FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Salinas, H Dursun, A Konstantinidis, I Nguyen, D Shellito, P Hodin, R Bordeianou, L AF Salinas, Harry Dursun, Abdulmentin Konstantinidis, Ioannis Nguyen, Deanna Shellito, Paul Hodin, Richard Bordeianou, Liliana TI Does preoperative total parenteral nutrition in patients with ulcerative colitis produce better outcomes? SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Inflammatory bowel disease; Ulcerative colitis; Colorectal surgery; Nutrition ID SURGERY AB Malnutrition is a frequent problem in patients with ulcerative colitis (UC) leading to increased postoperative complication rates. Preoperative total parenteral nutrition (TPN) has been shown to reduce complications in some subgroups of patients, but has not been studied in UC. We investigated the impact of preoperative TPN on postoperative complication rates in patients undergoing surgery for UC. This paper is a review of 235 patients who underwent surgery for UC; 56 received preoperative TPN and 179 did not. Postoperative complication rates were compared. Both had similar rates of anastomotic leak (5.4 vs. 2.8 %, p = 0.356), infection (12.5 vs. 20.1 %, p = 0.199), ileus/bowel obstruction (21.4 vs. 15.6 %, p = 0.315), cardiac complications (3.6 vs. 0 %, p = 0.056), wound dehiscence (3.6 vs. 1.7 %, p = 0.595), reoperation (10.7 vs. 3.9 %, p = 0.086), and death (1.8 vs. 0 %, p = 0.238). The TPN group was more malnourished (albumin 2.49 vs. 3.45, p < 0.001), more often on steroids (83.9 vs. 57.5 %, p < 0.001), had more emergent surgery (10.7 vs. 3.4 %, p = 0.029), more severe colitis (89.3 vs. 65.9 %, p = 0.001), and lower Surgical Apgar Score (6.15 vs. 6.57, p = 0.033). After controlling for these with logistic regression, the TPN group still had higher complication rates (OR 2.32, p = 0.04). When line infections were excluded, TPN did not significantly affect outcomes (OR 1.5, p = 0.311) There were no differences in postoperative complications when line infections were excluded. Our data does not support routine preoperative TPN in patients with UC. However, it may lead to equal surgical outcomes in the sickest and most malnourished patients at the cost of line-related morbidity. C1 [Nguyen, Deanna] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Dept Gastroenterol, Boston, MA 02114 USA. [Shellito, Paul; Hodin, Richard; Bordeianou, Liliana] Massachusetts Gen Hosp, Crohns & Colitis Ctr, Dept Surg, Boston, MA 02114 USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Dept Surg, 15 Parkman St,ACC 460, Boston, MA 02114 USA. EM lbordeianou@partners.org NR 8 TC 4 Z9 4 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD NOV PY 2012 VL 27 IS 11 BP 1479 EP 1483 DI 10.1007/s00384-012-1535-2 PG 5 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 024DK UT WOS:000310088000011 PM 23011545 ER PT J AU Chan, HN Rush, AJ Nierenberg, AA Trivedi, M Wisniewski, SR Balasubramani, GK Friedman, ES Gaynes, BN Davis, L Morris, D Fava, M AF Chan, Herng Nieng Rush, A. John Nierenberg, Andrew A. Trivedi, Madhukar Wisniewski, Stephen R. Balasubramani, G. K. Friedman, Edward S. Gaynes, Bradley N. Davis, Lori Morris, David Fava, Maurizio TI Correlates and outcomes of depressed out-patients with greater and fewer anxious symptoms: a CO-MED report SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Anxiety; depression; outcomes; treatment prediction ID STAR-ASTERISK-D; MEASUREMENT-BASED CARE; DIAGNOSTIC SCREENING QUESTIONNAIRE; NONANXIOUS DEPRESSION; MAJOR DEPRESSION; CLINICAL-PRACTICE; QUICK INVENTORY; RATING-SCALE; OUTPATIENTS; DISORDER AB The objective of this paper was to determine whether the presence of more vs. fewer anxious symptom features, at baseline, are associated with other clinical features and treatment outcomes in out-patients with major depressive disorder (MDD). This single-blind, randomized trial enrolled 665 MDD outpatients to compare the efficacy of two antidepressant medication combinations against escitalopram after 12-wk acute treatment and follow-up (total 28 wk). The sample was divided into those with greater (vs. fewer) anxiety features using the anxiety/somatization subscale of the baseline 17-item Hamilton Rating Scale for Depression. Baseline sociodemographic and clinical features, treatment features and outcomes compared these two groups. Overall, 74.7% of participants met the threshold for 'anxious features'. They were more likely to be female, have other concurrent anxiety disorders, more severe depression, more lethargic and melancholic features and poorer cognitive and physical functioning, quality of life and work and social adjustment. In acute treatment, participants with anxious features received comparatively higher doses of mirtazapine and venlafaxine and reported more side-effects. The groups with and without anxious features did not differ in treatment outcomes and side-effect burden. Despite being associated with a distinct clinical profile, baseline anxious features were not clinically useful in predicting acute treatment outcomes or differential treatment response. C1 [Trivedi, Madhukar; Morris, David] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Chan, Herng Nieng] Singapore Gen Hosp, Dept Psychiat, Singapore 0316, Singapore. [Rush, A. John] Natl Univ Singapore, Duke NUS Grad Med Sch, Singapore 117548, Singapore. [Nierenberg, Andrew A.; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Wisniewski, Stephen R.; Balasubramani, G. K.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Gaynes, Bradley N.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Davis, Lori] VA Med Ctr, Res & Dev Serv, Tuscaloosa, AL USA. [Davis, Lori] Univ Alabama Birmingham, Sch Med, Dept Psychiat, Birmingham, AL USA. [Morris, David] Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, New York, NY USA. [Morris, David] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. RP Trivedi, M (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM madhukar.trivedi@utsouthwestern.edu RI Trivedi, Madhukar/A-9029-2013; OI Wisniewski, Stephen/0000-0002-3877-9860; Gaynes, Bradley/0000-0002-8283-5030; Rush, Augustus/0000-0003-2004-2382; Goundappa K, Balasubramani/0000-0001-7221-1825 FU Abbott Laboratories, Inc.; AstraZeneca; Bristol-Myers Squibb Company (BMS); Eisai Pharmaceuticals; Janssen; VA, NIMH, Shire; Southwestern Oncology Group, Department of Defense (DoD); Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Bristol-Myers Squibb Company; Cephalon; Forest Pharmaceuticals Inc.; GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Eli Lilly Company; Lorex Pharmaceuticals; Novartis; Organon Inc.; PamLab, LLC; Pfizer Inc.; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories; Indevus; Pfizer; Sanofi-Aventis; Wyeth-Ayerst; Cyberonics; NorthStar/St. Jude Medical; Medtronics; Repligen; National Institute of Mental Health; Agency for Healthcare Research and Quality; M-3 Information; MGH from NIMH; Pam labs; Pfizer Pharmaceuticals and Shire; Astra Zeneca; Eli Lilly; Janssen Pharmaceuticals; Bristol-Myers Squibb; University of Michigan, Brain Resource; Otsuka Pharmaceuticals; royalties from Guilford Publications; University of Texas Southwestern Medical Center; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Forest Pharmaceuticals; Janssen Pharmaceutica; Merck; National Alliance for Research in Schizophrenia and Depression; Pharmacia Upjohn; Predix Pharmaceuticals FX Dr Davis has received research support (no personal income) from Abbott Laboratories, Inc.; AstraZeneca; Bristol-Myers Squibb Company (BMS); Eisai Pharmaceuticals; Janssen; VA, NIMH, Shire; AstraZeneca; Southwestern Oncology Group, Department of Defense (DoD). She has done advising/consulting for Cyberonics; Abbott; Shire; Constella; Eli Lilly, has done speaking engagements for Abbott Laboratories; Cyberonics; Sanofi-Aventis; and AstraZeneca and has equity holdings in Pfizer (until 2009). Dr Fava has received research support from Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Bristol-Myers Squibb Company; Cephalon; Forest Pharmaceuticals Inc.; GlaxoSmithKline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Eli Lilly & Company; Lorex Pharmaceuticals; Novartis; Organon Inc.; PamLab, LLC; Pfizer Inc.; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories. He has provided advisory/consulting services to Aspect Medical Systems; Astra-Zeneca; Bayer AG; Biovail Pharmaceuticals, Inc.; BrainCells, Inc.; Bristol-Myers Squibb Company; Cephalon; Compellis; Cypress Pharmaceuticals; Dov Pharmaceuticals; EPIX Pharmaceuticals; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Grunenthal GmBH; J & J Pharmaceuticals; Janssen Pharmaceutica; Jazz Pharmaceuticals; Knoll Pharmaceutical Company; Eli Lilly & Company; Lundbeck; MedAvante, Inc.; Novartis; Nutrition 21; Organon Inc.; PamLab, LLC; Pfizer Inc.; PharmaStar; Pharmavite; Roche; Sanofi/Synthelabo; Sepracor; Solvay Pharmaceuticals, Inc.; Somerset Pharmaceuticals; Wyeth-Ayerst Laboratories. He has been on speaking bureaus for AstraZeneca; Bristol-Myers Squibb Company; Cephalon; Forest Pharmaceuticals Inc.; GlaxoSmithKline; Eli Lilly & Company; Novartis; Organon Inc.; Pfizer Inc.; PharmaStar; Wyeth-Ayerst Laboratories. Dr Fava has equity holdings (excluding mutual funds/blinded trusts) with Compellis and MedAvante. Dr Friedman has received grant/research support: Aspect Medical Systems; Indevus; AstraZeneca; Bristol-Myers Squibb; Pfizer; Sanofi-Aventis; Wyeth-Ayerst; Cyberonics; Novartis; NorthStar/St. Jude Medical; Medtronics; Repligen. He has been on speaker bureaus or advisory boards for AstraZeneca; GlaxoSmithKline; Pfizer; Wyeth-Ayerst. Dr Gaynes has received grant/research from the National Institute of Mental Health; Agency for Healthcare Research and Quality; and M-3 Information. Dr Nierenberg is a full time employee of the Massachusetts General Hospital (MGH). He has served as a consultant to the American Psychiatric Association (only travel expenses paid) and Appliance Computing Inc. (Mindsite), Brandeis University. Through the MGH Clinical Trials Network and Institute, he has consulted for Brain Cells, Inc Dianippon Sumitomo/Sepracor Novartis, PGx Health, Shire, Schering-Plough, Targacept and Takeda/lundbeck Pharmaceuticals. He received grant/research support through MGH from NIMH, Pam labs, Pfizer Pharmaceuticals and Shire. He received honoraria from Belvior Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, IMEDEX, MJ Consulting, New York State, MBl Publishing, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin and the University of Pisa. Dr Nierenberg is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA).; The education programs conducted by the MGHPA were supported through Independent Medical Education (IME) grants from the following pharmaceutical companies in 2008: Astra Zeneca, Eli Lilly and Janssen Pharmaceuticals; in 2009 Astra Zeneca, Eli Lilly and Bristol-Myers Squibb. No speaker bureaus or boards since 2003. He is on the advisory boards of Appliance Computing, Inc., Brain Cells, Inc., Eli Lilly and Company and Takeda/lundbeck and Targacept. Dr Nierenberg owns stock options in Appliance Computing, Inc. and Brain Cells, Inc. Through MGH, he is named for copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute (CTNI). Also, through MGH, Dr Nierenberg has a patent extension application for the combination of buspirone, bupropion and melatonin for the treatment of depression. Dr Rush has received consultant fees from University of Michigan, Brain Resource; speaking fees from Otsuka Pharmaceuticals; research support from National Institute of Mental Health and royalties from Guilford Publications and the University of Texas Southwestern Medical Center. Dr Trivedi has been a consultant for Abbott Laboratories, Inc.; Akzo (Organon Pharmaceuticals Inc.); AstraZeneca; Bayer; Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Fabre-Kramer Pharmaceuticals, Inc. Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Johnson & Johnson PRD; Eli Lilly & Company; Meade Johnson; Neuronetics; Parke-Davis Pharmaceuticals, Inc.; Pfizer, Inc.; Pharmacia & Upjohn; Sepracor; Solvay Pharmaceuticals, Inc.; VantagePoint; and Wyeth-Ayerst Laboratories. He has served on speakers bureaus for Abdi Brahim; Akzo (Organon Pharmaceuticals Inc.); Bristol-Myers Squibb Company; Cephalon, Inc.; Cyberonics, Inc.; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica Products, LP; Eli Lilly & Company; Pharmacia & Upjohn; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. He has also received grant support from Bristol-Myers Squibb Company; Cephalon, Inc.; Corcept Therapeutics, Inc.; Cyberonics, Inc.; Eli Lilly & Company; Forest Pharmaceuticals; GlaxoSmithKline; Janssen Pharmaceutica; Merck; National Institute of Mental Health; National Alliance for Research in Schizophrenia and Depression; Novartis; Pfizer Inc.; Pharmacia & Upjohn; Predix Pharmaceuticals; Solvay Pharmaceuticals, Inc.; and Wyeth-Ayerst Laboratories. Dr Wisniewski has been a consultant for: Cyberonic Inc. (2005-2009), ImaRx Therapeutics, Inc. (2006), Bristol-Myers Squibb Company (2007-08), Organon (2007), Case-Western University (2007), Singapore Clinical Research Institute (2009), Dey Pharmaceuticals (2010), Venebio (2010), Dey (2010). NR 47 TC 11 Z9 12 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD NOV PY 2012 VL 15 IS 10 BP 1387 EP 1399 DI 10.1017/S1461145711001660 PG 13 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 019LD UT WOS:000309740200003 PM 22129562 ER PT J AU Galimberti, F Busch, AM Chinyengetere, F Ma, T Sekula, D Memoli, VA Dragnev, KH Liu, F Johnson, KC Guo, YL Freemantle, SJ Andrew, AS Greninger, P Robbins, DJ Settleman, J Benes, C Dmitrovsky, E AF Galimberti, Fabrizio Busch, Alexander M. Chinyengetere, Fadzai Ma, Tian Sekula, David Memoli, Vincent A. Dragnev, Konstantin H. Liu, Fang Johnson, Kevin C. Guo, Yongli Freemantle, Sarah J. Andrew, Angeline S. Greninger, Patricia Robbins, David J. Settleman, Jeff Benes, Cyril Dmitrovsky, Ethan TI Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE hedgehog; smoothened; patched; lung cancer ID GENOTYPE-CORRELATED SENSITIVITY; HEDGEHOG PATHWAY INHIBITOR; LUNG-CANCER; CYCLIN-E; KINASE INHIBITORS; SIGNALING PATHWAY; KRAS MUTATIONS; SONIC-HEDGEHOG; RESISTANCE; GROWTH AB Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth response to the Smo inhibitor cyclopamine and for expressed HH pathway-regulated species in a linked genetic database. Ptch and Smo mutations that respectively conferred Smo inhibitor response or resistance were undetected. Previous studies revealed HH pathway activation in lung cancers. Therefore, findings were validated using lung cancer cell lines, transgenic and transplantable murine lung cancer models, and human normal-malignant lung tissue arrays in addition to testing other Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6) (P=0.000004) levels. Gli family members were associated with response. Cyclopamine resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response. Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH pathway activation. Cyclopamine treatment significantly reduced proliferation of murine and human lung cancers. Smo inhibition reduced lung cancer formation in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin E, IGFBP6, Glil and GILZ were each differentially expressed. Together, these findings indicate that Smo inhibitors should be considered in cancers beyond those with activating HH pathway mutations. This includes tumors that express genes indicating basal HH pathway activation. C1 [Galimberti, Fabrizio; Busch, Alexander M.; Chinyengetere, Fadzai; Ma, Tian; Sekula, David; Liu, Fang; Johnson, Kevin C.; Guo, Yongli; Freemantle, Sarah J.; Robbins, David J.; Dmitrovsky, Ethan] Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA. [Memoli, Vincent A.] Geisel Sch Med Dartmouth, Dept Pathol, Hanover, NH 03755 USA. [Andrew, Angeline S.] Geisel Sch Med Dartmouth, Dept Community & Family Med, Hanover, NH 03755 USA. [Dragnev, Konstantin H.; Dmitrovsky, Ethan] Geisel Sch Med Dartmouth, Dept Med, Hanover, NH 03755 USA. [Memoli, Vincent A.; Dragnev, Konstantin H.; Andrew, Angeline S.; Robbins, David J.; Dmitrovsky, Ethan] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Hanover, NH 03755 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03756 USA. [Greninger, Patricia; Settleman, Jeff; Benes, Cyril] Massachusetts Gen Hosp, Ctr Canc, Ctr Mol Therapeut, Charlestown, MA 02129 USA. RP Dmitrovsky, E (reprint author), Geisel Sch Med Dartmouth, Dept Pharmacol & Toxicol, Hanover, NH 03755 USA. EM ethan.dmitrovsky@dartmouth.edu FU National Institutes of Health (NIH); National Cancer Institute (NCI) [R01-CA087546, R01-CA111422, R03-CA132166]; Samuel Waxman Cancer Research Foundation; Merck; American Cancer Society; FM Kirby Foundation; NIH National Research Service [T32-CA009658] FX This study was supported by National Institutes of Health (NIH) and National Cancer Institute (NCI) grants R01-CA087546 (E.D.), R01-CA111422 (E.D.), R03-CA132166 (E.D.), a Samuel Waxman Cancer Research Foundation award (E.D.), a research grant from Merck (E.D.) and an American Cancer Society Clinical Research Professorship (E.D.) supported by a gift from the FM Kirby Foundation. A.M.B. was supported by an NIH National Research Service Award (T32-CA009658). We thank Dr Jason Sparkowski (Merck) for providing MK-4101. NR 38 TC 6 Z9 7 U1 0 U2 3 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 NOV PY 2012 VL 41 IS 5 BP 1751 EP 1761 DI 10.3892/ijo.2012.1599 PG 11 WC Oncology SC Oncology GA 024MU UT WOS:000310114100025 PM 22923130 ER PT J AU Subramanian, RR Yamakawa, A AF Subramanian, Romesh R. Yamakawa, Akio TI Combination therapy targeting Raf-1 and MEK causes apoptosis of HCT116 colon cancer cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE Raf; MEK; apoptosis; cancer; RNA interference ID NF-KAPPA-B; KINASE-ACTIVITY; NEOPLASTIC PHENOTYPE; SIGNALING PATHWAYS; TUMOR-CELLS; RAS GENES; PHOSPHORYLATION; ACTIVATION; MUTATIONS; INDUCTION AB Members of the Ras protooncogene family are mutated in approximately 75% of colon cancers. The Raf kinases (Raf-1, b-Raf and a-Raf) directly interact with Ras and serve as mediators of mitogenic signals. Expression of the constitutively active alleles of Raf or Ras gene families results in oncogenesis in a number of model systems. Previous studies emphasized the importance of Raf-1 and b-Raf in preventing apoptosis in addition to their roles in cell growth. In the present study, we examined whether inhibition of the Raf-1 or b-Raf kinase decreases cell growth and increases apoptosis in colon cancer cells. c-Raf and b-Raf were depleted in colon cancer cell lines, such as HCT116, HT29 and Colo205, containing Ras or b-Raf mutations by RNA interference (RNAi). The results showed that colon cancer cells with activating Ras mutations undergo apoptosis following Raf-1 inhibition, as determined by cell cycle analysis and the release of cytochrome c. Moreover, in b-Raf mutant colon cancers, the inhibition of b-Raf as compared to Raf-1 is crucial for cancer cell death. There is increasing evidence for both MEK-independent Raf signaling and Raf-independent MEK signaling. Thus, we investigated whether targeting multiple points of the mitogen-activated protein kinase (MAPK) pathway with a MEK inhibitor and Raf RNAi increases cancer cell death. The results showed that combination therapy, inhibiting Raf and MEK kinases simultaneously, increased apoptosis in colon cancer cells. Taken together, our data demonstrate that combination therapy targeting the MAPK pathway at two distinct points, Raf kinase and MEK, has greater efficacy in increasing cancer cell death and is likely to improve therapeutic outcomes for patients. C1 [Subramanian, Romesh R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Subramanian, Romesh R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Subramanian, RR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM romesh.r.subramanian@gmail.com NR 38 TC 6 Z9 6 U1 0 U2 2 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 NOV PY 2012 VL 41 IS 5 BP 1855 EP 1862 DI 10.3892/ijo.2012.1602 PG 8 WC Oncology SC Oncology GA 024MU UT WOS:000310114100036 PM 22922669 ER PT J AU Maserejian, NN Hauser, R Tavares, M Trachtenberg, FL Shrader, P McKinlay, S AF Maserejian, N. N. Hauser, R. Tavares, M. Trachtenberg, F. L. Shrader, P. McKinlay, S. TI Dental Composites and Amalgam and Physical Development in Children SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE composite resins; bisphenol A-glycidyl methacrylate; dental amalgam; body mass index; menarche; child ID BISPHENOL-A EXPOSURE; BIS-GMA; BEVERAGE CONSUMPTION; TRIAL; FERTILITY; BEHAVIOR; RELEASE; MERCURY; RESIN; MICE AB Resin-based composite dental restoration materials may release bisphenol-A, an endocrine-disrupting chemical. Using secondary analysis of a randomized clinical safety trial of amalgam vs. composites, we tested the hypothesis that dental restoration materials affect children's growth. Children (N = 218 boys, N = 256 girls) aged 6 to 10 yrs at baseline with >= 2 decayed posterior teeth were randomized to amalgam or composites (bisphenol-A-diglycidyl-dimethacrylate composite for permanent teeth, urethane-dimethacrylate compomer for primary teeth) for treatment of posterior caries throughout follow-up. Primary outcomes for this analysis were 5-year changes in BMI-for-age z-scores, body fat percentage (BF%), and height velocity; exploratory analyses (n = 113) examined age at menarche. Results showed no significant differences between treatment assignment and changes in physical development in boys [(composites vs. amalgam) BF%, 4.9 vs. 5.7, p = 0.49; (BMI-z-score) 0.13 vs. 0.25, p = 0.36] or girls (8.8 vs. 7.7, p = 0.95; 0.36 vs. 0.21, p = 0.49). Children with more treatment on primary teeth had greater increases in BF% regardless of material type. Girls assigned to composites had lower risk of menarche during follow-up (hazard ratio = 0.57, 95% CI 0.35-0.95). Overall, there were no significant differences in physical development over 5 years in children treated with composites or amalgam. Additional studies examining these restoration materials in relation to age at menarche are warranted (clinicaltrials.gov number NCT00065988). C1 [Maserejian, N. N.; Trachtenberg, F. L.; Shrader, P.; McKinlay, S.] New England Res Inst, Watertown, MA 02472 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hauser, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hauser, R.] Harvard Univ, Sch Med, Boston, MA USA. [Tavares, M.] Forsyth Inst, Cambridge, MA USA. RP Maserejian, NN (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM nmaserejian@neriscience.com FU National Institute of Environmental Health Sciences (NIEHS) [R01ES019155] FX The analyses presented in this paper were funded by Award Number R01ES019155 from the National Institute of Environmental Health Sciences (NIEHS). The NIEHS had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The data collection was supported by a cooperative agreement (U01 DE11886) between the New England Research Institutes and the National Institute of Dental and Craniofacial Research (NIDCR), both of which participated in the design and conduct of the New England Children's Amalgam Trial, including collection and management of data. The NIDCR had no role in the analyses or interpretation of data for this manuscript, or in the preparation, review, or approval of the manuscript. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Institute of Dental and Craniofacial Research, or the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article. NR 34 TC 11 Z9 11 U1 1 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 NOV PY 2012 VL 91 IS 11 BP 1019 EP 1025 DI 10.1177/0022034512458691 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 022CG UT WOS:000309932100004 PM 22972857 ER PT J AU Ahluwalia, SC Gordon, HS AF Ahluwalia, Sangeeta C. Gordon, Howard S. TI Advance Care Planning Safeguards SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Letter C1 [Ahluwalia, Sangeeta C.] Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. [Gordon, Howard S.] Univ Illinois, Jesse Brown Vet Affairs Med Ctr, Chicago, IL USA. RP Ahluwalia, SC (reprint author), Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, 11301 Wilshire Blvd,111-G, Los Angeles, CA 90073 USA. EM sangeeta.ahluwalia@va.gov RI Gordon, Howard/E-4420-2010 OI Gordon, Howard/0000-0002-6712-5954 NR 3 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1404 EP 1404 DI 10.1007/s11606-012-2190-6 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500005 PM 22878859 ER PT J AU Billings, JA AF Billings, J. Andrew TI Advance Care Planning Safeguards SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Letter C1 [Billings, J. Andrew] Massachusetts Gen Hosp, Cambridge Hlth Alliance, Cambridge, MA 02138 USA. [Billings, J. Andrew] Harvard Univ, Sch Med, Ctr Palliat Care, Cambridge, MA 02138 USA. RP Billings, JA (reprint author), Massachusetts Gen Hosp, Cambridge Hlth Alliance, 11 1-2 Hilliard St, Cambridge, MA 02138 USA. EM jbillings@partners.org NR 5 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1405 EP 1405 DI 10.1007/s11606-012-2191-5 PG 1 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500006 ER PT J AU Morris, DA Johnson, KS Ammarell, N Arnold, RM Tulsky, JA Steinhauser, KE AF Morris, Deborah A. Johnson, Kimberly S. Ammarell, Natalie Arnold, Robert M. Tulsky, James A. Steinhauser, Karen E. TI What is Your Understanding of Your Illness? A Communication Tool to Explore Patients' Perspectives of Living with Advanced Illness SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE communication; qualitative research; advanced illness; patient-centered care; palliative care ID OBSTRUCTIVE PULMONARY-DISEASE; OF-LIFE CARE; BREAKING BAD-NEWS; ADVANCED CANCER; HEART-FAILURE; PALLIATIVE-CARE; PROGNOSIS; AWARENESS; PREFERENCES; INFORMATION AB Provider communication courses and guidelines stress the use of open-ended questions, such as "what is your understanding of your illness?," to explore patients' perceptions of their illness severity, yet descriptions of patients' responses are largely absent from the current literature. These questions are most often used by clinicians as they deliver bad news to cancer patients or address code status at the end of life, but have not been well studied in other diseases or earlier in the disease course. To explore the responses of patients living with serious illness to the question "what is your understanding of your illness?" and to identify similarities and differences in themes and language used by cancer and non-cancer patients to discuss their illness. We conducted a qualitative analysis of patients' responses to "what is your understanding of your illness?" Two hundred nine subjects, 69 with cancer, 70 CHF, and 70 COPD, who had an estimated 50 % 2-year survival. Mean age was 66 years. Responses were recorded at the baseline interview of a larger, longitudinal study of patients with advanced life-limiting illness (cancer, CHF, or COPD). After thematic content analysis using open coding, investigators conducted pattern analysis to examine variation associated with diagnosis. We identified five major themes: naming the diagnosis or describing the pathophysiology, illness history, prognosis, symptoms, and causality. Responses varied by diagnosis. Cancer patients' responses more often included specific diagnostic details and prognosis, while non-cancer patients referenced symptoms and causality. Patients' responses to the open-ended question "what is your understanding of your illness?" can provide the clinician with important information and insight on how they view their illness in a non-acute setting. The identified themes can serve as a foundation for patient-centered communication strategies as we strive to build a mutual understanding of illness with patients. C1 [Morris, Deborah A.] VA Med Ctr, Durham, NC 27701 USA. [Morris, Deborah A.] Duke Med Ctr, Durham, NC 27701 USA. [Morris, Deborah A.; Johnson, Kimberly S.; Ammarell, Natalie; Tulsky, James A.; Steinhauser, Karen E.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Johnson, Kimberly S.] Durham Vet Affairs Med Ctr, Geriatr Res & Clin Ctr, Durham, NC USA. [Tulsky, James A.; Steinhauser, Karen E.] Duke Univ, Ctr Palliat Care, Durham, NC USA. [Morris, Deborah A.; Johnson, Kimberly S.; Tulsky, James A.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Johnson, Kimberly S.] Duke Univ, Sch Med, Div Geriatr, Durham, NC USA. [Ammarell, Natalie; Tulsky, James A.] Duke Univ, Sch Nursing, Durham, NC USA. [Arnold, Robert M.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Arnold, Robert M.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Morris, DA (reprint author), VA Med Ctr, 411 W Chapel Hill St,Suite 500, Durham, NC 27701 USA. EM damorri1@gmail.com FU Durham NC VA Medical Center; NIH/NINR RFP [PA-00-127]; Beeson Career Development Award in Aging Research [5K08AG028975] FX This material is the result of work supported with resources and the use of facilities at the Durham NC VA Medical Center. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.; This research was supported by a grant from the NIH/NINR RFP PA-00-127 "Trajectories of Serious Illness Patients and Caregivers" and the 5K08AG028975 Beeson Career Development Award in Aging Research (KSJ). NR 37 TC 6 Z9 7 U1 0 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1460 EP 1466 DI 10.1007/s11606-012-2109-2 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500014 PM 22638605 ER PT J AU Roy, B Castiglioni, A Kraemer, RR Salanitro, AH Willett, LL Shewchuk, RM Qu, HY Heudebert, G Centor, RM AF Roy, Brita Castiglioni, Analia Kraemer, Ryan R. Salanitro, Amanda H. Willett, Lisa L. Shewchuk, Richard M. Qu, Haiyan Heudebert, Gustavo Centor, Robert M. TI Using Cognitive Mapping to Define Key Domains for Successful Attending Rounds SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medical education; clinical teaching; ward rounds ID NOMINAL GROUP TECHNIQUE; WARD ROUNDS; MEDICINE; PHYSICIAN; RESIDENTS; ATTITUDES; TEACHER AB Ward attending rounds are an integral part of internal medicine education. Being a good teacher is necessary, but not sufficient for successful rounds. Understanding perceptions of successful attending rounds (AR) may help define key areas of focus for enhancing learning, teaching and patient care. We sought to expand the conceptual framework of 30 previously identified attributes contributing to successful AR by: 1) identifying the most important attributes, 2) grouping similar attributes, and 3) creating a cognitive map to define dimensions and domains contributing to successful rounds. Multi-institutional, cross-sectional study design. We recruited residents and medical students from a university-based internal medicine residency program and a community-based family medicine residency program. Faculty attending a regional general medicine conference, affiliated with multiple institutions, also participated. Participants performed an unforced card-sorting exercise, grouping attributes based on perceived similarity, then rated the importance of attributes on a 5-point Likert scale. We translated our data into a cognitive map through multi-dimensional scaling and hierarchical cluster analysis. Thirty-six faculty, 49 residents and 40 students participated. The highest rated attributes (mean rating) were "Teach by example (bedside manner)" (4.50), "Sharing of attending's thought processes" (4.46), "Be approachable-not intimidating" (4.45), "Insist on respect for all team members" (4.43), "Conduct rounds in an organized, efficient & timely fashion" (4.39), and "State expectations for residents/students" (4.37). Attributes were plotted on a two-dimensional cognitive map, and adequate convergence was achieved. We identified five distinct domains of related attributes: 1) Learning Atmosphere, 2) Clinical Teaching, 3) Teaching Style, 4) Communicating Expectations, and 5) Team Management. We identified five domains of related attributes essential to the success of ward attending rounds. C1 [Roy, Brita] Univ Alabama Birmingham, Dept Internal Med, Birmingham, AL 35294 USA. [Castiglioni, Analia; Heudebert, Gustavo; Centor, Robert M.] Birmingham VA Med Ctr, Birmingham, AL USA. [Salanitro, Amanda H.] Tennessee Valley Healthcare Syst Geriatr Res Educ, Dept Vet Affairs, Nashville, TN USA. [Salanitro, Amanda H.] Vanderbilt Univ, Sect Hosp Med, Nashville, TN USA. [Willett, Lisa L.] Univ Alabama Birmingham, Dept Med, Div Gen Internal Med, Birmingham, AL 35294 USA. [Shewchuk, Richard M.; Qu, Haiyan] Univ Alabama Birmingham, Sch Hlth Profess, Dept Hlth Serv Adm, Birmingham, AL USA. [Heudebert, Gustavo] Univ Alabama Birmingham, Sch Publ Hlth, Birmingham, AL 35294 USA. RP Roy, B (reprint author), Univ Alabama Birmingham, Dept Internal Med, Birmingham, AL 35294 USA. EM britaroy@uab.edu NR 21 TC 10 Z9 10 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1492 EP 1498 DI 10.1007/s11606-012-2121-6 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500018 PM 22722975 ER PT J AU Huetsch, JC Uman, JE Udris, EM Au, DH AF Huetsch, John C. Uman, Jane E. Udris, Edmunds M. Au, David H. TI Predictors of Adherence to Inhaled Medications Among Veterans with COPD SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medication adherence; pulmonary diseases; health behavior; veterans ID OBSTRUCTIVE PULMONARY-DISEASE; REFILL ADHERENCE; NONADHERENCE; SALMETEROL; THERAPY; FLUTICASONE; PERSISTENCE; TRIAL; DRUGS AB Factors contributing to medication nonadherence among patients with chronic obstructive pulmonary disease (COPD) are poorly understood. To identify patient characteristics that are predictive of adherence to inhaled medications for COPD and, for patients on multiple inhalers, to assess whether adherence to one medication class was associated with adherence to other medication classes. Cohort study using data from Veteran Affairs (VA) electronic databases. This study included 2,730 patients who underwent pulmonary function testing between 2003 and 2007 at VA facilities in the Northwestern United States, and who met criteria for COPD. We used pharmacy records to estimate adherence to inhaled corticosteroids (ICS), ipratropium bromide (IP), and long-acting beta-agonists (LABA) over two consecutive six month periods. We defined patients as adherent if they had refilled medications to have 80 % of drug available over the time period. We also collected information on their demographics, behavioral habits, COPD severity, and comorbidities. Adherence to medications was poor, with 19.8 % adherent to ICS, 30.6 % adherent to LABA, and 25.6 % adherent to IP. Predictors of adherence to inhaled therapies were highly variable and dependent on the medication being examined. In adjusted analysis, being adherent to a medication at baseline was the strongest predictor of future adherence to that same medication [(Odds ratio, 95 % confidence interval) ICS: 4.79 (3.22-7.12); LABA: 6.60 (3.92-11.11); IP: 14.13 (10.00-19.97)], but did not reliably predict adherence to other classes of medication. Among patients with COPD, past adherence to one class of inhaled medication strongly predicted future adherence to the same class of medication, but only weakly predicted adherence to other classes of medication. C1 [Huetsch, John C.; Uman, Jane E.; Udris, Edmunds M.; Au, David H.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98101 USA. [Huetsch, John C.] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Au, David H.] Univ Washington, Div Pulm & Crit Care Med, 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 dau@uw.edu FU American Lung Association [CI-51755N]; HSR&D, VA Puget Sound Health Care System; NHLBI; AHRQ; Department of Veterans Affairs; Gilead Sciences FX This project was funded by the American Lung Association, grant # CI-51755N. Dr. Au was funded by HSR&D, VA Puget Sound Health Care System. The views expressed in this manuscript are those of the authors and do not necessarily represent the opinions of the Department of Veterans Affairs.; Dr. Huetsch, Mr. Udris, and Ms. Uman report no conflicts of interest. Dr. Au is a research advisor for Bosch. He also receives grants from NHLBI, AHRQ, the Department of Veterans Affairs, and Gilead Sciences. NR 29 TC 14 Z9 14 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1506 EP 1512 DI 10.1007/s11606-012-2130-5 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500020 PM 22782274 ER PT J AU Patel, MS Volpp, KG AF Patel, Mitesh S. Volpp, Kevin G. TI Leveraging Insights from Behavioral Economics to Increase the Value of Health-Care Service Provision SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE health-care costs; health-care value; restaurant food labeling; asymmetric paternalism; nudges ID RESTAURANTS; CHARGES; CHOICES AB United States health expenditures continue to escalate at unsustainable rates. A recent movement around increasing price transparency has been suggested as a way of reducing the rate of increase in expenditures, with legislative efforts taking place at both the state and federal level. While this seems on the surface like a good idea, simply providing information on prices to physicians, particularly trainees, may not achieve the type of large changes in practice patterns that proponents expect. The manner in which price transparency is implemented will likely play a significant role in its effectiveness as an intervention. In this article, the authors review efforts of transparency and default options from other contexts and leverage insights from behavioral economics to provide recommendations for increasing the likelihood that price transparency will lead to physicians weighing the relative value of interventions. C1 [Patel, Mitesh S.; Volpp, Kevin G.] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Penn CMU Roybal P30 Ctr Behav Econ & Hlth, Philadelphia, PA USA. [Volpp, Kevin G.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Patel, MS (reprint author), Hosp Univ Penn, Dept Med, 3400 Spruce St,100 Centrex, Philadelphia, PA 19104 USA. EM Mitesh.Patel@uphs.upenn.edu NR 24 TC 9 Z9 9 U1 4 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2012 VL 27 IS 11 BP 1544 EP 1547 DI 10.1007/s11606-012-2050-4 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 025CJ UT WOS:000310161500024 PM 22549296 ER PT J AU Abuabara, K Freeman, EE Dellavalle, R AF Abuabara, Katrina Freeman, Esther E. Dellavalle, Robert TI The Role of Systematic Reviews and Meta-analysis in Dermatology SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Review ID RANDOMIZED CONTROLLED-TRIALS; RESEARCH QUESTION; CLINICAL-TRIALS; PATIENT-CARE; QUALITY C1 [Abuabara, Katrina] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Freeman, Esther E.] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dellavalle, Robert] Denver VA Med Ctr, Dermatol Serv, Denver, CO USA. RP Abuabara, K (reprint author), Univ Penn, Dept Dermatol, 3400 Spruce St,2 Maloney, Philadelphia, PA 19104 USA. EM Katrina_abuabara@uphs.upenn.edu RI Dellavalle, Robert/L-2020-2013 OI Dellavalle, Robert/0000-0001-8132-088X NR 14 TC 7 Z9 7 U1 0 U2 4 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 NOV PY 2012 VL 132 IS 11 BP 1 EP 5 DI 10.1038/jid.2012.392 PG 5 WC Dermatology SC Dermatology GA 022XJ UT WOS:000309997200001 PM 23069910 ER PT J AU Guo, SZ Som, AT Waeber, C Lo, EH AF Guo, Shuzhen Som, Angel T. Waeber, Christian Lo, Eng H. TI Vascular neuroprotection via TrkB- and Akt-dependent cell survival signaling SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE human cerebral endothelial cells; neural cell death; neurovascular unit; trophic coupling ID BLOOD-BRAIN-BARRIER; NEUROTROPHIC FACTOR; ENDOTHELIAL-CELLS; TROPHIC SUPPORT; IN-VITRO; DEATH; ISCHEMIA; AUTOPHAGY; NEURONS; STROKE AB The cerebral endothelium can be a vital source of signaling factors such as brain-derived neurotrophic factor that defends the neuronal parenchyma against stress and injury. But the underlying mechanisms remain to be fully defined. Here, we use cell models to ask how vascular neuroprotection is sustained. Human brain endothelial cells were grown in culture, and conditioned media were transferred to primary rat cortical neurons. Brain endothelial cell-conditioned media activated neuronal Akt signaling and protected neurons against hypoxia and oxygen-glucose deprivation. Blockade of Akt phosphorylation with the PI3-kinase inhibitor LY294002 negated this vascular neuroprotective effect. Upstream of Akt signaling, the brain-derived neurotrophic factor receptor TrkB (neurotrophic tyrosine kinase receptor, type 2) was involved because depletion with TrkB/Fc eliminated the ability of endothelial-conditioned media to protect neurons against hypoxia. Downstream of Akt signaling, activation of GSK-3 beta (glycogen synthase kinase 3 beta), caspase 9, caspase 3 and Bad pathways were detected. Taken together, these findings suggest that the molecular basis for vascular neuroprotection involves TrkB-Akt signaling that ameliorates neuronal apoptosis. Further investigation of these mechanisms may reveal new approaches for augmenting endogenous vascular neuroprotection in stroke, brain injury, and neurodegeneration. C1 [Guo, Shuzhen; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neuroprotect Res Lab, Charlestown, MA 02129 USA. [Guo, Shuzhen; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Guo, SZ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Neuroprotect Res Lab, Charlestown, MA 02129 USA. EM Sguo@partners.org; Lo@helix.mgh.harvard.edu RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 FU National Institutes of Health [P01-NS55104]; Massachusetts General Hospital FX This study is supported in part by National Institutes of Health Grant P01-NS55104, and a Claflin award from Massachusetts General Hospital to S.G. NR 35 TC 9 Z9 11 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2012 VL 123 SU 2 SI SI BP 58 EP 64 DI 10.1111/j.1471-4159.2012.07944.