, E Hurwitz, MD AF Duarte, Catherine Sarkisian, Natasha Paul Linh Nguyen Garroutte, Eva Hurwitz, Mark D. TI Impact of race on prostate cancer selection and cause-specific mortality: A SEER database analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Boston Coll, Chestnut Hill, MA 02167 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 248 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400249 PM 28143253 ER PT J AU Efstathiou, JA Paulus, R Smith, MR Jones, CU Leibenhaut, MH Husain, SM Rotman, M Souhami, L Sandler, HM Shipley, WU AF Efstathiou, Jason Alexander Paulus, Rebecca Smith, Matthew R. Jones, Christopher U. Leibenhaut, Mark H. Husain, Siraj M. Rotman, Marvin Souhami, Luis Sandler, Howard Mark Shipley, William U. TI Cardiovascular mortality following short-term androgen deprivation in clinically localized prostate cancer: An analysis of RTOG 94-08 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RTOG, Philadelphia, PA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Radiol Associates Sacramento, Sacramento, CA USA. Baker Canc Ctr, Calgary, AB, Canada. SUNY Hlth Sci Ctr, Brooklyn, NY USA. McGill Univ, Montreal, PQ, Canada. Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 18 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400020 PM 28142889 ER PT J AU Gagnon, RC Liu, Y Choueiri, TK Martin, AM Rosenberg, JE Signoretti, S Pandite, LN AF Gagnon, Robert C. Liu, Yuan Choueiri, Toni K. Martin, Anne-Marie Rosenberg, Jonathan E. Signoretti, Sabina Pandite, Lini N. TI Assessment of a cell-line-derived HIF1 alpha gene signature in tumor tissue from a metastatic renal cell carcinoma (RCC) trial of pazopanib. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 GlaxoSmithKline, Collegeville, PA USA. GlaxoSmithKline, Res & Dev, Collegeville, PA USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol,Med Sch, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. GlaxoSmithKline, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 408 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400407 PM 28143103 ER PT J AU Gray, PJ Fedewa, SA Shipley, WU Efstathiou, JA Virgo, KS Zietman, AL AF Gray, Phillip J. Fedewa, Stacey A. Shipley, William U. Efstathiou, Jason Alexander Virgo, Katherine S. Zietman, Anthony L. TI Receipt of aggressive therapies for muscle-invasive bladder cancer: Results from the National Cancer Data Base SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Amer Canc Soc, Atlanta, GA 30329 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 272 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400272 PM 28143299 ER PT J AU Gray, PJ Paly, JJ Sanda, MG Sandler, HM Michalski, JM Talcott, JA Coen, J Shipley, WU Zietman, AL Bekelman, JE Efstathiou, JA AF Gray, Phillip J. Paly, Jonathan J. Sanda, Martin G. Sandler, Howard Mark Michalski, Jeff M. Talcott, James Austin Coen, John Shipley, William U. Zietman, Anthony L. Bekelman, Justin E. Efstathiou, Jason Alexander CA PROST-QA Consortium TI Bowel and bladder toxicity patterns in patients with prostate cancer treated with proton beam versus intensity-modulated radiation therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. Washington Univ, Sch Med, St Louis, MO USA. Continuum Canc Care Consortium, New York, NY USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. RI Sanda, Martin/B-2023-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 22 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400024 PM 28142916 ER PT J AU Guancial, EA Werner, L Stack, E Lis, R Signoretti, S Loda, M Gallardo, E Rojo, F Lloreta, J Regan, MM Park, R O'Brien, R Berman, DM Bellmunt, J Rosenberg, JE AF Guancial, Elizabeth Ann Werner, Lillian Stack, Edward Lis, Rosina Signoretti, Sabina Loda, Massimo Gallardo, Enrique Rojo, Federico Lloreta, Jose Regan, Meredith M. Park, Rachel O'Brien, Robert Berman, David M. Bellmunt, Joaquim Rosenberg, Jonathan E. TI Association of DNA repair factors with overall survival in advanced urothelial carcinoma treated with platinum-based chemotherapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Corporacio Parc Tauli, Sabadell, Spain. IMIM Hosp del Mar, Canc Res Grp, Barcelona, Spain. Univ Hosp del Mar IMIM, Barcelona, Spain. Johns Hopkins Univ Sch Med, Baltimore, MD USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol,Brigham & Womens Hos, Boston, MA 02115 USA. RI Lloreta, J/I-2112-2014; Rojo, Federico/S-6551-2016 OI Lloreta, J/0000-0003-1644-9470; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 291 PG 2 WC Oncology SC Oncology GA V31OH UT WOS:000208892400290 PM 28143170 ER PT J AU Hattangadi, JA Chen, MH Sun, L D'Amico, AV AF Hattangadi, Jona Ashok Chen, Ming-Hui Sun, Leon D'Amico, Anthony Victor TI Early detection of high-grade prostate cancer using digital rectal examination in men with a normal PSA and risk of death. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Radiat Oncol Program, Boston, MA USA. Univ Connecticut, Storrs, CT USA. NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 147 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400148 PM 28143304 ER PT J AU Heng, DYC Lee, JL Harshman, LC Bjarnason, GA Razak, AR MacKenzie, MJ Wood, L Vaishampayan, UN Tan, MH Rha, SY Donskov, F Agarwal, N Kollmannsberger, CK North, SA Rini, BI Choueiri, TK AF Heng, Daniel Yick Chin Lee, Jae-Lyun Harshman, Lauren Christine Bjarnason, Georg A. Razak, Albiruni R. MacKenzie, Mary J. Wood, Lori Vaishampayan, Ulka N. Tan, Min-Han Rha, Sun Young Donskov, Frede Agarwal, Neeraj Kollmannsberger, Christian K. North, Scott A. Rini, Brian I. Choueiri, Toni K. CA Int mRCC Database Consortium TI A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma (mRCC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. Univ Ulsan, Coll Med, Dept Oncol, Asan Med Ctr, Seoul, South Korea. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. London Reg Canc Program, London, ON, Canada. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Natl Canc Ctr, Singapore, Singapore. Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 387 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400386 PM 28143319 ER PT J AU Heng, DYC Choueiri, TK Lee, JL Harshman, LC Bjarnason, GA Knox, JJ MacKenzie, MJ Vaishampayan, UN Tan, MH Rha, SY Donskov, F Agarwal, N Kollmannsberger, CK North, SA Rini, BI Wood, L AF Heng, Daniel Yick Chin Choueiri, Toni K. Lee, Jae-Lyun Harshman, Lauren Christine Bjarnason, Georg A. Knox, Jennifer J. MacKenzie, Mary J. Vaishampayan, Ulka N. Tan, Min-Han Rha, Sun Young Donskov, Frede Agarwal, Neeraj Kollmannsberger, Christian K. North, Scott A. Rini, Brian I. Wood, Lori CA Int mRCC Database Consortium TI A multicentered population-based analysis of outcomes of patients with metastatic renal cell carcinoma (mRCC) who do not meet eligibility criteria for clinical trials. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. London Reg Canc Program, London, ON, Canada. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Natl Canc Ctr, Singapore, Singapore. Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 353 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400352 PM 28143049 ER PT J AU Hutson, TE Dang, LH Lauer, RC Starodub, A Hauke, RJ Logan, T Bylow, KA Galsky, MD Bibby, DC Kremmidiotis, G Doolin, EE Lavranos, TC Leske, AF Hahn, NM Sonpavde, G Sweeney, C Sarantopoulos, J AF Hutson, Thomas E. Dang, Long H. Lauer, Richard C. Starodub, Alexander Hauke, Ralph J. Logan, Theodore Bylow, Kathryn A. Galsky, Matt D. Bibby, David C. Kremmidiotis, Gabriel Doolin, Elizabeth E. Lavranos, Tina C. Leske, Annabell F. Hahn, Noah M. Sonpavde, Guru Sweeney, Christopher Sarantopoulos, John CA Hoosier Oncology Grp TI Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 US Oncol Res LLC, McKesson Specialty Hlth, The Woodlands, TX USA. Baylor Sammons Canc Ctr Texas Oncol PA, Dallas, TX USA. Univ Florida, Gainesville, FL USA. Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. Goshen Ctr Canc Care, Goshen, IN USA. Nebraska Canc Specialists, Omaha, NE USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Mt Sinai Med Ctr, Tisch Canc Inst, New York, NY 10029 USA. Bionomics Ltd, Thebarton, Australia. Deke Slayton Canc Ctr, Webster, TX USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas Hlth Sci Ctr San Antonio, Inst Drug Dev, San Antonio, TX 78229 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 373 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400372 PM 28143228 ER PT J AU Katz, LM Efstathiou, JA Opraseuth, J Killoran, J Paly, JJ Weathers, R Stovall, M Beard, C AF Katz, Leah Minnie Efstathiou, Jason Alexander Opraseuth, Jonathan Killoran, Joseph Paly, Jonathan J. Weathers, Rita Stovall, Marilyn Beard, Clair TI Normal tissue exposure during retroperitoneal radiotherapy for pure seminoma of the testis. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 334 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400333 PM 28142971 ER PT J AU Klein, EA Thompson, I Tangen, CM Lucia, MS Goodman, P Minasian, LM Ford, LG Parnes, HL Gaziano, JM Karp, DD Lieber, MM Walther, PJ Parsons, JK Chin, J Darke, AK Lippman, SM Goodman, GE Meyskens, FL Baker, LH AF Klein, Eric A. Thompson, Ian Tangen, Catherine M. Lucia, M. Scott Goodman, Phyllis Minasian, Lori M. Ford, Leslie G. Parnes, Howard L. Gaziano, J. Michael Karp, Daniel D. Lieber, Michael M. Walther, Philip John Parsons, J. Kellogg Chin, Joseph Darke, Amy K. Lippman, Scott Michael Goodman, Gary E. Meyskens, Frank L. Baker, Laurence H. TI Vitamin E and the risk of prostate cancer: Updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Glickman Urol & Kidney Inst, Cleveland, OH 44106 USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Colorado, Sch Med, Aurora, CO USA. SWOG Stat Ctr, Seattle, WA USA. NCI, Bethesda, MD 20892 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Mayo Clin, Rochester, MN USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. London Hlth Sci Ctr, London, ON, Canada. Swedish Canc Inst, Seattle, WA USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 7 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400009 PM 28143337 ER PT J AU Mak, RH Hunt, D Shipley, WU Efstathiou, JA Tester, WJ Hagan, MP Kaufman, DS Heney, NM Zietman, AL AF Mak, Raymond H. Hunt, Daniel Shipley, William U. Efstathiou, Jason Alexander Tester, William J. Hagan, Michael P. Kaufman, Donald S. Heney, Niall M. Zietman, Anthony L. TI Long-term outcomes in patients with muscle-invasive bladder cancer after bladder-preserving combined-modality therapy: A pooled analysis of RTOG 8802, 8903, 9506, 9706, 9906, and 0233 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 264 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400265 PM 28143313 ER PT J AU Murciano-Goroff, YR Wolfsberger, LD Parekh, A Fennessy, FM Tuncali, K Orio, PF Niedermayr, T Suh, WW Devlin, PM Tempany, CM Nguyen, PL AF Murciano-Goroff, Yonina R. Wolfsberger, Luciant D. Parekh, Arti Fennessy, Fiona M. Tuncali, Kemal Orio, Peter F. Niedermayr, Thomas Suh, W. Warren Devlin, Phillip M. Tempany, Clare M. Paul Linh Nguyen TI Variability in prostate volume as determined by MRI versus ultrasound and its impact on treatment