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 019LK UT WOS:000309740900007 PM 23050643 ER PT J AU Khan, M Dhammu, TS Sakakima, H Shunmugavel, A Gilg, AG Singh, AK Singh, I AF Khan, Mushfiquddin Dhammu, Tajinder S. Sakakima, Harutoshi Shunmugavel, Anadakumar Gilg, Anne G. Singh, Avtar K. Singh, Inderjit TI The inhibitory effect of S-nitrosoglutathione on blood-brain barrier disruption and peroxynitrite formation in a rat model of experimental stroke SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE BBB; endothelial dysfunction; GSNO; ischemia reperfusion; peroxynitrite; S-nitrosylation ID FOCAL CEREBRAL-ISCHEMIA; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; ACID PHENETHYL ESTER; NEUROPROTECTIVE EFFICACY; PLATELET ACTIVATION; NITROSO-GLUTATHIONE; NEUROVASCULAR UNIT; ENDOTHELIAL-CELLS; DOPAMINE NEURONS AB The hallmark of stroke injury is endothelial dysfunction leading to bloodbrain barrier (BBB) leakage and edema. Among the causative factors of BBB disruption are accelerating peroxynitrite formation and the resultant decreased bioavailability of nitric oxide (NO). S-nitrosoglutathione (GSNO), an S-nitrosylating agent, was found not only to reduce the levels of peroxynitrite but also to protect the integrity of BBB in a rat model of cerebral ischemia and reperfusion (IR). A treatment with GSNO (3 mu mol/kg) after IR reduced 3-nitrotyrosine levels in and around vessels and maintained NO levels in brain. This mechanism protected endothelial function by reducing BBB leakage, increasing the expression of Zonula occludens-1 (ZO-1), decreasing edema, and reducing the expression of matrix metalloproteinase-9 and E-selectin in the neurovascular unit. An administration of the peroxynitrite-forming agent 3-morpholino sydnonimine (3 mu mol/kg) at reperfusion increased BBB leakage and decreased the expression of ZO-1, supporting the involvement of peroxynitrite in BBB disruption and edema. Mechanistically, the endothelium-protecting action of GSNO was invoked by reducing the activity of nuclear factor kappa B and increasing the expression of S-nitrosylated proteins. Taken together, the results support the ability of GSNO to improve endothelial function by reducing nitroxidative stress in stroke. C1 [Khan, Mushfiquddin; Dhammu, Tajinder S.; Sakakima, Harutoshi; Shunmugavel, Anadakumar; Gilg, Anne G.; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Singh, Avtar K.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, 171 Ashley Ave, Charleston, SC 29425 USA. EM khanm@musc.edu FU NIH [NS-72511, NS-22576, NS-37766]; Veteran Administration; NIH from the Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823, C06 RR015455] FX These studies were supported by grants from NIH (NS-72511, NS-22576 and NS-37766) and Veteran Administration merit awards. This work was also supported by the NIH, Grants C06 RR018823 and No C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. We are grateful to Dr. Tom Smith from the MUSC Writing Center for his valuable editing and correction of the manuscript. The authors have no conflict of interest and have not received grants etc. from any commercial body. NR 61 TC 19 Z9 19 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2012 VL 123 SU 2 SI SI BP 86 EP 97 DI 10.1111/j.1471-4159.2012.07947.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 019LK UT WOS:000309740900010 PM 23050646 ER PT J AU Stetler, RA Leak, RK Yin, W Zhang, LL Wang, SP Gao, YQ Chen, J AF Stetler, R. Anne Leak, Rehana K. Yin, Wei Zhang, Lili Wang, Suping Gao, Yanqin Chen, Jun TI Mitochondrial biogenesis contributes to ischemic neuroprotection afforded by LPS pre-conditioning SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE ischemia; ischemic tolerance; mitochondrial biogenesis; neurons; pre-conditioning ID RESPIRATORY FACTOR-I; TOLL-LIKE RECEPTORS; BRAIN-INJURY; NEONATAL-RAT; NEURONS; LIPOPOLYSACCHARIDE; ACTIVATION; GROWTH; DYSFUNCTION; RESISTANCE AB Although alterations in mitochondrial dynamics are associated with cellular responses to injury, the functional role of these dynamic changes in ischemic neurons is underexplored. One of these dynamic responses to injury includes mitochondrial biogenesis. Various sublethal pre-conditioning stimuli that induce an ischemic-tolerant state [e.g., lipopolysaccharide (LPS)] may also induce mitochondrial biogenesis. Using neuron-enriched cultures, we found that sublethal LPS pre-conditioning induced both ischemic tolerance and markers of mitochondrial biogenesis with overlapping doseresponse temporal kinetics. Sublethal LPS transiently increased the expression of critical components of the mitochondrial transcriptional machinery, including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), as well as mtDNA copy number, mitochondrial protein levels, and markers of functional mitochondria, such as increased cellular ATP content, citrate synthase activity, and maximal respiration capacity. Importantly, knockdown of TFAM abrogated both the induction of mitochondrial biogenesis and the neuroprotective pre-conditioning effects of LPS. Several signaling pathways coordinated these events. AMPK inhibition suppressed NRF1 and TFAM expression by LPS, whereas PI3K/Akt signaling was necessary for the nuclear translocation of NRF1 and subsequent induction of TFAM. This is the first demonstration that LPS pre-conditioning initiates multiple signaling pathways leading to mitochondrial biogenesis in neurons and that these dynamic changes contribute to ischemic tolerance. C1 [Stetler, R. Anne; Yin, Wei; Zhang, Lili; Wang, Suping; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Stetler, R. Anne; Zhang, Lili; Gao, Yanqin; Chen, Jun] State Key Lab Med Neurobiol, Shanghai, Peoples R China. [Stetler, R. Anne; Zhang, Lili; Gao, Yanqin; Chen, Jun] Inst Brain Sci, Shanghai, Peoples R China. [Stetler, R. Anne; Wang, Suping; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Leak, Rehana K.] Duquesne Univ, Mylan Sch Pharm, Div Pharmaceut Sci, Pittsburgh, PA 15219 USA. [Stetler, R. Anne; Yin, Wei; Zhang, Lili; Wang, Suping; Chen, Jun] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. EM stetlerra@upmc.edu; chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016; OI Gao, Yanqin/0000-0002-4915-9819; Leak, Rehana/0000-0003-2817-7417 FU NIH/NINDS [NS43802, NS45048, NS36736, NS56118]; Chinese Natural Science Foundation [30670642, 30870794, 81020108021]; VA Career Scientist Award FX This project was supported by NIH/NINDS grants NS43802, NS45048, NS36736, and NS56118 (to J.C.); and Chinese Natural Science Foundation grants 30670642, 30870794, and 81020108021 (to Y.G.). J.C. is the RK Mellon Endowed Chair of UPMC and a recipient of the VA Career Scientist Award. We thank Pat Strickler for excellent secretarial support. NR 43 TC 14 Z9 16 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2012 VL 123 SU 2 SI SI BP 125 EP 137 DI 10.1111/j.1471-4159.2012.07951.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 019LK UT WOS:000309740900014 PM 23050650 ER PT J AU Chen, SZ Charness, ME AF Chen, Suzhen Charness, Michael E. TI Ethanol disrupts axon outgrowth stimulated by netrin-1, GDNF, and L1 by blocking their convergent activation of Src family kinase signaling (Retracted article. See vol. 132, pg. 756, 2015) SO JOURNAL OF NEUROCHEMISTRY LA English DT Article; Retracted Publication DE alcohol; axon outgrowth; CGN; GDNF; netrin-1; Src family kinase ID CEREBELLAR GRANULE CELLS; DEPENDENT NEUROPROTECTIVE PROTEIN; NEURITE OUTGROWTH; TYROSINE PHOSPHORYLATION; ADHESION MOLECULE; NERVOUS-SYSTEM; LIPID RAFTS; C-RET; NEURONS; GUIDANCE AB Pre-natal alcohol exposure causes fetal alcohol spectrum disorders (FASD), the most common, preventable cause of developmental disability. The developing cerebellum is particularly vulnerable to the effects of ethanol. We reported that ethanol inhibits the stimulation of axon outgrowth in cerebellar granule neurons (CGN) by NAP, an active motif of activity-dependent neuroprotective protein (ADNP), by blocking NAP activation of Fyn kinase and its downstream signaling molecule, the scaffolding protein Cas. Here, we asked whether ethanol inhibits the stimulation of axon outgrowth by diverse axon guidance molecules through a common action on the Src family kinases (SFK). We first demonstrated that netrin-1, glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule L1 stimulate axon outgrowth in CGNs by activating SFK, Cas, and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The specific SFK inhibitor, PP2, blocked the stimulation of axon outgrowth and the activation of the SFK-Cas-ERK1/2 signaling pathway by each of these axon-guidance molecules. In contrast, brain-derived neurotrophic factor (BDNF) stimulated axon outgrowth and activated ERK1/2 without first activating SFK or Cas. Clinically relevant concentrations of ethanol inhibited axon outgrowth and the activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, and L1, but did not disrupt BDNF-induced axon outgrowth or ERK1/2 activation. These results indicate that SFK, but not ERK1/2, is a primary target for ethanol inhibition of axon outgrowth. The ability of ethanol to block the convergent activation of the SFK-Cas-ERK1/2 pathway by netrin-1, GDNF, L1, and ADNP could contribute significantly to the pathogenesis of FASD. C1 [Chen, Suzhen] VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. Harvard Univ, Dept Neurol, Sch Med, W Roxbury, MA USA. RP Chen, SZ (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM suzhen_chen@hms.harvard.edu FU ABMRF; National Institute on Alcohol Abuse and Alcoholism [2R01AA012974]; NIAAA, as a component of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders [U24-AA014811]; Medical Research Service, Department of Veterans Affairs FX We thank Carrie Menkari, Devon M. Fitzgerald, and Lazaros Yiannos for their excellent technical assistance. This study was supported in part by the ABMRF Award (S. C.), the National Institute on Alcohol Abuse and Alcoholism Grant 2R01AA012974 (M. E. C.), NIAAA U24-AA014811, as a component of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (M. E. C) and the Medical Research Service, Department of Veterans Affairs (M. E. C). Dr. Charness is a member of the scientific advisory board for Allon Therapeutics, which is developing clinical applications for NAPVSIPQ (NAP). Dr. Charness holds stock options in Allon Therapeutics, and has two patents related to the study to declare. This does not alter the authors' adherence to all the Journal of Neurochemistry policies on sharing data and materials. Conceived and designed the experiments: SC, MC; Performed the experiments: SC; Analyzed the data: SC, MC; Wrote the paper: SC, MC. NR 52 TC 9 Z9 11 U1 1 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2012 VL 123 IS 4 BP 602 EP 612 DI 10.1111/j.1471-4159.2012.07954.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 021WU UT WOS:000309916900014 PM 22924694 ER PT J AU Zanetta, VC Rosman, BM Bromley, B Shipp, TD Chow, JS Campbell, JB Herndon, CDA Passerotti, CC Cendron, M Retik, AB Nguyen, HT AF Zanetta, Vitor C. Rosman, Brian M. Bromley, Bryan Shipp, Thomas D. Chow, Jeanne S. Campbell, Jeffrey B. Herndon, C. D. Anthony Passerotti, Carlo C. Cendron, Marc Retik, Alan B. Nguyen, Hiep T. TI Variations in Management of Mild Prenatal Hydronephrosis Among Maternal-Fetal Medicine Obstetricians, and Pediatric Urologists and Radiologists SO JOURNAL OF UROLOGY LA English DT Article DE data collection; hydronephrosis; pediatrics; prenatal diagnosis; pyelectasis ID RENAL PELVIS DILATION; ANTENATAL HYDRONEPHROSIS; DETECTED HYDRONEPHROSIS; CYSTOURETHROGRAPHY; INFANTS AB Purpose: There are no current guidelines for diagnosing and managing mild prenatal hydronephrosis. Variations in physician approach make it difficult to analyze outcomes and establish optimal management. We determined the variability of diagnostic approach and management regarding prenatal hydronephrosis among maternal-fetal medicine obstetricians, pediatric urologists and pediatric radiologists. Materials and Methods: Online surveys were sent to mailing lists for national societies for each specialty. Participants were surveyed regarding criteria for diagnosing mild prenatal hydronephrosis and recommendations for postnatal management, including use of antibiotic prophylaxis, followup scheduling and type of followup imaging. Results: A total of 308 maternal-fetal medicine obstetricians, 126 pediatric urologists and 112 pediatric radiologists responded. Pediatric urologists and radiologists were divided between Society for Fetal Urology criteria and use of anteroposterior pelvic diameter for diagnosis, while maternal-fetal medicine obstetricians preferred using the latter. For postnatal evaluation radiologists preferred using personal criteria, while urologists preferred using anteroposterior pelvic diameter or Society for Fetal Urology grading system. There was wide variation in the use of antibiotic prophylaxis among pediatric urologists. Regarding the use of voiding cystourethrography/radionuclide cystography in patients with prenatal hydronephrosis, neither urologists nor radiologists were consistent in their recommendations. Finally, there was no agreement on length of followup for mild prenatal hydronephrosis. Conclusions: We observed a lack of uniformity regarding grading criteria in diagnosing hydronephrosis prenatally and postnatally among maternal-fetal medicine obstetricians, pediatric urologists and pediatric radiologists. There was also a lack of agreement on the management of mild intermittent prenatal hydronephrosis, resulting in these cases being managed inconsistently. A unified set of guidelines for diagnosis, evaluation and management of mild intermittent prenatal hydronephrosis would allow more effective evaluation of outcomes. C1 [Zanetta, Vitor C.; Rosman, Brian M.; Cendron, Marc; Retik, Alan B.; Nguyen, Hiep T.] Childrens Hosp, Dept Urol, Boston, MA 02115 USA. [Chow, Jeanne S.] Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Bromley, Bryan; Shipp, Thomas D.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Campbell, Jeffrey B.] Childrens Hosp, Dept Pediat Urol, Aurora, CO USA. [Herndon, C. D. Anthony] Univ Virginia, Dept Urol, Charlottesville, VA USA. [Passerotti, Carlo C.] Univ Sao Paulo, Dept Urol, Sao Paulo, Brazil. RP Nguyen, HT (reprint author), Childrens Hosp, Dept Urol, Hunnewell 353,300 Longwood Ave, Boston, MA 02115 USA. EM Hiep.Nguyen@childrens.harvard.edu NR 23 TC 15 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2012 VL 188 IS 5 BP 1935 EP 1939 DI 10.1016/j.juro.2012.07.011 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 028QY UT WOS:000310438600091 PM 22999539 ER PT J AU Kumar, V Gu, YH Basu, S Berglund, A Eschrich, SA Schabath, MB Forster, K Aerts, HJWL Dekker, A Fenstermacher, D Goldgof, DB Hall, LO Lambin, P Balagurunathan, Y Gatenby, RA Gillies, RJ AF Kumar, Virendra Gu, Yuhua Basu, Satrajit Berglund, Anders Eschrich, Steven A. Schabath, Matthew B. Forster, Kenneth Aerts, Hugo J. W. L. Dekker, Andre Fenstermacher, David Goldgof, Dmitry B. Hall, Lawrence O. Lambin, Philippe Balagurunathan, Yoganand Gatenby, Robert A. Gillies, Robert J. TI Radiomics: the process and the challenges SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Radiomics; Imaging; Image features; Tumor; Segmentation ID CONTRAST-ENHANCED MRI; FALSE DISCOVERY RATE; IMAGE SEGMENTATION; GRAPH-CUTS; SPATIAL HETEROGENEITY; SURVIVAL PREDICTION; FEATURE-SELECTION; CROSS-VALIDATION; TEXTURE ANALYSIS; MEDICAL IMAGES AB "Radiomics" refers to the extraction and analysis of large amounts of advanced quantitative imaging features with high throughput from medical images obtained with computed tomography, positron emission tomography or magnetic resonance imaging. Importantly, these data are designed to be extracted from standard-of-care images, leading to a very large potential subject pool. Radiomics data are in a mineable form that can be used to build descriptive and predictive models relating image features to phenotypes or gene protein signatures. The core hypothesis of radiomics is that these models, which can include biological or medical data, can provide valuable diagnostic, prognostic or predictive information. The radiomics enterprise can be divided into distinct processes, each with its own challenges that need to be overcome: (a) image acquisition and reconstruction, (b) image segmentation and rendering, (c) feature extraction and feature qualification and (d) databases and data sharing for eventual (e) ad hoc informatics analyses. Each of these individual processes poses unique challenges. For example, optimum protocols for image acquisition and reconstruction have to be identified and harmonized. Also, segmentations have to be robust and involve minimal operator input. Features have to be generated that robustly reflect the complexity of the individual volumes, but cannot be overly complex or redundant. Furthermore, informatics databases that allow incorporation of image features and image annotations, along with medical and genetic data, have to be generated. Finally, the statistical approaches to analyze these data have to be optimized, as radiomics is not a mature field of study. Each of these processes will be discussed in turn, as well as some of their unique challenges and proposed approaches to solve them. The focus of this article will be on images of non-small-cell lung cancer. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kumar, Virendra; Gu, Yuhua; Balagurunathan, Yoganand; Gillies, Robert J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Imaging & Metab, Tampa, FL 33612 USA. [Basu, Satrajit; Goldgof, Dmitry B.; Hall, Lawrence O.] Univ S Florida, Dept Comp Sci & Engn, Tampa, FL 33620 USA. [Berglund, Anders; Eschrich, Steven A.; Fenstermacher, David] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Bioinformat, Tampa, FL 33612 USA. [Schabath, Matthew B.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA. [Forster, Kenneth] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, Tampa, FL 33612 USA. [Aerts, Hugo J. W. L.; Dekker, Andre; Lambin, Philippe] Maastricht Univ, Med Ctr, GROW Sch Oncol & Dev Biol, Dept Radiat Oncol MAASTRO, Maastricht, Netherlands. [Gatenby, Robert A.; Gillies, Robert J.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Radiol, Tampa, FL 33612 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol,Computat Biol & Func, Boston, MA 02115 USA. RP Gillies, RJ (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Imaging & Metab, Tampa, FL 33612 USA. EM robert.gillies@moffitt.org RI Eschrich, Steven/K-6848-2013; Aerts, Hugo/P-6350-2015; Kumar, Virendra/H-4874-2016; Schabath, Matthew/J-3763-2016; OI Gillies, Robert/0000-0002-8888-7747; Aerts, Hugo/0000-0002-2122-2003; Kumar, Virendra/0000-0002-1569-1989; Schabath, Matthew/0000-0003-3241-3216; Dekker, Andre/0000-0002-0422-7996 FU NCI NIH HHS [P30 CA076292, U01 CA143062] NR 97 TC 116 Z9 120 U1 33 U2 83 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1234 EP 1248 DI 10.1016/j.mri.2012.06.010 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000005 PM 22898692 ER PT J AU Kapur, T Egger, J Damato, A Schmidt, EJ Viswanathan, AN AF Kapur, Tina Egger, Jan Damato, Antonio Schmidt, Ehud J. Viswanathan, Akila N. TI 3-T MR-guided brachytherapy for gynecologic malignancies SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Brachytherapy; Segmentation; Bias correction; MR susceptibility artifact; Visualization; Registration ID SOCIETY CONSENSUS GUIDELINES; LOCALLY ADVANCED-CARCINOMA; CERVICAL-CANCER BRACHYTHERAPY; DOSE-RATE BRACHYTHERAPY; AMERICAN BRACHYTHERAPY; VOLUME PARAMETERS; SEGMENTATION; RECOMMENDATIONS; RECONSTRUCTION; REGISTRATION AB Gynecologic malignancies are a leading cause of death in women worldwide. Standard treatment for many primary and recurrent gynecologic cancer cases includes external-beam radiation followed by brachytherapy. Magnetic resonance (MR) imaging is beneficial in diagnostic evaluation, in mapping the tumor location to tailor radiation dose and in monitoring the tumor response to treatment. Initial studies of MR guidance in gynecologic brachytherapy demonstrate the ability to optimize tumor coverage and reduce radiation dose to normal tissues, resulting in improved outcomes for patients. In this article, we describe a methodology to aid applicator placement and treatment planning for 3 Tesla (3-1) MR-guided brachytherapy that was developed specifically for gynecologic cancers. This methodology has been used in 18 cases from September 2011 to May 2012 in the Advanced Multimodality Image Guided Operating (AMIGO) suite at Brigham and Women's Hospital. AMIGO comprises state-of-the-art tools for MR imaging, image analysis and treatment planning. An MR sequence using three-dimensional (3D)-balanced steady-state free precession in a 3-T MR scanner was identified as the best sequence for catheter identification with ballooning artifact at the tip. 3D treatment planning was performed using MR images. Items in development include software designed to support virtual needle trajectory planning that uses probabilistic bias correction, graph-based segmentation and image registration algorithms. The results demonstrate that 3-T MR image guidance has a role in gynecologic brachytherapy. These novel developments have the potential to improve targeted treatment to the tumor while sparing the normal tissues. (C) 2012 Elsevier Inc. All rights reserved. C1 [Damato, Antonio; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Damato, Antonio; Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kapur, Tina; Egger, Jan; Schmidt, Ehud J.] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM aviswanathan@lroc.harvand.edu FU NIH [P41EB015898, P41RR019703, R03EB013792, U54EB005149, K07CA117979] FX The authors would like to acknowledge the support of the AMIGO clinical staff in enabling this clinical study; Brendan Whalen and Dan Kacher for providing AMIGO architectural plans; Sam Song, PhD, for generating the CAD models of gynecologic devices; Jorgen Hansen for providing photos of the applicators; and Junichi Tokuda, PhD, for the AMIGO photo. We thank Prof. Dr. Horst K. Hahn and Fraunhofer MeVis in Bremen, Germany, for their support by providing an academic license for MeVisLab software. We thank Barbara Silver for proofreading the manuscript. The work was supported by NIH grants P41EB015898, P41RR019703, R03EB013792 and U54EB005149. Dr. Viswanathan has received support from NIH grant K07CA117979. NR 40 TC 36 Z9 36 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1279 EP 1290 DI 10.1016/j.mri.2012.06.003 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000009 PM 22898699 ER PT J AU Kurland, BF Gerstner, ER Mountz, JM Schwartz, LH Ryan, CW Graham, MM Buatti, JM Fennessy, FM Eikman, EA Kumar, V Forster, KM Wahl, RL Lieberman, FS AF Kurland, Brenda F. Gerstner, Elizabeth R. Mountz, James M. Schwartz, Lawrence H. Ryan, Christopher W. Graham, Michael M. Buatti, John M. Fennessy, Fiona M. Eikman, Edward A. Kumar, Virendra Forster, Kenneth M. Wahl, Richard L. Lieberman, Frank S. TI Promise and pitfalls of quantitative imaging in oncology clinical trials SO MAGNETIC RESONANCE IMAGING LA English DT Article DE MRI; CT; PET; Quantitative imaging; Clinical trials; Cancer ID POSITRON-EMISSION-TOMOGRAPHY; ADVANCED BREAST-CANCER; GASTROINTESTINAL STROMAL TUMORS; CELL LUNG-CANCER; APPARENT DIFFUSION-COEFFICIENT; STANDARDIZED UPTAKE VALUES; LOCALIZED PROSTATE-CANCER; SOFT-TISSUE SARCOMAS; NEOADJUVANT CHEMOTHERAPY; RESPONSE CRITERIA AB Quantitative imaging using computed tomography, magnetic resonance imaging and positron emission tomography modalities will play an increasingly important role in the design of oncology trials addressing molecularly targeted, personalized therapies. The advent of molecularly targeted therapies, exemplified by antiangiogenic drugs, creates new complexities in the assessment of response. The Quantitative Imaging Network addresses the need for imaging modalities which can accurately and reproducibly measure not just change in tumor size but changes in relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to tumor and differentiation of apoptotic cell death from other changes in tumor volume. This article provides an overview of the applications of quantitative imaging to phase 0 through phase 3 oncology trials. We describe the use of a range of quantitative imaging modalities in specific tumor types including malignant gliomas, lung cancer, head and neck cancer, lymphoma, breast cancer, prostate cancer and sarcoma. In the concluding section, we discuss potential constraints on clinical trials using quantitative imaging, including complexity of trial conduct, impact on subject recruitment, incremental costs and institutional barriers. Strategies for overcoming these constraints are presented. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kurland, Brenda F.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98019 USA. [Gerstner, Elizabeth R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mountz, James M.; Lieberman, Frank S.] Univ Pittsburgh, Pittsburgh, PA USA. [Schwartz, Lawrence H.] Columbia Univ, New York, NY USA. [Ryan, Christopher W.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Graham, Michael M.; Buatti, John M.] Univ Iowa, Iowa City, IA USA. [Fennessy, Fiona M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Eikman, Edward A.; Kumar, Virendra; Forster, Kenneth M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Wahl, Richard L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Kurland, BF (reprint author), Fred Hutchinson Canc Res Ctr, Seattle, WA 98019 USA. EM bkurland@fhcrc.org RI Kumar, Virendra/H-4874-2016; OI Kumar, Virendra/0000-0002-1569-1989; Kurland, Brenda/0000-0002-5669-0595 FU National Institutes of Health, Quantitative Imaging Network [U01-CA148131] FX This work is supported by the National Institutes of Health, Quantitative Imaging Network (U01-CA148131). The authors are grateful to Robert Nordstrom, Larry Clarke, Hannah Linden, David Mankoff, Mark Muzi, Savannah Partridge, Mia Levy and Daniel Rubin for helpful discussions and to Alicia DePastino for administrative support. NR 103 TC 27 Z9 27 U1 0 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1301 EP 1312 DI 10.1016/j.mri.2012.06.009 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000011 PM 22898682 ER PT J AU Fedorov, A Beichel, R Kalpathy-Cramer, J Finet, J Fillion-Robin, JC Pujol, S Bauer, C Jennings, D Fennessy, F Sonka, M Buatti, J Aylward, S Miller, JV Pieper, S Kikinis, R AF Fedorov, Andriy Beichel, Reinhard Kalpathy-Cramer, Jayashree Finet, Julien Fillion-Robin, Jean-Christophe Pujol, Sonia Bauer, Christian Jennings, Dominique Fennessy, Fiona Sonka, Milan Buatti, John Aylward, Stephen Miller, James V. Pieper, Steve Kikinis, Ron TI 3D Slicer as an image computing platform for the Quantitative Imaging Network SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Cancer imaging; Quantitative imaging; Software tools; Medical imaging; Imaging biomarkers; Image analysis; MRI; PET; CT; Brain; Head and neck; Prostate; Glioblastima; Cancer treatment response ID RESPONSE CRITERIA; SOLID TUMORS; MRI DATA; VISUALIZATION; DIFFUSION; SEGMENTATION; TRACTOGRAPHY; SYSTEM; DICOM; THERAPY AB Quantitative analysis has tremendous but mostly unrealized potential in healthcare to support objective and accurate interpretation of the clinical imaging. In 2008, the National Cancer Institute began building the Quantitative Imaging Network (QIN) initiative with the goal of advancing quantitative imaging in the context of personalized therapy and evaluation of treatment response. Computerized analysis is an important component contributing to reproducibility and efficiency of the quantitative imaging techniques. The success of quantitative imaging is contingent on robust analysis methods and software tools to bring these methods from bench to bedside. 3D Slicer is a free open-source software application for medical image computing. As a clinical research tool, 3D Slicer is similar to a radiology workstation that supports versatile visualizations but also provides advanced functionality such as automated segmentation and registration for a variety of application domains. Unlike a typical radiology workstation, 3D Slicer is free and is not tied to specific hardware. As a programming platform, 3D Slicer facilitates translation and evaluation of the new quantitative methods by allowing the biomedical researcher to focus on the implementation of the algorithm and providing abstractions for the common tasks of data communication, visualization and user interface development. Compared to other tools that provide aspects of this functionality, 3D Slicer is fully open source and can be readily extended and redistributed. In addition, 3D Slicer is designed to facilitate the development of new functionality in the form of 3D Slicer extensions. In this paper, we present an overview of 3D Slicer as a platform for prototyping, development and evaluation of image analysis tools for clinical research applications. To illustrate the utility of the platform in the scope of QIN, we discuss several use cases of 3D Slicer by the existing QIN teams, and we elaborate on the future directions that can further facilitate development and validation of imaging biomarkers using 3D Slicer. (C) 2012 Elsevier Inc. All rights reserved. C1 [Fedorov, Andriy; Pujol, Sonia; Fennessy, Fiona; Kikinis, Ron] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Beichel, Reinhard; Bauer, Christian; Sonka, Milan; Buatti, John] Univ Iowa, Iowa City, IA 52242 USA. [Kalpathy-Cramer, Jayashree; Jennings, Dominique] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. [Finet, Julien; Fillion-Robin, Jean-Christophe; Aylward, Stephen] Kitware Inc, Clifton Pk, NY 12065 USA. [Miller, James V.] GE Res, Niskayuna, NY 12309 USA. [Pieper, Steve] Isomics Inc, Cambridge, MA 02138 USA. RP Fedorov, A (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM fedorov@bwh.harvard.edu OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618; Fedorov, Andrey/0000-0003-4806-9413 FU NIH [U01CA151261, P41EB015898, P41RR13218, U54EB005149, 1R01CA111288, U01-CA140206, 1U01CA154601-01, 4R00LM009889-03] FX We would like to thank all current and past users and developers of 3D Slicer for their contribution to this software. The authors have been supported in part by the following NIH grants. BWH: U01CA151261, P41EB015898, P41RR13218, U54EB005149 and 1R01CA111288; University of Iowa: U01-CA140206; GE: P41RR13218 and U54EB005149; MGH: 1U01CA154601-01 and 4R00LM009889-03. We are grateful to the various agencies and programs that funded support and development of 3D Slicer over the years. NR 69 TC 411 Z9 422 U1 11 U2 76 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1323 EP 1341 DI 10.1016/j.mri.2012.05.001 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000013 PM 22770690 ER PT J AU Yankeelov, TE Peterson, TE Abramson, RG Garcia-Izquierdo, D Arlinghaus, LR Li, X Atuegwu, NC Catana, C Manning, HC Fayad, ZA Gore, JC AF Yankeelov, Thomas E. Peterson, Todd E. Abramson, Richard G. Garcia-Izquierdo, David Arlinghaus, Lori R. Li, Xia Atuegwu, Nkiruka C. Catana, Ciprian Manning, H. Charles Fayad, Zahi A. Gore, John C. TI Simultaneous PET-MRI m oncology: a solution looking for a problem? SO MAGNETIC RESONANCE IMAGING LA English DT Article DE PET; MRI; Attenuation; Motion; Reconstruction; AIF; Multimodality ID POSITRON-EMISSION-TOMOGRAPHY; PARTIAL-VOLUME CORRECTION; IRON-OXIDE NANOPARTICLES; IN-VIVO EVALUATION; WHOLE-BODY MRI; MAGNETIC-RESONANCE; ATTENUATION-CORRECTION; COMPUTED-TOMOGRAPHY; RESPIRATORY MOTION; SIMULTANEOUS PET/MRI AB With the recent development of integrated positron emission tomography magnetic resonance imaging (PET-MRI) scanners, new possibilities for quantitative molecular imaging of cancer are realized. However, the practical advantages and potential clinical benefits of the ability to record PET and MRI data simultaneously must be balanced against the substantial costs and other requirements of such devices. In this review, we highlight several of the key areas where integrated PET MRI measurements, obtained simultaneously, are anticipated to have a significant impact on clinical and/or research studies. These areas include the use of MR-based motion corrections and/or a priori anatomical information for improved reconstruction of PET data, improved arterial input function characterization for PET kinetic modeling, the use of dual-modality contrast agents, and patient comfort and practical convenience. For widespread acceptance, a compelling case could be made if the combination of quantitative MRI and specific PET biomarkers significantly improves our ability to assess tumor status and response to therapy, and some likely candidates are now emerging. We consider the relative advantages and disadvantages afforded by PET MRI and summarize current opinions and evidence as to the likely value of PET MRI in the management of cancer. (C) 2012 Elsevier Inc. All rights reserved. C1 [Yankeelov, Thomas E.] Vanderbilt Univ, Inst Imaging Sci, Med Ctr, Med Ctr N AA 1105, Nashville, TN 37232 USA. [Yankeelov, Thomas E.; Peterson, Todd E.; Abramson, Richard G.; Arlinghaus, Lori R.; Li, Xia; Atuegwu, Nkiruka C.; Manning, H. Charles; Gore, John C.] Vanderbilt Univ, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA. [Yankeelov, Thomas E.; Peterson, Todd E.; Gore, John C.] Vanderbilt Univ, Dept Phys & Astron, Nashville, IN 37232 USA. [Yankeelov, Thomas E.; Manning, H. Charles; Gore, John C.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37232 USA. [Yankeelov, Thomas E.] Vanderbilt Univ, Dept Canc Biol, Nashville, TN 37232 USA. [Garcia-Izquierdo, David; Fayad, Zahi A.] Mt Sinai Med Ctr, Translat & Mol Imaging Inst, New York, NY 10029 USA. [Garcia-Izquierdo, David; Fayad, Zahi A.] Mt Sinai Med Ctr, Dept Radiol, New York, NY 10029 USA. [Catana, Ciprian] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Catana, Ciprian] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Manning, H. Charles] Vanderbilt Univ, Dept Neurosurg, Nashville, TN 37232 USA. [Fayad, Zahi A.] Mt Sinai Med Ctr, Dept Cardiol, New York, NY 10029 USA. [Gore, John C.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. RP Yankeelov, TE (reprint author), Vanderbilt Univ, Inst Imaging Sci, Med Ctr, Med Ctr N AA 1105, Nashville, TN 37232 USA. EM thomas.yankeelov@vanderbilt.edu FU National Institutes of Health [NCI U01 CA142565, NCI R01CA138599, NCI 1P50 CA098131, NCI P30 CA68485, NCI 1R01 CA140628, NCI K25 CA127349, NCI 1RC1 CA145138, NHLBI R01 HL071021, R01 HL078667, NCI 1 R01 CA137254-01A1, NCI U01CA154601-01] FX T.E.Y., T.E.P, H.C.M., L.R.A., X.L., N.C.A. and J.C.G. thank the National Institutes of Health for support through NCI U01 CA142565, NCI R01CA138599, NCI 1P50 CA098131, NCI P30 CA68485, NCI 1R01 CA140628, NCI K25 CA127349 and NCI 1RC1 CA145138. Additionally, we thank the Kleberg Foundation for generous support of the molecular imaging program at Vanderbilt University. D.I.G. and Z.A.F. thank the NIH for support through NHLBI R01 HL071021 and R01 HL078667. C.C. and B.R. thank the NIH for support through NCI 1 R01 CA137254-01A1 and NCI U01CA154601-01. We thank Dr. Bruce Rosen, M.D., Ph.D. for reviewing and editing an early version of the manuscript. NR 99 TC 41 Z9 42 U1 1 U2 32 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X EI 1873-5894 J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD NOV PY 2012 VL 30 IS 9 SI SI BP 1342 EP 1356 DI 10.1016/j.mri.2012.06.001 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 022GO UT WOS:000309946000014 PM 22795930 ER PT J AU Danagoulian, GS Qin, L Nayak, KS Colen, RR Mukundan, S Harris, MB Jolesz, FA Shankaranarayanan, A Copen, WA Schmidt, EJ AF Danagoulian, Giovanna S. Qin, Lei Nayak, Krishna S. Colen, Rivka R. Mukundan, Srinivasan, Jr. Harris, Mitchell B. Jolesz, Ferenc A. Shankaranarayanan, Ajit Copen, William A. Schmidt, Ehud J. TI Comparison of wideband steady-state free precession and T2-weighted fast spin echo in spine disorder assessment at 1.5 and 3 T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; Spine; Myelography; nerves ID LOW-BACK-PAIN; MAGNETIZATION-TRANSFER; DIFFUSION; MYELOGRAPHY; RESOLUTION; TISSUE; TESLA; SSFP; CT AB Wideband steady-state free precession (WB-SSFP) is a modification of balanced steady-state free precession utilizing alternating repetition times to reduce susceptibility-induced balanced steady-state free precession limitations, allowing its use for high-resolution myelographic-contrast spinal imaging. Intertissue contrast and spatial resolution of complete-spine-coverage 3D WB-SSFP were compared with those of 2D T2-weighted fast spin echo, currently the standard for spine T2-imaging. Six normal subjects were imaged at 1.5 and 3 T. The signal-to-noise ratio efficiency (SNR per unit-time and unit-volume) of several tissues was measured, along with four intertissue contrast-to-noise ratios; nerve-ganglia:fat, intradural-nerves:cerebrospinal fluid, nerve-ganglia:muscle, and muscle:fat. Patients with degenerative and traumatic spine disorders were imaged at both MRI fields to demonstrate WB-SSFP clinical advantages and disadvantages. At 3 T, WB-SSFP provided spinal contrast-to-noise ratios 3.75.2 times that of fast spin echo. At 1.5 T, WB-SSFP contrast-to-noise ratio was 33.5 times that of fast spin echo, excluding a 1.7 ratio for intradural-nerves:cerebrospinal fluid. WB-SSFP signal-to-noise ratio efficiency was also higher. Three-dimensional WB-SSFP disadvantages relative to 2D fast spin echo are reduced edema hyperintensity, reduced muscle signal, and higher motion sensitivity. WB-SSFP's high resolution and contrast-to-noise ratio improved visualization of intradural nerve bundles, foraminal nerve roots, and extradural nerve bundles, improving detection of nerve compression in radiculopathy and spinal-stenosis. WB-SSFP's high resolution permitted reformatting into orthogonal planes, providing distinct advantages in gauging fine spine pathology. Magn Reson Med, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Danagoulian, Giovanna S.; Qin, Lei; Colen, Rivka R.; Mukundan, Srinivasan, Jr.; Jolesz, Ferenc A.; Schmidt, Ehud J.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Nayak, Krishna S.] Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. [Harris, Mitchell B.