recommendations for patients with favorable-risk prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Canc Ctr Santa Barbara, Santa Barbara, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 249 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400250 PM 28143244 ER PT J AU Paly, JJ Efstathiou, JA Hedgire, S Chung, PWM O'Malley, M Shah, A Bekelman, JE Harisinghani, M Zietman, AL Shipley, WU Beard, C AF Paly, Jonathan J. Efstathiou, Jason Alexander Hedgire, Sandeep Chung, Peter W. M. O'Malley, Martin Shah, Anand Bekelman, Justin E. Harisinghani, Mukesh Zietman, Anthony L. Shipley, William U. Beard, Clair TI Mapping patterns of nodal metastases in seminoma: Rethinking radiotherapy fields SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. Princess Margaret Hosp, Dept Med Imaging, Toronto, ON M4X 1K9, Canada. Hosp Univ Penn, Philadelphia, PA 19104 USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 324 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400323 PM 28143011 ER PT J AU Parekh, A Chen, MH Hoffman, KE Choueiri, TK Hu, JC Bennett, CL Kattan, MW Sartor, AO Stein, K D'Amico, AV Nguyen, PL AF Parekh, Arti Chen, Ming-Hui Hoffman, Karen Elizabeth Choueiri, Toni K. Hu, Jim C. Bennett, Charles L. Kattan, Michael W. Sartor, A. Oliver Stein, Karen D'Amico, Anthony Victor Paul Linh Nguyen TI Incidence of reduced penis size among men with recurrent prostate cancer previously treated with surgery, radiation plus androgen deprivation, or radiation alone SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol Surg, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. South Carolina Coll Pharm, Charleston, SC USA. Hollings Canc Ctr, Charleston, SC USA. Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. Tulane Univ, Dept Med, New Orleans, LA 70118 USA. Tulane Univ, Dept Urol, New Orleans, LA 70118 USA. Eisai Pharmaceut, Woodcliff Lake, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 38 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400040 PM 28142900 ER PT J AU Nguyen, PL Chen, MH Zhang, YY Tempany, CM Cormack, RA Beard, C Hurwitz, MD Suh, WW D'Amico, AV AF Paul Linh Nguyen Chen, Ming-Hui Zhang, Yuanye Tempany, Clare M. Cormack, Robert A. Beard, Clair Hurwitz, Mark D. Suh, W. Warren D'Amico, Anthony Victor TI Long-term results of MRI-guided partial prostate brachytherapy for favorable-risk prostate cancer: Implications for focal therapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Storrs, CT USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Canc Ctr Santa Barbara, Santa Barbara, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 114 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400115 PM 28143026 ER PT J AU Petrylak, DP Kantoff, PW Mega, AE Dreicer, R Frank, RC Shore, ND Morris, S Olson, WC Israel, RJ AF Petrylak, Daniel Peter Kantoff, Philip W. Mega, Anthony E. Dreicer, Robert Frank, Richard C. Shore, Neal D. Morris, Stephen Olson, William C. Israel, Robert Joseph TI Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in men with prostate cancer previously treated with taxane. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brown Univ, Oncol Grp, Providence, RI 02912 USA. Cleveland Clin, Cleveland, OH 44106 USA. Norwalk Med Grp, Norwalk, CT USA. Carolina Urol Res Ctr, Myrtle Beach, SC USA. Progen Pharmaceut Inc, Tarrytown, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 107 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400108 PM 28143055 ER PT J AU Psutka, SP McGovern, FJ Mueller, P McDougal, WS Gervais, D Feldman, AS AF Psutka, Sarah P. McGovern, Francis J. Mueller, Peter McDougal, W. Scott Gervais, Debra Feldman, Adam S. TI Long-term durable oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 384 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400383 PM 28143317 ER PT J AU Psutka, SP Olumi, AF Feldman, AS Saylor, PJ Kaufman, DS Lee, RJ AF Psutka, Sarah P. Olumi, Aria F. Feldman, Adam S. Saylor, Philip James Kaufman, Donald S. Lee, Richard J. TI Pathologic down-staging and complete pathologic response with gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma of the bladder SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 307 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400306 PM 28143141 ER PT J AU Qu, AQ Cheng, SC Atkins, MB Signoretti, S Choueiri, TK AF Qu, Angela Q. Cheng, SuChun Atkins, Michael B. Signoretti, Sabina Choueiri, Toni K. TI Carbonic anhydrase IX (CAIX) as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma (mccRCC) in patients (pts) receiving sorafenib: Analysis of a randomized controlled trial (TARGET). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Dana Farber Harvard Canc Ctr, Boston, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 352 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400351 PM 28143040 ER PT J AU Richards, CJ Je, YJ Schutz, FAB Choueiri, TK AF Richards, Christopher J. Je, Youjin Schutz, Fabio A. B. Choueiri, Toni K. TI Meta-analysis of randomized control trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol,Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 349 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400348 PM 28143053 ER PT J AU Rini, BI Escudier, BJ Michaelson, MD Negrier, S Gore, ME Oudard, S Clark, J Tarazi, JC Rosbrook, B Kim, S Motzer, RJ AF Rini, Brian I. Escudier, Bernard J. Michaelson, M. Dror Negrier, Sylvie Gore, Martin Eric Oudard, Stephane Clark, Joseph Tarazi, Jamal Christo Rosbrook, Brad Kim, Sinil Motzer, Robert John TI Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Inst Gustave Roussy, Villejuif, France. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Leon Berard Canc Ctr, Lyon, France. Royal Marsden Hosp, London SW3 6JJ, England. Georges Pompidou European Hosp, Paris, France. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Pfizer Oncol, La Jolla, CA USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 354 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400353 PM 28143045 ER PT J AU Roach, M Yan, Y Lawton, CA Hsu, ICJ Lustig, RA Jones, CU Rotman, M Zeitzer, KL Werner-Wasik, M Kim, H Thomas, CR Shipley, WU Sandler, HM AF Roach, Mack Yan, Yan Lawton, Colleen Anne Hsu, I-Chow Joe Lustig, Robert A. Jones, Christopher U. Rotman, Marvin Zeitzer, Kenneth Lee Werner-Wasik, Maria Kim, Harold Thomas, Charles R. Shipley, William U. Sandler, Howard Mark TI Radiation Therapy Oncology Group (RTOG) 9413: Randomized trial comparing whole pelvic radiotherapy (WPRT) to prostate only (PORT) and neoadjuvant hormone therapy (NHT) to adjuvant hormone therapy (AHT). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Radiat Therapy Oncol Grp, Philadelphia, PA USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Hosp Univ Penn, Philadelphia, PA 19104 USA. Radiol Associates Sacramento, Sacramento, CA USA. SUNY Hlth Sci Ctr, Brooklyn, NY USA. Albert Einstein Med Ctr, Philadelphia, PA 19141 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 96 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400097 PM 28143343 ER PT J AU Rudman, SM Gray, KP Kasperzyk, J Pitt, M Giovannucci, E Loda, M Mucci, L Sweeney, C AF Rudman, Sarah Maria Gray, Kathryn P. Kasperzyk, Julie Pitt, Michael Giovannucci, Edward Loda, Massimo Mucci, Lorelei Sweeney, Christopher TI Association of metabolic syndrome with reduced survival among men receiving androgen deprivation therapy for nonmetastatic prostate cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Guys Hosp, Div Canc Studies, Kings Coll London, London SE1 9RT, England. Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Channing Lab, Boston, MA USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 56 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400058 PM 28142922 ER PT J AU Saylor, PJ Karoly, ED Smith, MR AF Saylor, Philip James Karoly, Edward D. Smith, Matthew Raymond TI Changes in plasma metabolomic profiles during the first 3 months of androgen-deprivation therapy for prostate cancer. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Metabolon Inc, Morrisville, NC USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 116 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400117 PM 28143032 ER PT J AU Scher, HI Fizazi, K Saad, F Taplin, ME Sternberg, CN Miller, K De Wit, R Mulders, P Hirmand, M Selby, B De Bono, JS AF Scher, Howard I. Fizazi, Karim Saad, Fred Taplin, Mary-Ellen Sternberg, Cora N. Miller, Kurt De Wit, Ronald Mulders, Peter Hirmand, Mohammad Selby, Bryan De Bono, Johann Sebastian CA AFFIRM Investigators TI Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. Univ Montreal Hosp Ctr, Montreal, PQ, Canada. Dana Farber Canc Inst, Boston, MA 02115 USA. San Camillo Hosp, Rome, Italy. Forlanini Hosp, Rome, Italy. Charite, Dept Urol, D-13353 Berlin, Germany. Erasmus Univ, Med Ctr, Rotterdam, Netherlands. Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. Medivation, San Francisco, CA USA. Inst Canc Res, Sutton, Surrey, England. Royal Marsden Hosp, Sutton, Surrey, England. RI Mulders, Peter/H-8076-2014 NR 0 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA LBA1 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400002 PM 28142898 ER PT J AU Sharma, J Gray, KP Nakabayashi, M Petrozziello, G Evan, C Fichorova, R Kantoff, PW Sweeney, C AF Sharma, Jaya Gray, Kathryn P. Nakabayashi, Mari Petrozziello, Gillian Evan, Carolyn Fichorova, Raina Kantoff, Philip W. Sweeney, Christopher TI Use of elevated insulin-like growth factor binding protein-1 (IGFBP-1) to predict outcomes in men with metastatic prostate cancer treated with androgen-deprivation therapy (ADT). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. IBCSG Stat Ctr, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RI Fichorova, Raina/G-9969-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 191 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400192 PM 28143201 ER PT J AU Sharma, J Gray, KP Nakabayashi, M Petrozziello, G Evan, C Fichorova, R Kantoff, PW Sweeney, C AF Sharma, Jaya Gray, Kathryn P. Nakabayashi, Mari Petrozziello, Gillian Evan, Carolyn Fichorova, Raina Kantoff, Philip W. Sweeney, Christopher TI Use of elevated baseline IL-8, CCL-2, and TNF alpha to predict for shorter overall survival (OS) in men with metastatic prostate cancer initiating androgen-deprivation therapy (ADT) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RI Fichorova, Raina/G-9969-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 13 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400015 PM 28142894 ER PT J AU Small, AC Tsao, CK Moshier, E Godbold, J Sonpavde, G Oh, WK Galsky, MD AF Small, Alexander C. Tsao, Che-Kai Moshier, Erin Godbold, James Sonpavde, Guru Oh, William K. Galsky, Matt D. TI Prevalence and characteristics of patients with metastatic prostate cancer who receive no anticancer therapy. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY USA. Texas Oncol, Houston, TX USA. Baylor Coll Med, Dept Med, Sect Med Oncol, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 101 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400102 PM 28143086 ER PT J AU Small, EJ Weinberg, VK Ryan, CJ Higano, CS Lin, AM Maruca, Y Alumkal, JJ Yu, EY Rosenberg, JE Beer, TM AF Small, Eric Jay Weinberg, Vivian K. Ryan, Charles J. Higano, Celestia S. Lin, Amy Mimi Maruca, Yvonne Alumkal, Joshi J. Yu, Evan Y. Rosenberg, Jonathan E. Beer, Tomasz M. TI A prospective randomized phase II trial evaluating maintenance GM-CSF in an intermittent chemotherapy (chemo) regimen for metastatic castration-resistant prostate cancer (mCRPC): A DoD prostate cancer clinical trials consortium trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 35 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400037 PM 28142903 ER PT J AU Smith, MR Saad, F Shore, ND Oudard, S Miller, K Tombal, B Sieber, P Fizazi, K Van Veldhuizen, PJ Damiao, R Marx, GM Morote, J Feng, A Dansey, R Goessl, CD AF Smith, Matthew R. Saad, Fred Shore, Neal D. Oudard, Stephane Miller, Kurt Tombal, Bertrand Sieber, Paul Fizazi, Karim Van Veldhuizen, Peter J. Damiaeo, Ronaldo Marx, Gavin M. Morote, Juan Feng, Amy Dansey, Roger Goessl, Carsten Dietrich TI Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Univ Montreal Hosp Ctr, Montreal, PQ, Canada. Carolina Urol Res Ctr, Myrtle Beach, SC USA. Georges Pompidou European Hosp, Paris, France. Charite, Dept Urol, D-13353 Berlin, Germany. Catholic Univ Louvain, Clin Univ St Luc, B-1200 Brussels, Belgium. Urol Associates Lancaster Ltd, Lancaster, PA USA. Univ Paris Sud, Inst Gustave Roussy, Villejuif, France. Kansas City VA Med Ctr, Kansas City, MO USA. Hosp Univ Pedro Ernesto, Rio De Janeiro, Brazil. Sydney Haematol Oncol Clin, Sydney, NSW, Australia. Vall dHebron Univ Hosp, Dept Urol, Barcelona, Spain. Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 6 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400008 PM 28143335 ER PT J AU Srinivasan, R Bottaro, DP Choueiri, TK Vaishampayan, UN Rosenberg, JE Logan, T Harzstark, AL Rini, BI Srinivas, S Adams, LM Laubscher, K Ottesen, LH McDermott, DF Linehan, WM AF Srinivasan, Ramaprasad Bottaro, Donald P. Choueiri, Toni K. Vaishampayan, Ulka N. Rosenberg, Jonathan E. Logan, Theodore Harzstark, Andrea Lynne Rini, Brian I. Srinivas, Sandy Adams, Laurel M. Laubscher, Kevin Ottesen, Lone Harild McDermott, David F. Linehan, W. Marston TI Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. Stanford Med Ctr, Stanford, CA USA. GlaxoSmithKline, Res Triangle Pk, NC USA. GlaxoSmithKline Oncol R&D, Uxbridge, Middx, England. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 372 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400371 PM 28143239 ER PT J AU Tadros, NN Farris, PE Shannon, J Beer, TM Garzotto, M AF Tadros, Nicholas N. Farris, Paige E. Shannon, Jackilen Beer, Tomasz M. Garzotto, Mark TI The safety of prostate biopsy procedures in the research setting: A 10-year multicenter experience. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 87 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400089 PM 28143351 ER PT J AU Tsao, CK Moshier, E Small, AC Sonpavde, G Godbold, J Oh, WK Galsky, MD AF Tsao, Che-Kai Moshier, Erin Small, Alexander C. Sonpavde, Guru Godbold, James Oh, William K. Galsky, Matt D. TI Cytoreductive nephrectomy in the United States: Patterns of care and patient characteristics. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY USA. Texas Oncol, Houston, TX USA. Baylor Coll Med, Dept Med, Sect Med Oncol, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 366 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400365 PM 28143249 ER PT J AU Wang, Y Choueiri, TK Lee, JL Tan, MH Rha, SY North, SA Kollmannsberger, CK Heng, DYC AF Wang, Ying Choueiri, Toni K. Lee, Jae-Lyun Tan, Min-Han Rha, Sun Young North, Scott A. Kollmannsberger, Christian K. Heng, Daniel Yick Chin TI Vascular endothelial growth factor (VEGF) therapy in metastatic renal cell carcinoma (mRCC): Differences between Asian and non-Asian patients. SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ Calgary, Calgary, AB, Canada. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lank Ctr Genitourinary Oncol,Dana Farber Canc Ins, Boston, MA 02115 USA. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Oncol, Seoul, South Korea. Natl Canc Ctr, Singapore, Singapore. Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul, South Korea. Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Univ Calgary, Tom Baker Canc Ctr, Calgary, AB, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2012 VL 30 IS 5 SU S MA 451 PG 1 WC Oncology SC Oncology GA V31OH UT WOS:000208892400450 PM 28142982 ER PT J AU Singh, JA AF Singh, Jasvinder A. TI Can racial disparities in optimal gout treatment be reduced? Evidence from a randomized trial SO BMC MEDICINE LA English DT Editorial Material DE Gout; Disparity; Race; treatment; Febuxostat; Allopurinol; randomized; African-American ID ACUTE MYOCARDIAL-INFARCTION; SERUM URATE; INDEPENDENT IMPACT; JOINT ARTHROPLASTY; UNITED-STATES; CARE; HYPERURICEMIA; ALLOPURINOL; POPULATION; PREVALENCE AB There is a disproportionate burden of gout in African-Americans in the U. S. due to a higher disease prevalence and lower likelihood of receiving urate-lowering therapy (ULT), compared to Caucasians. There is an absence of strong data as to whether the response to ULT differs by race/ethnicity. BMC Musculoskeletal Disorders recently published a secondary analyses of the CONFIRMS trial, a large randomized controlled, double-blind trial of 2,269 gout patients. The authors reported that the likelihood of achieving the primary study efficacy end-point of achieving serum urate < 6 mg/dl was similar between African-Americans and Caucasians, for all three treatment