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Shankaranarayanan, Ajit] GE Healthcare Appl Sci Lab, Menlo Pk, CA USA. [Copen, William A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Schmidt, EJ (reprint author), Brigham & Womens Hosp, Dept Radiol, Rm 11C,221 Longwood Ave, Boston, MA 02115 USA. EM eschmidt3@partners.org FU NIH [U41RR019703, R25-CA89017-06A2] FX Grant sponsor: NIH; Grant numbers: U41RR019703 and R25-CA89017-06A2 NR 30 TC 0 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2012 VL 68 IS 5 BP 1527 EP 1535 DI 10.1002/mrm.24163 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 023UR UT WOS:000310062300019 PM 22287191 ER PT J AU Korenjak, M Anderssen, E Ramaswamy, S Whetstine, JR Dyson, NJ AF Korenjak, Michael Anderssen, Endre Ramaswamy, Sridhar Whetstine, Johnathan R. Dyson, Nicholas J. TI RBF Binding to both Canonical E2F Targets and Noncanonical Targets Depends on Functional dE2F/dDP Complexes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RETINOBLASTOMA TUMOR-SUPPRESSOR; CELL-CYCLE PROGRESSION; TRANSCRIPTION FACTOR; DROSOPHILA EMBRYOGENESIS; PROLIFERATING CELLS; CDC2 PROMOTER; PROTEIN; DIFFERENTIATION; GENE; EXPRESSION AB The retinoblastoma (RB) family of proteins regulate transcription. These proteins lack intrinsic DNA-binding activity but are recruited to specific genomic locations through interactions with sequence-specific DNA-binding factors. The best-known target of RB protein (pRB) is the E2F transcription factor; however, many other chromatin-associated proteins have been described that may allow RB family members to act at additional sites. To gain a perspective on the scale of E2F-dependent and E2F-independent functions, we generated genome-wide binding profiles of RBF1 and dE2F proteins in Drosophila larvae. RBF1 and dE2F2 associate with a large number of binding sites at genes with diverse biological functions. In contrast, dE2F1 was detected at a smaller set of promoters, suggesting that it overrides repression by RBF1/dE2F2 at a specific subset of targets. Approximately 15% of RBF1-bound regions lacked consensus E2F-binding motifs. To test whether RBF1 action at these sites is E2F independent, we examined dDP mutant larvae that lack any functional dE2F/dDP heterodimers. As measured by chromatin immunoprecipitation-microarray analysis (ChIP-chip), ChIP-quantitative PCR (qPCR), and cell fractionation, the stable association of RBF1 with chromatin was eliminated in dDP mutants. This requirement for dDP was seen at classic E2F-regulated promoters and at promoters that lacked canonical E2F-binding sites. These results suggest that E2F/DP complexes are essential for all genomic targeting of RBF1. C1 [Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. EM Dyson@helix.mgh.harvard.edu FU Tosteson Postdoctoral Fellowship Award; DFG Forschungsstipendium; National Cancer Institute; National Institutes of Health [R01CA64402, GM053203]; Ellison Medical Foundation [CA059267, R01GM097360] FX M.K. was supported by a Tosteson Postdoctoral Fellowship Award and a DFG Forschungsstipendium. Research reported in this publication was supported by awards from the National Cancer Institute and National Institutes of Health grants R01CA64402 and GM053203 (to N.J.D). N.J.D. is the Saltonstall Scholar of the Massachusetts General Hospital Cancer Center. J.R.W. is supported by the Ellison Medical Foundation, grants CA059267 and R01GM097360. NR 68 TC 21 Z9 22 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV PY 2012 VL 32 IS 21 BP 4375 EP 4387 DI 10.1128/MCB.00536-12 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022OS UT WOS:000309969300011 PM 22927638 ER PT J AU Bourdette, D Yadav, V AF Bourdette, Dennis Yadav, Vijayshree TI Treat patients with radiologically isolated syndrome when the MRI brain scan shows dissemination in time: No SO MULTIPLE SCLEROSIS JOURNAL LA English DT Editorial Material ID UNSUSPECTED MULTIPLE-SCLEROSIS C1 [Bourdette, Dennis; Yadav, Vijayshree] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [Bourdette, Dennis; Yadav, Vijayshree] Portland VA Med Ctr, MS Ctr Excellence W, Portland, OR USA. RP Bourdette, D (reprint author), Oregon Hlth & Sci Univ, Dept Neurol L226, Portland, OR 97239 USA. EM bourdett@ohsu.edu NR 10 TC 6 Z9 6 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD NOV PY 2012 VL 18 IS 11 BP 1529 EP 1530 DI 10.1177/1352458512462075 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 026BM UT WOS:000310245100005 PM 23100523 ER PT J AU Calado, DP Sasaki, Y Godinho, SA Pellerin, A Kochert, K Sleckman, BP de Alboran, IM Janz, M Rodig, S Rajewsky, K AF Calado, Dinis Pedro Sasaki, Yoshiteru Godinho, Susana A. Pellerin, Alex Koechert, Karl Sleckman, Barry P. Moreno de Alboran, Ignacio Janz, Martin Rodig, Scott Rajewsky, Klaus TI The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers SO NATURE IMMUNOLOGY LA English DT Article ID CENTER B-CELLS; TRANSCRIPTION FACTOR; KAPPA-B; PROTOONCOGENE EXPRESSION; GENE-EXPRESSION; IN-VIVO; BCL6; RESPONSES; ORIGIN; MICE AB Germinal centers (GCs) are sites of intense B cell proliferation and are central for T cell dependent antibody responses. However, the role of c-Myc, a key cell-cycle regulator, in this process has been questioned. Here we identified c-Myc(+) B cell subpopulations in immature and mature GCs and found, by genetic ablation of Myc, that they had indispensable roles in the formation and maintenance of GCs. The identification of these functionally critical cellular subsets has implications for human B cell lymphomagenesis, which originates mostly from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the c-Myc(+) GC subpopulations may be at a particularly high risk for malignant transformation. C1 [Calado, Dinis Pedro; Pellerin, Alex; Rajewsky, Klaus] Harvard Univ, Childrens Hosp, Program Cellular & Mol Med, Sch Med, Boston, MA 02115 USA. [Calado, Dinis Pedro; Pellerin, Alex; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Calado, Dinis Pedro; Koechert, Karl; Janz, Martin; Rajewsky, Klaus] Max Delbruck Ctr Mol Med, Berlin, Germany. [Sasaki, Yoshiteru] Kyoto Univ, Dept Mol & Cellular Physiol, Grad Sch Med, Kyoto, Japan. [Godinho, Susana A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Dept Cell Biol, Boston, MA 02115 USA. [Sleckman, Barry P.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Moreno de Alboran, Ignacio] Natl Biotechnol Ctr, Dept Immunol & Oncol, Madrid, Spain. [Janz, Martin] Univ Med Sch, Charite, Berlin, Germany. [Rodig, Scott] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Calado, DP (reprint author), Harvard Univ, Childrens Hosp, Program Cellular & Mol Med, Sch Med, Boston, MA 02115 USA. EM dinis.calado@mdc-berlin.de; klaus.rajewsky@mdc-berlin.de FU National Cancer Institute [PO1CA092625]; Leukemia and Lymphoma Society; European Research Council FX We thank D. Ghitza, J. Wang, J. Grundy, J. Xia, C. Grosse, B. Wollert-Wulff and M. Bamberg for technical assistance; M. Ottaviano and M. Bezohra for administrative assistance; the Rajewsky laboratory members for critical comments and suggestions; and D. Dominguez-Sola and R. Dalla-Favera for sharing unpublished results. Supported by the National Cancer Institute (PO1CA092625 to KR.), the Leukemia and Lymphoma Society (KR. and D.P.C.) and the European Research Council (KR.). NR 48 TC 77 Z9 78 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2012 VL 13 IS 11 BP 1092 EP 1100 DI 10.1038/ni.2418 PG 9 WC Immunology SC Immunology GA 024EO UT WOS:000310091700012 PM 23001146 ER PT J AU Gautier, EL Shay, T Miller, J Greter, M Jakubzick, C Ivanov, S Helft, J Chow, A Elpek, KG Gordonov, S Mazloom, AR Ma'ayan, A Chua, WJ Hansen, TH Turley, SJ Merad, M Randolph, GJ AF Gautier, Emmanuel L. Shay, Tal Miller, Jennifer Greter, Melanie Jakubzick, Claudia Ivanov, Stoyan Helft, Julie Chow, Andrew Elpek, Kutlu G. Gordonov, Simon Mazloom, Amin R. Ma'ayan, Avi Chua, Wei-Jen Hansen, Ted H. Turley, Shannon J. Merad, Miriam Randolph, Gwendalyn J. CA Immunological Genome Consortium TI Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages SO NATURE IMMUNOLOGY LA English DT Article ID DENDRITIC CELL; STEADY-STATE; BONE-MARROW; IN-VIVO; DIFFERENTIATION; HETEROGENEITY; PROGENITORS; HOMEOSTASIS; ACTIVATION; REVEALS AB We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and Fc gamma R1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-alpha, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells. C1 [Gautier, Emmanuel L.; Jakubzick, Claudia; Randolph, Gwendalyn J.] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Gautier, Emmanuel L.; Miller, Jennifer; Greter, Melanie; Jakubzick, Claudia; Helft, Julie; Chow, Andrew; Merad, Miriam; Randolph, Gwendalyn J.] Mt Sinai Sch Med, Inst Immunol, New York, NY USA. [Gautier, Emmanuel L.; Ivanov, Stoyan; Chua, Wei-Jen; Hansen, Ted H.; Randolph, Gwendalyn J.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Miller, Jennifer; Greter, Melanie; Helft, Julie; Chow, Andrew; Merad, Miriam] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Miller, Jennifer; Greter, Melanie; Helft, Julie; Chow, Andrew; Merad, Miriam] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Shay, Tal] Broad Inst, Cambridge, MA USA. [Elpek, Kutlu G.; Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Elpek, Kutlu G.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Gordonov, Simon; Mazloom, Amin R.; Ma'ayan, Avi] Mt Sinai Sch Med, Dept Pharmacol, New York, NY USA. [Gordonov, Simon; Mazloom, Amin R.; Ma'ayan, Avi] Mt Sinai Sch Med, Syst Therapeut & Syst Biol Ctr New York, New York, NY USA. RP Randolph, GJ (reprint author), Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. EM grandolph@path.wustl.edu RI Shay, Tal/J-4028-2016; Gautier, Emmanuel L./E-2259-2017; OI Shay, Tal/0000-0003-0755-1350; Gautier, Emmanuel L./0000-0003-2976-7566; Yankelevich, Wei-Jen/0000-0002-5234-7845; Malhotra, Deepali/0000-0002-8215-7639; Ivanov, Stoyan/0000-0002-0527-2297; Gazit, Roi/0000-0002-0548-2147; Kim, Charles/0000-0001-6474-8227 FU National Institute of Allergy and Infectious Diseases of the US National Institutes of Health [R24 AI072073]; US National Institutes of Health [R01AI049653, R01AI061741, P50GM071558-03, R01DK08854, 5T32DA007135-27]; American Heart Association [10POST4160140] FX We thank our colleagues of the ImmGen Project consortium; V. Jojic, J. Ericson, S. Davis and C. Benoist for contributions; eBioscience and Affymetrix for material support of the ImmGen Project; and M. Colonna (Washington University School of Medicine) for monoclonal antibodies (including anti-Siglec-H) and other reagents. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to fund the ImmGen Project, spearheaded by C. Benoist), the US National Institutes of Health (R01AI049653 and R01AI061741 to G.J.R.; P50GM071558-03 and R01DK08854 to A.M.; and5T32DA007135-27 to ARM.) and the American Heart Association (10POST4160140 to E.L.G.). NR 34 TC 489 Z9 494 U1 11 U2 63 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD NOV PY 2012 VL 13 IS 11 BP 1118 EP 1128 DI 10.1038/ni.2419 PG 11 WC Immunology SC Immunology GA 024EO UT WOS:000310091700015 PM 23023392 ER PT J AU Stelmack, JA Tang, XYC Reda, DJ Stroupe, KT Rinne, S Massof, RW AF Stelmack, Joan A. Tang, Xiaoyin C. Reda, Domenic J. Stroupe, Kevin T. Rinne, Stephen Massof, Robert W. CA LOVIT II Study Grp TI VA LOVIT II: a protocol to compare low vision rehabilitation and basic low vision SO OPHTHALMIC AND PHYSIOLOGICAL OPTICS LA English DT Article DE low vision; low vision rehabilitation; reading rehabilitation; vision rehabilitation ID QUALITY-OF-LIFE; VISUAL FUNCTIONING QUESTIONNAIRE; INTERVENTION TRIAL LOVIT; VETERANS-AFFAIRS; IMPAIRED VISION; MACULAR DEGENERATION; OLDER-PEOPLE; DEPRESSION; OUTCOMES; HEALTH AB Citation information: Stelmack JA, Tang XC, Reda DJ, Stroupe KT, Rinne S & Massof RW. VA LOVIT II: a protocol to compare low vision rehabilitation and basic low vision. Ophthalmic Physiol Opt 2012, 32, 461471. doi: 10.1111/j.1475-1313.2012.00933.x Abstract Purpose: To compare the effectiveness of low vision rehabilitation (LVR) and basic low vision (LV) in a single masked multicentre randomised controlled trial (RCT). Methods: Three hundred and thirty patients eligible for US. Veterans Affairs (VA) healthcare services with primary eye diagnosis (better-seeing eye) of macular disease and best-corrected distance visual acuity of 0.401.00 logMAR (6/15 to 6/60 or 20/50 to 20/200 Snellen) are being enrolled at seven VA facilities. All participants receive an optometric LV examination; and they are eligible to receive the same LV devices that are provided without charge. In LVR, a LV therapist dispenses devices and provides 2 or 3 (1(1/2) to 2(1/2) h) therapy sessions with assigned homework to teach effective use of remaining vision and LV devices. Contact time with the therapist depends upon the devices prescribed and the patients progress in learning the skills that are taught. In basic LV, devices are dispensed by the optometrist without LV therapy. Contact time for dispensing is one hour or less depending on LV devices prescribed. The primary outcome measure is a comparison of the changes in visual reading ability (estimated from patients difficulty ratings of reading items on the VA LV VFQ-48 questionnaire) between the treatment and control arms from pre-intervention baseline to 4 months (2 months after completion of treatment). Secondary outcome measures are changes in overall visual ability, visual ability domain scores calculated from subsets of items (mobility, visual information processing and visual motor skills), Short Form-36, and Minnesota Low Vision Reading Test scores. Cost-effectiveness analysis will be conducted using VA LV VFQ-48 scores and QALYS computed from EuroQol scores. Results: A total of 137 patients representing 41.5% of the study target of 330 patients were randomised from October 2010 to March 2012. Among those 137 patients, mean age was 80.2 (S.D. +/- 9.9) years at enrollment; 97.1% of the patients were males; 94.2% were white. Mean best corrected VA was 0.65 (S.D. +/- 0.3) logMAR (approximately Snellen 6/27 or 20/90) at baseline. Conclusions: LOVIT II is the first multicentre RCT comparing the effectiveness and cost-effectiveness of LVR and basic LV for patients with macular diseases and near normal or moderate levels of visual impairment. C1 [Stelmack, Joan A.; Tang, Xiaoyin C.; Reda, Domenic J.; Stroupe, Kevin T.; Rinne, Stephen] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Stelmack, Joan A.] Univ Illinois, Chicago Sch Med, Dept Ophthalmol & Visual Sci, Chicago, IL USA. [Stelmack, Joan A.; Rinne, Stephen] Illinois Coll Optometry, Chicago, IL USA. [Massof, Robert W.] Johns Hopkins Wilmer Eye Inst, Baltimore, MD USA. RP Stelmack, JA (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. EM joan.stelmack@med.va.gov RI Raasch, Thomas/A-3588-2013 FU Department of Veterans Affairs Rehabilitation Research and Development Service [C958R] FX Funding for this research was provided by the Department of Veterans Affairs Rehabilitation Research and Development Service grant C958R. NR 42 TC 4 Z9 4 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-5408 J9 OPHTHAL PHYSL OPT JI Ophthalmic Physiol. Opt. PD NOV PY 2012 VL 32 IS 6 BP 461 EP 471 DI 10.1111/j.1475-1313.2012.00933.x PG 11 WC Ophthalmology SC Ophthalmology GA 019NW UT WOS:000309747600004 PM 22958237 ER PT J AU Janas, MM Wang, BB Harris, AS Aguiar, M Shaffer, JM Subrahmanyam, YVBK Behlke, MA Wucherpfennig, KW Gygi, SP Gagnon, E Novina, CD AF Janas, Maja M. Wang, Bingbing Harris, Abigail S. Aguiar, Mike Shaffer, Jonathan M. Subrahmanyam, Yerramilli V. B. K. Behlke, Mark A. Wucherpfennig, Kai W. Gygi, Steven P. Gagnon, Etienne Novina, Carl D. TI Alternative RISC assembly: Binding and repression of microRNA-mRNA duplexes by human Ago proteins SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE Argonautes; fluorescence lifetime imaging microscopy (FLIM); microRNAs; RISC loading ID CYTOPLASMIC PROCESSING BODIES; ARGONAUTE SILENCING COMPLEX; CRYSTAL-STRUCTURE; POSTTRANSCRIPTIONAL REGULATION; TRANSLATIONAL REPRESSION; DEPENDENT LOCALIZATION; MAMMALIAN-CELLS; MIRNA PATHWAY; IN-VITRO; EXPRESSION AB MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate protein output from the majority of human mRNAs. In contrast to the consensus view that all miRNAs are associated with Argonaute (Ago) proteins, we determine that miRNAs are expressed in a 13-fold excess relative to Agos in HeLa cells and that miRNAs are bound to mRNAs in a sevenfold excess relative to Agos, implying the existence of miRNA-mRNA duplexes not stoichiometrically bound by Agos. We show that all four human Agos can repress miRNA-mRNA duplexes, but only Ago2 can cleave small interfering RNA-mRNA duplexes in vitro. We visualize direct Ago binding to miRNA-mRNA duplexes in live cells using fluorescence lifetime imaging microscopy. In contrast to the consensus view that Agos bind miRNA duplexes, these data demonstrate that Agos can bind and repress miRNA-mRNA duplexes and support a model of catalytic Ago function in translational repression. C1 [Janas, Maja M.; Wang, Bingbing; Wucherpfennig, Kai W.; Gagnon, Etienne; Novina, Carl D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Janas, Maja M.; Wang, Bingbing; Novina, Carl D.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Janas, Maja M.; Wang, Bingbing; Novina, Carl D.] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Harris, Abigail S.; Shaffer, Jonathan M.; Subrahmanyam, Yerramilli V. B. K.] Qiagen Inc, Frederick, MD 21703 USA. [Aguiar, Mike; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Behlke, Mark A.] Integrated DNA Technol, Coralville, IA USA. RP Gagnon, E (reprint author), Univ Montreal, Dept Microbiol & Immunol, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada. EM etienne.gagnon@umontreal.ca; carl_novina@dfci.harvard.edu FU Cancer Research Institute Postdoctoral Fellowship; Distinguished Young Scholars Award from the W.M. Keck Foundation FX We thank Dr. Lisa Cameron for help with microscopy, Dr. Ashish Lal (National Institutes of Health) for the RL-MYC 3' UTR reporter plasmid, and Dr. Zissimos Mourelatos (University of Pennsylvania) for anti-pan Ago antibody. All microscopy was performed at the confocal microscopy core at Dana-Farber Cancer Institute. This work was supported by the Cancer Research Institute Postdoctoral Fellowship to E.G. and a Distinguished Young Scholars Award from the W.M. Keck Foundation to C.D.N. NR 63 TC 36 Z9 37 U1 0 U2 15 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD NOV PY 2012 VL 18 IS 11 BP 2041 EP 2055 DI 10.1261/rna.035675.112 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 023TH UT WOS:000310058000009 PM 23019594 ER PT J AU Paik, DY Janzen, DM Schafenacker, AM Velasco, VS Shung, MS Cheng, DH Huang, JT Witte, ON Memarzadeh, S AF Paik, Daniel Y. Janzen, Deanna M. Schafenacker, Amanda M. Velasco, Victor S. Shung, May S. Cheng, Donghui Huang, Jiaoti Witte, Owen N. Memarzadeh, Sanaz TI Stem-Like Epithelial Cells Are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation SO STEM CELLS LA English DT Article DE Adult stem cells; Clonal assays; Self-renewal; Tissue-specific stem cells ID CILIARY BEAT FREQUENCY; OVARIAN-CANCER; PROSTATE-CANCER; MENSTRUAL-CYCLE; ELECTRON-MICROSCOPY; COLORECTAL-CANCER; ANDROGEN RECEPTOR; MULLERIAN DUCT; ORIGIN; MOUSE AB The reproductive role of the fallopian tube is to transport the sperm and egg. The tube is positioned to act as a bridge between the ovary where the egg is released and the uterus where implantation occurs. Throughout reproductive years, the fallopian tube epithelium undergoes repetitive damage and regeneration. Although a reservoir of adult epithelial stem cells must exist to replenish damaged cells, they remain unidentified. Here, we report isolation of a subset of basally located human fallopian tube epithelia (FTE) that lack markers of ciliated (beta-tubulin; TUBB4) or secretory (PAX8) differentiated cells. These undifferentiated cells expressed cell surface antigens: epithelial cell adhesion molecule, CD44, and integrin a 6. This FTE subpopulation was fivefold enriched for cells capable of clonal growth and self-renewal suggesting that they contain the FTE stem-like cells (FTESCs). A twofold enrichment of the FTESC was found in the distal compared to the proximal end of the tube. The distal fimbriated end of the fallopian tube is a well-characterized locus for initiation of serous carcinomas. An expansion of the cells expressing markers of FTESC was detected in tubal intraepithelial carcinomas and in fallopian tubes from patients with invasive serous cancer. These findings suggest that FTESC may play a role in the initiation of serous tumors. Characterization of these stem-like cells will provide new insight into how the FTE regenerate, respond to injury, and may initiate cancer. STEM CELLS2012;30:24872497 C1 [Witte, Owen N.; Memarzadeh, Sanaz] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA. [Paik, Daniel Y.; Janzen, Deanna M.; Schafenacker, Amanda M.; Velasco, Victor S.; Shung, May S.; Memarzadeh, Sanaz] Univ Calif Los Angeles, Dept Obstet & Gynecol, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Cheng, Donghui; Witte, Owen N.] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90024 USA. [Huang, Jiaoti] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. [Witte, Owen N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Memarzadeh, Sanaz] VA Greater Angeles Hlth Care Syst, Los Angeles, CA USA. RP Memarzadeh, S (reprint author), Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, 610 Charles E Young Dr E,3017 Terasaki Life Sci B, Los Angeles, CA 90095 USA. EM smemarzadeh@mednet.ucla.edu FU Veteran Affairs CDA-2 Career Development Award; Mary Kay Foundation Award; Prostate Cancer Foundation Young Investigators Award; STOP Cancer Award; Broad Stem Cell Research Center Research Award; Liz Tilberis Scholars Program from the Ovarian Cancer Research Fund, Inc.; Gynecologic Cancer Foundation St. Louis Ovarian Cancer Awareness Research Grant; Ovarian Cancer Circle FX We thank Brooke Nakamura for technical support. We thank Drs. Andrew Goldstein and Yang Zong for helpful conversations related to this project. We thank the UCLA Tissue Procurement Core Laboratory for their assistance in providing human fallopian tube specimens. S. M. is supported by a Veteran Affairs CDA-2 Career Development Award, a gift from the Scholars in Translational Medicine Program, Mary Kay Foundation Award, Prostate Cancer Foundation Young Investigators Award, STOP Cancer Award, and the Broad Stem Cell Research Center Research Award. This work was also supported by the Liz Tilberis Scholars Program from the Ovarian Cancer Research Fund, Inc., the Gynecologic Cancer Foundation St. Louis Ovarian Cancer Awareness Research Grant, and the Ovarian Cancer Circle inspired by Robin Babbini. O.N.W. is a Howard Hughes Medical Institute investigator. NR 52 TC 35 Z9 37 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2012 VL 30 IS 11 BP 2487 EP 2497 DI 10.1002/stem.1207 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 023ZP UT WOS:000310077000013 PM 22911892 ER PT J AU Kilbourne, AM Greenwald, DE Bauer, MS Charns, MP Yano, EM AF Kilbourne, Amy M. Greenwald, Devra E. Bauer, Mark S. Charns, Martin P. Yano, Elizabeth M. TI Mental Health Provider Perspectives Regarding Integrated Medical Care for Patients with Serious Mental Illness SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Article DE Integrated care; Serious mental illness; Quality of care ID QUALITY-OF-CARE; BIPOLAR DISORDER; VETERANS-AFFAIRS; PROGRAMS; DISEASE; ACCESS; SATISFACTION; INCENTIVES; CONTINUITY; SERVICES AB Integrated care for medical conditions is essential for persons with serious mental illness (SMI). This qualitative study describes mental health provider perspectives regarding barriers and facilitators of integrated care for patients with SMI. We interviewed providers from a national sample of Veterans Health Administration facilities that scored in the top or bottom percentile in medical care quality. Providers from high-performing sites reported substantial in-person contacts with general medical providers, while providers from low-performing sites reported stigma and limited communication with medical providers as major concerns. Interventions to improve mental health and medical provider communication may facilitate integrated care for persons with SMI. C1 [Kilbourne, Amy M.] VA Ann Arbor Ctr Clin Management Res, Ann Arbor, MI 48105 USA. [Kilbourne, Amy M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. [Greenwald, Devra E.] VA Pittsburgh Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Bauer, Mark S.; Charns, Martin P.] VA Boston Ctr Org Management & Leadership Res COL, Boston, MA USA. [Bauer, Mark S.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Charns, Martin P.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Yano, Elizabeth M.] VA Greater Angeles Healthcare Syst, VA Greater Angeles HSR&D, Ctr Excellence Study Healthcare Provider Behav, Los Angeles, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90024 USA. RP Kilbourne, AM (reprint author), VA Ann Arbor Ctr Clin Management Res, 2215 Fuller Rd, Ann Arbor, MI 48105 USA. EM amykilbo@umich.edu OI Charns, Martin/0000-0002-7102-5331 NR 42 TC 9 Z9 9 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD NOV PY 2012 VL 39 IS 6 BP 448 EP 457 DI 10.1007/s10488-011-0365-9 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 021CM UT WOS:000309862900004 PM 21735302 ER PT J AU Kim, K Brown, EE Choi, CB Alarc, ME Kelly, JA Glenn, SB Ojwang, JO Adler, A Lee, HS Boackle, SA Criswell, LA Alarc, GS Edberg, JC Stevens, AM Jacob, CO Gilkeson, GS Kamen, DL Tsao, BP Anaya, JM Guthridge, JM Nath, SK Richardson, B Sawalha, AH Kang, YM Shim, SC Suh, CH Lee, SK Kim, CS Merrill, JT Petri, M Ramsey-Goldman, R Vil, LM Niewold, TB Martin, J Pons-Estel, BA Vyse, TJ Freedman, BI Moser, KL Gaffney, PM Williams, A Comeau, M Reveille, JD James, JA Eld, RHS Langefeld, CD Kaufman, KM Harley, JB Kang, C Kimberly, RP Bae, SC AF Kim, Kwangwoo Brown, Elizabeth E. Choi, Chan-Bum Alarc, Marta E. Kelly, Jennifer A. Glenn, Stuart B. Ojwang, Joshua O. Adler, Adam Lee, Hye-Soon Boackle, Susan A. Criswell, Lindsey A. Alarc, Graciela S. Edberg, Jeffrey C. Stevens, Anne M. Jacob, Chaim O. Gilkeson, Gary S. Kamen, Diane L. Tsao, Betty P. Anaya, Juan-Manuel Guthridge, Joel M. Nath, Swapan K. Richardson, Bruce Sawalha, Amr H. Kang, Young Mo Shim, Seung Cheol Suh, Chang-Hee Lee, Soo-Kon Kim, Chang-sik Merrill, Joan T. Petri, Michelle Ramsey-Goldman, Rosalind Vil, Luis M. Niewold, Timothy B. Martin, Javier Pons-Estel, Bernardo A. Vyse, Timothy J. Freedman, Barry I. Moser, Kathy L. Gaffney, Patrick M. Williams, Adrienne Comeau, Mary Reveille, John D. James, Judith A. Eld, R. Hal Sco Langefeld, Carl D. Kaufman, Kenneth M. Harley, John B. Kang, Changwon Kimberly, Robert P. Bae, Sang-Cheol CA BIOLUPUS GENLES TI Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; FUNCTIONAL VARIANT; DISEASE-ACTIVITY; CELL-ADHESION; INTEGRIN; ITGAM; GENE; EXPRESSION; METAANALYSIS; SELECTIN AB Objective Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin a. (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. Methods The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. Results The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta = 1.16, 95% CI 1.11 to 1.22; p = 4.88 x 10(-10) and ORmeta = 1.67, 95% CI 1.55 to 1.79; p = 3.32 x 10(-46), respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p = 3.91 x 10(-5)). Conclusion These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE. C1 [Kim, Kwangwoo; Kang, Changwon] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. [Brown, Elizabeth E.; Alarc, Graciela S.; Edberg, Jeffrey C.; Kimberly, Robert P.] Univ Alabama Birmingham, Sch Med, Dept Med, Birmingham, AL 35294 USA. [Brown, Elizabeth E.; Alarc, Graciela S.; Edberg, Jeffrey C.; Kimberly, Robert P.] Univ Alabama Birmingham, Sch Med, Dept Epidemiol, Birmingham, AL 35294 USA. [Brown, Elizabeth E.; Alarc, Graciela S.; Edberg, Jeffrey C.; Kimberly, Robert P.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. [Brown, Elizabeth E.; Alarc, Graciela S.; Edberg, Jeffrey C.; Kimberly, Robert P.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Med, Birmingham, AL 35294 USA. [Choi, Chan-Bum; Lee, Hye-Soon; Bae, Sang-Cheol] Hanyang Univ Hosp Rheumat Dis, Dept Rheumatol, Seoul 133792, South Korea. [Alarc, Marta E.; Kelly, Jennifer A.; Glenn, Stuart B.; Ojwang, Joshua O.; Adler, Adam; Guthridge, Joel M.; Nath, Swapan K.; Sawalha, Amr H.; Merrill, Joan T.; Moser, Kathy L.; Gaffney, Patrick M.; Kaufman, Kenneth M.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Program, Oklahoma City, OK 73104 USA. [Alarc, Marta E.; BIOLUPUS] Univ Granada Junta de Andaluca, Area Human DNA Variabil, Ctr Gen & Invest Oncol GENYO, Granada, Spain. [Boackle, Susan A.] Univ Colorado, Div Rheumatol, Denver Sch Med, Aurora, CO USA. [Criswell, Lindsey A.] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA. [Stevens, Anne M.] Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA. [Jacob, Chaim O.] Univ So Calif, Lupus Genet Grp, Los Angeles, CA USA. [Gilkeson, Gary S.; Kamen, Diane L.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Tsao, Betty P.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Anaya, Juan-Manuel] Univ Nacl Rosario, Ctr Autoimmune Dis Res, Bogota, Colombia. [Richardson, Bruce] Univ Michigan, Div Rheumatol, Ann Arbor, MI 48109 USA. [Richardson, Bruce] US Dept Vet Affairs, Med Ctr, Ann Arbor, MI USA. [Sawalha, Amr H.; James, Judith A.; Eld, R. Hal Sco] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Sawalha, Amr H.; Kaufman, Kenneth M.] US Dept Vet Affairs, Dept Med, Med Ctr, Oklahoma City, OK USA. [Kang, Young Mo] Kyungpook Natl Univ, Dept Internal Med Rheumatol, Sch Med, Taegu, South Korea. [Shim, Seung Cheol] Eulji Univ, Div Rheumatol, Dept Med, Eulji Medi Bio Res Inst, Taejon, South Korea. [Suh, Chang-Hee] Ajou Univ, Dept Rheumatol, Sch Med, Suwon 441749, South Korea. [Lee, Soo-Kon] Yonsei Univ, Coll Med, Dept Internal Med, Seoul, South Korea. [Kim, Chang-sik] Chungnam Natl Univ, Dept Ophthalmol, Sch Med, Taejon, South Korea. [Petri, Michelle] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Vil, Luis M.] Univ Puerto Rico, Dept Med, San Juan, PR 00936 USA. [Niewold, Timothy B.] Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. [Martin, Javier] CSIC, Dept Immunol, Inst Biomed Parasitologa L pez Neyra, Granada, Spain. [Pons-Estel, Bernardo A.; GENLES] Sanatorio Parque, Dept Med, Rosario, Argentina. [Vyse, Timothy J.] Kings Coll London, Div Genet, Guys Hosp, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Mol Med, Guys Hosp, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Immunol, Guys Hosp, London WC2R 2LS, England. [Vyse, Timothy J.] Kings Coll London, Div Infect & Inammatory Dis, Guys Hosp, London WC2R 2LS, England. [Freedman, Barry I.; Williams, Adrienne; Comeau, Mary; Langefeld, Carl D.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Freedman, Barry I.; Williams, Adrienne; Comeau, Mary; Langefeld, Carl D.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Div Rheumatol, Houston, TX USA. [Harley, John B.] Cincinnati Childrens Hosp Med Ctr, US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. RP Kang, C (reprint author), Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. EM ckang@kaist.ac.kr; Robert.Kimberly@ccc.uab.edu; scbae@hanyang.ac.kr RI Kang, Changwon/C-1938-2011; Martin, Javier/B-8141-2008; Anaya, Juan-Manuel/J-1960-2016; OI Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Kimberly, Robert/0000-0002-5330-3086; Suh, Chang-Hee/0000-0001-6156-393X; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154; Niewold, Timothy/0000-0003-3532-6660 FU US NIH [AR042460, AR043274, AR043814, AR044804, AR048940, AR052300, AR053483, AR058554, AR060366, AR43727, AR62277, CA141700-01, GM063483, HD07463, K08-AI083790, K24-AR002138, M01-RR00079, N01-AR-6-227, P01-AR49084, P30-DK42086, P30-AR055385]; Lupus Foundation of America; Alliance for Lupus Research; Kirkland Scholar Award; US Department of Veterans Affairs; Korean Healthcare Technology Research and Development Project [A111218-11-GM01]; Korea Research Program for New Drug Target Discovery [20090083335]; National Research Foundation of Korea [2010-0014162]; Lupus Research Institute Novel Research Grant; Alliance for Lupus Research Target Identification in Lupus Grant; Arthritis National Research Foundation Eng Tan Scholar Award; ESF in the framework of the Research Networking Programme European Science Foundation-The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) [07-RNP-083]; Swedish Research Council; Swedish Association against Rheumatism; Swedish International Development Agency; Gustaf Vth 80th-Jubilee Foundation; Instituto de Salud Carlos III [PS09/00129]; FEDER funds of the European Union; Consejer'a de Salud de la Junta de Andaluc'a FX The work was supported by grants from US NIH (AI063622, AI071651, AI082714, AI083194, AI094377, AI24717, AR042460, AR043274, AR043814, AR044804, AR048940, AR052300, AR053483, AR058554, AR060366, AR43727, AR62277, CA141700-01, GM063483, HD07463, K08-AI083790, K24-AR002138, M01-RR00079, N01-AR-6-227, P01-AR49084, P30-DK42086, P30-AR055385, P60-AR049459 P60-AR053308, P60-2-AR30692, PO1-AR49084, PR094002, R01-AR33062, R21-AI070304, RR015577, RR020143, UL1RR024999, UL1RR025005, UL1RR025741, UL1RR029882 and 5UL1RR025777), the Lupus Foundation of America, the Alliance for Lupus Research, a Kirkland Scholar Award, the US Department of Veterans Affairs, the Korean Healthcare Technology Research and Development Project (A111218-11-GM01), the Korea Research Program for New Drug Target Discovery (20090083335), the National Research Foundation of Korea (2010-0014162), the Lupus Research Institute Novel Research Grant, the Alliance for Lupus Research Target Identification in Lupus Grant, the Arthritis National Research Foundation Eng Tan Scholar Award, the ESF in the framework of the Research Networking Programme European Science Foundation-The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) 07-RNP-083, the Swedish Research Council, the Swedish Association against Rheumatism, the Swedish International Development Agency, the Gustaf Vth 80th-Jubilee Foundation, the Instituto de Salud Carlos III (PS09/00129) partly financed by the FEDER funds of the European Union, and a grant from the Consejer'a de Salud de la Junta de Andaluc'a. NR 30 TC 16 Z9 16 U1 1 U2 7 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD NOV PY 2012 VL 71 IS 11 BP 1809 EP 1814 DI 10.1136/annrheumdis-2011-201110 PG 6 WC Rheumatology SC Rheumatology GA 018IZ UT WOS:000309654900009 PM 22523428 ER PT J AU Stein, NR Mills, MA Arditte, K Mendoza, C Borah, AM Resick, PA Litz, BT AF Stein, Nathan R. Mills, Mary Alice Arditte, Kimberly Mendoza, Crystal Borah, Adam M. Resick, Patricia A. Litz, Brett T. CA STRONG STAR Consortium TI A Scheme for Categorizing Traumatic Military Events SO BEHAVIOR MODIFICATION LA English DT Article DE PTSD; trauma; OEF/OIF; classification ID POSTTRAUMATIC-STRESS-DISORDER; VIETNAM COMBAT VETERANS; WAR ZONE STRESSORS; PSYCHOMETRIC PROPERTIES; INVENTORY; EXPOSURE; SEVERITY; VICTIMS; RELIABILITY; VALIDATION AB A common assumption among clinicians and researchers is that war trauma primarily involves fear-based reactions to life-threatening situations. However, the authors believe that there are multiple types of trauma in the military context, each with unique perievent and postevent response patterns. To test this hypothesis, they reviewed structured clinical interviews of 122 active duty service members and assigned the reported index (principal, most currently distressing) events to one or more of the following categories: Life Threat to Self, Life Threat to Others, Aftermath of Violence, Traumatic Loss, Moral Injury by Self, and Moral Injury by Others. They found high interrater reliability for the coding scheme and support for the construct validity of the categorizations. In addition, they discovered that certain categories were related to psychiatric symptoms (e.g., reexperiencing of the traumatic event, guilt, anger) and negative thoughts about the world. Their study provides tentative support for use of these event categories. C1 [Stein, Nathan R.; Mills, Mary Alice; Arditte, Kimberly; Resick, Patricia A.; Litz, Brett T.] VA Boston Healthcare Syst, Boston, MA USA. [Resick, Patricia A.; Litz, Brett T.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Borah, Adam M.] Carl R Darnall Army Med Ctr, Ft Hood, TX USA. [Mendoza, Crystal] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Stein, NR (reprint author), 1 Corp Pl, Middletown, RI 02842 USA. EM nathan.stein@va.gov NR 38 TC 20 Z9 20 U1 3 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD NOV PY 2012 VL 36 IS 6 SI SI BP 787 EP 807 DI 10.1177/0145445512446945 PG 21 WC Psychology, Clinical SC Psychology GA 022BP UT WOS:000309930300003 PM 22679239 ER PT J AU Hassija, CM Jakupcak, M Gray, MJ AF Hassija, Christina M. Jakupcak, Matthew Gray, Matt J. TI Numbing and Dysphoria Symptoms of Posttraumatic Stress Disorder Among Iraq and Afghanistan War Veterans: A Review of Findings and Implications for Treatment SO BEHAVIOR MODIFICATION LA English DT Article DE PTSD; numbing; dysphoria; veterans ID CONFIRMATORY FACTOR-ANALYSIS; BORDERLINE PERSONALITY-DISORDER; DIALECTICAL BEHAVIOR-THERAPY; RANDOMIZED CONTROLLED-TRIAL; ADMINISTERED PTSD SCALE; MENTAL-HEALTH PROBLEMS; WORLD-TRADE-CENTER; QUALITY-OF-LIFE; FUNCTIONAL IMPAIRMENT; PROLONGED EXPOSURE AB Iraq and Afghanistan war veterans experience significant rates of posttraumatic stress disorder (PTSD) and other trauma-related mental health conditions. Understanding how specific PTSD symptomatology affects physical health and psychosocial functioning may be useful in improving the conceptualization of PTSD nosology and informing treatment approaches for this population. Confirmatory factor analytic evidence supports four-factor models of PTSD symptoms that classify emotional numbing and/or dysphoria symptoms as a distinct PTSD symptom cluster, and these symptoms appear to be related to poorer psychological adjustment among returning Iraq and Afghanistan war veterans. This review briefly describes current conceptualizations of numbing/dysphoria symptoms of PTSD and summarizes research on the factor structure of PTSD symptoms. Then, the literature on the influence of numbing/dysphoria symptoms on physical and psychological health among these veterans is reviewed, and implications for treatment and directions for future research are presented. C1 [Hassija, Christina M.] Natl Ctr PTSD VA Palo Alto Hlth Care Syst, Menlo Pk, CA USA. [Hassija, Christina M.; Gray, Matt J.] Univ Wyoming, Laramie, WY 82071 USA. [Jakupcak, Matthew] VA Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA USA. [Jakupcak, Matthew] Univ Washington, Seattle, WA 98195 USA. RP Hassija, CM (reprint author), VA Palo Alto Hlth Care Syst, Natl Ctr Posttraumat Stress Disorder, 795 Willow Rd, Menlo Pk, CA 94025 USA. EM Christina.Hassija2@va.gov NR 67 TC 9 Z9 9 U1 5 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD NOV PY 2012 VL 36 IS 6 SI SI BP 834 EP 856 DI 10.1177/0145445512453735 PG 23 WC Psychology, Clinical SC Psychology GA 022BP UT WOS:000309930300005 PM 22977267 ER PT J AU Steenkamp, MM Nickerson, A Maguen, S Dickstein, BD Nash, WP Litz, BT AF Steenkamp, Maria M. Nickerson, Angela Maguen, Shira Dickstein, Benjamin D. Nash, William P. Litz, Brett T. TI Latent Classes of PTSD Symptoms in Vietnam Veterans SO BEHAVIOR MODIFICATION LA English DT Article DE PTSD; veterans; latent class; Vietnam ID POSTTRAUMATIC-STRESS-DISORDER; PERITRAUMATIC DISSOCIATION; THEATER VETERANS; SEXUAL ASSAULT; MENTAL-HEALTH; RISK-FACTORS; SUBTHRESHOLD; PREVALENCE; RESILIENCE; SURVIVORS AB The authors examined heterogeneity in posttraumatic stress disorder (PTSD) symptom presentation among veterans (n = 335) participating in the clinical interview subsample of the National Vietnam Veterans Readjustment Study. Latent class analysis was used to identify clinically homogeneous subgroups of Vietnam War combat veterans. Consistent with previous research, three classes emerged from the analysis, namely, veterans with no disturbance (61.4% of the cohort), intermediate disturbance (25.6%), and pervasive disturbance (12.5%). The authors also examined physical injury, war-zone stressor exposure, peritraumatic dissociation, and general dissociation as predictors of class membership. The findings are discussed in the context of recent conceptual frameworks that posit a range of posttraumatic outcomes and highlight the sizable segment of military veterans who suffer from intermediate (subclinical) PTSD symptoms. C1 [Steenkamp, Maria M.; Nickerson, Angela; Dickstein, Benjamin D.; Litz, Brett T.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Nickerson, Angela] Univ New S Wales, Sch Psychol, Kensington, NSW 2033, Australia. [Maguen, Shira] San Francisco VA Med Ctr, San Francisco, CA USA. [Maguen, Shira] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Litz, Brett T.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Nash, William P.] VA San Diego Healthcare Syst, San Diego, CA USA. [Steenkamp, Maria M.; Litz, Brett T.] Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. RP Steenkamp, MM (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM maria.steenkamp2@va.gov NR 42 TC 21 Z9 21 U1 3 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD NOV PY 2012 VL 36 IS 6 SI SI BP 857 EP 874 DI 10.1177/0145445512450908 PG 18 WC Psychology, Clinical SC Psychology GA 022BP UT WOS:000309930300006 PM 22798638 ER PT J AU Martin, NE Chen, MH Nguyen, PL Beard, CJ Loffredo, MJ Kantoff, PW D'Amico, AV AF Martin, Neil E. Chen, Ming-Hui Nguyen, Paul L. Beard, Clair J. Loffredo, Marian J. Kantoff, Philip W. D'Amico, Anthony V. TI Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and 6 months of combined androgen blockade SO BJU INTERNATIONAL LA English DT Article DE testosterone; prostatic neoplasms; radiotherapy; androgen blockade ID LOCALIZED PROSTATE-CANCER; RANDOMIZED CONTROLLED-TRIAL; HORMONE AGONIST TREATMENT; SERUM TESTOSTERONE; RADICAL PROSTATECTOMY; DEPRIVATION THERAPY; NORMALIZATION; TIME; STEROIDOGENESIS; RADIOTHERAPY AB OBJECTIVE To determine whether the biopsy Gleason score is associated with duration of testosterone suppression following 6 months of combined androgen blockade (CAB) and radiation therapy (RT) in men with prostate cancer (PCa). PATIENTS AND METHODS The study cohort consisted of 221 men with PCa treated with RT and 6 months of CAB between 1996 and 2005. We defined the duration of testosterone suppression as the time between the last day of CAB and the date the testosterone returned to >= 252 ng/dL. We used Cox regression multivariable analysis to relate biopsy Gleason score to duration of testosterone suppression following cessation of CAB. RESULTS A biopsy Gleason score of 8-10 had an adjusted hazard ratio (AHR) of 1.56 (95% confidence interval [CI] 1.04, 2.34; P = 0.03) for a shorter time to testosterone normalization relative to Gleason 6. Specifically, the 51 men with biopsy Gleason score of 8-10 had a median time to testosterone normalization of 17.0 months compared with 22.1 months and 23.8 months for those with biopsy Gleason <= 6 and 7, respectively. Increasing age was significantly associated with a longer duration of testosterone suppression (AHR of 0.95 [95% CI 0.92, 0.97; P < 0.001]) as was a higher baseline PSA (AHR 0.82 [95% CI 0.69, 0.97; P = 0.02]). CONCLUSION A biopsy Gleason score of 8-10 was associated with a shorter period of testosterone suppression following 6 months of CAB and RT. These data are consistent with the hypothesis that a factor released from high-grade PCa cells may impact on testosterone production. C1 [Martin, Neil E.] Harvard Univ, Dana Farber Canc Inst, Dept Radiat Oncol, Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Kantoff, Philip W.] Harvard Univ, Dana Farber Canc Inst, Dept Med Oncol, Sch Med, Boston, MA 02115 USA. RP Martin, NE (reprint author), Harvard Univ, Dana Farber Canc Inst, Dept Radiat Oncol, Brigham & Womens Hosp,Med Sch, 75 Francis St,ASB I L2, Boston, MA 02115 USA. EM neil_martin@dfci.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Prostate Cancer Foundation FX NEM is supported by a Young Investigator award from the Prostate Cancer Foundation. PLN is supported by a generous gift from an anonymous donor. NR 31 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD NOV PY 2012 VL 110 IS 9 BP 1252 EP 1256 DI 10.1111/j.1464-410X.2012.11118.