arms (Febuxostat 40 mg and 80 mg and allopurinol 300/200 mg). More importantly, rates were similar in subgroups of patients with mild or moderate renal insufficiency. Adverse event rates were similar, as were the rates of gout flares. These findings constitute a convincing evidence to pursue aggressive ULT in gout patients, regardless of race/ethnicity. This approach will likely help to narrow the documented racial disparities in gout care. Please see related article: http://www.biomedcentral.com/1471-2474/13/15 C1 [Singh, Jasvinder A.] Univ Alabama Birmingham, Med Serv, Birmingham VA Med Ctr, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Birmingham VA Med Ctr, Ctr Surg Med Acute Care Res & Transit C SMART, Birmingham, AL USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Sch Publ Hlth, Div Epidemiol, Birmingham, AL 35294 USA. [Singh, Jasvinder A.] Mayo Clin, Sch Med, Dept Orthoped Surg, Rochester, MN USA. [Singh, Jasvinder A.] Univ Alabama Birmingham, Fac Off Tower 805B, Birmingham, AL 35294 USA. RP Singh, JA (reprint author), Univ Alabama Birmingham, Med Serv, Birmingham VA Med Ctr, Birmingham, AL 35294 USA. EM Jasvinder.md@gmail.com OI singh, jasvinder/0000-0003-3485-0006 NR 26 TC 3 Z9 3 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 9 PY 2012 VL 10 AR 15 DI 10.1186/1741-7015-10-15 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 932ZA UT WOS:000303327800001 PM 22316088 ER PT J AU Bungartz, G Land, H Scadden, DT Emerson, SG AF Bungartz, Gerd Land, Hannah Scadden, David T. Emerson, Stephen G. TI NF-Y is necessary for hematopoietic stem cell proliferation and survival SO BLOOD LA English DT Article ID SELF-RENEWAL; CYCLIN B1; CBF/NF-Y; IN-VIVO; TRANSCRIPTION; NOTCH1; GENE; EXPRESSION; COMPLEX; BMI-1 AB HSC function depends on the tight control of proliferation and the balance between self-renewal and differentiation. Here, we report that the trimeric transcription factor NF-Y is critical for the survival of cycling, but not quiescent HSCs. With the use of a conditional knockout mouse model, we demonstrate that NF-Ya deletion creates an accumulation of HSCs in G(2)/M and prompts apoptosis, causing hematopoietic failure and death of the animal. These defects are accompanied by the dysregulation of multiple genes that influence cell cycle control (cyclin b1 and p21), apoptosis (Bcl-2), and self-renewal (HoxB4, Notch1, Bmi-1) and are independent of p53. Our results identify NF-Y as a pivotal upstream participant in a regulatory network necessary for the preservation of cycling HSCs. (Blood. 2012; 119(6): 1380-1389) C1 [Bungartz, Gerd; Land, Hannah; Emerson, Stephen G.] Haverford Coll, Haverford, PA 19041 USA. [Bungartz, Gerd; Emerson, Stephen G.] Univ Penn, Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Bungartz, Gerd; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Bungartz, Gerd; Scadden, David T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bungartz, Gerd; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Emerson, SG (reprint author), Haverford Coll, 370 Lancaster Ave, Haverford, PA 19041 USA. EM scadden.david@MGH.Harvard.edu; semerson@haverford.edu FU National Institute of Health [5R01CA090833]; Deutsche Forschungs-Gemeinschaft; Leukemia & Lymphoma Society FX This work was supported by the National Institute of Health (grant 5R01CA090833, S.G.E.) and grants from the Deutsche Forschungs-Gemeinschaft and the Leukemia & Lymphoma Society (G.B.). NR 38 TC 27 Z9 27 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 9 PY 2012 VL 119 IS 6 BP 1380 EP 1389 DI 10.1182/blood-2011-06-359406 PG 10 WC Hematology SC Hematology GA 894IR UT WOS:000300420900014 PM 22072554 ER PT J AU Azab, AK Quang, P Azab, F Pitsillides, C Thompson, B Chonghaile, T Patton, JT Maiso, P Monrose, V Sacco, A Ngo, HT Flores, LM Lin, CP Magnani, JL Kung, AL Letai, A Carrasco, R Roccaro, AM Ghobrial, IM AF Azab, Abdel Kareem Quang, Phong Azab, Feda Pitsillides, Costas Thompson, Brian Chonghaile, Triona Patton, John T. Maiso, Patricia Monrose, Val Sacco, Antonio Ngo, Hai T. Flores, Ludmila M. Lin, Charles P. Magnani, John L. Kung, Andrew L. Letai, Anthony Carrasco, Ruben Roccaro, Aldo M. Ghobrial, Irene M. TI P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment SO BLOOD LA English DT Article ID SIALYL-LEWIS-X; BIOLOGICAL EVALUATION; INHIBITORS; ADHESION; DESIGN; METASTASIS; ANTAGONIST; THERAPY; PSGL-1; TARGET AB Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells and its interaction with selectins in the BM microenvironment. We show that PSGL-1 is highly expressed on MM cells and regulates the adhesion and homing of MM cells to cells in the BM microenvironment in vitro and in vivo. This interaction involves both endothelial cells and BM stromal cells. Using loss-of-function studies and the small-molecule pan-selectin inhibitor GMI-1070, we show that PSGL-1 regulates the activation of integrins and downstream signaling. We also document that this interaction regulates MM-cell proliferation in coculture with BM microenvironmental cells and the development of drug resistance. Furthermore, inhibiting this interaction with GMI-1070 enhances the sensitization of MM cells to bortezomib in vitro and in vivo. These data highlight the critical contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in MM in the context of the BM microenvironment. (Blood. 