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 024DC UT WOS:000310087000009 PM 22564379 ER PT J AU Klippel, S Jakubikova, J Delmore, J Ooi, M McMillin, D Kastritis, E Laubach, J Richardson, PG Anderson, KC Mitsiades, CS AF Klippel, Steffen Jakubikova, Jana Delmore, Jake Ooi, Melissa McMillin, Douglas Kastritis, Efstathios Laubach, Jacob Richardson, Paul G. Anderson, Kenneth C. Mitsiades, Constantine S. TI Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE multiple myeloma; jasmonates; ATP depletion; metabolic activity; aldo-keto reductases ID METHYL JASMONATE; PROSTATE-CANCER; INDUCE APOPTOSIS; DRUG-RESISTANCE; LUNG-CANCER; AKR1C2; OVEREXPRESSION; METABOLISM; EXPRESSION; BORTEZOMIB AB Jasmonates, plant stress hormones, have been demonstrated to be effective in killing various types of cancer cells. We therefore tested if methyljasmonate (MJ) has activity against multiple myeloma (MM) in vitro and in vivo. MM cell lines and primary MM tumour cells responded to MJ in vitro at concentrations that did not significantly affect normal haematopoietic cells, without stroma-mediated resistance. Brief MJ exposures of MM cells caused release of Hexokinase 2 (HK2) from mitochondria, rapid ATP depletion, perturbation of major intracellular signalling pathways, and ensuing mainly apoptotic cell death. Sensitivity to MJ correlated with lower cellular glucose consumption and lactate production, as well as lower intracellular protein levels of HK2, phosphorylated Voltage-dependent anion channel 2/3 (pVDAC2/3) and Aldo-keto reductase family 1 member C1 (AKR1C1), which represent potential biomarkers of responsiveness to MJ treatment, especially as AKR1C1 transcript levels also correlate with clinical outcome in bortezomib- or dexamethasone-treated MM patients. Interestingly, MJ synergized with bortezomib in vitro and prolonged survival of immunocompromised mice harbouring diffuse lesions of MM.1S cells compared to vehicle-treated mice (P=0.0046). These studies indicate that jasmonates represent a new, promising strategy to treat MM. C1 [Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02215 USA. RP Mitsiades, CS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Constantine_Mitsiades@dfci.harvard.edu FU Dana-Farber Cancer Institute; Chambers Medical Foundation; Paul Stepanian Fund; Richard Corman Fund; National Institutes of Health [RO1-50947]; OSI Pharmaceuticals; Amgen Pharmaceuticals; AVEO Pharma; EMD Serono; Sunesis; Gloucester Pharmaceuticals; Genzyme; Johnson Johnson FX Supported by 'Dunkin Donuts Rising Stars' Program at the Dana-Farber Cancer Institute (to C. S. M), the Chambers Medical Foundation (P. G. R and C. S. M.), the Paul Stepanian Fund (C. S. M, P. G. R.), the Richard Corman Fund (P. G. R., C.S.M.) and National Institutes of Health Grants RO1-50947 ( C. S. M and K.C.A).; CSM has received in the past honoraria from Millennium Pharmaceuticals, Novartis Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Centrocor, Celgene, Arno Therapeutics; licensing royalties from PharmaMar; and research funding from OSI Pharmaceuticals, Amgen Pharmaceuticals, AVEO Pharma, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme and Johnson & Johnson. PGR is on Advisory Boards of Millennium Pharmaceuticals, Celgene, Novartis, Bristol-Myers Squibb and Johnson & Johnson. KCA is on Advisory Boards of Millennium Pharmaceuticals, Celgene, Bristol Myers Squibb, Merck, and Onyx. NR 26 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD NOV PY 2012 VL 159 IS 3 BP 340 EP 351 DI 10.1111/j.1365-2141.2012.09253.x PG 12 WC Hematology SC Hematology GA 019DO UT WOS:000309717500010 PM 22970818 ER PT J AU Inglott, MA Lerner, EA Pilowsky, PM Farnham, MMJ AF Inglott, Melissa A. Lerner, Ethan A. Pilowsky, Paul M. Farnham, Melissa M. J. TI Activation of PAC1 and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetized rat SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE PACAP; vasoactive intestinal polypeptide; maxadilan; PACAP(6-38); blood pressure; sympathetic; adrenaline; noradrenaline; adrenal medulla ID VASOACTIVE-INTESTINAL-PEPTIDE; BLOOD-FLOW; IN-VIVO; ARRIVE GUIDELINES; CHROMAFFIN CELLS; NERVE ACTIVITY; SAND FLIES; POLYPEPTIDE; MAXADILAN; INCREASES AB BACKGROUND AND PURPOSE Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide with central and peripheral cardiovascular actions. Intrathecal PACAP increases splanchnic sympathetic nerve activity and heart rate, but not mean arterial pressure (MAP). We hypothesize that the three PACAP receptors (PAC1, VPAC1 and VPAC2) have different actions in central cardiovascular control, and that their summed effect results in the lack of MAP response observed following intrathecal PACAP injection. EXPERIMENTAL APPROACH The effects of the PACAP receptors on baseline cardiovascular parameters were investigated using selective agonists and antagonists administered into the intrathecal space of urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats. KEY RESULTS Selective activation of the PACAP receptors had different effects on MAP. When activated by maxadilan, PAC1 receptors increased MAP. The VPAC receptors decreased MAP when both were activated with vasoactive intestinal polypeptide or when only VPAC1 receptors were activated. The PAC1 and VPAC2 receptor antagonist PACAP(638) had no cardiovascular effects, suggesting that PACAP is not tonically released. CONCLUSIONS AND IMPLICATIONS PACAP neurotransmission was not responsible for the moment-to-moment tonic regulation of central cardiovascular control mechanisms. Nevertheless, PACAP release within the spinal cord may have pleiotropic effects on sympathetic outflow depending on the postsynaptic receptor type. PAC1 and VPAC receptor subtypes produced opposing changes in blood pressure when activated by intrathecal PACAP-38 in the anaesthetized Sprague-Dawley rat, resulting in no net change in MAP. C1 [Inglott, Melissa A.; Pilowsky, Paul M.; Farnham, Melissa M. J.] Macquarie Univ, Australian Sch Adv Med, Sydney, NSW 2109, Australia. [Lerner, Ethan A.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Pilowsky, PM (reprint author), Macquarie Univ, Australian Sch Adv Med, F10A, Sydney, NSW 2109, Australia. EM paul.pilowsky@mq.edu.au OI Farnham, Melissa/0000-0002-7612-1015; Pilowsky, Paul/0000-0003-3500-467X FU National Health and Medical Research Council of Australia [457080, 457069, 604002, 1024489]; The Australian Research Council [DP110102110, DE120100992]; Macquarie University [9200800903, 9200901700]; National Heart Foundation of Australia [G11S5957]; National Institutes of Health (USA) [1R01AR057744]; Australian Postgraduate Award FX Work in the authors' laboratories is supported by grants from the National Health and Medical Research Council of Australia (457080, 457069, 604002, 1024489), The Australian Research Council (DP110102110, DE120100992), Macquarie University (9200800903, 9200901700), the National Heart Foundation of Australia (G11S5957) and the National Institutes of Health (USA; 1R01AR057744). M.A.I. was supported by an Australian Postgraduate Award. NR 34 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD NOV PY 2012 VL 167 IS 5 BP 1089 EP 1098 DI 10.1111/j.1476-5381.2012.02045.x PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 017OI UT WOS:000309599400014 PM 22612450 ER PT J AU Serafini, G Pompili, M Innamorati, M Rihmer, Z Sher, L Girardi, P AF Serafini, Gianluca Pompili, Maurizio Innamorati, Marco Rihmer, Zoltan Sher, Leo Girardi, Paolo TI Can Cannabis Increase the Suicide Risk in Psychosis? A Critical Review SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Cannabis use; suicidal behavior; psychosis; youths; prevention ID DELIBERATE SELF-HARM; SUBSTANCE USE; YOUNG-PEOPLE; AFFECTIVE TEMPERAMENTS; GENERAL-POPULATION; MENTAL-HEALTH; PSYCHIATRIC-PATIENTS; DEPRESSIVE SYMPTOMS; HIGHER HOPELESSNESS; COMPLETED SUICIDE AB Objectives: This paper aimed to critically review the current literature concerning the possible association between cannabis use and suicidal behavior in patients with psychosis and in non-psychotic samples. Methods: We performed a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters focusing on the association between cannabis use, and suicidal behavior during the period between 1980 and 2011. Results: Most, but not all studies reported an association between suicidal behavior and cannabis use both in psychotic and non-psychotic samples. However, there were also some studies suggesting a weak (not direct) association between these two phenomena. Overall, those who attempt or complete suicide are characterized by additional risk factors such as mood disorders, stressful life events, interpersonal problems, poor social support, lonely lives, and feelings of hopelessness. Limitations: It was not possible to perform a meta-analysis due to the high heterogeneity of individual data. Conclusions: Cannabis use was a relevant risk factor associated with both suicidal attempts and behaviors in psychotic and non-psychotic samples. Preventive programs should be directed on reducing cannabis use, particularly in psychotic subjects. Evidence suggests that targeted suicide prevention programs can be also developed in specific at-risk subgroups such as those at genetic or clinical high risk of psychosis. C1 [Serafini, Gianluca; Pompili, Maurizio; Girardi, Paolo] Univ Roma La Sapienza, St Andrea Hosp, Dept Neurosci Mental Hlth & Sensory Organs, Suicide Prevent Ctr, I-00189 Rome, Italy. [Pompili, Maurizio; Innamorati, Marco] Harvard Univ, Sch Med, McLean Hosp, Cambridge, MA 02138 USA. [Rihmer, Zoltan] Semmelweis Univ, Dept Clin & Theoret Mental Hlth, Kutvolgyi Clin Ctr, H-1125 Budapest, Hungary. [Rihmer, Zoltan] Semmelweis Univ, Dept Psychiat & Psychotherapy, H-1125 Budapest, Hungary. [Sher, Leo] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Sher, Leo] James J Peters Vet Adm Med Ctr, Dept Psychiat, New York, NY USA. RP Serafini, G (reprint author), Univ Roma La Sapienza, St Andrea Hosp, Dept Neurosci Mental Hlth & Sensory Organs, Suicide Prevent Ctr, 1035-1039 Via Grottarossa, I-00189 Rome, Italy. EM gianluca.serafini@uniroma1.it RI Innamorati, Marco/H-8877-2013; OI Innamorati, Marco/0000-0003-1389-2290; Pompili, Maurizio/0000-0003-1886-4977 NR 87 TC 11 Z9 11 U1 5 U2 20 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD NOV PY 2012 VL 18 IS 32 BP 5165 EP 5187 PG 23 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 016JA UT WOS:000309512900028 PM 22716157 ER PT J AU McGrath, LM Weill, S Robinson, EB MacRae, R Smoller, JW AF McGrath, Lauren M. Weill, Sydney Robinson, Elise B. MacRae, Rebecca Smoller, Jordan W. TI Bringing a developmental perspective to anxiety genetics SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID GENOME-WIDE ASSOCIATION; COMORBIDITY SURVEY REPLICATION; ENVIRONMENTAL RISK-FACTORS; DSM-IV DISORDERS; PANIC DISORDER; BEHAVIORAL-INHIBITION; JAPANESE POPULATION; MIDDLE CHILDHOOD; SOCIAL ANXIETY; PRESCHOOL-CHILDREN AB Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review the psychiatric and genetic epidemiological evidence that supports such a framework, including the early onset and chronic course of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders. C1 [McGrath, Lauren M.; Weill, Sydney; Robinson, Elise B.; Smoller, Jordan W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [MacRae, Rebecca] MIT, Cambridge, MA 02139 USA. RP McGrath, LM (reprint author), Massachusetts Gen Hosp, Simches Res Bldg,6th Floor,185 Cambridge St, Boston, MA 02114 USA. EM mcgrath@pngu.mgh.harvard.edu OI Robinson, Elise/0000-0003-2314-2792; McGrath, Lauren/0000-0001-6928-9656 FU NIMH NIH HHS [K24 MH094614, K24-MH094614, T32 MH016259, T32 MH017119, T32-MH017119, T32-MH16259] NR 147 TC 11 Z9 11 U1 4 U2 31 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD NOV PY 2012 VL 24 IS 4 SI SI BP 1179 EP 1193 DI 10.1017/S0954579412000636 PG 15 WC Psychology, Developmental SC Psychology GA 021ZX UT WOS:000309925800003 PM 23062290 ER PT J AU Xavier, R AF Xavier, Ramnik TI GWAS, Genes and IBD Pathogenesis SO DIGESTIVE DISEASES AND SCIENCES LA English DT Meeting Abstract C1 [Xavier, Ramnik] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik] Harvard Univ, Sch Med, Broad Inst Harvard & MIT, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 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 NOV PY 2012 VL 57 IS 11 BP 2728 EP 2728 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 021EJ UT WOS:000309867800005 ER PT J AU Akiba, Y Kaunitz, JD AF Akiba, Yasutada Kaunitz, Jonathan D. TI May the Truth Be with You: Lubiprostone as EP Receptor Agonist/ClC-2 Internalizing "Inhibitor" SO DIGESTIVE DISEASES AND SCIENCES LA English DT Editorial Material ID IRRITABLE-BOWEL-SYNDROME; TRANSMEMBRANE CONDUCTANCE REGULATOR; CHLORIDE CHANNEL ACTIVATOR; CYSTIC-FIBROSIS; CLC-2 CHLORIDE; BICARBONATE SECRETION; EPITHELIAL-CELLS; CLINICAL-TRIAL; CONSTIPATION; COLON C1 [Akiba, Yasutada] W Los Angeles VA Med Ctr, Los Angeles, CA 90073 USA. [Akiba, Yasutada; Kaunitz, Jonathan D.] Greater Los Angles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Akiba, Yasutada; Kaunitz, Jonathan D.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Akiba, Yasutada; Kaunitz, Jonathan D.] Brentwood Biomed Res Inst, Los Angeles, CA 90073 USA. RP Akiba, Y (reprint author), W Los Angeles VA Med Ctr, 11301 Wilshire Blvd,Bldg 114,Suite 217, Los Angeles, CA 90073 USA. EM yakiba@mednet.ucla.edu FU NIDDK NIH HHS [R01 DK54221] NR 32 TC 2 Z9 2 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD NOV PY 2012 VL 57 IS 11 BP 2740 EP 2742 DI 10.1007/s10620-012-2410-2 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 021EJ UT WOS:000309867800022 PM 23001408 ER PT J AU Krestin, GP Grenier, PA Hricak, H Jackson, VP Khong, PL Miller, JC Muellner, A Schwaiger, M Thrall, JH AF Krestin, G. P. Grenier, P. A. Hricak, H. Jackson, V. P. Khong, P. L. Miller, J. C. Muellner, A. Schwaiger, M. Thrall, J. H. TI Integrated diagnostics: proceedings from the 9th biennial symposium of the International Society for Strategic Studies in Radiology SO EUROPEAN RADIOLOGY LA English DT Article DE Radiology; Diagnostic techniques and procedures; Informatics; Algorithms; Efficiency; Organizational ID HEALTH-CARE QUALITY; ACUTE CHEST-PAIN; IN-VIVO; ROTTERDAM SCAN; MEDICINE; TECHNOLOGY; TOMOGRAPHY; VALIDATION; BIOMARKERS; DISEASE AB The International Society for Strategic Studies in Radiology held its 9th biennial meeting in August 2011. The focus of the programme was integrated diagnostics and massive computing. Participants discussed the opportunities, challenges, and consequences for the discipline of radiology that will likely arise from the integration of diagnostic technologies. Diagnostic technologies are increasing in scope, including advanced imaging techniques, new molecular imaging agents, and sophisticated point-of-use devices. Advanced information technology (IT), which is increasingly influencing the practice of medicine, will aid clinical communication and the development of "population images" that represent the phenotype of particular diseases, which will aid the development of diagnostic algorithms. Integrated diagnostics offer increased operational efficiency and benefits to patients through quicker and more accurate diagnoses. As physicians with the most expertise in IT, radiologists are well placed to take the lead in introducing IT solutions and cloud computing to promote integrated diagnostics. To achieve this, radiologists must adapt to include quantitative data on biomarkers in their reports. Radiologists must also increase their role as participating physicians, collaborating with other medical specialties, not only to avoid being sidelined by other specialties but also to better prepare as leaders in the selection and sequence of diagnostic procedures. Key Points aEuro cent New diagnostic technologies are yielding unprecedented amounts of diagnostic information. aEuro cent Advanced IT/cloud computing will aid integration and analysis of diagnostic data. aEuro cent Better diagnostic algorithms will lead to faster diagnosis and more rapid treatment. C1 [Krestin, G. P.] Univ Med Ctr Rotterdam, Dept Radiol, Erasmus MC, Rotterdam, Netherlands. [Grenier, P. A.] Hop La Pitie Salpetriere, Serv Radiol Polyvalente Diagnost & Intervent, Paris 13, France. [Hricak, H.; Muellner, A.] Mem Sloane Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA. [Jackson, V. P.] Indiana Univ Sch Med, Dept Radiol, Indianapolis, IN 46202 USA. [Khong, P. L.] Univ Hong Kong, Dept Radiol, Queen Mary Hosp, Hong Kong, Hong Kong, Peoples R China. [Miller, J. C.; Thrall, J. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Miller, J. C.; Thrall, J. H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schwaiger, M.] Tech Univ Munich, Klinikum Rechts Isar, Nukl Med Klin & Poliklin, D-81675 Munich, Germany. RP Krestin, GP (reprint author), Univ Med Ctr Rotterdam, Dept Radiol, Erasmus MC, Rotterdam, Netherlands. EM g.p.krestin@erasmusmc.nl OI schwaiger, markus /0000-0002-2305-7144 NR 75 TC 2 Z9 3 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD NOV PY 2012 VL 22 IS 11 BP 2283 EP 2294 DI 10.1007/s00330-012-2510-6 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 021EZ UT WOS:000309869400001 PM 22699871 ER PT J AU Haas, RLM DeLaney, TF O'Sullivan, B Keus, RB Le Pechoux, C Olmi, P Poulsen, JP Seddon, B Wang, D AF Haas, Rick L. M. DeLaney, Thomas F. O'Sullivan, Brian Keus, Ronald B. Le Pechoux, Cecile Olmi, Patricia Poulsen, Jan-Peter Seddon, Beatrice Wang, Dian TI Radiotherapy for Management of Extremity Soft Tissue Sarcomas: Why, When, and Where? SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review DE Radiotherapy; Soft tissue sarcoma; Target volume delineation ID MODULATED RADIATION-THERAPY; LOCAL-CONTROL; POSTOPERATIVE RADIOTHERAPY; RANDOMIZED-TRIAL; PREOPERATIVE RADIOTHERAPY; SPARING SURGERY; PHASE-II; COMPLICATIONS; FRACTURES; CHEMORADIATION AB This critical review will focus on published data on the indications for radiotherapy in patients with extremity soft tissue sarcomas and its role in local control, survival, and treatment complications. The differences between pre- and postoperative radiotherapy will be discussed and consensus recommendations on target volume delineation proposed. (C) 2012 Elsevier Inc. C1 [Haas, Rick L. M.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. [DeLaney, Thomas F.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [O'Sullivan, Brian] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M4X 1K9, Canada. [Keus, Ronald B.] Arnhems Radiotherapeut Inst, Dept Radiotherapy, Arnhem, Netherlands. [Le Pechoux, Cecile] Inst Gustave Roussy, Dept Radiotherapy, F-94805 Villejuif, France. [Olmi, Patricia] Ist Nazl Studio & Cura Tumori, Dept Radiotherapy, Milan, Italy. [Poulsen, Jan-Peter] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Radiotherapy, Oslo, Norway. [Seddon, Beatrice] Univ Coll London Hosp, Dept Radiotherapy, London, England. [Wang, Dian] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA. RP Haas, RLM (reprint author), Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands. EM r.haas@nki.nl NR 31 TC 39 Z9 40 U1 1 U2 10 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 NOV 1 PY 2012 VL 84 IS 3 BP 572 EP 580 DI 10.1016/j.ijrobp.2012.01.062 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 017AI UT WOS:000309560600034 PM 22520481 ER PT J AU Pashtan, IM Recht, A Ancukiewicz, M Brachtel, E Abi-Raad, RF D'Alessandro, HA Levy, A Wo, JY Hirsch, AE Kachnic, LA Goldberg, S Specht, M Gadd, M Smith, BL Powell, SN Taghian, AG AF Pashtan, Itai M. Recht, Abram Ancukiewicz, Marek Brachtel, Elena Abi-Raad, Rita F. D'Alessandro, Helen A. Levy, Antonin Wo, Jennifer Y. Hirsch, Ariel E. Kachnic, Lisa A. Goldberg, Saveli Specht, Michelle Gadd, Michelle Smith, Barbara L. Powell, Simon N. Taghian, Alphonse G. TI External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID CONFORMAL RADIATION-THERAPY; CONSERVING THERAPY; PROGESTERONE-RECEPTOR; CONSENSUS STATEMENT; ESTROGEN-RECEPTOR; AMERICAN SOCIETY; RANDOMIZED-TRIAL; CANCER; RISK; RADIOTHERAPY AB Purpose: External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. Methods and Materials: From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twicedaily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative-phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Results: Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P = . 0537). Conclusions: Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates. (c) 2012 Elsevier Inc. C1 [Abi-Raad, Rita F.; Levy, Antonin; Wo, Jennifer Y.; Goldberg, Saveli; Powell, Simon N.; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Pashtan, Itai M.] Harvard Radiat Oncol Program, Boston, MA USA. [Recht, Abram] Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. [Brachtel, Elena] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [D'Alessandro, Helen A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hirsch, Ariel E.] Boston Univ, Sch Med, Dept Radiat Oncol, Boston Med Ctr, Boston, MA 02118 USA. [Kachnic, Lisa A.; Specht, Michelle; Gadd, Michelle; 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 , Antonin/0000-0003-4798-8899 FU National Institutes of Health (NIH) National Cancer Institute (NCI) [R01CA139118, P50CA089393] FX This work was supported in part by National Institutes of Health (NIH) National Cancer Institute (NCI) grants R01CA139118 and P50CA089393 (to A.G.T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or NCI. NR 20 TC 19 Z9 19 U1 0 U2 1 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 NOV 1 PY 2012 VL 84 IS 3 BP E271 EP E277 DI 10.1016/j.ijrobp.2012.04.019 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 017AI UT WOS:000309560600002 PM 22652104 ER PT J AU Vargas-Lowy, D Chitnis, T AF Vargas-Lowy, David Chitnis, Tanuja TI Pathogenesis of Pediatric Multiple Sclerosis SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE pathogenesis; multiple sclerosis; demyelination ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; VITAMIN-D-RECEPTOR; EPSTEIN-BARR-VIRUS; CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; B-CELL FOLLICLES; BLOOD MONONUCLEAR-CELLS; REGULATORY T-CELLS; EARLY-ONSET MS AB Onset of multiple sclerosis in childhood occurs in 3-5% of patients. There is limited, but growing knowledge about the underlying pathobiology of pediatric MS. It is crucial to better understand this area in order to address central questions in the field: 1) Can pediatric multiple sclerosis inform us about factors related to disease initiation and propagation? 2) What are the biomarkers of disease course in pediatric multiple sclerosis; 3) Does pediatric multiple sclerosis pathogenesis differ from adult-onset multiple sclerosis; 4) How can we optimize treatment in pediatric demyelinating diseases? 5) Can pediatric multiple sclerosis provide insights into the environmental risk factors for multiple sclerosis in general? Here we review the current knowledge of the pathogenesis of multiple sclerosis in children, and address the five questions raised above. C1 [Vargas-Lowy, David; Chitnis, Tanuja] Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA. [Chitnis, Tanuja] Massachusetts Gen Hosp, Partners Pediat MS Ctr, Boston, MA 02114 USA. RP Chitnis, T (reprint author), Massachusetts Gen Hosp Children, Partners Pediat Multiple Sclerosis Ctr, Boston, MA 02114 USA. EM tchitnis@partners.org NR 169 TC 12 Z9 13 U1 2 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2012 VL 27 IS 11 BP 1394 EP 1407 DI 10.1177/0883073812456084 PG 14 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 023IL UT WOS:000310026000004 PM 22952316 ER PT J AU Lawson, EH Gibbons, MM Ko, CY Shekelle, PG AF Lawson, Elise H. Gibbons, Melinda Maggard Ko, Clifford Y. Shekelle, Paul G. TI The appropriateness method has acceptable reliability and validity for assessing overuse and underuse of surgical procedures SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Review DE Appropriateness; Surgery; Reliability; Validity; Overuse; Underuse ID UPPER GASTROINTESTINAL ENDOSCOPY; CORONARY REVASCULARIZATION; EXPERT PANELS; CAROTID-ENDARTERECTOMY; MYOCARDIAL-INFARCTION; EXPLICIT CRITERIA; PHYSICIAN RATINGS; KNEE REPLACEMENT; CATARACT-SURGERY; GUIDELINES AB Objective: To summarize the findings of methodological studies on the RAND/University of California Los Angeles (RAND/UCLA) appropriateness method, which was developed to assess if variation in the use of surgical procedures is because of overuse and/or underuse. Study Design and Setting: A MEDLINE literature search was performed. Studies were included if they assessed the reliability or validity of the RAND/UCLA appropriateness method for a surgical procedure or the effect of altering panelist composition or eliminating in-person discussion between rating rounds. Information was abstracted on procedure, study design, and findings. Results: One thousand six hundred one titles were identified, and 37 met the inclusion criteria. The test-retest reliability is good to very good (kappa, 0.64-0.81) for total knee and hip joint replacement, coronary artery bypass grafting (CABG), and carotid endarterectomy (CEA). The interpanel reliability is moderate to very good (kappa, 0.52-0.83) for CABG and hysterectomy. Construct validity has been demonstrated by comparing the appropriateness method with guidelines and/or evidence-based approaches for endoscopy, colonoscopy, CABG, hysterectomy, and CEA. Predictive validity has been studied for cardiac revascularization, in which concordance with appropriateness classification is associated with better clinical outcomes. Conclusion: Our findings support use of the appropriateness method to assess variation in the rates of the procedures studied by identifying overuse and underuse. Further methodological research should be conducted as appropriateness criteria are developed and implemented for a broader range of procedures. (C) 2012 Elsevier Inc. All rights reserved. C1 [Lawson, Elise H.] Univ Calif Los Angeles, Med Ctr, Dept Surg, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lawson, Elise H.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Gibbons, Melinda Maggard] Olive View UCLA Med Ctr, Dept Surg, Sylmar, CA 91342 USA. [Ko, Clifford Y.; Shekelle, Paul G.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA 90073 USA. [Ko, Clifford Y.; Shekelle, Paul G.] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. [Shekelle, Paul G.] RAND Corp, Santa Monica, CA 90401 USA. RP Lawson, EH (reprint author), Univ Calif Los Angeles, Med Ctr, Dept Surg, David Geffen Sch Med, 10833 LeConte Ave,CHS 72-215, Los Angeles, CA 90095 USA. EM elawson@mednet.ucla.edu FU American College of Surgeons through RWJF CSP FX The authors acknowledge Dr Angela Ingraham for her help with the initial screening of articles. This study received no external funding. Dr Lawson's time was supported by the American College of Surgeons through RWJF CSP. The remaining three authors participated through their roles as advisors to the RWJF CSP. NR 59 TC 23 Z9 23 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD NOV PY 2012 VL 65 IS 11 BP 1133 EP 1143 DI 10.1016/j.jclinepi.2012.07.002 PG 11 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 017DY UT WOS:000309571500002 PM 23017632 ER PT J AU Hao, SC Hunter, TD Gunnarsson, C March, JL White, SA Ladapo, JA Reynolds, MR AF Hao, Steven C. Hunter, Tina D. Gunnarsson, Candace March, Jamie L. White, Sarah A. Ladapo, Joseph A. Reynolds, Matthew R. TI Acute safety outcomes in younger and older patients with atrial fibrillation treated with catheter ablation SO JOURNAL OF INTERVENTIONAL CARDIAC ELECTROPHYSIOLOGY LA English DT Article DE Catheter ablation; Atrial fibrillation; Radiofrequency ablation; Stroke ID ANTIARRHYTHMIC-DRUGS; RADIOFREQUENCY ABLATION; PREVALENCE; MANAGEMENT; TRIAL; EFFICACY; THERAPY; HEALTH; RISK; AGE AB Catheter ablation for atrial fibrillation (AF) has been demonstrated to be safe and effective in subsets of patients with AF, but primarily in patients age < 65. This study compared acute safety in patients age a parts per thousand yen65 vs. those < 65 who have undergone catheter ablation for AF. A retrospective analysis of data from two Thomson Reuters MarketScanA (R) research databases was performed on 5,947 patients who underwent catheter ablation for treatment of AF. Acute safety was measured as a composite endpoint of procedure-related adverse events coded a parts per thousand currency sign7 days post-procedure. A logistic regression model was fitted to this endpoint, using age (< 65, a parts per thousand yen65) and relevant covariates. Peri-procedural mortality rates were examined among patients with inpatient ablation procedures, where death rates could be determined by discharge status. The acute safety event rate was nearly identical between both groups. This finding persisted after adjusting for covariates in the logistic regression model (p = 0.6648). There were no peri-procedural mortalities among the 3,575 index ablation procedures performed in an inpatient setting. Acute safety of catheter ablation for AF in patients a parts per thousand yen65 was consistent with that of younger patients. A prior history of hypertension and stroke was associated with a high risk for complications with AF ablation. These findings in a large, real world population may have implications for Medicare patients with AF. C1 [Hunter, Tina D.; Gunnarsson, Candace] S2 Stat Solut Inc, Cincinnati, OH 45241 USA. [Hao, Steven C.] Sutter Pacific Med Fdn, San Francisco, CA 94115 USA. [March, Jamie L.; White, Sarah A.] Biosense Webster Inc, Global Hlth Econ Outcomes Res & Policy, Diamond Bar, CA 91765 USA. [Ladapo, Joseph A.] New York Univ, Sch Med, Dept Med, New York, NY 10016 USA. [Reynolds, Matthew R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Reynolds, Matthew R.] VA Boston Healthcare Syst, Cardiol, W Roxbury, MA 02132 USA. RP Gunnarsson, C (reprint author), S2 Stat Solut Inc, 11176 Main St, Cincinnati, OH 45241 USA. EM candaceg@s2stats.com OI Ladapo, Joseph/0000-0002-8518-4800 FU Biosense Webster, Inc.; Sanofi-Aventis; Biosense Webster, Inc., Diamond Bar, CA FX Steven Hao, MD, FACC, FHRS is a consultant for Biosense Webster, Inc., and Medtronic. Tina Hunter, PhD and Candace Gunnarsson, EdD are employees of S2 Statistical Solutions, Inc., which is a paid consultant to Biosense Webster, Inc. Jamie March, MBA, and Sarah White, MPH were employed by Biosense Webster, Inc., when the research was conducted. Joseph Ladapo, MD, PhD is a paid consultant for S2 Statistical Solutions, Inc. Matthew Reynolds, MD, MSc has received research grants on behalf of Biosense Webster, Inc., and Sanofi-Aventis and consulting/honoraria from Biosense Webster, Inc., Sanofi-Aventis, and St. Jude Medical. This study was funded by Biosense Webster, Inc., Diamond Bar, CA NR 27 TC 6 Z9 6 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1383-875X J9 J INTERV CARD ELECTR JI J. Interv. Card. Electrophysiol. PD NOV PY 2012 VL 35 IS 2 BP 173 EP 182 DI 10.1007/s10840-012-9690-5 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 021CF UT WOS:000309862200007 PM 22714547 ER PT J AU Kloverpris, HN Harndahl, M Leslie, AJ Carlson, JM Ismail, N van der Stok, M Huang, KHG Chen, FB Riddell, L Steyn, D Goedhals, D van Vuuren, C Frater, J Walker, BD Carrington, M Ndung'u, T Buus, S Goulder, P AF Kloverpris, Henrik N. Harndahl, Mikkel Leslie, Alasdair J. Carlson, Jonathan M. Ismail, Nasreen van der Stok, Mary Huang, Kuan-Hsiang Gary Chen, Fabian Riddell, Lynn Steyn, Dewald Goedhals, Dominique van Vuuren, Cloete Frater, John Walker, Bruce D. Carrington, Mary Ndung'u, Thumbi Buus, Soren Goulder, Philip TI HIV Control through a Single Nucleotide on the HLA-B Locus SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; CLASS-I ALLELES; IMMUNE CONTROL; ANTIGEN PRESENTATION; SELECTION PRESSURE; MICROPOLYMORPHISM; EPITOPES; AIDS; ASSOCIATIONS AB Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B(star)42:01 and HLA-B(star)42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay (P = 2 x 10(-10)) and functionally through CTL escape mutation (P = 2 x 10(-8)). HLA-B(star)42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral-load set point than HLA-B(star)42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A(star)30:01/B(star)42/Cw(star)17:01 haplotype is equivalent to 75% of that of HLA-B(star)57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control. C1 [Kloverpris, Henrik N.; Leslie, Alasdair J.; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford, England. [Harndahl, Mikkel; Buus, Soren] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, Copenhagen, Denmark. [Ismail, Nasreen; van der Stok, Mary; Walker, Bruce D.; Ndung'u, Thumbi; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Program, Durban, South Africa. [Walker, Bruce D.; Carrington, Mary; Ndung'u, Thumbi; Goulder, Philip] Massachusetts Inst Technol & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Chen, Fabian] Royal Berkshire Hosp, Dept Sexual Hlth, Reading RG1 5AN, Berks, England. [Riddell, Lynn] Northampton Gen Hosp, Northamptonshire Healthcare Natl Hlth Serv Trust, Dept Genitourinary Med, Northampton, England. [Huang, Kuan-Hsiang Gary; Frater, John] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Carlson, Jonathan M.] Microsoft Res, eSci Grp, Los Angeles, CA USA. [Steyn, Dewald; Goedhals, Dominique; van Vuuren, Cloete] Univ Orange Free State, Bloemfontein, South Africa. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Carrington, Mary] SAIC Frederick Inc, Canc & Inflammat Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Kloverpris, HN (reprint author), Univ Oxford, Dept Paediat, Oxford, England. EM henrik.kloverpris@paediatrics.ox.ac.uk RI Buus, Soren/F-5446-2010; OI Buus, Soren/0000-0001-8363-1999; Ndung'u, Thumbi/0000-0003-2962-3992 FU Wellcome Trust; National Institutes of Health [RO1 AI46995]; Frederick National Laboratory for Cancer Research [HHSN261200800001E]; NIH, Frederick National Laboratory, Center for Cancer Research FX This work was supported by the Wellcome Trust (P.G.) and National Institutes of Health grant RO1 AI46995. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research. NR 52 TC 20 Z9 20 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11493 EP 11500 DI 10.1128/JVI.01020-12 PG 8 WC Virology SC Virology GA 018JT UT WOS:000309657100008 PM 22896606 ER PT J AU Vomaske, J Denton, M Kreklywich, C Andoh, T Osborn, JM Chen, D Messaoudi, I Orloff, SL Streblow, DN AF Vomaske, Jennifer Denton, Michael Kreklywich, Craig Andoh, Takeshi Osborn, Jessica M. Chen, Daniel Messaoudi, Ilhem Orloff, Susan L. Streblow, Daniel N. TI Cytomegalovirus CC Chemokine Promotes Immune Cell Migration SO JOURNAL OF VIROLOGY LA English DT Article ID TRANSPLANT VASCULAR SCLEROSIS; LATENT HUMAN CYTOMEGALOVIRUS; APOE KNOCKOUT MICE; RAT SMALL-BOWEL; CHRONIC REJECTION; ALLOGRAFT-REJECTION; CARDIAC ALLOGRAFTS; HEART-TRANSPLANTS; INFECTION; RECEPTOR AB Cytomegaloviruses manipulate the host chemokine/receptor axis by altering cellular chemokine expression and by encoding multiple chemokines and chemokine receptors. Similar to human cytomegalovirus (HCMV), rat cytomegalovirus (RCMV) encodes multiple CC chemokine-analogous proteins, including r129 (HCMV UL128 homologue) and r131 (HCMV UL130 and MCMV m129/130 homologues). Although these proteins play a role in CMV entry, their function as chemotactic cytokines remains unknown. In the current study, we examined the role of the RCMV chemokine r129 in promoting cellular migration and in accelerating transplant vascular sclerosis (TVS) in our rat heart transplant model. We determined that r129 protein is released into culture supernatants of infected cells and is expressed with late viral gene kinetics during RCMV infection and highly expressed in heart and salivary glands during in vivo rat infections. Using the recombinant r129 protein, we demonstrated that r129 induces migration of lymphocytes isolated from rat peripheral blood, spleen, and bone marrow and from a rat macrophage cell line. Using antibody-mediated cell sorting of rat splenocytes, we demonstrated that r129 induces migration of naive/central memory CD4(+) T cells. Through ligand-binding assays, we determined that r129 binds rat CC chemokine receptors CCR3, CCR4, CCR5, and CCR7. In addition, mutational analyses identified functional domains of r129 resulting in recombinant proteins that fail to induce migration (r129-Delta NT and -C31A) or alter the chemotactic ability of the chemokine (r129-F43A). Two of the mutant proteins (r129-C31A and -Delta NT) also act as dominant negatives by inhibiting migration induced by wild-type r129. Furthermore, infection of rat heart transplant recipients with RCMV containing the r129-Delta NT mutation prevented CMV-induced acceleration of TVS. Together our findings indicate that RCMV r129 is highly chemotactic, which has important implications during RCMV infection and reactivation and acceleration of TVS. C1 [Vomaske, Jennifer; Denton, Michael; Osborn, Jessica M.; Chen, Daniel; Messaoudi, Ilhem; Streblow, Daniel N.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Kreklywich, Craig; Andoh, Takeshi; Orloff, Susan L.] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Kreklywich, Craig; Andoh, Takeshi; Orloff, Susan L.] Portland VA Med Ctr, Portland, OR USA. [Vomaske, Jennifer; Denton, Michael; Osborn, Jessica M.; Chen, Daniel; Messaoudi, Ilhem; Streblow, Daniel N.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Portland, OR 97201 USA. RP Streblow, DN (reprint author), Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. EM streblow@ohsu.edu FU National Institutes of Health [HL 083194, HL 66238-01, HL 088603] FX This work was supported by research grants from the National Institutes of Health to D. N. Streblow (HL 083194), S. L. Orloff (HL 66238-01), and J. A. Nelson (HL 088603). NR 55 TC 13 Z9 13 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2012 VL 86 IS 21 BP 11833 EP 11844 DI 10.1128/JVI.00452-12 PG 12 WC Virology SC Virology GA 018JT UT WOS:000309657100039 PM 22915808 ER PT J AU Kelly, JM Bianchi, MT AF Kelly, Jessica M. Bianchi, Matt T. TI Mammalian sleep genetics SO NEUROGENETICS LA English DT Review DE Phenotype; Architecture; Electroencephalogram; Transgenic; Circadian ID EYE-MOVEMENT SLEEP; KNOCK-OUT MICE; TRANSGENIC MOUSE MODEL; GABA(A) RECEPTOR SUBTYPE; PROTEIN-DEFICIENT MICE; GATED ION CHANNELS; OREXIN-NULL MICE; PRION PROTEIN; REM-SLEEP; ALZHEIMERS-DISEASE AB Mammalian sleep is a complex phenomenon governed by the interplay of neural circuits and signaling systems. The impact of genetic manipulations on sleep-wake dynamics provides important insights into this complex behavior. Here we review the sleep-related phenotypes of over 50 transgenic animal models spanning a variety of signaling systems. This heterogeneous literature includes outcomes spanning motor activity patterns, sleep-wake stage architecture, responses to sleep deprivation, circadian rhythmicity, and other perturbations such as food restriction, temperature challenge, and infection exposure. Insights from these animal experiments hold potential to converge with the well-known sleep-wake neurocircuitry as well as the increasingly available human genetic information, especially in patient populations exhibiting sleep-wake pathology. C1 [Kelly, Jessica M.; Bianchi, Matt T.] Massachusetts Gen Hosp, Dept Neurol, Sleep Div, Boston, MA 02114 USA. RP Bianchi, MT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Sleep Div, 55 Fruit St, Boston, MA 02114 USA. EM mtbianchi@partners.org FU Department of Neurology, Massachusetts General Hospital; Center for Integration of Medicine and Innovative Technology; Harvard Catalyst KL2 Medical Research Investigator Fellowship FX Dr. Bianchi receives funding from the Department of Neurology, Massachusetts General Hospital, a Young Clinician Award from the Center for Integration of Medicine and Innovative Technology, and a Harvard Catalyst KL2 Medical Research Investigator Fellowship. NR 173 TC 5 Z9 5 U1 2 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD NOV PY 2012 VL 13 IS 4 BP 287 EP 326 DI 10.1007/s10048-012-0341-x PG 40 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 021DV UT WOS:000309866400001 PM 22976546 ER PT J AU Flaherty, KT Infante, JR Daud, A Gonzalez, R Kefford, RF Sosman, J Hamid, O Schuchter, L Cebon, J Ibrahim, N Kudchadkar, R Burris, HA Falchook, G Algazi, A Lewis, K Long, GV Puzanov, I Lebowitz, P Singh, A Little, S Sun, P Allred, A Ouellet, D Kim, KB Patel, K Weber, J AF Flaherty, Keith T. Infante, Jeffery R. Daud, Adil Gonzalez, Rene Kefford, Richard F. Sosman, Jeffrey Hamid, Omid Schuchter, Lynn Cebon, Jonathan Ibrahim, Nageatte Kudchadkar, Ragini Burris, Howard A., III Falchook, Gerald Algazi, Alain Lewis, Karl Long, Georgina V. Puzanov, Igor Lebowitz, Peter Singh, Ajay Little, Shonda Sun, Peng Allred, Alicia Ouellet, Daniele Kim, Kevin B. Patel, Kiran Weber, Jeffrey TI Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DOSE-ESCALATION TRIAL; CELL LUNG-CANCER; RAF INHIBITORS; METASTATIC MELANOMA; IMPROVED SURVIVAL; RESISTANCE; KINASE; EFFICACY; PATHWAY; SAFETY AB Background Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. Methods In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. Results Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03). Conclusions Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.) C1 [Kudchadkar, Ragini; Weber, Jeffrey] Univ S Florida, H Lee Moffitt Canc Ctr, Comprehens Melanoma Res Ctr, Tampa, FL 33612 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Ibrahim, Nageatte] Dana Farber Canc Inst, Boston, MA 02115 USA. [Infante, Jeffery R.; Burris, Howard A., III] Vanderbilt Univ, Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA. [Sosman, Jeffrey; Puzanov, Igor] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Daud, Adil; Algazi, Alain] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gonzalez, Rene; Lewis, Karl] Univ Colorado, Ctr Canc, Aurora, CO USA. [Kefford, Richard F.; Long, Georgina V.] Univ Sydney, Melanoma Inst Australia, Westmead Inst Canc Res, Sydney, NSW 2006, Australia. [Kefford, Richard F.; Long, Georgina V.] Univ Sydney, Westmead Hosp, Sydney, NSW 2006, Australia. [Cebon, Jonathan] Austin Hosp, Ludwig Inst Canc Res, Heidelberg, Vic 3084, Australia. [Hamid, Omid] Angeles Clin & Res Inst, Los Angeles, CA USA. [Schuchter, Lynn] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Falchook, Gerald] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. [Kim, Kevin B.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Div Canc Med, Houston, TX 77030 USA. [Lebowitz, Peter; Singh, Ajay; Little, Shonda; Sun, Peng; Allred, Alicia; Ouellet, Daniele; Patel, Kiran] GlaxoSmithKline, Collegeville, PA USA. RP Weber, J (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Comprehens Melanoma Res Ctr, Tampa, FL 33612 USA. EM jeffrey.weber@moffitt.org RI Long, Georgina/C-1771-2013 FU GlaxoSmithKline FX Supported by GlaxoSmithKline. NR 27 TC 801 Z9 814 U1 5 U2 95 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 NOV 1 PY 2012 VL 367 IS 18 BP 1694 EP 1703 DI 10.1056/NEJMoa1210093 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 028RS UT WOS:000310440800006 ER PT J AU Greene, MF AF Greene, Michael F. TI Two Hundred Years of Progress in the Practice of Midwifery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID IN-VITRO FERTILIZATION; SICKLE-CELL-ANEMIA; MATERNAL PLASMA; PRENATAL-DIAGNOSIS; PREGNANCY; DNA; DELIVERY; TRIAL; RATES; ERYTHROBLASTOSIS C1 [Greene, Michael F.] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02114 USA. [Greene, Michael F.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. RP Greene, MF (reprint author), Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, 55 Fruit St, Boston, MA 02114 USA. EM mfgreene@partners.org NR 50 TC 5 Z9 6 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD NOV 1 PY 2012 VL 367 IS 18 BP 1732 EP 1740 DI 10.1056/NEJMra1209764 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 028RS UT WOS:000310440800010 PM 23113484 ER PT J AU Rosenbaum, L AF Rosenbaum, Lisa TI How Much Would You Give to Save a Dying Bird? Patient Advocacy and Biomedical Research SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HIGH-DOSE CHEMOTHERAPY; BREAST-CANCER C1 [Rosenbaum, Lisa] Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Rosenbaum, Lisa] Univ Penn, Robert Wood Johnson Fdn, Clin Scholars Program, Philadelphia, PA 19104 USA. RP Rosenbaum, L (reprint author), Univ Penn, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. NR 8 TC 2 Z9 2 U1 0 U2 4 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 NOV 1 PY 2012 VL 367 IS 18 BP 1755 EP 1759 DI 10.1056/NEJMms1207114 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 028RS UT WOS:000310440800016 PM 23113489 ER PT J AU Eckstein, F Mc Culloch, CE Lynch, JA Nevitt, M Kwoh, CK Maschek, S Hudelmaier, M Sharma, L Wirth, W AF Eckstein, F. Mc Culloch, C. E. Lynch, J. A. Nevitt, M. Kwoh, C. K. Maschek, S. Hudelmaier, M. Sharma, L. Wirth, W. CA OA Initiative Investigators Grp TI How do short-term rates of femorotibial cartilage change compare to long-term changes? Four year follow-up data from the osteoarthritis initiative SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Short term; Long term; Knee; Cartilage thickness; Magnetic resonance imaging; Osteoarthritis ID MULTICENTER CLINICAL-TRIAL; SYMPTOMATIC KNEE OSTEOARTHRITIS; QUANTITATIVE MRI; 3 TESLA; PRECISION; PROGRESSION; MORPHOLOGY; SENSITIVITY; MORPHOMETRY; DESIGN AB Objective: To compare unbiased estimates of short- vs long-term cartilage loss in osteoarthritic knees. Method: 441 knees [216 Kellgren Lawrence (KL) grade 2, 225 la grade 3] from participants of the Osteoarthritis Initiative were studied over a 4-year period. Femorotibial cartilage thickness was determined using 3 T double echo steady state magnetic resonance imaging, the readers being blinded to time points. Because common measurement time points bias correlations, short-term change (year-1 to year-2: Y1 -> Y2) was compared with long-term change (baseline to year-4: BL -> Y4), and initial (BL -> Y1) with subsequent (Y2 -> Y4) observation periods. Results: The mean femorotibial cartilage thickness change (standardized response mean) was -1.2%/-0.8% (-0.42/-0.28) over 1 (BL -> Y1/Y1 -> Y2), -2.1%/-2.5% (-0.56/-0.55) over 2 (BL -> Y2/Y2 -> Y4), -3.3% (-0.63) over 3 (Y1 -> Y4), and -4.5% (-0.78) over 4 years. Spearman correlations were 0.33 for Y1 -> Y2 vs BL -> Y4, and 0.17 for BL -> Y1 vs Y2 -> Y4 change. Percent agreement between knees showing progression during Y1 -> Y2 vs BL -> Y4 was 59%, and 64% for BL -> Y1 vs Y2 -> Y4. The area under the receiver operating characteristic curve was 0.66 for using Y1 -> Y2 to predict BL -> Y4, and 0.59 for using BL -> Y1 to predict Y2 -> Y4 change. Conclusion: Weak to moderate correlations and agreement were observed between individual short- vs long-term cartilage loss, and between initial and subsequent observation periods. Hence, longer observation periods are recommended to achieve robust results on cartilage loss in individual knees. At cohort and subcohort level (e.g., KLG3 vs KLG2 knees), the mean cartilage loss increased almost linearly with the length of the observation period and was constant throughout the study. (C) 2012 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 [Eckstein, F.; Maschek, S.; Hudelmaier, M.; Wirth, W.] Paracelsus Med Univ, Inst Anat & Musculoskeletal Res, Salzburg, Austria. [Eckstein, F.; Maschek, S.; Hudelmaier, M.; Wirth, W.] Chondrometr GmbH, Ainring, Germany. [Mc Culloch, C. E.; Lynch, J. A.; Nevitt, M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kwoh, C. K.] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA USA. [Kwoh, C. K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Sharma, L.] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Evanston, IL 60208 USA. RP Eckstein, F (reprint author), PMU, Inst Anat & Musculoskeletal Res, Strubergasse 21, A-5020 Salzburg, Austria. EM felix.eckstein@pmu.ac.at RI Wirth, Wolfgang/C-8724-2011 OI Wirth, Wolfgang/0000-0002-2297-8283 FU OAI [N01-AR-2-2258, N01-AR-2-2259, N01-AR-2-2260, N01-AR-2-2261, N01-AR-2-2262]; National Institutes of Health, a branch of the Department of Health and Human Services; Merck Research Laboratories; Novartis Pharmaceuticals Corporation; GlaxoSmithKline; Pfizer, Inc.; OAI coordinating center at UCSF [N01-AR-2-2258]; Division of Rheumatology, Feinberg School of Medicine, Northwestern University [R01 AR52918]; University of Pittsburgh [HHSN2682010000 21C] FX The study and image acquisition was funded by the OAI, a public private partnership comprised five contracts (N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260; N01-AR-2-2261; N01-AR-2-2262), funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Merck Research Laboratories; Novartis Pharmaceuticals Corporation; GlaxoSmithKline; and Pfizer, Inc. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. The image analysis of this study was funded by a vendor contract from the OAI coordinating center at UCSF (N01-AR-2-2258), an ancillary study to the OAI held by the Division of Rheumatology, Feinberg School of Medicine, Northwestern University (R01 AR52918), and a contract held by the University of Pittsburgh [Pivotal OAI MRI Analyses (POMA), NIH/NHLBI Contract No. HHSN2682010000 21C]. The sponsors were not directly involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. However, the manuscript has received approval of the OAI Publications Committee based on a review of its scientific content and data interpretation. NR 30 TC 20 Z9 20 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD NOV PY 2012 VL 20 IS 11 BP 1250 EP 1257 DI 10.1016/j.joca.2012.06.019 PG 8 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 020YV UT WOS:000309853400006 PM 22800771 ER PT J AU Hostetler, CM Anacker, AMJ Loftis, JM Ryabinin, AE AF Hostetler, Caroline M. Anacker, Allison M. J. Loftis, Jennifer M. Ryabinin, Andrey E. TI Social housing and alcohol drinking in male-female pairs of prairie voles (Microtus ochrogaster) SO PSYCHOPHARMACOLOGY LA English DT Article DE Prairie voles; Social behavior; Alcohol self-administration; Social influence ID EXTENDED OLFACTORY AMYGDALA; RAT LINES; NUCLEUS-ACCUMBENS; ANXIETY DISORDERS; ETHANOL INTAKE; VOLUNTARY ETHANOL; BEHAVIOR; AMPHETAMINE; MODULATION; AGGRESSION AB Social environment influences alcohol consumption in humans; however, animal models have only begun to address biological underpinnings of these effects. We investigated whether social influences on alcohol drinking in the prairie vole are specific to the sex of the social partner. In Experiment 1, control, sham, and gonadectomized voles were placed either in mesh-divided housing with a same-sex sibling or isolation with access to ethanol. In Experiment 2, animals were given an elevated plus maze test (EPM) and then females were paired with a castrated male followed by isolation or mesh-divided housing with access to ethanol. In Experiment 3, subjects categorized as low or high drinkers based on initial ethanol intake were placed in mesh-divided housing with an opposite-sex partner of the same or opposite drinking group and ethanol access. Subjects were then moved back to isolation for a final ethanol access period. Same-sex pairs showed social facilitation of drinking similar to previous reports. Gonadectomy did not affect alcohol drinking. Opposite-sex paired animals in Experiment 2 did not differ in alcohol drinking based on social housing. EPM measures suggested a relationship between anxiety-like behaviors and drinking that depended on social environment. Experiment 3 identified moderate changes in alcohol preference based on social housing, but these effects were influenced by the animal's own drinking behavior and were independent of their partner's drinking. Social influences on alcohol self-administration in prairie voles differ based on the sex of a social partner, consistent with human drinking behavior. C1 [Hostetler, Caroline M.; Anacker, Allison M. J.; Ryabinin, Andrey E.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Loftis, Jennifer M.] Portland VA Med Ctr, Res & Dev Serv, Portland, OR 97239 USA. [Loftis, Jennifer M.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. RP Hostetler, CM (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. EM caroline.hostetler@gmail.com FU NIH [5T32AA007468-24, AA016886]; Portland VA Medical Center, Portland, Oregon FX We gratefully acknowledge Davelle Cocking, Lindsay Swanson, and the Veterinary Medical Unit (VMU) animal care staff from the Portland VA Medical Center for assistance on this project. This research was funded by NIH 5T32AA007468-24 (to CMH) and NIH AA016886 (to AER). This material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center, Portland, Oregon. NR 62 TC 15 Z9 15 U1 5 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2012 VL 224 IS 1 BP 121 EP 132 DI 10.1007/s00213-012-2836-4 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 018SB UT WOS:000309681900011 PM 22903359 ER PT J AU Negahdar, M Aukrust, I Johansson, BB Molnes, J Molven, A Matschinsky, FM Sovik, O Kulkarni, RN Flatmark, T Njolstad, PR Bjorkhaug, L AF Negahdar, Maria Aukrust, Ingvild Johansson, Bente B. Molnes, Janne Molven, Anders Matschinsky, Franz M. Sovik, Oddmund Kulkarni, Rohit N. Flatmark, Torgeir Njolstad, Pal Rasmus Bjorkhaug, Lise TI GCK-MODY diabetes associated with protein misfolding, cellular self-association and degradation SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE GCK-MODY; Catalytic activity; Protein misfolding; Self-association; Dimerization; Degradation ID HUMAN PANCREATIC GLUCOKINASE; YOUNG TYPE-2 MODY-2; REGULATORY PROTEIN; BETA-CELL; BINDING PROTEIN; WILD-TYPE; MUTATIONS; GLUCOSE; STABILITY; HYPERGLYCEMIA AB GCK-MODY, dominantly inherited mild fasting hyperglycemia, has been associated with >600 different mutations in the glucokinase (GK)-encoding gene (GCK). When expressed as recombinant pancreatic proteins, some mutations result in enzymes with normal/near-normal catalytic properties. The molecular mechanism(s) of GCK-MODY due to these mutations has remained elusive. Here, we aimed to explore the molecular mechanisms for two such catalytically 'normal' GCK mutations (S263P and G264S) in the F260-L270 loop of GK. When stably overexpressed in HEK293 cells and MIN6 beta-cells, the S263P- and G264S-encoded mutations generated misfolded proteins with an increased rate of degradation (S263P>G264S) by the protein quality control machinery, and a propensity to self-associate (G264S>S263P) and form dimers (SDS resistant) and aggregates (partly Triton X-100 insoluble), as determined by pulse-chase experiments and subcellular fractionation. Thus, the GCK-MODY mutations S263P and G264S lead to protein misfolding causing destabilization, cellular dimerization/aggregation and enhanced rate of degradation. In silico predicted conformational changes of the F260-L270 loop structure are considered to mediate the dimerization of both mutant proteins by a domain swapping mechanism. Thus, similar properties may represent the molecular mechanisms for additional unexplained GCK-MODY mutations, and may also contribute to the disease mechanism in other previously characterized GCK-MODY inactivating mutations. (C) 2012 Elsevier B.V. All rights reserved. C1 [Negahdar, Maria; Aukrust, Ingvild; Johansson, Bente B.; Molnes, Janne; Sovik, Oddmund; Njolstad, Pal Rasmus; Bjorkhaug, Lise] Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. [Negahdar, Maria; Aukrust, Ingvild; Johansson, Bente B.; Bjorkhaug, Lise] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Negahdar, Maria; Aukrust, Ingvild; Flatmark, Torgeir] Univ Bergen, Dept Biomed, N-5020 Bergen, Norway. [Aukrust, Ingvild; Kulkarni, Rohit N.] Harvard Univ, Sect Islet Cell Biol & Regenerat Med, Bingham & Womans Hosp, Joslin Diabet Ctr,Sch Med, Boston, MA 02215 USA. [Johansson, Bente B.; Molnes, Janne; Njolstad, Pal Rasmus] Haukeland Hosp, Dept Pediat, N-5021 Bergen, Norway. [Molven, Anders] Univ Bergen, Gade Inst, N-5020 Bergen, Norway. [Molven, Anders] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Norway. [Matschinsky, Franz M.] Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Matschinsky, Franz M.] Univ Penn, Sch Med, Diabet Res Ctr, Philadelphia, PA 19104 USA. RP Njolstad, PR (reprint author), Univ Bergen, Dept Clin Med, N-5020 Bergen, Norway. EM pal.njolstad@uib.no OI Johansson, Bente Berg/0000-0001-8893-1915; Gundersen, Lise Bjorkhaug/0000-0002-9695-4559 FU Research Council of Norway, Helse Vest; Novo Nordisk Foundation; Nils Norman Foundation; Bergen Medical Research Foundation; Meltzer Foundation; KG Jebsen Foundation; University of Bergen; Norwegian Research Council FX This work was supported by funds from the Research Council of Norway, Helse Vest, the Novo Nordisk Foundation, the Nils Norman Foundation, the Bergen Medical Research Foundation, the Meltzer Foundation, the KG Jebsen Foundation, and the University of Bergen. We thank Joao Leandro, Department of Biomedicine, University of Bergen, for his supporting information and Ali Sepulveda Munoz, Department of Biomedicine, University of Bergen, for expert technical assistance with the French press. The mass spectrometry analyses were conducted by the Proteomics Unit at the University of Bergen (PROBE), supported by the National Program for Research in Functional Genomics (FUGE) funded by the Norwegian Research Council. NR 65 TC 5 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD NOV PY 2012 VL 1822 IS 11 BP 1705 EP 1715 DI 10.1016/j.bbadis.2012.07.005 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 017BX UT WOS:000309566200007 PM 22820548 ER PT J AU Moyer, CE Delevich, KM Fish, KN Asafu-Adjei, JK Sampson, AR Dorph-Petersen, KA Lewis, DA Sweet, RA AF Moyer, Caitlin E. Delevich, Kristen M. Fish, Kenneth N. Asafu-Adjei, Josephine K. Sampson, Allan R. Dorph-Petersen, Karl-Anton Lewis, David A. Sweet, Robert A. TI Reduced Glutamate Decarboxylase 65 Protein Within Primary Auditory Cortex Inhibitory Boutons in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE GAD65; postmortem human tissue; primary auditory cortex; quantitative microscopy; schizophrenia; stereology ID GAMMA OSCILLATION FREQUENCY; MISMATCH NEGATIVITY GENERATION; DORSOLATERAL PREFRONTAL CORTEX; ACTIVITY-DEPENDENT REGULATION; DENDRITIC SPINE DENSITY; SUPERIOR TEMPORAL GYRUS; STEADY-STATE RESPONSES; SHORT-TERM-MEMORY; VISUAL-CORTEX; ACID DECARBOXYLASE AB Background: Schizophrenia is associated with perceptual and physiological auditory processing impairments that may result from primary auditory cortex excitatory and inhibitory circuit pathology. High-frequency oscillations are important for auditory function and are often reported to be disrupted in schizophrenia. These oscillations may, in part, depend on upregulation of gamma-aminobutyric acid synthesis by glutamate decarboxylase 65 (GAD65) in response to high interneuron firing rates. It is not known whether levels of GAD65 protein or GAD65-expressing boutons are altered in schizophrenia. Methods: We studied two cohorts of subjects with schizophrenia and matched control subjects, comprising 27 pairs of subjects. Relative fluorescence intensity, density, volume, and number of GAD65-immunoreactive boutons in primary auditory cortex were measured using quantitative confocal microscopy and stereologic sampling methods. Bouton fluorescence intensities were used to compare the relative expression of GAD65 protein within boutons between diagnostic groups. Additionally, we assessed the correlation between previously measured dendritic spine densities and GAD65-immunoreactive bouton fluorescence intensities. Results: GAD65-immunoreactive bouton fluorescence intensity was reduced by 40% in subjects with schizophrenia and was correlated with previously measured reduced spine density. The reduction was greater in subjects who were not living independently at time of death. In contrast, GAD65-immunoreactive bouton density and number were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. Conclusions: Decreased expression of GAD65 protein within inhibitory boutons could contribute to auditory impairments in schizophrenia. The correlated reductions in dendritic spines and GAD65 protein suggest a relationship between inhibitory and excitatory synapse pathology in primary auditory cortex. C1 [Sweet, Robert A.] Univ Pittsburgh, Dept Psychiat, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Moyer, Caitlin E.; Fish, Kenneth N.; Lewis, David A.; Sweet, Robert A.] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15213 USA. [Asafu-Adjei, Josephine K.; Sampson, Allan R.] Univ Pittsburgh, Dept Stat, Pittsburgh, PA 15213 USA. [Lewis, David A.] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15213 USA. [Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Sweet, Robert A.] Vet Affairs Pittsburgh Healthcare Syst, Vet Integrated Serv Network Mental Illness Res 4, Educ & Clin Ctr, Pittsburgh, PA USA. [Dorph-Petersen, Karl-Anton] Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark. [Dorph-Petersen, Karl-Anton] Aarhus Univ, Ctr Stochast Geometry & Adv Bioimaging, Aarhus, Denmark. RP Sweet, RA (reprint author), Univ Pittsburgh, Dept Psychiat, Western Psychiat Inst & Clin, Biomed Sci Tower,Room W1645,3811 OHara St, Pittsburgh, PA 15213 USA. EM SweetRA@upmc.edu RI Lewis, David/G-4053-2014; Dorph-Petersen, Karl-Anton/A-9039-2015; OI Lewis, David/0000-0002-3225-6778; Dorph-Petersen, Karl-Anton/0000-0002-6676-034X; Moyer, Caitlin/0000-0002-2571-2595; Delevich, Kristen/0000-0001-5698-0093 FU Bristol-Myers Squibb Foundation; Bristol-Myers Squibb; Curridium Ltd; Pfizer; [MH071533]; [MH084053]; [MH085108] FX This work was supported by Grants MH071533 (RAS), MH084053 (DAL), and MH085108 (KNF).; ARS is a statistical consultant to Johnson & Johnson Pharmaceutical Research and Development. DAL currently receives investigator-initiated research support from the Bristol-Myers Squibb Foundation, Bristol-Myers Squibb, Curridium Ltd, and Pfizer and in 2007 to 2010 served as a consultant in the areas of target identification and validation and new compound development to AstraZeneca, BioLine RX, Bristol-Myers Squibb, Hoffman-Roche, Lilly, Merck, Neurogen, and SK Life Science. CEM, KMD, KNF, JKA-A, K-AD-P, and RAS have no biomedical financial interests or potential conflicts of interest to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, the Department of Veterans Affairs, or the United States Government. NR 90 TC 14 Z9 14 U1 3 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD NOV 1 PY 2012 VL 72 IS 9 BP 734 EP 743 DI 10.1016/j.biopsych.2012.04.010 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 017SF UT WOS:000309610500005 PM 22624794 ER PT J AU Whitesell, L Santagata, S Lin, NU AF Whitesell, L. Santagata, S. Lin, N. U. TI Inhibiting HSP90 to Treat Cancer: A Strategy in Evolution SO CURRENT MOLECULAR MEDICINE LA English DT Review DE Cancer evolution; clinical trial; combination chemotherapy; drug resistance ID HEAT-SHOCK-PROTEIN; PHASE-II TRIAL; REFRACTORY ADVANCED CANCERS; TYROSINE KINASE INHIBITORS; METASTATIC PROSTATE-CANCER; C-TERMINAL DOMAIN; CELL LUNG-CANCER; BREAST-CANCER; DRUG-RESISTANCE; SOLID TUMORS AB Since the identification of the first HSP90 inhibitor almost two decades ago, there has been substantial progress made in the development of potent and selective molecules that inhibit this chaperone and that have anticancer activity. In turn, these compounds have been invaluable for probing how HSP90 supports the profound changes in cellular physiology that characterize the malignant state. Unfortunately, when used as single agents HSP90 inhibitors have demonstrated disappointing activity against advanced cancers in most of the clinical trials reported to date. This problem may be due to the major pharmacological liabilities of the first-generation HSP90 inhibitors that have been most extensively studied. We suggest, however, that it may well be intrinsic to the target itself. Systemically tolerable exposure to HSP90 inhibitors may not be highly cytotoxic for the majority of common clinical cancers. Instead, HSP90 inhibitors might better be used to enhance the activity of other antineoplastic agents while simultaneously reducing the capacity of tumors to adapt and evolve drug resistance; the overall result being more durable disease control. This review will focus on these fundamental issues with the goal of suggesting ways to make the clinical development of HSP90 inhibitors become less empiric and ultimately more successful. C1 [Whitesell, L.; Santagata, S.] Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Santagata, S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lin, N. U.] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Whitesell, L (reprint author), Nine Cambridge Ctr, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM whitesell@wi.mit.edu FU Komen Foundation; Johnson and Johnson Focused Funding Program; NIH [K08-NS064168]; Valvano foundation; Brain Science Foundation; Berry Junior Faculty Award FX Our gratitude goes to Susan Lindquist and members of the Lindquist lab for valuable conversations, advice and insights. L.W. is supported in part by funds from the Komen Foundation and the Johnson and Johnson Focused Funding Program. S.S. is supported by grants from the NIH (K08-NS064168), the Valvano foundation and the Brain Science Foundation. N.U.L. acknowledges support from a Berry Junior Faculty Award. We apologize to many of our colleagues for being unable to cite and discuss their important work in this rapidly advancing field due to space limitations. Their contributions in expanding our understanding of HSP90 and improving the care of cancer patients are invaluable. NR 153 TC 33 Z9 34 U1 3 U2 22 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 EI 1875-5666 J9 CURR MOL MED JI Curr. Mol. Med. PD NOV PY 2012 VL 12 IS 9 BP 1108 EP 1124 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 018KD UT WOS:000309658100003 PM 22804235 ER PT J AU Brashear, A Mink, JW Hill, DF Boggs, N Mccall, WV Stacy, MA Snively, B Light, LS Sweadner, KJ Ozelius, LJ Morrison, L AF Brashear, Allison Mink, Jonathan W. Hill, Deborah F. Boggs, Niki Mccall, W. Vaughn Stacy, Mark A. Snively, Beverly Light, Laney S. Sweadner, Kathleen J. Ozelius, Laurie J. Morrison, Leslie TI ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article ID GENE AB We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystoniaParkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties. C1 [Brashear, Allison; Hill, Deborah F.] Wake Forest Sch Med, Dept Neurol, Winston Salem, NC 27157 USA. [Mink, Jonathan W.] Univ Rochester, Sch Med, Dept Neurol, Rochester, NY USA. [Boggs, Niki; Mccall, W. Vaughn] Wake Forest Sch Med, Dept Psychiat, Winston Salem, NC 27157 USA. [Stacy, Mark A.] Duke Univ, Sch Med, Dept Neurol, Durham, NC USA. [Snively, Beverly; Light, Laney S.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC 27157 USA. [Sweadner, Kathleen J.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Sweadner, Kathleen J.] Harvard Univ, Sch Med, Boston, MA USA. [Ozelius, Laurie J.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Ozelius, Laurie J.] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Morrison, Leslie] Univ New Mexico, Dept Neurol, Albuquerque, NM 87131 USA. RP Brashear, A (reprint author), Wake Forest Sch Med, Dept Neurol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM abrashea@wakehealth.edu RI Brashear, Allison/G-3853-2015; OI Morrison, Leslie/0000-0002-0092-193X FU National Institute of Neurological Disorders and Stroke [5R01NS058949-05]; Lung GO Sequencing Project [HL-102923]; WHI Sequencing Project [HL-102924]; Broad GO Sequencing Project [HL-102925]; Seattle GO Sequencing Project [HL-102926]; Heart GO Sequencing Project [HL-103010] FX This study was supported by the National Institute of Neurological Disorders and Stroke 5R01NS058949-05 (to AB). We thank Dr William B Dobyns for his initial description of RDP. We also thank the National Heart, Lung, and Blood Institute GO Exome Sequencing Project 10 and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). NR 10 TC 41 Z9 42 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD NOV PY 2012 VL 54 IS 11 BP 1065 EP 1067 DI 10.1111/j.1469-8749.2012.04421.x PG 3 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 017OB UT WOS:000309598500025 PM 22924536 ER PT J AU Liu, CT Ng, MCY Rybin, D Adeyemo, A Bielinski, SJ Boerwinkle, E Borecki, I Cade, B Chen, YDI Djousse, L Fornage, M Goodarzi, MO Grant, SFA Guo, X Harris, T Kabagambe, E Kizer, JR Liu, Y Lunetta, KL Mukamal, K Nettleton, JA Pankow, JS Patel, SR Ramos, E Rasmussen-Torvik, L Rich, SS Rotimi, CN Sarpong, D Shriner, D Sims, M Zmuda, JM Redline, S Kao, WH Siscovick, D Florez, JC Rotter, JI Dupuis, J Wilson, JG Bowden, DW Meigs, JB AF Liu, C-T Ng, M. C. Y. Rybin, D. Adeyemo, A. Bielinski, S. J. Boerwinkle, E. Borecki, I. Cade, B. Chen, Y. D. I. Djousse, L. Fornage, M. Goodarzi, M. O. Grant, S. F. A. Guo, X. Harris, T. Kabagambe, E. Kizer, J. R. Liu, Y. Lunetta, K. L. Mukamal, K. Nettleton, J. A. Pankow, J. S. Patel, S. R. Ramos, E. Rasmussen-Torvik, L. Rich, S. S. Rotimi, C. N. Sarpong, D. Shriner, D. Sims, M. Zmuda, J. M. Redline, S. Kao, W. H. Siscovick, D. Florez, J. C. Rotter, J. I. Dupuis, J. Wilson, J. G. Bowden, D. W. Meigs, J. B. TI Transferability and fine-mapping of glucose and insulin quantitative trait loci across populations: CARe, the Candidate Gene Association Resource SO DIABETOLOGIA LA English DT Article DE African ancestry; Genetics; Genome-wide association; LD mapping; Minorities; Type 2 diabetes ID GENOME-WIDE ASSOCIATION; LARGE-SCALE ASSOCIATION; AFRICAN-AMERICANS; FASTING GLUCOSE; SUSCEPTIBILITY LOCI; ATHEROSCLEROSIS RISK; DIABETES-MELLITUS; TCF7L2 GENE; TYPE-2; VARIANTS AB Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs. We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within +/- 250 kb around each EuA SNP in AfAs. Allele frequency differences ranged from 0.6% to 54%. F-st exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were < 2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 x 10(-8); MTNR1B, p = 8.5 x 10(-9); and FADS1, p = 2.2 x 10(-4)) or FI (GCKR, p = 5.9 x 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r (2) < 0.2), suggesting allelic heterogeneity for association with FG at these loci. Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping. C1 [Djousse, L.; Mukamal, K.; Florez, J. C.; Meigs, J. B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Liu, C-T; Lunetta, K. L.; Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ng, M. C. Y.; Liu, Y.; Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Diabet Res, Ctr Genom & Personalized Med Res, Winston Salem, NC USA. [Rybin, D.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Adeyemo, A.; Ramos, E.; Rotimi, C. N.; Shriner, D.] NHGRI, Bethesda, MD 20892 USA. [Bielinski, S. J.] Mayo Clin, Rochester, MN USA. [Boerwinkle, E.; Fornage, M.; Nettleton, J. A.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Borecki, I.] Washington Univ, St Louis, MO USA. [Cade, B.; Djousse, L.; Patel, S. R.; Redline, S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Y. D. I.; Goodarzi, M. O.; Guo, X.; Rotter, J. I.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Djousse, L.] Boston VA Healthcare Syst, Boston, MA USA. [Grant, S. F. A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Kabagambe, E.] Univ Alabama Birmingham, Birmingham, AL USA. [Kizer, J. R.] Cornell Univ, New York, NY 10021 USA. [Liu, Y.] Wake Forest Univ, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Lunetta, K. L.; Dupuis, J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Pankow, J. S.] Univ Minnesota, Minneapolis, MN USA. [Rasmussen-Torvik, L.] Northwestern Univ, Chicago, IL 60611 USA. [Rich, S. S.] Univ Virginia, Charlottesville, VA USA. [Sarpong, D.] Jackson State Univ, Jackson, MS USA. [Zmuda, J. M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Kao, W. H.] Johns Hopkins Univ, Baltimore, MD USA. [Siscovick, D.] Univ Washington, Seattle, WA 98195 USA. [Florez, J. C.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Florez, J. C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, J. C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. [Bowden, D. W.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Sims, M.; Wilson, J. G.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. RP Meigs, JB (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM jmeigs@partners.org RI Bielinski, Suzette/A-2238-2009; Djousse, Luc/F-5033-2017; OI Bielinski, Suzette/0000-0002-2905-5430; Djousse, Luc/0000-0002-9902-3047; Lunetta, Kathryn/0000-0002-9268-810X; Rybin, Denis/0000-0002-3657-4829; Dupuis, Josee/0000-0003-2871-3603; Adeyemo, Adebowale/0000-0002-3105-3231; Patel, Sanjay/0000-0002-9142-5172 FU NIDDK [R01 2 DK078616, K24 DK080140]; Doris Duke Charitable Foundation; NHLBI MESA [N01HC95165-21-0-1]; NHBLI [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022]; CFS: Case Western Reserve University [NIH HL 46380, M01RR00080]; Jackson State University [N01-HC-95170]; University of Mississippi [N01-HC-95171]; Tougaloo College [N01-HC-95172]; University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]; University of Minnesota [N01-HC-48048]; Northwestern University [N01-HC-48049]; Kaiser Foundation Research Institute [N01-HC-48050]; Tufts-New England Medical Center [N01-HC-45204]; Wake Forest University [N01-HC-45205]; Harbor-UCLA Research and Education Institute [N01-HC-05187]; University of California Irvine [N01-HC-45134, N01-HC-95100]; [RO1 DK066358]; [5RC1HL099911-025UC2HL103010-02]; [N01-HD-95159]; [N01-HC-95169]; [RR-024156]; [R01-HL-071205] FX This work was supported by NIDDK R01 2 DK078616 and NIDDK K24 DK080140 to J. B. Meigs, a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. Florez, RO1 DK066358 to D. W. Bowden, 5RC1HL099911-025UC2HL103010-02 and the NHLBI MESA contract N01HC95165-21-0-1 to S. S. Rich.; ARIC is carried out as a collaborative study supported by NHBLI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. CFS: Case Western Reserve University (NIH HL 46380, M01RR00080).; JHS is carried out as a collaborative study supported by Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), Tougaloo College (N01-HC-95172);; MESA is conducted and supported by the NHLBI in collaboration with MESA investigators. Support is provided by grants and contracts N01-HD-95159 through N01-HC-95169, RR-024156, and R01-HL-071205.; CARDIA is carried out as a collaborative study supported by University of Alabama at Birmingham (N01-HC-48047), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), University of Alabama at Birmingham (N01-HC-95095), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California Irvine (N01-HC-45134, N01-HC-95100). NR 57 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD NOV PY 2012 VL 55 IS 11 BP 2970 EP 2984 DI 10.1007/s00125-012-2656-4 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 017AR UT WOS:000309561600013 PM 22893027 ER PT J AU Ho, T Gerber, L Aronson, WJ Terris, MK Presti, JC Kane, CJ Amling, CL Freedland, SJ AF Ho, Tammy Gerber, Leah Aronson, William J. Terris, Martha K. Presti, Joseph C. Kane, Christopher J. Amling, Christopher L. Freedland, Stephen J. TI Obesity, Prostate-Specific Antigen Nadir, and Biochemical Recurrence After Radical Prostatectomy: Biology or Technique? Results from the SEARCH Database SO EUROPEAN UROLOGY LA English DT Article DE Prostate cancer; PSA nadir; Obesity; Radical prostatectomy; Biochemical recurrence ID BODY-MASS INDEX; NATURAL-HISTORY; CANCER; RISK; MEN; PROGRESSION; INSULIN; DISEASE; IMPACT; LEVEL AB Background: Obesity is associated with an increased risk of biochemical recurrence (BCR) after radical prostatectomy (RP). It is unclear whether this is due to technical challenges related to operating on obese men or other biologic factors. Objective: To examine whether obesity predicts higher prostate-specific antigen (PSA) nadir (as a measure of residual PSA-producing tissue) after RP and if this accounts for the greater BCR risk in obese men. Design, setting, and participants: A retrospective analysis of 1038 RP patients from 2001 to 2010 in the multicenter US Veterans Administration-based Shared Equal Access Regional Cancer Hospital database with median follow-up of 41 mo. Intervention: All patients underwent RP. Outcome measurements and statistical analysis: We evaluated the relationship between body mass index (BMI) and ultrasensitive PSA nadir within 6 mo after RP. Adjusted proportional hazards models were used to examine the association between BMI and BCR with and without PSA nadir. Results and limitations: Mean BMI was 28.5 kg/m(2). Higher BMI was associated with higher PSA nadir on both univariable (p = 0.001) and multivariable analyses (p < 0.001). Increased BMI was associated with increased BCR risk (hazard ratio [HR]: 1.06; p = 0.007). Adjusting for PSA nadir slightly attenuated, but did not eliminate, this association (HR: 1.04, p = 0.043). When stratified by PSA nadir, obesity only significantly predicted BCR in men with an undetectable nadir (p = 0.006). Unfortunately, other clinically relevant end points such as metastasis or mortality were not available. Conclusions: Obese men are more likely to have a higher PSA nadir, suggesting that either more advanced disease or technical issues confound an ideal operation. However, even after adjusting for the increased PSA nadir, obesity remained predictive of BCR, suggesting that tumors in obese men are growing faster. This provides further support for the idea that obesity is biologically associated with prostate cancer progression. Published by Elsevier B.V. on behalf of European Association of Urology. C1 [Freedland, Stephen J.] Duke Univ, Sch Med, Div Urol, Dept Pathol, Durham, NC 27710 USA. [Ho, Tammy; Gerber, Leah; Freedland, Stephen J.] Duke Univ, Sch Med, Duke Prostate Ctr, Div Urol Surg,Dept Surg, Durham, NC 27710 USA. [Ho, Tammy; Gerber, Leah; Freedland, Stephen J.] Vet Affairs Med Ctr, Dept Surg, Urol Sect, Durham, NC USA. [Aronson, William J.] Vet Affairs Greater Los Angeles Healthcare Syst, Urol Sect, Los Angeles, CA USA. [Aronson, William J.] Univ Calif Los Angeles, Los Angeles Sch Med, Dept Urol, Los Angeles, CA USA. [Terris, Martha K.] Vet Affairs Med Ctr, Urol Sect, Augusta, GA USA. [Terris, Martha K.] Med Coll Georgia, Urol Sect, Augusta, GA 30912 USA. [Presti, Joseph C.] Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA 94304 USA. [Presti, Joseph C.] Vet Affairs Med Ctr, Urol Sect, Palo Alto, CA 94304 USA. [Kane, Christopher J.] Univ Calif San Diego, Sch Med, Div Urol, San Diego, CA 92103 USA. [Amling, Christopher L.] Oregon Hlth & Sci Univ, Div Urol, Portland, OR 97201 USA. RP Freedland, SJ (reprint author), Duke Univ, Sch Med, Div Urol, Dept Pathol, Box 2626 DUMC, Durham, NC 27710 USA. EM steve.freedland@duke.edu OI Terris, Martha/0000-0002-3843-7270 FU US Department of Veterans Affairs; US Department of Defense Prostate Cancer Research Program; American Urological Association Foundation/Astellas Rising Star in Urology Award; Georgia Cancer Coalition; National Institutes of Health [P50 CA58236, R01CA100938, P50 CA92131-01A1] FX This study was supported by the US Department of Veterans Affairs, US Department of Defense Prostate Cancer Research Program, the American Urological Association Foundation/Astellas Rising Star in Urology Award, National Institutes of Health Specialized Programs of Research Excellence Grant P50 CA58236, the Georgia Cancer Coalition, National Institutes of Health R01CA100938, and National Institutes of Health Specialized Programs of Research Excellence Grant P50 CA92131-01A1. Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. NR 30 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD NOV PY 2012 VL 62 IS 5 BP 910 EP 916 DI 10.1016/j.eururo.2012.08.015 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 016WE UT WOS:000309549700034 PM 22921964 ER PT J AU Choueiri, TK Cheville, J Palescandolo, E Fay, AP Kantoff, PW Atkins, MB McKenney, JK Brown, V Lampron, ME Zhou, M Hirsch, MS Signoretti, S AF Choueiri, Toni K. Cheville, John Palescandolo, Emanuele Fay, Andre P. Kantoff, Philip W. Atkins, Michael B. McKenney, Jesse K. Brown, Victoria Lampron, Megan E. Zhou, Ming Hirsch, Michelle S. Signoretti, Sabina TI BRAF Mutations in Metanephric Adenoma of the Kidney SO EUROPEAN UROLOGY LA English DT Article DE Small renal mass; Diagnosis; BRAF; Mutation; Metanephric adenoma ID HUMAN CANCER; SENESCENCE; NEOPLASMS; MELANOMA; GENE; LESIONS; IMPACT; NEVI AB Background: Metanephric adenoma(MA) of the kidney is a rare, indolent tumor that may be difficult to differentiate from other small renal masses (SRMs). Genetic alterations associated with MA remain largely unknown. Objective: We aimed at defining genetic events in MA of the kidney and determining their influence in the management of this disease. Design, setting, and participants: Multiplexed mass spectrometric genotyping was performed on 29 MA cases after tumor DNA extraction. We also conducted a mutational screen in an additional 129 renal neoplasms. Immunohistochemistry was performed on the MA cases to assess molecular markers of signaling pathway activation. Patients' baseline characteristics, as well as follow-up data, were captured. Outcome measurements and statistical analysis: We used descriptive statistics for baseline clinical characteristics and incidence of mutations. The Wilcoxon rank-sum test was used to correlate patient characteristics with mutational status. Results and limitations: We identified the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation in 26 of 29 MA cases. These results were validated in all cases using the commercially available BRAF Pyro Kit (QIAGEN). In contrast, BRAF mutations were rare in the other 129 non-MA renal neoplasms that were screened. We detected a BRAF mutation (V600E) in only one papillary renal cell carcinoma case. In all MA tumors, we documented expression of phosphorylated mitogen-activated protein kinase and phosphorylated extracellular signal-regulated kinase, accompanied by immunoreactivity for p16 (INK4a). All patients were treated with a partial or radical nephrectomy, and after a median follow-up of 26.5 mo, there were no local or distant recurrences. Limitations include the retrospective nature of this study. Conclusions: BRAF V600E mutations are present in approximately 90% of all MA cases, serving as a potential valuable diagnostic tool in the differential diagnosis of SRMs undergoing a percutaneous biopsy. The presence of BRAF V600E and mitogen-activated protein kinase activation in a largely benign tumor supports the necessity for secondary events (eg, p16 loss) in BRAF-driven oncogenesis. (C) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. C1 [Choueiri, Toni K.; Palescandolo, Emanuele; Fay, Andre P.; Kantoff, Philip W.; Lampron, Megan E.; Signoretti, Sabina] Dana Farber Canc Inst, Boston, MA 02215 USA. [Choueiri, Toni K.; Kantoff, Philip W.; Brown, Victoria; Hirsch, Michelle S.; Signoretti, Sabina] Brigham & Womens Hosp, Boston, MA 02115 USA. [Choueiri, Toni K.; Kantoff, Philip W.; Atkins, Michael B.; Hirsch, Michelle S.; Signoretti, Sabina] Harvard Univ, Sch Med, Boston, MA USA. [Cheville, John] Mayo Clin, Rochester, MN USA. [Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [McKenney, Jesse K.] Stanford Univ, Stanford, CA 94305 USA. [Zhou, Ming] Cleveland Clin, Cleveland, OH 44106 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; ssignoretti@partners.org FU Dana-Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer SPORE Director's Choice Award; Trust Family Fund for Kidney Cancer Research FX This work was supported by a Dana-Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer SPORE Director's Choice Award to Sabina Signoretti and Toni K. Choueiri, and by the Trust Family Fund for Kidney Cancer Research. NR 28 TC 25 Z9 28 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0302-2838 J9 EUR UROL JI Eur. Urol. PD NOV PY 2012 VL 62 IS 5 BP 917 EP 922 DI 10.1016/j.eururo.2012.05.051 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 016WE UT WOS:000309549700035 PM 22727996 ER PT J AU Xi, MC Fung, SJ Zhang, JH Sampogna, S Chase, MH AF Xi, Mingchu Fung, Simon J. Zhang, Jianhua Sampogna, Sharon Chase, Michael H. TI The amygdala and the pedunculopontine tegmental nucleus: Interactions controlling active (rapid eye movement) sleep SO EXPERIMENTAL NEUROLOGY LA English DT Article DE REM sleep; Amygdala; PPT; Electrical stimulation; Intracellular recording ID ANTERODORSAL PONTINE TEGMENTUM; PARADOXICAL SLEEP; BRAIN-STEM; REM-SLEEP; RETICULAR-FORMATION; PONTOGENICULOOCCIPITAL WAVES; ELECTRICAL-STIMULATION; ACETYLCHOLINE-RELEASE; INDUCTION ZONE; MEDULLA-OBLONGATA AB There is a consensus that active sleep (AS; i.e., REM sleep) is produced by cholinergic projections from the pedunculopontine tegmental nuclei (PPT) that activate AS-on neurons in the nucleus pontis oralis (NPO) that are components of the AS-Generator. However, there is a growing body of evidence indicating that other sites, such as the amygdala, also participate in the control of AS by inducing the discharge of AS-Generator neurons. In this regard, we recently reported that there are direct, excitatory (glutamatergic) projections from the central nucleus of the amygdala (CNA) to presumptive AS-Generator neurons in the NPO. We therefore hypothesized that the CNA and the PPT act alone, as well as in concert, to promote AS. To test this hypothesis, the effects of stimulation of the CNA and the PPT on the activity of NPO neurons, recorded intracellularly, were examined in urethane-anesthetized rats. Stimulation of either the CNA or the PPT evoked short-latency excitatory postsynaptic potentials (EPSPs) in the same neurons within the NPO. The amplitude of PPT-evoked EPSPs that were recorded from NPO neurons increased by 20.1 to 58.6% when stimulation of the PPT was preceded by stimulation of the CNA at an interval of 0 to 12 ms: maximal potentiation occurred at an interval of 4 to 6 ms. Concurrent subthreshold stimulation of the CNA and the PPT resulted in the discharge of NPO neurons. NPO neurons that were activated following CNA and/or PPT stimulation were identified morphologically and found to be multipolar with diameters >20 mu m; similar neurons in the same NPO site have been previously identified as AS-Generator neurons. The present data demonstrate the presence of converging excitatory synaptic inputs from the CNA and the PPT that are capable of promoting the discharge of AS-Generator neurons in the NPO. Therefore, we suggest that the occurrence of AS depends upon interactions between cholinergic projections from the PVT and glutamatergic projections from the CNA as well as inputs from other sites that project to AS-Generator neurons. Published by Elsevier Inc. C1 [Xi, Mingchu; Fung, Simon J.; Zhang, Jianhua; Sampogna, Sharon; Chase, Michael H.] WebSci Int, Los Angeles, CA 90024 USA. [Xi, Mingchu; Fung, Simon J.; Zhang, Jianhua; Chase, Michael H.