2012; 119(6): 1468-1478) C1 [Azab, Abdel Kareem; Quang, Phong; Azab, Feda; Chonghaile, Triona; Maiso, Patricia; Monrose, Val; Sacco, Antonio; Ngo, Hai T.; Flores, Ludmila M.; Kung, Andrew L.; Letai, Anthony; Carrasco, Ruben; Roccaro, Aldo M.; Ghobrial, Irene M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pitsillides, Costas; Thompson, Brian; Lin, Charles P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Patton, John T.; Magnani, John L.] GlycoMimetics Inc, Gaithersburg, MD USA. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 44 Binney St,Mayer 548A, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu RI Ni Chonghaile, Triona/L-9418-2015; Sacco, Antonio/K-4681-2016; OI Ni Chonghaile, Triona/0000-0002-3041-4031; Sacco, Antonio/0000-0003-2945-9416; Maiso, Patricia/0000-0003-3745-1924; Roccaro, Aldo/0000-0002-1872-5128; Kung, Andrew/0000-0002-9091-488X FU Multiple Myeloma Research Foundation; National Institutes of Health [R01CA125690, 1R01CA152607] FX This study was supported in part by the Multiple Myeloma Research Foundation and by the National Institutes of Health (grants R01CA125690 and 1R01CA152607). NR 37 TC 38 Z9 39 U1 0 U2 3 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 FEB 9 PY 2012 VL 119 IS 6 BP 1468 EP 1478 DI 10.1182/blood-2011-07-368050 PG 11 WC Hematology SC Hematology GA 894IR UT WOS:000300420900023 PM 22096244 ER PT J AU Srinivasan, M Flynn, R Price, A Ranger, A Browning, JL Taylor, PA Ritz, J Antin, JH Murphy, WJ Luznik, L Shlomchik, MJ Panoskaltsis-Mortari, A Blazar, BR AF Srinivasan, Mathangi Flynn, Ryan Price, Andrew Ranger, Ann Browning, Jeffrey L. Taylor, Patricia A. Ritz, Jerome Antin, Joseph H. Murphy, William J. Luznik, Leo Shlomchik, Mark J. Panoskaltsis-Mortari, Angela Blazar, Bruce R. TI Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW TRANSPLANTATION; SALIVARY-GLAND INVOLVEMENT; CD4(+) T-CELLS; AUTOIMMUNE-DISEASE; MONOCLONAL-ANTIBODY; MODEL; MICE; IMMUNOTHERAPY; RESPONSES AB Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT after a conditioning regimen of cyclophosphamide and total-body radiation results in pulmonary dysfunction and airway obliteration, which leads to bronchiolitis obliterans (BO), which is pathognomonic for cGVHD of the lung. We now report cGVHD manifestations in a wide spectrum of target organs, including those with mucosal surfaces. Fibrosis was demonstrated in the lung and liver and was associated with CD4(+) (T) cells and B220(+) B-cell infiltration and alloantibody deposition. Donor bone marrow obtained from mice incapable of secreting IgG alloantibody resulted in less BO and cGVHD. Robust germinal center reactions were present at the time of cGVHD disease initiation. Blockade of germinal center formation with a lymphotoxin-receptor-immunoglobulin fusion protein suppressed cGVHD and BO. We conclude that cGVHD is caused in part by alloantibody secretion, which is associated with fibrosis and cGVHD manifestations including BO, and that treatment with a lymphotoxin-beta receptorimmunoglobulin fusion protein could be beneficial for cGVHD prevention and therapy. (Blood. 2012; 119(6): 1570-1580) C1 [Srinivasan, Mathangi; Flynn, Ryan; Price, Andrew; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Srinivasan, Mathangi; Flynn, Ryan; Price, Andrew; Taylor, Patricia A.; Panoskaltsis-Mortari, Angela; Blazar, Bruce R.] Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. [Ranger, Ann; Browning, Jeffrey L.] Biogen Idec Inc, Dept Immunobiol, Cambridge, MA USA. [Ritz, Jerome; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ritz, Jerome; Antin, Joseph H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Murphy, William J.] Univ Calif Davis Canc Ctr & Sch Med, Dept Dermatol, Sacramento, CA USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Luznik, Leo] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Shlomchik, Mark J.] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT USA. [Shlomchik, Mark J.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. RP Blazar, BR (reprint author), Univ Minnesota, Masonic Canc Ctr, MMC 109,420 Delaware St SE, Minneapolis, MN 55455 USA. EM blaza001@umn.edu OI Browning, Jeffrey/0000-0001-9168-5233; Ritz, Jerome/0000-0001-5526-4669 FU National Center for Research Resources Shared Instrumentation [1 S10 RR16851]; National Institutes of Health [P01 CA142106-06A1] FX The authors thank Dr Qing Zhou and Dr Christine Goetz for their technical assistance and discussions. They acknowledge the use of the confocal microscope made available through a National Center for Research Resources Shared Instrumentation Grant (#1 S10 RR16851).; This work was supported in part by National Institutes of Health grant P01 CA142106-06A1. NR 43 TC 73 Z9 76 U1 0 U2 3 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 FEB 9 PY 2012 VL 119 IS 6 BP 1570 EP 1580 DI 10.1182/blood-2011-07-364414 PG 11 WC Hematology SC Hematology GA 894IR UT WOS:000300420900034 PM 22072556 ER PT J AU Kachadourian, R Day, BJ Pugazhenti, S Franklin, CC Genoux-Bastide, E Mahaffey, G Gauthier, C Di Pietro, A Boumendjel, A AF Kachadourian, Remy Day, Brian J. Pugazhenti, Subbiah Franklin, Christopher C. Genoux-Bastide, Estelle Mahaffey, Gregory Gauthier, Charlotte Di Pietro, Attilio Boumendjel, Ahcene TI A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GLUTAMATE-CYSTEINE LIGASE; CANCER RESISTANCE PROTEIN; HEME OXYGENASE-1; IN-VITRO; CELLS; EXPRESSION; KINASE; INHIBITOR; NRF2; 2'-HYDROXYCHALCONE AB Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2',5'-dihydroxychalcone (2',5'-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure-activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F andCl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4',6'-dimethoxy-2'-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements. C1 [Kachadourian, Remy; Day, Brian J.; Pugazhenti, Subbiah] Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. [Kachadourian, Remy; Day, Brian J.; Pugazhenti, Subbiah] Univ Colorado, Dept Med, Aurora, CO 80045 USA. [Day, Brian J.; Franklin, Christopher C.] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Aurora, CO 80045 USA. [Pugazhenti, Subbiah; Mahaffey, Gregory] Denver VA Med Ctr, Denver, CO 80220 USA. [Genoux-Bastide, Estelle; Boumendjel, Ahcene] UJF Grenoble 1, CNRS, Dept Pharmacochim Mol, UMR 5063, F-38041 Grenoble, France. [Gauthier, Charlotte; Di Pietro, Attilio] Univ Lyon 1, Inst Biol & Chim Prot, Equipe Labellisee Ligue 2009, BMSSI,UMR5086, F-69367 Lyon 7, France. RP Kachadourian, R (reprint author), Natl Jewish Hlth, Dept Med, Denver, CO 80206 USA. EM remyka@gmail.com FU NIH [HL755223, HL84469, ES015678, ES017582]; VA Merit Review [NEUD-004-07F]; Ligue Nationale Contre le Cancer (Equipe Labelisee Ligue) FX We are grateful to Madeleine Blanc and Chantal Beney for technical assistance in the synthesis of the chalcones. We also thank Dr. Joe M. McCord (University of Colorado, Aurora) for providing the MCF-7/AREc32 cell line generated by Dr. C. Roland Wolf (University of Dundee, United Kingdom). This work was supported by NIH Grants HL755223, HL84469, ES015678, and ES017582 to B.J.D. and VA Merit Review NEUD-004-07F to S.P. C.G. is the recipient of a doctoral fellowship from the Ligue Nationale Contre le Cancer (Equipe Labelisee Ligue 2009). B.J.D. is a consultant for and holds equity in Aeolus Pharmaceuticals that is commercially developing metalloporphyrins as human therapeutic agents. NR 41 TC 20 Z9 20 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 9 PY 2012 VL 55 IS 3 BP 1382 EP 1388 DI 10.1021/jm2016073 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 888DV UT WOS:000299984900033 PM 22239485 ER PT J AU Hu, Y Park, KK Yang, L Wei, X Yang, Q Cho, KS Thielen, P Lee, AH Cartoni, R Glimcher, LH Chen, DF He, ZG AF Hu, Yang Park, Kevin K. Yang, Liu Wei, Xin Yang, Qiang Cho, Kin-Sang Thielen, Peter Lee, Ann-Hwee Cartoni, Romain Glimcher, Laurie H. Chen, Dong Feng He, Zhigang TI Differential Effects of Unfolded Protein Response Pathways on Axon Injury-Induced Death of Retinal Ganglion Cells SO NEURON LA English DT Article ID OPEN-ANGLE GLAUCOMA; TRANSCRIPTION FACTOR XBP-1; ENDOPLASMIC-RETICULUM; MESSENGER-RNA; ER STRESS; RETINITIS-PIGMENTOSA; OCULAR HYPERTENSION; OXIDATIVE STRESS; MOUSE MODELS; OPTIC-NERVE AB Loss of retinal ganglion cells (RGCs) accounts for visual function deficits after optic nerve injury, but how axonal insults lead to neuronal death remains elusive. By using an optic nerve crush model that results in the death of the majority of RGCs, we demonstrate that axotomy induces differential activation of distinct pathways of the unfolded protein response in axotomized RGCs. Optic nerve injury provokes a sustained CCAAT/enhancer binding homologous protein (CHOP) upregulation, and deletion of CHOP promotes RGC survival. In contrast, IRE/XBP-1 is only transiently activated, and forced XBP-1 activation dramatically protects RGCs from axon injury-induced death. Importantly, such differential activations of CHOP and XBP-1 and their distinct effects on neuronal cell death are also observed in RGCs with other types of axonal insults, such as vincristine treatment and intraocular pressure elevation, suggesting a new protective strategy for neurodegeneration associated with axonal damage. C1 [Hu, Yang; Park, Kevin K.; Yang, Liu; Cartoni, Romain; He, Zhigang] Harvard Univ, Sch Med, FM Kirby Neurobiol Ctr, Childrens Hosp, Boston, MA 02115 USA. [Hu, Yang; Park, Kevin K.; Yang, Liu; Cartoni, Romain; He, Zhigang] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Wei, Xin; Yang, Qiang; Cho, Kin-Sang; Chen, Dong Feng] Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA 02114 USA. [Thielen, Peter; Lee, Ann-Hwee; Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Thielen, Peter; Lee, Ann-Hwee; Glimcher, Laurie H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Hu, Yang] Temple Univ, Sch Med, Shriners Hosp Pediat Res Ctr, Philadelphia, PA 19140 USA. [Park, Kevin K.] Univ Miami, Sch Med, Miami Project Cure Paralysis, Miami, FL 33136 USA. [Chen, Dong Feng] Boston Healthcare Syst, Ctr Innovat Visual Rehabil, Vet Affairs, Boston, MA 02130 USA. RP Hu, Y (reprint author), Harvard Univ, Sch Med, FM Kirby Neurobiol Ctr, Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM yanghu@temple.edu; dongfeng.chen@schepens.harvard.edu; zhigang.he@childrens.harvard.edu FU National Eye Institute; Miami Project to Cure Paralysis; Department of Veterans Affairs; National Institutes of Health (NIH) [AI32412]; NIH National Research Service FX We thank B. Xu and L. Connolly for technical support. Our work was supported by grants from the National Eye Institute (Z.H.), Miami Project to Cure Paralysis (K.K.P.), Department of Veterans Affairs (D.F.C.), National Institutes of Health (NIH) grant AI32412, and a grant from an anonymous foundation (L.H.G.). Y.H. was supported by an NIH National Research Service Award Postdoctoral Fellowship. Y.H., K.K.P., L.Y., Q.Y., X.W., P.T., and A.H.L. performed the experiments and analyzed the data. Y.H., L.H.G., D.F.C., and Z.H. designed experiments and prepared the manuscript. NR 47 TC 51 Z9 53 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 9 PY 2012 VL 73 IS 3 BP 445 EP 452 DI 10.1016/j.neuron.2011.11.026 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 890JJ UT WOS:000300140600007 PM 22325198 ER EF