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Chase, Michael H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90025 USA. RP Xi, MC (reprint author), WebSci Int, 1251 Westwood Blvd, Los Angeles, CA 90024 USA. EM mxi@websciences.org FU NIH [NS 60917] FX This research was supported by NIH grant NS 60917. We are grateful to Mr. Vincent Lim, Ms. Nichole Stevens and Mr. Daniel Bronson for their excellent technical assistance. NR 60 TC 7 Z9 7 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD NOV PY 2012 VL 238 IS 1 BP 44 EP 51 DI 10.1016/j.expneurol.2012.08.001 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 017XV UT WOS:000309625400006 PM 22971360 ER PT J AU Yock, TI Caruso, PA AF Yock, Torunn I. Caruso, Paul A. TI RISK OF SECOND CANCERS AFTER PHOTON AND PROTON RADIOTHERAPY: A REVIEW OF THE DATA SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; cancer; health effects; medical radiation ID CENTRAL-NERVOUS-SYSTEM; ATOMIC-BOMB SURVIVORS; INITIAL CLINICAL-OUTCOMES; LONG-TERM SURVIVORS; CHILDHOOD-CANCER; RADIATION-THERAPY; 5-YEAR SURVIVORS; ADULT SURVIVORS; BRAIN-TUMORS; SOLID CANCER AB Control rates for pediatric and adult malignancies are now approximately 80 and 60%, respectively, due to dramatic improvements in surgery, chemotherapy, and radiotherapy. However, radiotherapy is responsible for many of the adverse late effects of treatment, which is now well documented in the literature. The most serious and life threatening side effect of radiotherapy that affects both children and adults is radiation-induced second primary cancers. Health Phys. 103(5):577-585; 2012 C1 [Yock, Torunn I.; Caruso, Paul A.] Massachusetts Gen Hosp, Dept Radiat Oncol, COXLL, Boston, MA 02114 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, COXLL, 100 Blossom St, Boston, MA 02114 USA. EM tyock@partners.org NR 71 TC 11 Z9 12 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2012 VL 103 IS 5 BP 577 EP 585 DI 10.1097/HP.0b013e3182609ba4 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 016MI UT WOS:000309522300011 PM 23032887 ER PT J AU Paganetti, H AF Paganetti, Harald TI ASSESSMENT OF THE RISK FOR DEVELOPING A SECOND MALIGNANCY FROM SCATTERED AND SECONDARY RADIATION IN RADIATION THERAPY SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; risk estimates; medical radiation; radiation damage ID CHILDHOOD-CANCER SURVIVOR; ATOMIC-BOMB SURVIVORS; OUT-OF-FIELD; RELATIVE BIOLOGICAL EFFECTIVENESS; NEUTRON DOSE-EQUIVALENT; JAPANESE A-BOMB; LONG-TERM RISK; PROTON THERAPY; SOLID CANCER; PROSTATE-CANCER AB With the average age of radiation therapy patients decreasing and the advent of more complex treatment options comes the concern that the incidences of radiation-induced cancer might increase in the future. The carcinogenic effects of radiation are not well understood for the entire dose range experienced in radiation therapy. Longer epidemiologic studies are needed to improve current risk models and reduce uncertainties of current risk model parameters. On the other hand, risk estimations are needed today to judge the risks versus benefits of modern radiation therapy techniques. This paper describes the current state-of-the-art in risk modeling for radiation-induced malignancies in radiation therapy, distinguishing between two volumes: first, the organs within the main radiation field receiving low or intermediate doses (typically between 0.1 and 50 Gy); and second, the organs far away from the treatment volume receiving low doses mainly due to scattered and secondary radiation (typically below 0.1 Gy). The dosimetry as well as the risk model formalisms are outlined. Furthermore, example calculations and results are presented for intensity-modulated photon therapy versus proton therapy. Health Phys. 103(5):652-661; 2012 C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@partners.org FU NCI NIH HHS [P01 CA021239] NR 96 TC 11 Z9 12 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2012 VL 103 IS 5 BP 652 EP 661 DI 10.1097/HP.0b013e318261113d PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 016MI UT WOS:000309522300019 PM 23032895 ER PT J AU Held, KD AF Held, Kathryn D. TI SUMMARY: ACHIEVEMENTS, CRITICAL ISSUES, AND THOUGHTS ON THE FUTURE SO HEALTH PHYSICS LA English DT Article DE National Council on Radiation Protection and Measurements; cancer; exposure, radiation; medical radiation AB The number of individuals exposed to particle radiations in cancer treatment worldwide is increasing rapidly, and space agencies are developing plans for long duration, deep space missions in which humans could be exposed to significant levels of radiation from charged particles. Hence, the NCRP 47th Annual Meeting on "Scientific and Policy Challenges of Particle Radiations in Medical Therapy and Space Missions" was a timely opportunity to showcase the current scientific knowledge regarding charged particles, enhance cross-fertilization between the oncology and space scientific communities, and identify common needs and challenges to both communities as well as ways to address those challenges. This issue of Health Physics contains papers from talks presented at that meeting and highlights provocative questions and the ample opportunities for synergism between space and particle-therapy research to further understanding of the biological impacts of particle radiations. Health Phys. 103(5):681-684; 2012 C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Held, KD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Cox 302,55 Fruit St, Boston, MA 02114 USA. EM kheld@partners.org FU NASA [NNX07AE40G, NNX12AB61G]; MGH Federal Share of Program Income [C06 CA059267] FX Research in K. D. Held's laboratory is supported by NASA grants #NNX07AE40G and NNX12AB61G and the MGH Federal Share of Program Income under C06 CA059267. NR 23 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD NOV PY 2012 VL 103 IS 5 BP 681 EP 684 DI 10.1097/HP.0b013e318264b2f5 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 016MI UT WOS:000309522300023 PM 23032899 ER PT J AU Hosseini, A Van de Velde, S Gill, TJ Li, GA AF Hosseini, Ali Van de Velde, Samuel Gill, Thomas J. Li, Guoan TI Tibiofemoral cartilage contact biomechanics in patients after reconstruction of a ruptured anterior cruciate ligament SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE anterior cruciate ligament (ACL); cartilage deformation; fluoroscopy; ACL reconstruction; postoperative osteoarthritis (OA) ID PATELLAR TENDON GRAFT; BONE-MARROW LESIONS; JOINT KINEMATICS; TIBIAL ROTATION; KNEE OSTEOARTHRITIS; ACL RECONSTRUCTION; SINGLE-BUNDLE; FOLLOW-UP; IN-VITRO; DEFORMATION AB We investigated the in vivo cartilage contact biomechanics of the tibiofemoral joint in patients after reconstruction of a ruptured anterior cruciate ligament (ACL). A dual fluoroscopic and MR imaging technique was used to investigate the cartilage contact biomechanics of the tibiofemoral joint during in vivo weight-bearing flexion of the knee in eight patients 6 months following clinically successful reconstruction of an acute isolated ACL rupture. The location of tibiofemoral cartilage contact, size of the contact area, cartilage thickness at the contact area, and magnitude of the cartilage contact deformation of the ACL-reconstructed knees were compared with those previously measured in intact (contralateral) knees and ACL-deficient knees of the same subjects. Contact biomechanics of the tibiofemoral cartilage after ACL reconstruction were similar to those measured in intact knees. However, at lower flexion, the abnormal posterior and lateral shift of cartilage contact location to smaller regions of thinner tibial cartilage that has been described in ACL-deficient knees persisted in ACL-reconstructed knees, resulting in an increase of the magnitude of cartilage contact deformation at those flexion angles. Reconstruction of the ACL restored some of the in vivo cartilage contact biomechanics of the tibiofemoral joint to normal. Clinically, recovering anterior knee stability might be insufficient to prevent post-operative cartilage degeneration due to lack of restoration of in vivo cartilage contact biomechanics. (c) 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:17811788, 2012 C1 [Hosseini, Ali; Van de Velde, Samuel; Gill, Thomas J.; Li, Guoan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bioengn Lab, Boston, MA 02114 USA. RP Li, GA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU NIH [R01 AR055612, F32 AR056451] FX The authors gratefully acknowledge the support of NIH (R01 AR055612, F32 AR056451) and thank Bijoy Thomas, Louis DeFrate, and Jeffrey Bingham for their technical assistance. NR 42 TC 36 Z9 38 U1 3 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD NOV PY 2012 VL 30 IS 11 BP 1781 EP 1788 DI 10.1002/jor.22122 PG 8 WC Orthopedics SC Orthopedics GA 015OL UT WOS:000309455700013 PM 22528687 ER PT J AU Hazlett, EA Collazo, T Zelmanova, Y Entis, JJ Chu, KW Goldstein, KE Roussos, P Haznedar, MM Koenigsberg, HW New, AS Buchsbaum, MS Hershowitz, JP Siever, LJ Byne, W AF Hazlett, Erin A. Collazo, Tyson Zelmanova, Yuliya Entis, Jonathan J. Chu, King-Wai Goldstein, Kim E. Roussos, Panos Haznedar, M. Mehmet Koenigsberg, Harold W. New, Antonia S. Buchsbaum, Monte S. Hershowitz, Julian P. Siever, Larry J. Byne, William TI Anterior limb of the internal capsule in schizotypal personality disorder: Fiber-tract counting, volume, and anisotropy SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizotypal personality disorder; Diffusion tensor imaging; Tractography; Magnetic resonance imaging; Anisotropy; Internal capsule ID THALAMIC MEDIODORSAL NUCLEUS; POOR-OUTCOME SCHIZOPHRENIA; WHITE-MATTER ABNORMALITIES; 1ST-EPISODE SCHIZOPHRENIA; TEMPORAL LOBES; BASAL GANGLIA; FRONTAL LOBES; DIFFUSION; MRI; BRAIN AB Mounting evidence suggests that white matter abnormalities and altered subcortical-cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age-and sex-matched individuals with SPD (n = 33) and healthy controls (HCs; n = 38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant's MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC-DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia. Published by Elsevier B.V. C1 [Hazlett, Erin A.; Collazo, Tyson; Zelmanova, Yuliya; Entis, Jonathan J.; Goldstein, Kim E.; Roussos, Panos; Haznedar, M. Mehmet; Koenigsberg, Harold W.; New, Antonia S.; Hershowitz, Julian P.; Siever, Larry J.; Byne, William] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Hazlett, Erin A.; Chu, King-Wai; Roussos, Panos; New, Antonia S.; Siever, Larry J.; Byne, William] James J Peters VAMC, VISN Mental Illness Res Educ & Clin Ctr MIRECC 3, Bronx, NY 10468 USA. [Haznedar, M. Mehmet; Koenigsberg, Harold W.; New, Antonia S.; Siever, Larry J.; Byne, William] James J Peters VAMC, Dept Psychiat, Bronx, NY 10468 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Buchsbaum, Monte S.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. RP Hazlett, EA (reprint author), James J Peters VAMC, Mental Illness Res Educ & Clin Ctr MIRECC VISN 3, 130 W Kingsbridge Rd,Room 6A-45, Bronx, NY 10468 USA. EM erin.hazlett@mssm.edu RI Roussos, Panos/J-7090-2013 OI Roussos, Panos/0000-0002-4640-6239 FU NIMH [1R01MH073911]; Mental Illness Research Education and Clinical Center; VISN3 Veterans Health Administration; National Center for Research Resources, National Institutes of Health [UL1RR029887] FX Funding for this study was provided by NIMH grant 1R01MH073911 to Dr. Erin Hazlett. Partial support was also provided by the Mental Illness Research Education and Clinical Center, VISN3 Veterans Health Administration, and grant UL1RR029887 from the National Center for Research Resources, National Institutes of Health. The funding sources had no role in the study design, collection, analysis, interpretation of data, writing of the manuscript, or in the decision to submit the paper for publication. NR 67 TC 9 Z9 9 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2012 VL 141 IS 2-3 BP 119 EP 127 DI 10.1016/j.schres.2012.08.022 PG 9 WC Psychiatry SC Psychiatry GA 016IN UT WOS:000309511300002 PM 22995934 ER PT J AU Li, XB Xia, SG Bertisch, HC Branch, CA DeLisi, LE AF Li, Xiaobo Xia, Shugao Bertisch, Hilary C. Branch, Craig A. DeLisi, Lynn E. TI Unique topology of language processing brain network: A systems-level biomarker of schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Genetic high risk; Language processing network; fMRI; Graph theoretical techniques ID SUPERIOR TEMPORAL GYRUS; SMALL-WORLD NETWORKS; HIGH-RISK; AUDITORY COMPREHENSION; LOW-FREQUENCY; ACTIVATION; FMRI; INDIVIDUALS; MRI; ABNORMALITIES AB Objective: Schizophrenia is a severe and heritable brain disorder. Language impairment has been hypothesized to spur its onset and underlie the characteristic symptoms. In this study, we investigate whether altered topological pattern of the language processing brain network exists and could be a potential biomarker of schizophrenia. We hypothesized that both patients with schizophrenia and the genetic high risk population would show significantly weakened efficiencies of the network hubs for normal language processing, especially at left inferior frontal and bilateral temporal lobes. Method: Language task-based fMRI data from 21 patients with schizophrenia, 22 genetic high risk subjects and 36 controls were analyzed. Graph theoretic and post hoc analyses of the fMRI data, and correlations between the functional network features and scores of language tests were carried out. Results: Compared to controls, patients with schizophrenia and the high risk subjects showed significantly weakened network hubs in left inferior frontal and right fusiform gyri. A unique topology of super active and intercommunicating network hubs at left fusiform gyrus and right inferior/middle frontal gyri, which were associated with the behavioral language impairment was found in the patient group, compared to the high risk and control groups. Conclusions: Aberrant systems-level topology of language processing network, especially significantly weakened network hubs in left inferior frontal and right fusiform gyri, may serve as a candidate biomarker of schizophrenia. Supported by existing findings, the hyperactive left fusiform gyrus communicating with right frontal lobe might be the key neurophysiological component causing hallucinations in schizophrenia. These findings provided a new systems-level diagnostic target for the disorder. (C) 2012 Elsevier B.V. All rights reserved. C1 [Li, Xiaobo] Yeshiva Univ, Albert Einstein Coll Med, Gruss Magnet Resonance Res Ctr, Dept Radiol, Bronx, NY 10461 USA. [Li, Xiaobo] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. [Li, Xiaobo] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Bertisch, Hilary C.] NYU, Sch Med, New York, NY 10003 USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Brockton, MA 02401 USA. RP Li, XB (reprint author), Yeshiva Univ, Albert Einstein Coll Med, Gruss Magnet Resonance Res Ctr, Dept Radiol, 1300 Morris Pk Ave,Gruss 204, Bronx, NY 10461 USA. EM xli.nki.cabi@gmail.com RI Xia, Shugao/F-6845-2013 OI Xia, Shugao/0000-0002-2960-3468 FU NIMH [R21 MH071720] FX This project was partially supported by a grant from NIMH, R21 MH071720. NR 41 TC 15 Z9 16 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2012 VL 141 IS 2-3 BP 128 EP 136 DI 10.1016/j.schres.2012.07.026 PG 9 WC Psychiatry SC Psychiatry GA 016IN UT WOS:000309511300003 PM 22917951 ER PT J AU Hill, M Crumlish, N Clarke, M Whitty, P Owens, E Renwick, L Browne, S Macklin, EA Kinsella, A Larkin, C Waddington, JL O'Callaghan, E AF Hill, Michele Crumlish, Niall Clarke, Mary Whitty, Peter Owens, Elizabeth Renwick, Laoise Browne, Stephen Macklin, Eric A. Kinsella, Anthony Larkin, Conall Waddington, John L. O'Callaghan, Eadbhard TI Prospective relationship of duration of untreated psychosis to psychopathology and functional outcome over 12 years SO SCHIZOPHRENIA RESEARCH LA English DT Article DE First-episode; Follow-up ID PERSISTENT NEGATIVE SYMPTOMS; 2-YEAR FOLLOW-UP; 1ST-EPISODE SCHIZOPHRENIA; SYNDROME-SCALE; 1ST EPISODE; ILLNESS; IMPACT; PREDICTORS; ASSOCIATION; DISORDER AB Background: The duration of untreated psychosis is well recognised as an independent predictor of symptomatic and functional outcome in the short term and has facilitated the development of worldwide early intervention programmes. However, the extent and mechanisms by which it might influence prognosis beyond a decade remain poorly understood. Methods: The authors examined the relationship between duration of untreated psychosis and outcome 12 years after a first episode of psychosis and assessed whether its relationship with function is affected by symptoms in a prospective, 12-year follow-up of an epidemiologically-based inception cohort. Results: Longer duration of untreated psychosis predicted poorer remission status, more severe positive and negative symptoms, and greater impairment in general functioning, social functioning and quality of life at 12 years on standardised measures, independent of other factors at baseline. It was not associated with gainful employment, for which education was the only predictor, or independent living, for which age was the only predictor. The relationship between duration of untreated psychosis and functional outcome was mediated by concurrent psychopathology, particularly negative symptoms. Conclusions: These results provide qualified support for the potential long-term benefit of reduction in the duration of untreated psychosis in terms of improvement in symptoms and functional outcome. Its failure to predict real-life outcomes such as independent living and gainful employment could reflect the importance of pre-existing socio-cultural factors such as individual opportunity. The relationship between duration of untreated psychosis and negative symptoms was largely responsible for its effect on function, suggesting a possible long-term protective mechanism against disability. (C) 2012 Elsevier B.V. All rights reserved. C1 [Hill, Michele; Macklin, Eric A.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Hill, Michele; Macklin, Eric A.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hill, Michele; Crumlish, Niall; Clarke, Mary; Whitty, Peter; Owens, Elizabeth; Renwick, Laoise; Browne, Stephen; Larkin, Conall; Waddington, John L.; O'Callaghan, Eadbhard] St John God Adult Psychiat Serv, Cluain Mhuire Family Ctr, Dublin, Ireland. [Crumlish, Niall] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland. [Hill, Michele; Clarke, Mary; Whitty, Peter; Browne, Stephen; Larkin, Conall; O'Callaghan, Eadbhard] Univ Coll Dublin, Dept Psychiat, Dublin 2, Ireland. [Macklin, Eric A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Clarke, Mary; Owens, Elizabeth; Renwick, Laoise; Kinsella, Anthony; O'Callaghan, Eadbhard] DELTA DETECT Early Intervent Psychosis Serv, Dun Laoghaire, Dublin, Ireland. [Waddington, John L.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. RP Hill, M (reprint author), Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. EM michelehill1@gmail.com RI Macklin, Eric/E-2955-2013; Renwick, Laoise/O-5128-2014 OI Macklin, Eric/0000-0003-1618-3502; Renwick, Laoise/0000-0001-7060-4537 FU Stanley Medical Research Institute, USA; Health Research Board of Ireland; NIH [UL1 RR 025758]; Harvard University and its affiliated academic health care centres FX This prospective study was initiated under funding from the Stanley Medical Research Institute, USA, with long-term follow-up funded by the Health Research Board of Ireland.; Assistance with analysis was supported by the Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (NIH Award # UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centres). NR 39 TC 33 Z9 34 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2012 VL 141 IS 2-3 BP 215 EP 221 DI 10.1016/j.schres.2012.08.013 PG 7 WC Psychiatry SC Psychiatry GA 016IN UT WOS:000309511300016 PM 23006501 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 (vol 135, pg 95, 2012) SO SCHIZOPHRENIA RESEARCH LA English DT Correction C1 [Horan, William P.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90073 USA. [Horan, William P.; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Foti, Dan; Hajcak, Greg] SUNY Stony Brook, Stony Brook, NY USA. RP Horan, WP (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 11301 Wilshire Blvd,Bldg 210,Mail Code 210A,Rm 11, Los Angeles, CA 90073 USA. EM horan@ucla.edu RI Wynn, Jonathan/H-3749-2014 OI Wynn, Jonathan/0000-0002-1763-8540 NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD NOV PY 2012 VL 141 IS 2-3 BP 288 EP 289 DI 10.1016/j.schres.2012.08.004 PG 2 WC Psychiatry SC Psychiatry GA 016IN UT WOS:000309511300033 ER PT J AU Ma, BY AF Ma, Bangyi TI Two-Step Method in Pediatric Chemistry Tests With Insufficient Sample Volume SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Ma, Bangyi] Massachusetts Gen Hosp, Dept Pathol, Chem Core Lab, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD NOV 1 PY 2012 VL 138 SU 2 MA 195 BP A195 EP A195 PG 1 WC Pathology SC Pathology GA V45XH UT WOS:000209848800155 ER PT J AU Knapp, H Anaya, HD AF Knapp, Herschel Anaya, Henry D. TI Implementation Science in the Real World: A Streamlined Model SO JOURNAL FOR HEALTHCARE QUALITY LA English DT Article DE implementation science; organizational change; performance improvement models; process design/redesign/reengineering; quality improvement AB The process of quality improvement may involve enhancing or revising existing practices or the introduction of a novel element. Principles of Implementation Science provide key theories to guide these processes, however, such theories tend to be highly technical in nature and do not provide pragmatic nor streamlined approaches to real-world implementation. This paper presents a concisely comprehensive six step theory-based Implementation Science model that we have successfully used to launch more than two-dozen self-sustaining implementations. In addition, we provide an abbreviated case study in which we used our streamlined theoretical model to successfully guide the development and implementation of an HIV testing/linkage to care campaign in homeless shelter settings in Los Angeles County. C1 [Knapp, Herschel; Anaya, Henry D.] US Dept Vet Affairs, Washington, DC 20422 USA. [Anaya, Henry D.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Knapp, H (reprint author), US Dept Vet Affairs, Washington, DC 20422 USA. EM Herschel.Knapp@va.gov NR 14 TC 3 Z9 3 U1 0 U2 4 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 NOV-DEC PY 2012 VL 34 IS 6 BP 27 EP 35 DI 10.1111/j.1945-1474.2012.00220.x PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA V36OQ UT WOS:000209221400004 PM 23163970 ER PT J AU Fields, BG Kuna, ST AF Fields, Barry G. Kuna, Samuel T. TI Comparing methods of respiratory event detection during the treatment of obstructive sleep apnea SO JOURNAL OF COMPARATIVE EFFECTIVENESS RESEARCH LA English DT Review DE apnea-hypopnea index; automatic event detection; obstructive sleep apnea; polysomnogram; positive airway pressure AB Renewed focus on comparative effectiveness research presents a unique opportunity to develop optimal clinical management pathways for patients with obstructive sleep apnea. With this momentum comes the challenge of measuring treatment effect on sleep-disordered breathing, especially in large, multisite studies. In-laboratory polysomnography, the current gold standard sleep assessment of obstructive sleep apnea severity, is costly and imposes significant participant burden. Alternatives include home unattended sleep testing and overnight pulse oximetry recording. Research studies using positive airway pressure treatment have the additional option of using the information recorded by the patient's positive airway pressure device to assess treatment effectiveness. Recent research has shown relatively good agreement between manual identification of residual respiratory events in overnight in-laboratory polysomnography and the automatic event detection utilized in positive airway pressure machines. In addition to assessing the effects of interventions on sleep disordered breathing, obstructive sleep apnea-related comparative effectiveness studies need to assess the impact of the interventions on patient burden, cost of therapy, timeliness of care, improved quality of life and other clinically relevant outcomes. C1 [Fields, Barry G.] Univ Penn, Philadelphia, PA 19104 USA. [Fields, Barry G.] Philadelphia Vet Affairs Med Ctr, Penn Sleep Ctr, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr 111P, Vet Integrated Serv Network Reg Sleep Ctr 4, Philadelphia, PA 19104 USA. RP Fields, BG (reprint author), Univ Penn, 3624 Market St,Suite 205, Philadelphia, PA 19104 USA. EM barry.fields@uphs.upenn.edu FU Philips-Respironics FX S Kuna receives grant support from Philips-Respironics. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 39 TC 0 Z9 0 U1 1 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 2042-6305 EI 2042-6313 J9 J COMP EFFECT RES JI J. Comp. Eff. Res. PD NOV PY 2012 VL 1 IS 6 BP 489 EP 499 DI 10.2217/CER.12.58 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA V32SL UT WOS:000208970800012 PM 24236468 ER PT J AU Abbott, KV Li, NYK Branski, RC Rosen, CA Grillo, E Steinhauer, K Hebda, PA AF Abbott, Katherine Verdolini Li, Nicole Y. K. Branski, Ryan C. Rosen, Clark A. Grillo, Elizabeth Steinhauer, Kimberly Hebda, Patricia A. TI Vocal Exercise May Attenuate Acute Vocal Fold Inflammation SO JOURNAL OF VOICE LA English DT Article DE Vocal fold inflammation; Wound healing; Tissue mobilization; Resonant voice ID PHONATION THRESHOLD PRESSURE; FIBEROPTIC LARYNGEAL SURGERY; RANDOMIZED CONTROLLED-TRIAL; CELLS IN-VITRO; MECHANICAL STRAIN; STEROID INJECTION; RABBIT MODEL; AIR-PRESSURE; VOICE; POLYMORPHISMS AB Objectives/Hypotheses. The objective was to assess the utility of selected "resonant voice" (RV) exercises for the reduction of acute vocal fold inflammation. The hypothesis was that relatively large-amplitude, low-impact vocal fold exercises associated with RV would reduce inflammation more than spontaneous speech (SS) and possibly more than voice rest. Study Design. The study design was prospective, randomized, and double blind. Methods. Nine vocally healthy adults underwent a 1-hour vocal loading procedure, followed by randomization to a SS condition, vocal rest condition, or RV exercise condition. Treatments were monitored in clinic for 4 hours and continued extraclinically until the next morning. At baseline (BL), immediately after loading, after the 4-hour in-clinic treatment, and 24 hours post-BL, secretions were suctioned from the vocal folds bilaterally and submitted to enzyme-linked immunosorbent assay to estimate concentrations of key markers of tissue injury and inflammation: interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor a, matrix metalloproteinase (MMP)-8, and IL-10. Results. Complete data sets were obtained for three markers-IL-1 beta, IL-6, and MMP-8-for one subject in each treatment condition. For these markers, results were poorest at 24-hour follow-up in the SS condition, sharply improved in the voice rest condition, and was the best in the RV condition. Average results for all markers and responsive subjects with normal BL mediator concentrations revealed an almost identical pattern. Conclusions. Some forms of tissue mobilization may be useful to attenuate acute vocal fold inflammation. C1 [Abbott, Katherine Verdolini; Rosen, Clark A.; Hebda, Patricia A.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15260 USA. [Abbott, Katherine Verdolini; Rosen, Clark A.] Univ Pittsburgh, Dept Otolaryngol, Voice Ctr, Sch Med, Pittsburgh, PA 15260 USA. [Abbott, Katherine Verdolini; Rosen, Clark A.; Hebda, Patricia A.] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15260 USA. [Li, Nicole Y. K.] Univ Wisconsin, Dept Surg, Madison, WI USA. [Branski, Ryan C.] NYU, Sch Med, Dept Otolaryngol, New York, NY USA. [Grillo, Elizabeth] W Chester Univ, Dept Commun Disorders, W Chester, PA 19380 USA. [Steinhauer, Kimberly] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Hebda, Patricia A.] Univ Pittsburgh, Dept Otolaryngol, Div Pediat, Otolaryngol Wound Healing Lab,Sch Med, Pittsburgh, PA 15260 USA. [Hebda, Patricia A.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15260 USA. RP Abbott, KV (reprint author), Univ Pittsburgh, Dept Commun Sci & Disorders, 4033 Forbes Tower, Pittsburgh, PA 15260 USA. OI Branski, Ryan/0000-0003-1190-9036 FU National Institute on Deafness and Other Communication Disorders [R01 DC5643] FX The study was supported by R01 DC5643 from the National Institute on Deafness and Other Communication Disorders. Preliminary data were presented at the 34th Symposium: Care of the Professional Voice; June 2005; Philadelphia, PA. The authors acknowledge the substantial contributions of Dr Priya Krishna and Maria Dietrich in data collection and management as well as Dr Elaine Rubenstein for statistical consulting and Mr Neil Szuminsky for the development of software for data analysis. NR 67 TC 4 Z9 4 U1 2 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0892-1997 EI 1873-4588 J9 J VOICE JI J. Voice PD NOV PY 2012 VL 26 IS 6 AR 814.e1 DI 10.1016/j.jvoice.2012.03.008 PG 13 WC Otorhinolaryngology SC Otorhinolaryngology GA 041VC UT WOS:000311428300030 ER PT J AU Ettenhofer, ML Melrose, RJ Delawalla, Z Castellon, SA Okonek, A AF Ettenhofer, Mark L. Melrose, Rebecca J. Delawalla, Zainab Castellon, Steven A. Okonek, Anna TI Correlates of Functional Status Among OEF/OIF Veterans With a History of Traumatic Brain Injury SO MILITARY MEDICINE LA English DT Article AB This study was conducted to identify factors related to functional status within a clinical sample of Veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OFF) with a history of traumatic brain injury (TBI). Medical chart review was conducted for a consecutive group of OEF/OIF Veterans who were referred for neuropsychological evaluation within a Veterans Affairs Medical Center Polytrauma Program related to history of TBI (n = 57). Level of involvement in occupational and academic activity, presence or absence of housing insecurity, and clinician ratings of overall functioning served as indicators of functional status. Reduced functional status was most strongly related to poorer cognitive function, particularly motor function, processing speed, and executive function. Lower levels of functioning were also related to increased severity of postconcussive symptoms, lower levels of education, and ongoing medication treatment for sleep or psychiatric symptoms. Comprehensive evaluation of cognitive, affective, and behavioral functioning among OEF/OIF Veterans with a history of TBI is likely to provide valuable information to inform rehabilitation strategies and identify potential warning signs for poor postdeployment reintegration. Increased awareness of these factors may aid clinicians in identifying patients at risk for poor outcomes and in more effectively targeting symptoms for intervention. C1 [Ettenhofer, Mark L.] Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Melrose, Rebecca J.; Delawalla, Zainab; Castellon, Steven A.; Okonek, Anna] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Melrose, Rebecca J.; Castellon, Steven A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Okonek, Anna] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Ettenhofer, ML (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. FU VA Greater Los Angeles Healthcare System; Uniformed Services University of the Health Sciences; Department of Veterans Affairs FX Financial support was provided by VA Greater Los Angeles Healthcare System, the Uniformed Services University of the Health Sciences, and the Department of Veterans Affairs (Career Development Award to R. Melrose; Office of Academic Affiliations, Special Fellowship Program in Advanced Geriatrics). NR 50 TC 9 Z9 9 U1 4 U2 7 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2012 VL 177 IS 11 BP 1272 EP 1278 DI 10.7205/MILMED-D-12-00095 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA V33OF UT WOS:000209027400007 PM 23198501 ER PT J AU Buerhaus, PI DesRoches, C Applebaum, S Hess, R Norman, LD Donelan, K AF Buerhaus, Peter I. DesRoches, Catherine Applebaum, Sandra Hess, Robert Norman, Linda D. Donelan, Karen TI Are Nurses Ready for Health Care Reform? A Decade of Survey Research SO NURSING ECONOMICS LA English DT Article AB As health care delivery organizations react to the changes brought about by public and private sector reform initiatives, RNs can anticipate that, in addition to intended outcomes, there will be unpredictable pressures and unintended consequences arising from reform. Biennial national surveys of RNs conducted over the past decade have explored various changes in the nursing workforce, quality of the workplace environment, staffing and payment policies, and RNs' views of health policy, including their expectations of health reform. The latest survey results offer a picture of RNs' capacity to practice successfully in a care delivery environment that, over the current decade, is expected to emphasize teams, care coordination, and become driven increasingly by payment incentives that reward quality, safety, and efficiency. If RNs are provided with strong clinical leadership, participate in developing an achievable vision of the future, and if supported to take risks and innovate to improve the quality and efficiency of care delivery, then the profession is likely to thrive rather than struggle during the health reform years that lie ahead. Increasing the education and preparation of nursing leaders, and particularly unit-level managers, will be increasingly vital for nursing to prosper in the future. C1 [Buerhaus, Peter I.] Vanderbilt Univ, Med Ctr, Inst Med & Publ Hlth, Ctr Interdisciplinary Hlth Workforce Studies, Nashville, TN 37235 USA. [DesRoches, Catherine] Math Policy Res, Princeton, NJ USA. [Applebaum, Sandra] Harris Interact, New York, NY USA. [Hess, Robert] Gannett Healthcare Grp, Global Programming, Voorhees, NJ USA. [Norman, Linda D.] Vanderbilt Univ, Sch Nursing, Nashville, TN 37240 USA. [Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Buerhaus, PI (reprint author), Vanderbilt Univ, Med Ctr, Inst Med & Publ Hlth, Ctr Interdisciplinary Hlth Workforce Studies, Nashville, TN 37235 USA. NR 10 TC 3 Z9 3 U1 0 U2 4 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD NOV-DEC PY 2012 VL 30 IS 6 BP 318 EP 330 PG 13 WC Nursing SC Nursing GA V35RR UT WOS:000209166500004 PM 23346730 ER PT J AU Lajonchere, C Jones, N Coury, DL Perrin, JM AF Lajonchere, Clara Jones, Nancy Coury, Daniel L. Perrin, James M. TI Leadership in Health Care, Research, and Quality Improvement for Children and Adolescents With Autism Spectrum Disorders: Autism Treatment Network and Autism Intervention Research Network on Physical Health SO PEDIATRICS LA English DT Article DE autism spectrum disorder C1 [Lajonchere, Clara; Jones, Nancy] Autism Speaks, Los Angeles, CA USA. [Coury, Daniel L.] Nationwide Childrens Hosp, Dept Pediat, Columbus, OH USA. [Coury, Daniel L.] Ohio State Univ, Sch Med, Columbus, OH 43210 USA. [Perrin, James M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Perrin, James M.] MassGen Hosp Children, Boston, MA USA. RP Perrin, JM (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, 100 Cambridge St 1542, Boston, MA 02114 USA. EM jperrin@partners.org RI Coury, Daniel/E-2925-2011 NR 32 TC 12 Z9 12 U1 4 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S62 EP S68 DI 10.1542/peds.2012-0900C PG 7 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500003 PM 23118255 ER PT J AU Mahajan, R Bernal, MP Panzer, R Whitaker, A Roberts, W Handen, B Hardan, A Anagnostou, E Veenstra-VanderWeele, J AF Mahajan, Rajneesh Bernal, Maria Pilar Panzer, Rebecca Whitaker, Agnes Roberts, Wendy Handen, Benjamin Hardan, Antonio Anagnostou, Evdokia Veenstra-VanderWeele, Jeremy TI Clinical Practice Pathways for Evaluation and Medication Choice for Attention-Deficit/Hyperactivity Disorder Symptoms in Autism Spectrum Disorders SO PEDIATRICS LA English DT Article DE ADHD symptoms; autism spectrum disorders; hyperactivity; impulsivity; inattention AB BACKGROUND AND OBJECTIVE: Hyperactivity, impulsivity, and inattention (referred to as "ADHD [attention-deficit/hyperactivity disorder] symptoms") occur in 41% to 78% of children with autism spectrum disorders ASDs). These symptoms often affect quality of life, interfering with learning or interventions that target primary ASD symptoms. This practice pathway describes the guidelines for evaluation and treatment of children and adolescents with ASD and comorbid ADHD symptoms. METHODS: Current research in this area is limited, and, therefore, these recommendations are based on a systematic literature review and expert consensus in the Autism Speaks Autism Treatment Network Psychopharmacology Committee. RESULTS: The recommended practice pathway includes the Symptom Evaluation Pathway for systematic assessment of ADHD symptoms across settings; examination for comorbid sleep, medical, or psychiatric comorbidities that may contribute to symptoms; and evaluation of behavioral interventions that may ameliorate these symptoms. For children for whom medication is being considered to target the ADHD symptoms, the medication choice pathway provides guidance on the selection of the appropriate agent based on a review of available research, assessment of specific advantages and disadvantages of each agent, and dosing considerations. CONCLUSIONS: These recommendations provide a framework for primary care providers treating children who have ASD and ADHD symptoms. Our systematic review of the current evidence indicates the need for more randomized controlled trials of the medications for ADHD symptoms in ASD. There will also be a need for studies of the effectiveness of these practice pathways in the future. C1 [Mahajan, Rajneesh] Kennedy Krieger Inst, Dept Psychiat, Baltimore, MD 21211 USA. [Mahajan, Rajneesh] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bernal, Maria Pilar] Kaiser Permanente No Calif, Dept Psychiat, San Jose, CA USA. [Panzer, Rebecca] MassGen Hosp Children, Dept Pediat, Boston, MA USA. [Whitaker, Agnes] Columbia Univ, Med Ctr, Dept Psychiat, New York, NY USA. [Whitaker, Agnes] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Roberts, Wendy] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Handen, Benjamin] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Handen, Benjamin] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Hardan, Antonio] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Anagnostou, Evdokia] Holland Bloorview Kids Rehabil Hosp, Dept Pediat, Toronto, ON, Canada. [Anagnostou, Evdokia] Univ Toronto, Toronto, ON, Canada. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Med Ctr, Dept Psychiat, Nashville, TN USA. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Veenstra-VanderWeele, Jeremy] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. RP Mahajan, R (reprint author), Kennedy Krieger Inst, Ctr Autism & Related Disorders, 3901 Green Spring Ave, Baltimore, MD 21211 USA. EM mahajan@kennedykrieger.org RI Veenstra-VanderWeele, Jeremy/K-1935-2015 OI Veenstra-VanderWeele, Jeremy/0000-0002-6349-1076 NR 66 TC 25 Z9 27 U1 7 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S125 EP S138 DI 10.1542/peds.2012-0900J PG 14 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500010 PM 23118243 ER PT J AU Malow, BA Byars, K Johnson, K Weiss, S Bernal, P Goldman, SE Panzer, R Coury, DL Glaze, DG AF Malow, Beth A. Byars, Kelly Johnson, Kyle Weiss, Shelly Bernal, Pilar Goldman, Suzanne E. Panzer, Rebecca Coury, Daniel L. Glaze, Dan G. TI A Practice Pathway for the Identification, Evaluation, and Management of Insomnia in Children and Adolescents With Autism Spectrum Disorders SO PEDIATRICS LA English DT Article DE actigraphy; education; sleep; sleep latency AB OBJECTIVE: This report describes the development of a practice pathway for the identification, evaluation, and management of insomnia in children and adolescents who have autism spectrum disorders (ASDs). METHODS: The Sleep Committee of the Autism Treatment Network (ATN) developed a practice pathway, based on expert consensus, to capture best practices for an overarching approach to insomnia by a general pediatrician, primary care provider, or autism medical specialist, including identification, evaluation, and management. A field test at 4 ATN sites was used to evaluate the pathway. In addition, a systematic literature review and grading of evidence provided data regarding treatments of insomnia in children who have neurodevelopmental disabilities. RESULTS: The literature review revealed that current treatments for insomnia in children who have ASD show promise for behavioral/educational interventions and melatonin trials. However, there is a paucity of evidence, supporting the need for additional research. Consensus among the ATN sleep medicine committee experts included: (1) all children who have ASD should be screened for insomnia; (2) screening should be done for potential contributing factors, including other medical problems; (3) the need for therapeutic intervention should be determined; (4) therapeutic interventions should begin with parent education in the use of behavioral approaches as a first-line approach; (5) pharmacologic therapy may be indicated in certain situations; and (6) there should be follow-up after any intervention to evaluate effectiveness and tolerance of the therapy. Field testing of the practice pathway by autism medical specialists allowed for refinement of the practice pathway. CONCLUSIONS: The insomnia practice pathway may help health care providers to identify and manage insomnia symptoms in children and adolescents who have ASD. It may also provide a framework to evaluate the impact of contributing factors on insomnia and to test the effectiveness of nonpharmacologic and pharmacologic treatment strategies for the nighttime symptoms and daytime functioning and quality of life in ASD. C1 [Malow, Beth A.; Bernal, Pilar] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN USA. [Malow, Beth A.] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. [Malow, Beth A.; Bernal, Pilar] Vanderbilt Univ, Med Ctr, Kennedy Ctr, Nashville, TN USA. [Byars, Kelly] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Johnson, Kyle] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Weiss, Shelly] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada. [Goldman, Suzanne E.] Kaiser Permanente Northern, San Jose, CA USA. [Panzer, Rebecca] MassGen Hosp Children, Boston, MA USA. [Coury, Daniel L.] Nationwide Childrens Hosp, Dept Pediat, Columbus, OH USA. [Glaze, Dan G.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Glaze, Dan G.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. RP Malow, BA (reprint author), Vanderbilt Sleep Disorders Div, 1161 21st Ave South,Room A-0116, Nashville, TN 37232 USA. EM beth.malow@vanderbilt.edu RI Coury, Daniel/E-2925-2011 NR 52 TC 42 Z9 44 U1 2 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S106 EP S124 DI 10.1542/peds.2012-0900I PG 19 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500009 PM 23118242 ER PT J AU Perrin, JM Coury, DL Hyman, SL Cole, L Reynolds, AM Clemons, T AF Perrin, James M. Coury, Daniel L. Hyman, Susan L. Cole, Lynn Reynolds, Ann M. Clemons, Traci TI Complementary and Alternative Medicine Use in a Large Pediatric Autism Sample SO PEDIATRICS LA English DT Article DE autism spectrum disorders; complementary and alternative medicine AB BACKGROUND AND OBJECTIVE: Children and adolescents with autism spectrum disorder (ASD) often use complementary and alternative medicine (CAM), usually along with other medical care. This study aimed to determine associations of ASD diagnostic category, co-existing conditions, and use of medications with use of CAM. METHODS: We used the Autism Speaks Autism Treatment Network patient registry, which collects information on CAM use, medical conditions, and psychotropic medication at enrollment. CAM was categorized as special diets versus "other" CAM; ASD was defined as autism, pervasive developmental disorder (PDD), or Asperger's. Gastrointestinal symptoms, seizure disorders, sleep problems, and medication use were determined from parent report. Child Behavior Checklist (CBCL) scores were used to measure behavioral symptoms. Logistic regression was used to determine associations of diagnostic category, other medical conditions, and medication use with CAM treatments, controlling for demographic characteristics. RESULTS: Of 3413 subjects in the registry as of April 2011, 3173 had complete data on CAM use: 896 (28%) reported any use; 548 (17%), special diets; and 643 (20%), other CAM. Higher rates of CAM use were associated with gastrointestinal symptoms (odds ratio [OR] = 1.88), seizures (OR = 1.58), and CBCL total score >70 (OR = 1.29). Children with PDD (OR = 0.62), Asperger's (OR = 0.66), or using medications (0.69) had lower rates. CONCLUSIONS: Children with ASD use more CAM when they have coexisting gastrointestinal symptoms, seizure disorders, and behavior problems. This study suggests the importance of asking about CAM use in children with ASD, especially those with complex symptoms. C1 [Perrin, James M.] Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, Boston, MA 02114 USA. [Coury, Daniel L.] Ohio State Univ, Sch Med, Nationwide Childrens Hosp, Columbus, OH 43210 USA. [Hyman, Susan L.; Cole, Lynn] Univ Rochester, Sch Med, Golisano Childrens Hosp, Rochester, NY USA. [Reynolds, Ann M.] Univ Colorado, Childrens Hosp Colorado, Aurora, CO USA. [Clemons, Traci] EMMES Corp, Rockville, MD USA. RP Perrin, JM (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, 100 Cambridge St,1542, Boston, MA 02114 USA. EM jperrin@partners.org RI Coury, Daniel/E-2925-2011; OI Reynolds, Ann/0000-0002-0836-746X NR 14 TC 25 Z9 25 U1 2 U2 7 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S77 EP S82 DI 10.1542/peds.2012-0900E PG 6 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500005 PM 23118257 ER PT J AU Perrin, JM Coury, DL Jones, N Lajonchere, C AF Perrin, James M. Coury, Daniel L. Jones, Nancy Lajonchere, Clara TI The Autism Treatment Network and Autism Intervention Research Network on Physical Health: Future Directions SO PEDIATRICS LA English DT Article DE autism spectrum disorder C1 [Perrin, James M.] Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, Boston, MA 02114 USA. [Coury, Daniel L.] Nationwide Childrens Hosp, Columbus, OH USA. [Coury, Daniel L.] Ohio State Univ, Sch Med, Columbus, OH 43210 USA. [Jones, Nancy; Lajonchere, Clara] Autism Speaks, Los Angeles, CA USA. RP Perrin, JM (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, 100 Cambridge St,1542, Boston, MA 02114 USA. EM jperrin@partners.org RI Coury, Daniel/E-2925-2011 NR 11 TC 3 Z9 3 U1 2 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S198 EP S201 DI 10.1542/peds.2012-0900S PG 4 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500019 PM 23118252 ER PT J AU Perrin, JM Coury, DL AF Perrin, James M. Coury, Daniel L. TI Untitled SO PEDIATRICS LA English DT Editorial Material C1 [Perrin, James M.] Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, Boston, MA 02114 USA. [Coury, Daniel L.] Ohio State Univ, Sch Med, Nationwide Childrens Hosp, Dept Pediat, Columbus, OH 43210 USA. RP Perrin, JM (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Dept Pediat, 100 Cambridge St 1542, Boston, MA 02114 USA. EM jperrin@partners.org NR 0 TC 3 Z9 3 U1 1 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD NOV PY 2012 VL 130 SU 2 BP S57 EP S58 DI 10.1542/peds.2012-0900A PG 2 WC Pediatrics SC Pediatrics GA V40NO UT WOS:000209485500001 PM 23118253 ER PT J AU Kim, SS Subramanian, SV Sorensen, G Perry, MJ Christiani, DC AF Kim, Seung-Sup Subramanian, S. V. Sorensen, Glorian Perry, Melissa J. Christiani, David C. TI Association between change in employment status and new-onset depressive symptoms in South Korea - a gender analysis SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE depression; gender difference; mental health AB Objectives This study aimed to investigate the association of change in employment status with new-onset depressive symptoms, particularly differences stemming from workers' gender, in South Korea. Methods We analyzed data from the ongoing Korean Welfare Panel Study. After excluding participants who had depressive symptoms at baseline (2007), we analyzed 2891 participants who became a precarious or permanent worker or unemployed at follow-up (2008) among waged workers who were permanent or precarious workers at baseline. Workers were classified as permanent workers if they had full-time, secure jobs and were directly hired by their employers; workers not meeting all these criteria were classified as precarious workers. Depressive symptoms were assessed annually using the 11-item Center for Epidemiologic Studies Depression Scale. To reduce potential bias due to pre-existing health conditions, we also examined the association in a subpopulation excluding participants with any pre-existing chronic disease or disability. Results Compared to those who maintained permanent employment, workers who became unemployed following precarious employment had higher odds of developing depressive symptoms [odds ratio (OR) 2.30, 95% confidence interval (95% CI) 1.01-5.25]. In gender-stratified analyses, new-onset depressive symptoms were strongly associated with the change from precarious to permanent employment (OR 2.57, 95% CI 1.20-5.52) as well as the change from permanent to precarious employment (OR 2.88, 95% CI 1.24-6.66) among females; no significant association was observed in the male subpopulation. Conclusions This study found that changes from precarious to permanent work or from permanent to precarious work were associated with new-onset depressive symptoms among South Korean women. C1 [Kim, Seung-Sup; Perry, Melissa J.] George Washington Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. [Subramanian, S. V.; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Sorensen, Glorian] Dana Faber Canc Inst, Ctr Community Based Res, Boston, MA USA. [Perry, Melissa J.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. RP Kim, SS (reprint author), George Washington Univ, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv, 2300 I St NW, Washington, DC 20037 USA. EM sskim@gwu.edu NR 52 TC 19 Z9 21 U1 3 U2 8 PU SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 EI 1795-990X J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD NOV PY 2012 VL 38 IS 6 BP 537 EP 545 DI 10.5271/sjweh.3286 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V31KY UT WOS:000208883700006 PM 22370923 ER PT J AU Illangasekare, S Tello, M Hutton, H Moore, R Anderson, J Baron, J Chander, G AF Illangasekare, Samantha Tello, Monique Hutton, Heidi Moore, Richard Anderson, Jean Baron, Jillian Chander, Geetanjali TI Clinical and Mental Health Correlates and Risk Factors for Intimate Partner Violence among HIV-Positive Women in an Inner-City HIV Clinic SO WOMENS HEALTH ISSUES LA English DT Article AB Background: Intimate partner violence (IPV) is a serious health concern for women in the United States, and HIV-positive women experience more frequent and severe abuse compared with HIV-negative women. The goals of this study were to determine the prevalence of IPV among HIV-infected women receiving care in an urban clinic and to determine the HIV clinical and mental health correlates of IPV among HIV-positive women. Methods: We conducted a cross-sectional survey among 196 women visiting an inner-city HIV clinic. Women were eligible if they were 18 years of age or older, English speaking, and received both HIV primary and gynecologic care at the clinic. The survey queried demographics, drug and alcohol history, depressive symptoms, and IPV, using the Partner Violence Scale. Antiretroviral therapy (ART), CD4 cell count, HIV-1 RNA level, and appointment adherence were abstracted from clinical records. Findings: Overall, 26.5% of women reported experiencing IPV in the past year. There were no differences in socio-demographics, substance use, ART prescription, CD4 count, or HIV-1 RNA level between women who experienced IPV and those who had not. Women with mild and severe depressive symptoms were significantly more likely to report IPV compared with those without, with adjusted odds ratios of 3.4 and 5.5, respectively. Women who missed gynecologic appointments were 1.9 times more likely to report experiencing IPV. Conclusions: IPV is prevalent among women presenting for HIV care, and depressive symptoms or missed gynecologic appointments should prompt further screening for IPV. Copyright (C) 2012 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Illangasekare, Samantha] Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Urban Hlth Inst, Baltimore, MD 21205 USA. [Tello, Monique] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Hutton, Heidi] Johns Hopkins Med Inst, Dept Psychiat, Baltimore, MD 21205 USA. [Moore, Richard; Baron, Jillian; Chander, Geetanjali] Johns Hopkins Med Inst, Div Gen Internal Med, Dept Med, Baltimore, MD 21205 USA. [Anderson, Jean] Johns Hopkins Med Inst, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. RP Illangasekare, S (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Johns Hopkins Urban Hlth Inst, 2013 E Monument St, Baltimore, MD 21205 USA. EM sillanga@jhsph.edu FU NIAAA NIH HHS [K23 AA015313]; NIDA NIH HHS [K24 DA000432]; NIMH NIH HHS [F31 MH084716] NR 30 TC 9 Z9 9 U1 3 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 NOV-DEC PY 2012 VL 22 IS 6 BP E563 EP E569 DI 10.1016/j.whi.2012.07.007 PG 7 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA V33SU UT WOS:000209039300008 PM 22939089 ER PT J AU Smith, RM Dyer, GSM Antonangeli, K Arredondo, N Bedlion, H Dalal, A Deveny, GM Joseph, G Lauria, D Lockhart, SH Lucien, S Marsh, S Rogers, SO Salzarulo, H Shah, S Toussaint, RJ Wagoner, J AF Smith, R. M. Dyer, G. S. M. Antonangeli, K. Arredondo, N. Bedlion, H. Dalal, A. Deveny, G. M. Joseph, G. Lauria, D. Lockhart, S. H. Lucien, S. Marsh, S. Rogers, S. O. Salzarulo, H. Shah, S. Toussaint, R. J. Wagoner, J. TI Disaster triage after the Haitian earthquake SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article DE Disaster triage; Compartment syndrome; Sepsis; Haiti earthquake ID WENCHUAN EARTHQUAKE; CRUSH INJURY; EXPERIENCE; CHINA AB In the aftermath of the devastating Haitian earthquake, we became the primary relief service for a large group of severely injured earthquake victims. Finding ourselves virtually isolated with extremely limited facilities and a group of critically injured patients whose needs vastly outstripped the available resources we employed a disaster triage system to organize their clinical care. This report describes the specific injury profile of this group of patients, their clinical course, and the management philosophy that we employed. It provides useful lessons for similar situations in the future. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Smith, R. M.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Dyer, G. S. M.; Bedlion, H.; Lucien, S.; Rogers, S. O.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wagoner, J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Shah, S.] Rhode Isl Hosp, Providence, RI USA. [Joseph, G.] Albert Einstein Hosp, Bronx, NY USA. [Marsh, S.; Salzarulo, H.] Blue Ridge Orthoped, Seneca, SC USA. [Marsh, S.; Salzarulo, H.] Partners Hlth, Boston, MA USA. [Lockhart, S. H.] Sutter Hlth, Walnut Creek, CA USA. RP Smith, RM (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, YAW3600C,55 Fruit St, Boston, MA 02114 USA. EM rmsmith1@partners.org NR 15 TC 3 Z9 4 U1 4 U2 12 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-1383 J9 INJURY JI Injury-Int. J. Care Inj. PD NOV PY 2012 VL 43 IS 11 BP 1811 EP 1815 DI 10.1016/j.injury.2011.07.015 PG 5 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA 014VR UT WOS:000309404300006 PM 21868011 ER PT J AU Helmerhorst, GTT Lindenhovius, ALC Vrahas, M Ring, D Kloen, P AF Helmerhorst, Gijs T. T. Lindenhovius, Anneluuk L. C. Vrahas, Mark Ring, David Kloen, Peter TI Satisfaction with pain relief after operative treatment of an ankle fracture SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article DE Narcotics; Opioid; Pain medication; Ankle fracture; Operative treatment ID ADULT ATTACHMENT; DISABILITY; PREDICTORS; INTENSITY AB Background: American patients are prescribed more opioid pain medication than Dutch patients after operative treatment of an ankle fracture, but it is possible that pain is undertreated in Dutch patients. This study tests if there is a difference in pain and satisfaction with pain relief between Dutch and American patients after operative treatment of ankle fractures. Methods: Thirty American and 30 Dutch patients were enrolled in a prospective comparative study prior to operative treatment of ankle fractures. Patients rated pain and satisfaction with pain relief on postoperative day 1 (POD1) and at time of suture removal (SR). Pain and satisfaction scores were compared and multivariable analysis identified their predictors. Results: At POD1, a third of Dutch patients used no opioids and a sixth took strong opioids. At SR, only 4 of 30 (13%) were taking tramadol and half were taking no medication. All of the American patients used strong opioid pain medication on POD1 and 19 of 30 (63%) were still taking strong opioids at SR. Patients that did not use opioids and Dutch patients had less pain and equivalent satisfaction with pain relief compared to patients that used opioids and American patients respectively. Nationality was the best predictor of pain intensity at POD1. Opioid medication was the best predictor of pain at SR and decreased satisfaction with pain management. Conclusions: Pain and satisfaction with pain relief are culturally mediated. Patients that use non-opioid pain medication report less pain and greater satisfaction with pain relief than patients managed with opioid pain medication. Level of evidence: Level I, Prognostic Study with more than 80% follow-up. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Helmerhorst, Gijs T. T.; Kloen, Peter] Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1105 AZ Amsterdam, Netherlands. [Vrahas, Mark] Massachusetts Gen Hosp, Orthopaed Trauma Serv, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Helmerhorst, GTT (reprint author), Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM ghelmerhorst@gmail.com; alclindenhovius@gmail.com; mvrahas@partners.org; dring@partners.org; p.kloen@amc.uva.nl FU Biomet; Skeletal Dynamics; Wright Medical FX David Ring is a Consultant for Wright Medical and Skeletal Dynamics; has research contracts with Biomet and Skeletal Dynamics; and receives royalties from Wright Medical. NR 13 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-1383 J9 INJURY JI Injury-Int. J. Care Inj. PD NOV PY 2012 VL 43 IS 11 BP 1958 EP 1961 DI 10.1016/j.injury.2012.08.018 PG 4 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA 014VR UT WOS:000309404300031 PM 22901424 ER PT J AU Lamus, C Hamalainen, MS Temereanca, S Brown, EN Purdon, PL AF Lamus, Camilo Haemaelaeinen, Matti S. Temereanca, Simona Brown, Emery N. Purdon, Patrick L. TI A spatiotemporal dynamic distributed solution to the MEG inverse problem SO NEUROIMAGE LA English DT Article DE MEG/EEG; Source localization; Inverse problem; Dynamic spatiotemporal modeling ID SURFACE-BASED ANALYSIS; HUMAN BRAIN; SOURCE RECONSTRUCTION; ELECTRICAL-ACTIVITY; SOURCE LOCALIZATION; MAXIMUM-LIKELIHOOD; BAYESIAN FRAMEWORK; EEG GENERATION; EM ALGORITHM; MCMC METHODS AB MEG/EEG are non-invasive imaging techniques that record brain activity with high temporal resolution. However, estimation of brain source currents from surface recordings requires solving an ill-conditioned inverse problem. Converging lines of evidence in neuroscience, from neuronal network models to resting-state imaging and neurophysiology, suggest that cortical activation is a distributed spatiotemporal dynamic process, supported by both local and long-distance neuroanatomic connections. Because spatiotemporal dynamics of this kind are central to brain physiology, inverse solutions could be improved by incorporating models of these dynamics. In this article, we present a model for cortical activity based on nearest-neighbor autoregression that incorporates local spatiotemporal interactions between distributed sources in a manner consistent with neurophysiology and neuroanatomy. We develop a dynamic Maximum a Posteriori Expectation-Maximization (dMAP-EM) source localization algorithm for estimation of cortical sources and model parameters based on the Kalman Filter, the Fixed Interval Smoother, and the EM algorithms. We apply the dMAP-EM algorithm to simulated experiments as well as to human experimental data. Furthermore, we derive expressions to relate our dynamic estimation formulas to those of standard static models, and show how dynamic methods optimally assimilate past and future data. Our results establish the feasibility of spatiotemporal dynamic estimation in large-scale distributed source spaces with several thousand source locations and hundreds of sensors, with resulting inverse solutions that provide substantial performance improvements over static methods. (C) 2011 Elsevier Inc. All rights reserved. C1 [Lamus, Camilo; Temereanca, Simona; Brown, Emery N.; Purdon, Patrick L.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Lamus, Camilo; Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Haemaelaeinen, Matti S.; Temereanca, Simona] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Haemaelaeinen, Matti S.; Brown, Emery N.] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. RP Lamus, C (reprint author), 77 Massachusetts Ave,Room 46-6057, Cambridge, MA 02139 USA. EM lamus@mit.edu RI Hamalainen, Matti/C-8507-2013 FU NIBIB NIH HHS [R01 EB006385, R01 EB006385-05]; NIH HHS [DP1 OD003646, DP1 OD003646-05, DP2 OD006454, DP2 OD006454-01] NR 73 TC 17 Z9 17 U1 0 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD NOV 1 PY 2012 VL 63 IS 2 BP 894 EP 909 DI 10.1016/j.neuroimage.2011.11.020 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 013VY UT WOS:000309335200025 PM 22155043 ER PT J AU Roth, MK Bingham, B Shah, A Joshi, A Frazer, A Strong, R Morilak, DA AF Roth, Megan K. Bingham, Brian Shah, Aparna Joshi, Ankur Frazer, Alan Strong, Randy Morilak, David A. CA STRONG STAR Consortium TI Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity SO NEUROPHARMACOLOGY LA English DT Article DE PTSD; Stress; Coping style; Anxiety; HPA-axis ID MEDIAL PREFRONTAL CORTEX; PITUITARY-ADRENOCORTICAL AXIS; NATIONAL COMORBIDITY SURVEY; URINARY CORTISOL EXCRETION; CHRONIC MILD STRESS; LEARNED HELPLESSNESS; BASOLATERAL AMYGDALA; EXTINGUISHED FEAR; STRIA TERMINALIS; MENTAL-DISORDERS AB Exposure to psychological trauma is the precipitating factor for PTSD. In addition, a history of chronic or traumatic stress exposure is a predisposing risk factor. We have developed a Chronic plus Acute Prolonged Stress (CAPS) treatment for rats that models some of the characteristics of stressful events that can lead to PTSD in humans. We have previously shown that CAPS enhances acute fear responses and impairs extinction of conditioned fear. Further, CAPS reduced the expression of glucocorticoid receptors in the medial prefrontal cortex. In this study we examined the effects of CAPS exposure on behavioral stress coping style, anxiety-like behaviors, and acute stress reactivity of the hypothalamic pituitary adrenal (HPA) axis. Male Sprague-Dawley rats were exposed to CAPS treatment, consisting of chronic intermittent cold stress (4 degrees C, 6 h/day, 14,days) followed on day 15 by a single 1-h session of sequential acute stressors (social defeat, immobilization, swim). After CAPS or control treatment, different groups were tested for shock probe defensive burying, novelty suppressed feeding, or evoked activation of adrenocorticotropic hormone (ACTH) and corticosterone release by an acute immobilization stress. CAPS resulted in a decrease in active burying behavior and an increase in immobility in the shock probe test. Further. CAPS-treated rats displayed increases in the latency to feed in the novelty suppressed feeding test, despite an increase in food intake in the home cage. CAPS treatment also reduced the HPA response to a subsequent acute immobilization stress. These results further validate CAPS treatment as a rat model of relevance to PTSD, and together with results reported previously, suggest that CAPS impairs fear extinction, shifts coping behavior from an active to a more passive strategy, increases anxiety, and alters HPA reactivity, resembling many aspects of human PTSD. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Roth, Megan K.; Bingham, Brian; Shah, Aparna; Joshi, Ankur; Frazer, Alan; Strong, Randy; Morilak, David A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Roth, Megan K.; Bingham, Brian; Shah, Aparna; Joshi, Ankur; Frazer, Alan; Strong, Randy; Morilak, David A.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Frazer, Alan; Strong, Randy] S Texas Vet Hlth Care Network, Audie L Murphy Div, San Antonio, TX 78229 USA. RP Morilak, DA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM morilak@uthscsa.edu OI Bingham, Brian/0000-0001-8266-203X FU NIMH [F32 MH090693, R01 MH053851]; Department of Veterans Affairs Office of Research and Development; Department of Defense through the U.S. Army Medical Research and Materiel Command [W81XWH-08-2-0118] FX This work was supported by a NIMH National Research Service Award individual postdoctoral fellowship F32 MH090693 (MKR), NIMH research grant R01 MH053851 (DAM), Department of Veterans Affairs Office of Research and Development (AF, RS), and by funding provided to the STRONG STAR Multidisciplinary PTSD Research Consortium by the Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program award W81XWH-08-2-0118. The views expressed in this paper are solely those of the authors and do not reflect an endorsement by or official policy of the Department of Defense or the U.S. Government. NR 74 TC 23 Z9 24 U1 2 U2 35 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 EI 1873-7064 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD NOV PY 2012 VL 63 IS 6 BP 1118 EP 1126 DI 10.1016/j.neuropharm.2012.07.034 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 015IC UT WOS:000309438600020 PM 22842072 ER PT J AU Granger, M Grupp, SA Kletzel, M Kretschmar, C Naranjo, A London, WB Diller, L AF Granger, Meaghan Grupp, Stephan A. Kletzel, Morris Kretschmar, Cynthia Naranjo, Arlene London, Wendy B. Diller, Lisa TI Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: A Report from the Children's Oncology Group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE high risk neuroblastoma; Myeloablative therapy; peripheral blood stem cell transplant; POG 9640; tandem transplant ID UNTREATED DISSEMINATED NEUROBLASTOMA; BONE-MARROW-TRANSPLANTATION; II INVESTIGATIONAL WINDOW; HIGH-DOSE THERAPY; MYELOABLATIVE THERAPY; 13-CIS-RETINOIC ACID; RANDOMIZED-TRIAL; RAPID-SEQUENCE; MEGATHERAPY; RESCUE AB Background The Pediatric Oncology Group performed a pilot study to assess the feasibility of tandem high dose chemotherapy (HDC) with stem cell rescue (HDC/SCR). We report here the results of this single arm trial of induction chemotherapy, local control measures (surgery and local radiation), and tandem HDC/SCR. Procedure Patients with high risk neuroblastoma (NBL) underwent five cycles of induction chemotherapy and resection of primary tumors. Peripheral blood stem cells (PBSC) were collected after Course 3 without exvivo manipulation. Myeloablative chemotherapy was performed in rapid sequence after induction chemotherapy and surgery. The ability of patients to complete both cycles of HDC/SCR was a primary endpoint. Transplant-related toxicity, progression-free survival (PFS) and overall survival (OS) were recorded. Results A total of 33 patients were enrolled. Twenty-two patients completed at least one HDC/SCR procedure and 17 patients completed both. Only one patient had insufficient stem cells collected for both transplants. There was one transplant-related death; engraftment was rapid and toxicity was as expected. The PFS of the 33 patients treated on this study is 24.2%+/- 7.5% and OS is 36.4%+/- 8.4% at 5 years. For patients who received at least one transplant PFS is 36.4%+/- 11.0% and OS is 45.5%+/- 11.2% at 5 years. Conclusions The treatment of high risk NBL with tandem HDC/SCR is feasible in terms of transplant-related mortality and the ability to collect adequate PBSC for two transplants. The outcomes from this intensified treatment have been used to design a Children's Oncology Group Phase III study testing the efficacy of tandem HDC/SCR. Pediatr Blood Cancer 2012; 59: 902907. (C) 2012 Wiley Periodicals, Inc. C1 [Granger, Meaghan] Cook Childrens Med Ctr, Dept Hematol & Oncol, Ft Worth, TX 76104 USA. [Grupp, Stephan A.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Oncol, Philadelphia, PA 19104 USA. [Kletzel, Morris] Childrens Mem Hosp, Div Oncol, Chicago, IL 60614 USA. [Kretschmar, Cynthia] Tufts Med Ctr, Div Pediat Oncol, Boston, MA USA. [Naranjo, Arlene] Univ Florida, Dept Biostat, Gainesville, FL 32611 USA. [London, Wendy B.; Diller, Lisa] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [London, Wendy B.; Diller, Lisa] Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Granger, M (reprint author), Cook Childrens Med Ctr, Dept Hematol & Oncol, 901 7th Ave,Suite 220, Ft Worth, TX 76104 USA. EM meaghan.grangermd@cookchildrens.org FU Sanford Trust; WW Smith Trust; Friends-for-Life Foundation; COG NIH [U10 CA98543, U10 CA98413]; POG [U10 CA29139, U10 CA57745] FX Grant sponsor: Sanford and WW Smith Trusts; Grant sponsor: Friends-for-Life Foundation; Grant sponsor: COG NIH Chairman's Grants; Grant numbers: U10 CA98543, U10 CA98413; Grant sponsor: POG Grants; Grant numbers: U10 CA29139, U10 CA57745. NR 17 TC 7 Z9 7 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2012 VL 59 IS 5 BP 902 EP 907 DI 10.1002/pbc.24207 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100024 PM 22744917 ER PT J AU Merryman, R Stevenson, KE Gostic, WJ Neuberg, D O'Brien, J Sallan, SE Silverman, LB AF Merryman, Reid Stevenson, Kristen E. Gostic, William J., II Neuberg, Donna O'Brien, Jane Sallan, Stephen E. Silverman, Lewis B. TI Asparaginase-associated myelosuppression and effects on dosing of other chemotherapeutic agents in childhood acute lymphoblastic leukemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute lymphoblastic leukemia (ALL); asparaginase; myelosuppression ID ONCOLOGY-GROUP AB Although L-asparaginase (ASP) is associated with several toxicities, its myelosuppressive effect has not been well characterized. On DFCI ALL Consortium Protocol 05-01 for children with newly diagnosed acute lymphoblastic leukemia, the Consolidation phase and the initial portion of the Continuation phase were identical for standard risk patients, except ASP was given only during Consolidation. Comparing the two treatment phases revealed that low blood counts during Consolidation with ASP resulted in more dosage reductions of 6-mercaptopurine and methotrexate. The myelosuppressive effect of ASP should be considered when designing treatment regimens to avoid excessive toxicity and dose reductions of other critical chemotherapy agents. Pediatr Blood Cancer 2012; 59: 925927. (C) 2012 Wiley Periodicals, Inc. C1 [Merryman, Reid; Gostic, William J., II; Sallan, Stephen E.; Silverman, Lewis B.] Harvard Univ, Sch Med, Boston, MA USA. [Stevenson, Kristen E.; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [O'Brien, Jane; Sallan, Stephen E.; Silverman, Lewis B.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Silverman, LB (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM Lewis_Silverman@dfci.harvard.edu FU Enzon Inc. FX Conflict of Interest: Dr. Sallan has received research funding from and acted as a consultant to Enzon Inc. Dr. Silverman has received honoraria from and acted as a consultant to EUSA Pharmaceuticals and Enzon Pharmaceuticals. NR 9 TC 5 Z9 8 U1 0 U2 0 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2012 VL 59 IS 5 BP 925 EP 927 DI 10.1002/pbc.24182 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100029 PM 22532399 ER PT J AU Fligor, BJ Krasker, JD Villaluna, D Krailo, M Frazier, AL AF Fligor, Brian J. Krasker, Jennie D. Villaluna, Doojduen Krailo, Mark Frazier, A. Lindsay TI "Accelerated ear-age": A new measure of chemotherapy-induced ototoxicity SO PEDIATRIC BLOOD & CANCER LA English DT Article DE chemotherapy; ototoxicity; pediatric hematology; oncology; pediatric oncology ID PRACTICAL GRADING SYSTEM; HEARING-LOSS; CISPLATIN OTOTOXICITY; CHILDREN AB Currently, there are several different scales that grade chemotherapy-induced ototoxicity. This report highlights how the implications of the conclusions drawn from each scale differ and compare these prior scales to a more functionally based scale developed at Children's Hospital Boston. Additionally, this report introduces the concept of ear-age, akin to the age at which one would expect the observed decrease in hearing as a consequence of normative aging (but documented in a child or young adult following chemotherapy). Pediatr Blood Cancer 2012; 59: 947949. (C) 2012 Wiley Periodicals, Inc. C1 [Fligor, Brian J.] Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA 02115 USA. [Fligor, Brian J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Krasker, Jennie D.] Wellesley Coll, Wellesley, MA 02181 USA. [Villaluna, Doojduen; Krailo, Mark] Childrens Oncol Grp, Arcadia, CA USA. [Frazier, A. Lindsay] Dana Farber Canc Inst, Boston, MA 02115 USA. [Frazier, A. Lindsay] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Fligor, BJ (reprint author), LO 367 300 Longwood Ave, Boston, MA 02115 USA. EM brian.fligor@childrens.harvard.edu NR 16 TC 2 Z9 2 U1 0 U2 3 PU WILEY PERIODICALS, INC PI SAN FRANCISCO PA ONE MONTGOMERY ST, SUITE 1200, SAN FRANCISCO, CA 94104 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD NOV PY 2012 VL 59 IS 5 BP 947 EP 949 DI 10.1002/pbc.24169 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 004BW UT WOS:000308656100036 PM 22492682 ER PT J AU Tsai, AC AF Tsai, Alexander C. TI A typology of structural approaches to HIV prevention: A commentary on Roberts and Matthews SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE AIDS/HIV; Behavioral interventions; Biomedicine; Developing countries; International health; Social determinants ID RESOURCE-LIMITED SETTINGS; SUB-SAHARAN AFRICA; INTIMATE-PARTNER VIOLENCE; SOUTH-AFRICA; ANTIRETROVIRAL THERAPY; PUBLIC-HEALTH; SOCIOECONOMIC DISPARITIES; PREEXPOSURE PROPHYLAXIS; HOSPITAL PERFORMANCE; MORTALITY TRENDS AB Renewed enthusiasm for biomedical HIV prevention strategies has followed the recent publication of several high-profile HIV antiretroviral therapy-based HIV prevention trials. In a recent article, Roberts and Matthews (2012) accurately note some of the shortcomings of these individually targeted approaches to HIV prevention and advocate for increased emphasis on structural interventions that have more fundamental effects on the population distribution of HIV. However, they make some implicit assumptions about the extent to which structural interventions are user-independent and more sustainable than biomedical or behavioral interventions. In this article. I elaborate a simple typology of structural interventions along these two axes and suggest that they may be neither user-independent nor sustainable and therefore subject to the same sustainability concerns, costs, and potential unintended consequences as biomedical and behavioral interventions. (C) 2012 Elsevier Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. RP Tsai, AC (reprint author), Massachusetts Gen Hosp, Ctr Global Hlth, Room 1529-E3,100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM actsai@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU U.S. National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award [K23 MH-096620] FX I thank David Bangsberg, MD, MPH, Ingrid Katz, MD, MHS, Mark Siedner, MD, MPH, and especially Kristin Hung, MD for thoughtful and constructive comments on earlier drafts of this manuscript. This acknowledgment should not be construed as permitting inference about their endorsement of any manuscript contents or conclusions. Salary support was provided through U.S. National Institute of Mental Health Mentored Patient-Oriented Research Career Development Award K23 MH-096620. NR 96 TC 11 Z9 11 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2012 VL 75 IS 9 BP 1562 EP 1567 DI 10.1016/j.socscimed.2012.06.033 PG 6 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 013IS UT WOS:000309299700002 PM 22877933 ER PT J AU Vahdat, LT Thomas, ES Roche, HH Hortobagyi, GN Sparano, JA Yelle, L Fornier, MN Martin, M Bunnell, CA Mukhopadhyay, P Peck, RA Perez, EA AF Vahdat, Linda T. Thomas, Eva S. Roche, Henri H. Hortobagyi, Gabriel N. Sparano, Joseph A. Yelle, Louise Fornier, Monica N. Martin, Miguel Bunnell, Craig A. Mukhopadhyay, Pralay Peck, Ronald A. Perez, Edith A. TI Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Neuropathy; Ixabepilone; Epothilone; Breast cancer; Microtubules ID METASTATIC BREAST-CANCER; EPOTHILONE-B-ANALOG; PLUS CAPECITABINE; ANTHRACYCLINE; BMS-247550; TAXANE; CHEMOTHERAPY; RESISTANT; PACLITAXEL; DOCETAXEL AB Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (a parts per thousand currency sign1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays. C1 [Vahdat, Linda T.] Weill Cornell Med Coll, Weill Cornell Breast Ctr, New York, NY USA. [Thomas, Eva S.] Kaiser Permanente, Oakland, CA USA. [Roche, Henri H.] Inst Claudius Regaud, Toulouse, France. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Sparano, Joseph A.] Albert Einstein Comprehens Canc Ctr, Bronx, NY USA. [Yelle, Louise] Hop Notre Dame de Bon Secours, Ctr Hosp Univ Montreal, Montreal, PQ H2L 4K8, Canada. [Fornier, Monica N.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Martin, Miguel] Hosp Gen Gregorio Maranon, Med Oncol Serv, Madrid, Spain. [Bunnell, Craig A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mukhopadhyay, Pralay; Peck, Ronald A.] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. RP Vahdat, LT (reprint author), Weill Cornell Med Coll, Weill Cornell Breast Ctr, New York, NY USA. EM ltv2001@med.cornell.edu RI Roche, Henri/O-9211-2014; OI Roche, Henri/0000-0001-7463-205X; Vahdat, Linda/0000-0002-3522-7382; MARTIN, MIGUEL/0000-0001-9237-3231 NR 30 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2012 VL 20 IS 11 BP 2661 EP 2668 DI 10.1007/s00520-012-1384-0 PG 8 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 013YS UT WOS:000309342800003 PM 22382588 ER PT J AU Varadarajan, P Toro, JJ Lee, S Schneider, D Neumon, B Frye, B Craig, RM Haile, DJ Freytes, CO AF Varadarajan, Prakash Toro, Juan J. Lee, Shuko Schneider, Deanna Neumon, Bonita Frye, Brenda Craig, Robert M. Haile, David J. Freytes, Cesar O. TI Hematopoietic progenitor cell transplantation toxicities in multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw: a longitudinal cohort study SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Autologous hematopoietic progenitor cell transplantation; Multiple myeloma; Osteonecrosis of the jaw ID ZOLEDRONIC ACID; CHEMOTHERAPY; TRIAL AB There is no information regarding the toxicity associated with autologous hematopoietic progenitor cell transplantation (AHPCT) in patients with multiple myeloma (MM) who have bisphosphonate-induced osteonecrosis of the jaw (ONJ). There is also limited information regarding long-term outcome of these patients. In this retrospective cohort study, we compared the toxicity after AHPCT in MM patients with and without ONJ. We also analyzed the response rate and overall survival of this population of patients. During the study period, 176 patients underwent AHPCT at our institution for MM. Ten patients with ONJ prior to AHPCT were matched to 40 control patients without ONJ. The incidence and severity of transplantation-associated toxicities were similar in both groups, including mucositis, 50 % in patients with ONJ vs. 68 % in controls (p = 0.889) and febrile days, median 1 vs. 3 days, respectively (p = 0.524). Myeloid engraftment and hospital length of stay were also similar between patients with ONJ and controls. There were significantly more complete remissions in patients with ONJ than in control patients (45 % vs. 15 %, p = 0.0336), but survival between the groups was not significantly different (log-rank p = 0.0818). We conclude that the incidence and severity of transplantation-associated toxicities are similar in MM patients with and without ONJ. Long-term survival was also similar between both groups. C1 [Varadarajan, Prakash; Toro, Juan J.; Lee, Shuko; Schneider, Deanna; Neumon, Bonita; Frye, Brenda; Craig, Robert M.; Haile, David J.; Freytes, Cesar O.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Varadarajan, Prakash; Toro, Juan J.; Haile, David J.; Freytes, Cesar O.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Varadarajan, P (reprint author), Mail Code 8221,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM varadarajan@uthscsa.edu NR 23 TC 1 Z9 1 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD NOV PY 2012 VL 20 IS 11 BP 2969 EP 2975 DI 10.1007/s00520-012-1429-4 PG 7 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 013YS UT WOS:000309342800038 PM 22418599 ER PT J AU Cardone, A Lopez, F Affortunato, F Busco, G Hofer, AM Mallamaci, R Martinelli, C Colella, M Farinola, GM AF Cardone, Antonio Lopez, Francesco Affortunato, Francesco Busco, Giovanni Hofer, Aldebaran M. Mallamaci, Rosanna Martinelli, Carmela Colella, Matilde Farinola, Gianluca M. TI An aryleneethynylene fluorophore for cell membrane staining SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE Aryleneethynylene; Fluorescent marker; pH-insensitive; Membranes; Cross-coupling ID FLUORESCENCE; POLYMERS; GLUCOSE; POLY(ARYLENEETHYNYLENE)S; SUBSTITUENTS; ETHYNYLENE)S; SENSITIVITY; MICROSCOPY; LIPOSOMES; OLIGOMERS AB The use of an amphiphilic aryleneethynylene fluorophore as a plasma membrane marker in fixed and living mammalian cells and liposome model systems is demonstrated. We show here that the optical properties of the novel dye are almost independent on pH, in the range 5.0-8.0. Spectroscopic characterization performed on unilamellar liposomes ascertained that the fluorescence intensity of the aryleneethynylene fluorophore greatly increases after incorporation in lipidic membranes. Experiments performed on different mammalian cells demonstrated that the novel membrane marker exhibits fast staining and a good photostability that make it a suitable tool for live cell imaging. Importantly, the aryleneethynylene fluorophore was also shown to be a fast and reliable blue membrane marker in classical multicolor immunofluorescence experiments. This study adds new important findings to the recent exploitation of the wide class of aryleneethynylene molecules as luminescent markers for biological investigations. (C) 2012 Elsevier B.V. All rights reserved. C1 [Farinola, Gianluca M.] Univ Bari Aldo Moro, Dipartimento Chim, I-70125 Bari, Italy. [Cardone, Antonio; Affortunato, Francesco; Martinelli, Carmela] UOS Bari, Consiglio Nazl Ric, Ist Chim Composti OrganoMetallici, I-70125 Bari, Italy. [Lopez, Francesco] Univ Molise, Dipartimento Agr Ambiente & Alimenti DIAAA, I-86100 Campobasso, Italy. [Lopez, Francesco] Univ Molise, CSGI, I-86100 Campobasso, Italy. [Busco, Giovanni; Mallamaci, Rosanna; Colella, Matilde] Univ Bari Aldo Moro, Dipartimento Biosci Biotecnol & Sci Farmacol, I-70125 Bari, Italy. [Hofer, Aldebaran M.] VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. [Hofer, Aldebaran M.] Brigham & Womens Hosp, Dept Surg, W Roxbury, MA 02132 USA. [Hofer, Aldebaran M.] Harvard Univ, Sch Med, W Roxbury, MA 02132 USA. RP Farinola, GM (reprint author), Univ Bari Aldo Moro, Dipartimento Chim, Via Orabona 4, I-70125 Bari, Italy. EM matilde.colella@uniba.it; farinola@chimica.uniba.it RI Lopez, Francesco/F-1282-2011; Colella, Matilde/G-9246-2011; OI Lopez, Francesco/0000-0003-4807-831X; Colella, Matilde/0000-0002-9584-7030; Farinola, Gianluca Maria/0000-0002-1601-2810 FU Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR); Fondo per gli Investimenti della Ricerca di Base (FIRB ITA-USA) [RBIN04PH77] FX This work was financially supported by the Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), "Progetto PRIN 2009 PRAM8L", and by Fondo per gli Investimenti della Ricerca di Base (FIRB ITA-USA). "grant RBIN04PH77". NR 44 TC 13 Z9 13 U1 0 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD NOV PY 2012 VL 1818 IS 11 BP 2808 EP 2817 DI 10.1016/j.bbamem.2012.06.011 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 010GC UT WOS:000309081700035 PM 22749749 ER PT J AU Guo, YQ Xu, F Lu, TJ Duan, ZF Zhang, Z AF Guo, Yuqi Xu, Feng Lu, Tianjian Duan, Zhenfeng Zhang, Zhan TI Interleukin-6 signaling pathway in targeted therapy for cancer SO CANCER TREATMENT REVIEWS LA English DT Review DE Interleukin-6; Stat3; Monoclonal antibodies; Targeted therapy; Cancer ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; EPITHELIAL OVARIAN-CANCER; SILTUXIMAB CNTO 328; MULTIPLE-MYELOMA; PROSTATE-CANCER; COLORECTAL-CANCER; BREAST-CANCER; RECEPTOR ANTIBODY AB Interleukin-6 (IL-6) is a multifunctional cytokine which plays an important role in a wide range of biologic activities in different types of cell including tumor cells. IL-6 is involved in the host immune defense mechanism as well as the modulation of growth and differentiation in various malignancies. These effects are mediated by several signaling pathways, in particular the signal transducer and transcription activator 3 (Stat3). There exists abundant evidence demonstrating that deregulated overexpression of IL-6 was associated with tumor progression through inhibition of cancer cell apoptosis, stimulation of angiogenesis, and drug resistance. Clinical studies have revealed that increased serum IL-6 concentrations in patients are associated with advanced tumor stages of various cancers (e.g., multiple myeloma, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, prostate cancer, breast cancer and ovarian cancer) and short survival in patients. Therefore, blocking IL-6 signaling is a potential therapeutic strategy for cancer (i.e., anti-IL-6 therapy) characterized by pathological IL-6 overproduction. Preliminary clinical evidence has shown that antibody targeted IL-6 therapy was well tolerated in cancer patients. In this review, we detail the progress of the current understanding of IL-6 signaling pathway in cancer as well as an antibody targeted IL-6 therapy for human cancer. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Guo, Yuqi; Zhang, Zhan] Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou 450052, Peoples R China. [Guo, Yuqi; Duan, Zhenfeng; Zhang, Zhan] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Xu, Feng; Lu, Tianjian] Xi An Jiao Tong Univ, Sch Life Sci & Technol, Minist Educ, Key Lab Biomed Informat Engn, Xian 710049, Peoples R China. [Xu, Feng; Lu, Tianjian] Xi An Jiao Tong Univ, Biomed Engn & Biomech Ctr, Xian 710049, Peoples R China. RP Zhang, Z (reprint author), Zhengzhou Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Zhengzhou 450052, Peoples R China. EM ttahozzu@yahoo.com OI Duan, Zhenfeng/0000-0002-8543-083X FU National Natural Science Foundation of China; National Cancer Institute, NIH (Nanotechnology Platform); Ovarian Cancer Research Foundation (OCRF); National 111 Project of China FX Dr. Zhang is supported by the National Natural Science Foundation of China. Dr. Duan work is supported, in part, through a Grant from The National Cancer Institute, NIH (Nanotechnology Platform) and a Grant from the Ovarian Cancer Research Foundation (OCRF). Dr.Xue's and Dr.Lu's work is supported by the National Natural Science Foundation of China and the National 111 Project of China. NR 122 TC 192 Z9 198 U1 13 U2 89 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0305-7372 EI 1532-1967 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD NOV PY 2012 VL 38 IS 7 BP 904 EP 910 DI 10.1016/j.ctrv.2012.04.007 PG 7 WC Oncology SC Oncology GA 011FD UT WOS:000309149400009 PM 22651903 ER PT J AU Korkmaz, O Ay, H Ulupinar, E Tuncel, N AF Korkmaz, OrhanTansel Ay, Hakan Ulupinar, Emel Tuncel, Nese TI Vasoactive Intestinal Peptide Enhances Striatal Plasticity and Prevents Dopaminergic Cell Loss in Parkinsonian Rats SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE Vasoactive intestinal peptide; Medium spiny neurons; 6-OHDA; Optical fractionator; TH immunohistochemistry; Striatum ID MEDIUM SPINY NEURONS; VIP-INDUCED NEUROPROTECTION; MAST-CELLS; CORTICAL REGULATION; SUBSTANTIA-NIGRA; TOTAL NUMBER; DISEASE; BRAIN; MOUSE; GLUTAMATE AB Destruction of the nigrostriatal dopaminergic pathway by the administration of 6-OHDA generates an animal model of Parkinson's disease. The main characteristic of this progressive neurological disorder is the loss of the dopaminergic neurons located in the substantia nigra pars compacta (SNc). Dopaminergic inputs from the SNc innervate the medium spiny neurons of the striatum and modulate the spontaneous activity of the primary output nuclei of the basal ganglia, globus pallidus interna, and substantia nigra pars reticulata. In our previous studies, we showed that systematically administered vasoactive intestinal peptide (VIP) is effective at reversing motor deficits, decreasing neuronal cell death, and repairing the myelin sheet in parkinsonian rats. In the current study, the effects of VIP on the dendritic morphology of the striatal neurons and the number of dopaminergic neurons in the SNc were examined in 6-OHDA-lesioned rats using Golgi-Cox staining and design-based stereological methods, respectively. Adult Sprague-Dawley rats were separated into sham-operated, bilaterally 6-OHDA lesioned and lesioned + i.p. VIP-injected (25 ng/kg) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection (every 2 days for 15 days). The 6-OHDA significantly decreased the total number of dopaminergic neurons, branching, and spine density of the medium spiny neurons in the striatum. VIP significantly increased the number of neurons immunostained with tyrosine hydroxylase and the density of spines without altering the branching and the total length of dendrites. In conclusion, VIP might display synaptogenetic activity by enhancing the spine density in the striatum of the parkinsonian rats. C1 [Korkmaz, OrhanTansel; Tuncel, Nese] Eskisehir Osmangazi Univ, Dept Physiol & Neurophysiol, Fac Med, TR-26040 Eskisehir, Turkey. [Ay, Hakan; Ulupinar, Emel] Eskisehir Osmangazi Univ, Dept Anat, Fac Med, TR-26040 Eskisehir, Turkey. [Korkmaz, OrhanTansel] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA. [Korkmaz, OrhanTansel] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Tuncel, N (reprint author), Eskisehir Osmangazi Univ, Dept Physiol & Neurophysiol, Fac Med, TR-26040 Eskisehir, Turkey. EM ntuncel@ogu.edu.tr NR 61 TC 4 Z9 5 U1 0 U2 6 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 EI 1559-1166 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2012 VL 48 IS 3 BP 565 EP 573 DI 10.1007/s12031-012-9781-x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 008LS UT WOS:000308959100011 PM 22544516 ER PT J AU Rajabi, H Ahmad, R Jin, CN Joshi, MD Guha, M Alam, M Kharbanda, S Kufe, D AF Rajabi, Hasan Ahmad, Rehan Jin, Caining Joshi, Maya Datt Guha, Minakshi Alam, Maroof Kharbanda, Surender Kufe, Donald TI MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells SO PROSTATE LA English DT Article DE MUC1-C; androgen receptor; prostate cancer; androgen-independent growth; targeted therapy ID CARCINOMA-ASSOCIATED ANTIGEN; BETA-CATENIN; MUCIN 1; MESENCHYMAL TRANSITION; REGULATORY LOOP; SIGNALING AXIS; C-SRC; RECEPTOR; EXPRESSION; GENE AB BACKGROUND The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer. METHODS Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors. RESULTS The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice. CONCLUSIONS These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition. Prostate 72:16591668, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Rajabi, Hasan; Ahmad, Rehan; Jin, Caining; Joshi, Maya Datt; Guha, Minakshi; Alam, Maroof; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kharbanda, Surender] Genus Oncol, Boston, MA USA. RP Kufe, D (reprint author), 44 Binney St,Dana 830, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU Department of Defense [W81XWH-08-1-0093]; National Cancer Institute [CA97098] FX Grant sponsor: Department of Defense Prostate Cancer Idea Award; Grant number: W81XWH-08-1-0093; Grant sponsor: National Cancer Institute; Grant number: CA97098. NR 51 TC 21 Z9 23 U1 1 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD NOV PY 2012 VL 72 IS 15 BP 1659 EP 1668 DI 10.1002/pros.22519 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 014WG UT WOS:000309405800007 PM 22473899 ER PT J AU Schonenberger, A Billeter, AT Seifert, B Neuhaus, V Trentz, O Turina, M AF Schoenenberger, Amadea Billeter, Adrian T. Seifert, Burkhardt Neuhaus, Valentin Trentz, Otmar Turina, Matthias TI Opportunities for improved trauma care of the elderly - A single center analysis of 2090 severely injured patients SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE Trauma; Injury; Mortality; Elderly; Age; Brain ID MULTIPLE-ORGAN FAILURE; BRAIN-INJURY; OLDER-ADULTS; AGE; OUTCOMES; PREDICTORS; MORTALITY; SCORE AB Purpose: Western trauma centers are increasingly confronted with elderly trauma patients in parallel to an increase of the elderly population. The purpose of this study was to identify shortcomings and opportunities for improvement in the treatment of elderly trauma patients. Materials and methods: Retrospective analysis of a prospectively collected single-center trauma database. Patients were grouped according to age and analyzed using univariate and multivariate analysis. Results: 158 patients (7.6%) were older than 75 years, and 604 patients (28.9%) were between 50 and 75 years. Although comparable with respect to injury severity (injury severity score (ISS) 29-33) and age-adjusted Acute Physiologic and Chronic Health Evaluation (APACHE) score, there was a significant increase in mortality beyond the age of 50 (>75 years: 63.9%), with age being an independent predictor of mortality. Despite a similar rate and severity of head injuries (affecting 71% of all patients), mortality of head injuries was highest in patients >75 years (70.2%), accounting for the increased mortality in this group. Patients >75 years old were less likely to undergo craniotomy, and withdrawal of medical support occurred five times more frequently. Surviving patients >50 years required shorter ICU care than patients below 50 years (7.8 vs. 12.4 days). Conclusions: With increasing life expectancy and sustained independence, elderly trauma patients have become a regular occurrence in trauma services. Despite comparable injury severity and physiologic status upon admission, these patients suffer from disproportionately high mortality rates. Closed head injuries account for the majority of fatalities, regardless of the extent of therapeutic measures applied. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Turina, Matthias] Cleveland Clin, Dept Colorectal Surg, Inst Digest Dis, Cleveland, OH 44195 USA. [Schoenenberger, Amadea; Billeter, Adrian T.; Neuhaus, Valentin; Trentz, Otmar; Turina, Matthias] Univ Zurich Hosp, Div Trauma Surg, Dept Surg, CH-8091 Zurich, Switzerland. [Billeter, Adrian T.] Univ Louisville Hosp, Price Inst Surg Res, Louisville, KY 40201 USA. [Seifert, Burkhardt] Univ Zurich, Inst Social & Prevent Med, Div Biostat, CH-8001 Zurich, Switzerland. [Neuhaus, Valentin] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Turina, M (reprint author), Cleveland Clin, Dept Colorectal Surg, Inst Digest Dis, Main Campus,Mail Code A-30,9500 Euclid Ave, Cleveland, OH 44195 USA. EM mturina73@hotmail.com OI Seifert, Burkhardt/0000-0002-5829-2478; Billeter, Adrian/0000-0001-8724-4793; Neuhaus, Valentin/0000-0003-4012-5628 NR 26 TC 5 Z9 5 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD NOV-DEC PY 2012 VL 55 IS 3 BP 660 EP 666 DI 10.1016/j.archger.2012.02.013 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 004GC UT WOS:000308667900022 PM 22465302 ER PT J AU Ferguson, KK Hauser, R Altshul, L Meeker, JD AF Ferguson, Kelly K. Hauser, Russ Altshul, Larisa Meeker, John D. TI Serum concentrations of p, p '-DDE, HCB, PCBs and reproductive hormones among men of reproductive age SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Persistent organic pollutants (POPS); Endocrine disruption; Male reproduction; Human; Environment; Fertility; Xenobiotics ID RAT LEYDIG-CELLS; POLYCHLORINATED-BIPHENYLS; ADULT MALE; ENDOGENOUS HORMONES; PLASMA-LEVELS; IN-VITRO; TESTOSTERONE; EXPOSURE; POPULATION; P,P-DDE AB Exposure to polychlorinated biphenyls (PCBs) has been associated with changes in reproductive hormone levels, however most groups studied have been highly exposed. We investigated the association of PCBs, hexachlorobenzene (HCB) and p, p'-DDE with serum sex hormones in 341 adult men from a US infertility clinic with exposure levels consistent with those observed in the general population. In crude regression models we observed several negative associations of PCBs and HCB with steroid hormone-binding globulin (SHBG) and total and free testosterone. After adjustment for lipids, age and BMI, nearly all significant associations were attenuated. A negative relationship remained between PCB 118 and SHBG (p < 0.01), and relationships of dioxin-like PCBs with SHBG and total testosterone, and between PCB 118 and total testosterone, were suggestive. These results suggest a minimal relationship between PCB exposures at low background levels similar to those observed in the general population of the US and circulating reproductive hormones. (c) 2012 Elsevier Inc. All rights reserved. C1 [Ferguson, Kelly K.; Meeker, John D.] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Hauser, Russ; Altshul, Larisa] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Altshul, Larisa] Environm Hlth & Engn Inc, Needham, MA USA. [Hauser, Russ] Massachusetts Gen Hosp, In Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, 6635 SPH Tower,1415 Washington Hts, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI Meeker, John/0000-0001-8357-5085; Ferguson, Kelly/0000-0001-8467-3250 FU National Institute of Environmental Health Sciences (NIEHS) [P30ES000002, R01ES009718, R01ES018872, P20ES018171, P42ES017198, P30ES017885]; US Environmental Protection Agency (USEPA) [RD83480001] FX This work was supported by grants P30ES000002, R01ES009718, R01ES018872, P20ES018171, P42ES017198, and P30ES017885 from the National Institute of Environmental Health Sciences (NIEHS), and RD83480001 from the US Environmental Protection Agency (USEPA). NR 44 TC 8 Z9 9 U1 1 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD NOV PY 2012 VL 34 IS 3 BP 429 EP 435 DI 10.1016/j.reprotox.2012.04.006 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 003NU UT WOS:000308619400019 PM 22564984 ER PT J AU Rich, S Ali, S Calkins, GW Michaelson, JS AF Rich, Stephanie Ali, Shihab Calkins, Geoffrey W. Michaelson, James S. TI SURVIVAL TRENDS IN CHILDHOOD HEMATOLOGICAL MALIGNANCIES SO INTERNATIONAL JOURNAL OF BIOMATHEMATICS LA English DT Article DE Childhood; hematological malignancies; survival trends AB Survival of patients with childhood hematological malignancies has increased markedly in the past decades. To examine the fine-scale details of how this progress has occurred, we carried out Kaplan-Meier cause-specific survival analysis using the Surveillance Epidemiology and End Results (SEER) dataset for patients with childhood hematological malignancies - Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Lymphoblastic Leukemia and Myeloid Leukemia - diagnosed in five eras: 1983-1987; 1988-1992; 1993-1997; 1998-2002 and 2003-2007. We generated Kaplan-Meier estimates of survival for each of the first 24 years after diagnosis. These figures agree with previously reported five- and ten-year values and attest to the remarkable increase in survival that has occurred over the past three decades of medical progress. The trend towards progressively increasing survival shows no sign of slowing, suggesting that we may expect further increases in survival in the years ahead. Most of the increase in survival for childhood hematological malignancies has occurred by reducing the risk of death in the first two years after diagnosis. This may be largely explained by the fact that this is the time period when patients are at highest risk of death. C1 [Rich, Stephanie; Ali, Shihab; Calkins, Geoffrey W.; Michaelson, James S.] Massachusetts Gen Hosp, Lab Quantitat Med, Cambridge, MA 02139 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Dept Surg, Cambridge, MA 02139 USA. [Michaelson, James S.] Massachusetts Gen Hosp, Dept Pathol, Cambridge, MA 02139 USA. RP Rich, S (reprint author), Massachusetts Gen Hosp, Lab Quantitat Med, 65 Landsdowne St,Suite 200, Cambridge, MA 02139 USA. EM michaelj@helix.mgh.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU WORLD SCIENTIFIC PUBL CO PTE LTD PI SINGAPORE PA 5 TOH TUCK LINK, SINGAPORE 596224, SINGAPORE SN 1793-5245 J9 INT J BIOMATH JI Int. J. Biomath. PD NOV PY 2012 VL 5 IS 6 AR 1250053 DI 10.1142/S1793524512500532 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 993IG UT WOS:000307850700006 ER PT J AU Haug, U Knudsen, AB Kuntz, KM AF Haug, Ulrike Knudsen, Amy B. Kuntz, Karen M. TI How should individuals with a false-positive fecal occult blood test for colorectal cancer be managed? A decision analysis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; screening; fecal occult blood ID LOW-DOSE ASPIRIN; NEGATIVE SCREENING COLONOSCOPY; SOCIETY-TASK-FORCE; LARGE-INTESTINE; LARGE-BOWEL; COST-EFFECTIVENESS; POLYPS; AUTOPSY; PREVALENCE; RISK AB Several industrialized nations recommend fecal occult blood testing (FOBT) to screen for colorectal cancer (CRC), but corresponding screening guidelines do not specify how individuals with a prior false-positive FOBT result (fpFOBT) should be managed in terms of subsequent CRC screening. Accordingly, we conducted a decision analysis to compare different strategies for managing such individuals. We used a previously developed CRC microsimulation model, SimCRC, to calculate life-years and the lifetime number of colonoscopies (as a measure of required resources) for a cohort of 50-year-olds to whom FOBT-based CRC screening is offered annually from 50 to 75 years. We compared three management strategies for individuals with a prior fpFOBT: (i) resume screening in 10 years with 10-yearly colonoscopy (SwitchCol_long); (ii) resume screening in 1 year with annual FOBT (ContinueFOBT_Short) and (iii) resume screening in 10 years (i.e., the recommended interval following a negative colonscopy) with annual FOBT (ContinueFOBT_long). We performed sensitivity analyses on various parameters and assumptions. When using different management strategies for individuals with a prior fpFOBT, the variation in the number of life-years gained relative to no screening was <2%, whereas the variation in the lifetime number of colonoscopies was 23% (percentages are calculated as the maximum difference across strategies divided by the lowest number across strategies). The ContinueFOBT_long strategy showed the lowest lifetime number of colonoscopies per life-year gained even when key assumptions were varied. In conclusion, the ContinueFOBT_long strategy was advantageous regarding both clinical benefit and required resources. Specifying an appropriate management strategy for individuals with a prior fpFOBT may substantially reduce required resources within a FOBT-based CRC screening program without limiting its effectiveness. C1 [Haug, Ulrike] German Canc Res Ctr, Div Prevent Oncol, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Knudsen, Amy B.] Massachusetts Gen Hosp, Dept Radiol, Inst Technol Assessment, Boston, MA 02114 USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. RP Haug, U (reprint author), German Canc Res Ctr, Div Prevent Oncol G110, Natl Ctr Tumor Dis, Neuenheimer Feld 460, D-69120 Heidelberg, Germany. EM u.haug@dkfz.de OI Haug, Ulrike/0000-0002-1886-2923 FU National Cancer Institute (NCI) [U01 CA 088204, U01 CA 152959-01]; German Cancer Aid (Deutsche Krebshilfe) [109421] FX Grant sponsor: The National Cancer Institute (NCI); Grant numbers: U01 CA 088204, U01 CA 152959-01; Grant sponsor: The German Cancer Aid (Deutsche Krebshilfe); Grant number: 109421 NR 39 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD NOV 1 PY 2012 VL 131 IS 9 BP 2094 EP 2102 DI 10.1002/ijc.27463 PG 9 WC Oncology SC Oncology GA 993XP UT WOS:000307893600016 PM 22307927 ER PT J AU Klein, BA Tenorio, EL Lazinski, DW Camilli, A Duncan, MJ Hu, LDT AF Klein, Brian A. Tenorio, Elizabeth L. Lazinski, David W. Camilli, Andrew Duncan, Margaret J. Hu, Linden T. TI Identification of essential genes of the periodontal pathogen Porphyromonas gingivalis SO BMC GENOMICS LA English DT Article DE Porphyromonas gingivalis; Transposon mutagenesis; Essential genes; Tn-seq; Periodontal disease ID TRANSPOSON MUTANT LIBRARY; GENOME-SCALE ANALYSIS; STREPTOCOCCUS-PNEUMONIAE; BACTEROIDES-GINGIVALIS; VIRULENCE FACTORS; DELETION MUTANTS; COG DATABASE; STRAIN W83; MUTAGENESIS; BACTERIUM AB Background: Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with periodontal disease onset and progression. Genetic tools for the manipulation of bacterial genomes allow for in-depth mechanistic studies of metabolism, physiology, interspecies and host-pathogen interactions. Analysis of the essential genes, protein-coding sequences necessary for survival of P. gingivalis by transposon mutagenesis has not previously been attempted due to the limitations of available transposon systems for the organism. We adapted a Mariner transposon system for mutagenesis of P. gingivalis and created an insertion mutant library. By analyzing the location of insertions using massively-parallel sequencing technology we used this mutant library to define genes essential for P. gingivalis survival under in vitro conditions. Results: In mutagenesis experiments we identified 463 genes in P. gingivalis strain ATCC 33277 that are putatively essential for viability in vitro. Comparing the 463 P. gingivalis essential genes with previous essential gene studies, 364 of the 463 are homologues to essential genes in other species; 339 are shared with more than one other species. Twenty-five genes are known to be essential in P. gingivalis and B. thetaiotaomicron only. Significant enrichment of essential genes within Cluster of Orthologous Groups 'D' (cell division), 'I' (lipid transport and metabolism) and 'J' (translation/ribosome) were identified. Previously, the P. gingivalis core genome was shown to encode 1,476 proteins out of a possible 1,909; 434 of 463 essential genes are contained within the core genome. Thus, for the species P. gingivalis twenty-two, seventy-seven and twenty-three percent of the genome respectively are devoted to essential, core and accessory functions. Conclusions: A Mariner transposon system can be adapted to create mutant libraries in P. gingivalis amenable to analysis by next-generation sequencing technologies. In silico analysis of genes essential for in vitro growth demonstrates that although the majority are homologous across bacterial species as a whole, species and strain-specific subsets are apparent. Understanding the putative essential genes of P. gingivalis will provide insights into metabolic pathways and niche adaptations as well as clinical therapeutic strategies. C1 [Klein, Brian A.; Lazinski, David W.; Camilli, Andrew; Hu, Linden T.] Tufts Univ, Dept Mol Biol & Microbiol, Sackler Sch Biomed Sci, Boston, MA 02111 USA. [Klein, Brian A.; Tenorio, Elizabeth L.; Hu, Linden T.] Tufts Med Ctr, Div Geog Med & Infect Dis, Boston, MA 02111 USA. [Lazinski, David W.; Camilli, Andrew] Tufts Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02111 USA. [Lazinski, David W.; Camilli, Andrew] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Duncan, Margaret J.] Forsyth Inst, Dept Mol Genet, Cambridge, MA 02142 USA. RP Hu, LDT (reprint author), Tufts Univ, Dept Mol Biol & Microbiol, Sackler Sch Biomed Sci, Boston, MA 02111 USA. EM Lhu@tuftsmedicalcenter.org RI Hu, Linden/L-6314-2016; OI Hu, Linden/0000-0003-1659-5558; Klein, Brian/0000-0002-7233-2114 FU National Institute Of Dental & Craniofacial Research [R21 DE016859, F31DE022491, R01 DE015931]; National Institute of Allergy and Infectious Diseases [R01 AI055058]; Howard Hughes Medical Institute; Russo Family Charitable Foundation; [T32 5T32GM007310]; [T32 5T32AI007389-20] FX This project was supported by Grants from the National Institute Of Dental & Craniofacial Research, R21 DE016859 (LTH), F31DE022491 (BAK) and R01 DE015931 (MJD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Dental & Craniofacial Research or the National Institutes of Health. Support was also received from T32 5T32GM007310 (BAK), T32 5T32AI007389-20 (ELT), National Institute of Allergy and Infectious Diseases R01 AI055058 (AC), Howard Hughes Medical Institute (AC) and from an award from the Russo Family Charitable Foundation. NR 73 TC 43 Z9 1998 U1 8 U2 93 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 31 PY 2012 VL 13 AR 578 DI 10.1186/1471-2164-13-578 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 085XC UT WOS:000314646600001 PM 23114059 ER PT J AU Dittrich, AS Winkler, T Wellman, T de Prost, N Musch, G Harris, RS Melo, MFV AF Dittrich, A. Susanne Winkler, Tilo Wellman, Tyler de Prost, Nicolas Musch, Guido Harris, R. Scott Melo, Marcos F. Vidal TI Modeling F-18-FDG Kinetics during Acute Lung Injury: Experimental Data and Estimation Errors SO PLOS ONE LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; POSITRON-EMISSION-TOMOGRAPHY; METABOLIC-ACTIVITY; MECHANICAL VENTILATION; NEUTROPHIL KINETICS; FDG-PET; INFLAMMATION; SHEEP; PERFUSION; LAVAGE AB Background: There is increasing interest in Positron Emission Tomography (PET) of 2-deoxy-2-[18F]flouro-D-glucose (F-18-FDG) to evaluate pulmonary inflammation during acute lung injury (ALI). We assessed the effect of extra-vascular lung water on estimates of F-18-FDG-kinetics parameters in experimental and simulated data using the Patlak and Sokoloff methods, and our recently proposed four-compartment model. Methodology/Principal Findings: Eleven sheep underwent unilateral lung lavage and 4 h mechanical ventilation. Five sheep received intravenous endotoxin (10 ng/kg/min). Dynamic F-18-FDG PET was performed at the end of the 4 h period. F-18-FDG net uptake rate (Ki), phosphorylation rate (k(3)), and volume of distribution (F-e) were estimated in three isogravitational regions for each method. Simulations of normal and ALI F-18-FDG-kinetics were conducted to study the dependence of estimated parameters on the transport rate constants to (k(5)) and from (k(6)) the extra-vascular extra-cellular compartment. The four-compartment model described 85.7% of the studied F-18-FDG-kinetics better than the Sokoloff model. Relative to the four-compartment model the Sokoloff model exhibited a consistent positive bias in Ki (3.32 [1.30-5.65] 10(-4)/min, p<0.001) and showed inaccurate estimates of the parameters composing Ki (k(3) and F-e), even when Ki was similar for those methods. In simulations, errors in estimates of Ki due to the extra-vascular extra-cellular compartment depended on both k(5) and k(5)/k(6), with errors for the Patlak and Sokoloff methods of 0.02 [-0.01-0.18] and 0.40 [0.18-0.60] 10(-3)/min for normal lungs and of -0.47 [-0.89-0.72] and 2.35 [0.85-3.68] 10(-3)/min in ALI. Conclusions/Significance: F-18-FDG accumulation in lung extra-vascular fluid, which is commonly increased during lung injury, can result in substantial estimation errors using the traditional Patlak and Sokoloff methods. These errors depend on the extra-vascular extra-cellular compartment volume and its transport rates with other compartments. The four-compartment model provides more accurate quantification of F-18-FDG-kinetics than those methods in the presence of increased extra-vascular fluid. C1 [Dittrich, A. Susanne; Winkler, Tilo; Wellman, Tyler; de Prost, Nicolas; Musch, Guido; Melo, Marcos F. Vidal] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Dittrich, A. Susanne; Winkler, Tilo; Wellman, Tyler; de Prost, Nicolas; Musch, Guido; Harris, R. Scott; Melo, Marcos F. Vidal] Harvard Univ, Sch Med, Boston, MA USA. [Harris, R. Scott] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Dittrich, A. Susanne] Univ Hosp Dresden, Dept Anesthesia & Intens Care Therapy, Dresden, Germany. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM VidalMelo.Marcos@mgh.harvard.edu RI Winkler, Tilo/B-5337-2009; OI Winkler, Tilo/0000-0002-7276-5550; de Prost, Nicolas/0000-0002-4833-4320 FU NHLBI (National Heart, Lung and Blood Institute) [5R01HL086827]; Family Klee Foundation (Stiftung Familie Klee); German National Academic Foundation (Studienstiftung des deutschen Volkes) FX This work was funded by NHLBI (National Heart, Lung and Blood Institute) grant 5R01HL086827 to MFVM. ASF was supported in part by the Family Klee Foundation (Stiftung Familie Klee, http://www.s-fk.de/) and by the German National Academic Foundation (Studienstiftung des deutschen Volkes, http://www.studienstiftung.de/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 7 Z9 7 U1 2 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 OCT 31 PY 2012 VL 7 IS 10 AR e47588 DI 10.1371/journal.pone.0047588 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 030WJ UT WOS:000310600500025 PM 23118881 ER PT J AU Higgs, MH Kuznetsova, MS Spain, WJ AF Higgs, Matthew H. Kuznetsova, Marina S. Spain, William J. TI Adaptation of Spike Timing Precision Controls the Sensitivity to Interaural Time Difference in the Avian Auditory Brainstem SO JOURNAL OF NEUROSCIENCE LA English DT Article ID COCHLEAR NUCLEUS; COINCIDENCE DETECTION; SOUND LOCALIZATION; TONAL STIMULI; NEURONS; LAMINARIS; CHICKEN; NERVE; OWL; MAGNOCELLULARIS AB While adaptation is widely thought to facilitate neural coding, the form of adaptation should depend on how the signals are encoded. Monaural neurons early in the interaural time difference (ITD) pathway encode the phase of sound input using spike timing rather than firing rate. Such neurons in chicken nucleus magnocellularis (NM) adapt to ongoing stimuli by increasing firing rate and decreasing spike timing precision. We measured NM neuron responses while adapting them to simulated physiological input, and used these responses to construct inputs to binaural coincidence detector neurons in nucleus laminaris (NL). Adaptation of spike timing in NM reduced ITD sensitivity in NL, demonstrating the dominant role of timing in the short-term plasticity as well as the immediate response of this sound localization circuit. C1 [Higgs, Matthew H.; Spain, William J.] Dept Vet Affairs Med Ctr, Neurol Sect, Seattle, WA 98108 USA. [Higgs, Matthew H.; Kuznetsova, Marina S.; Spain, William J.] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Kuznetsova, Marina S.] Univ Washington, Interdisciplinary Grad Program Neurobiol & Behav, Seattle, WA 98195 USA. [Spain, William J.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. RP Spain, WJ (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM spain@u.washington.edu FU US Department of Veterans Affairs, Office of Research and Development, Biomedical Laboratory Research Program; Veterans Affairs Merit Review; Veterans Affairs Epilepsy Center of Excellence; NIDCD [5F31DC009176] FX This material is based upon work supported in part by the US Department of Veterans Affairs, Office of Research and Development, Biomedical Laboratory Research Program. Funding was provided by a Veterans Affairs Merit Review to W.J.S., a Veterans Affairs Epilepsy Center of Excellence, and NIDCD Grant No. 5F31DC009176 (M. S. K.). We thank Jason Haensly for help performing the experiments with simulated spontaneous input to NM. We thank Sean Slee, Adrienne Fairhall, Marc Binder, David Perkel, and Ed Rubel for helpful discussions, Fred Rieke for comments on a previous version of the manuscript, and Sue Usher for excellent technical assistance. NR 36 TC 3 Z9 3 U1 0 U2 1 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 OCT 31 PY 2012 VL 32 IS 44 BP 15489 EP 15494 DI 10.1523/JNEUROSCI.1865-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 030LY UT WOS:000310573400025 PM 23115186 ER PT J AU Xiao, YH Isaacs, SN AF Xiao, Yuhong Isaacs, Stuart N. TI Enzyme-linked immunosorbent assay (ELISA) and blocking with bovine serum albumin (BSA)-not all BSAs are alike SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Enzyme-linked immunosorbent assay/methods; False positive reactions; Serum albumin; Bovine/immunology; Protein binding; Vaccinia virus complement control protein ID ANTIBODIES; COMPLEMENT; BINDING AB The enzyme-linked immunosorbent assay (ELISA) is an extremely common and powerful laboratory technique for detecting proteins by antibodies. Researchers frequently use bovine serum albumin (BSA) as a blocking agent to prevent non-specific binding of antigens and antibodies to the microtiter well. While studying the interactions of the vaccinia virus complement control protein (VCP) with complement, we found non-specific binding of VCP to BSA and identify a BSA preparation that did not result in non-specific binding. This work draws attention to the fact that not all BSA preparations are alike. It also highlights the need to perform critical controls to ensure that ELISA reactants do not inappropriately bind to the blocking agent. Published by Elsevier B.V. C1 [Xiao, Yuhong; Isaacs, Stuart N.] Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Isaacs, Stuart N.] Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. RP Isaacs, SN (reprint author), Univ Penn, Perelman Sch Med, Dept Med, Div Infect Dis, 502 Johnson Pavilion, Philadelphia, PA 19104 USA. EM isaacs@mail.med.upenn.edu FU NIH [U01 AI077913, U01 AI066333]; Middle Atlantic Regional Center of Excellence in Biodefense and Emerging Infectious Diseases [U54 AI057168]; Philadelphia Veterans Affairs Medical Center FX We would like to thank John Atkinson (Washington University, St. Louis) for the recombinant VCP. Partial funding of this work is from NIH grants U01 AI077913 and U01 AI066333, the Middle Atlantic Regional Center of Excellence in Biodefense and Emerging Infectious Diseases (U54 AI057168), and the Philadelphia Veterans Affairs Medical Center. NR 12 TC 22 Z9 22 U1 0 U2 29 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 OCT 31 PY 2012 VL 384 IS 1-2 BP 148 EP 151 DI 10.1016/j.jim.2012.06.009 PG 4 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 017EG UT WOS:000309572300018 PM 22732194 ER PT J AU Greenberg, CH Frosch, MP Goldstein, JN Rosand, J Greenberg, SM AF Greenberg, Charles H. Frosch, Matthew P. Goldstein, Joshua N. Rosand, Jonathan Greenberg, Steven M. TI Modeling Intracerebral Hemorrhage Growth and Response to Anticoagulation SO PLOS ONE LA English DT Article ID BLOOD-PRESSURE REDUCTION; FRESH-FROZEN PLASMA; CEREBRAL-HEMORRHAGE; HEMATOMA EXPANSION; INTRACRANIAL HEMORRHAGE; WARFARIN; THERAPY; COAGULOPATHY; MICROBLEEDS AB The mechanism for hemorrhage enlargement in the brain, a key determinant of patient outcome following hemorrhagic stroke, is unknown. We performed computer-based stochastic simulation of one proposed mechanism, in which hemorrhages grow in "domino" fashion via secondary shearing of neighboring vessel segments. Hemorrhages were simulated by creating an initial site of primary bleeding and an associated risk of secondary rupture at adjacent sites that decayed over time. Under particular combinations of parameters for likelihood of secondary rupture and time-dependent decay, a subset of lesions expanded, creating a bimodal distribution of microbleeds and macrobleeds. Systematic variation of the model to simulate anticoagulation yielded increases in both macrobleed occurrence (26.9%, 53.2%, and 70.0% of all hemorrhagic events under conditions simulating no, low-level, and high-level anticoagulation) and final hemorrhage size (median volumes 111, 276, and 412 under the same three conditions), consistent with data from patients with anticoagulant-related brain hemorrhages. Reversal from simulated high-level anticoagulation to normal coagulation was able to reduce final hemorrhage size only if applied relatively early in the course of hemorrhage expansion. These findings suggest that a model based on a secondary shearing mechanism can account for some of the clinically observed properties of intracerebral hemorrhage, including the bimodal distribution of volumes and the enhanced hemorrhage growth seen with anticoagulation. Future iterations of this model may be useful for elucidating the effects of hemorrhage growth of factors related to secondary shearing (such as small vessel pathology) or time-dependent decay (such as hemostatic agents). C1 [Rosand, Jonathan; Greenberg, Steven M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Greenberg, Charles H.] Univ Calif San Francisco, Dept Pharmaceut Chem, Dept Bioengn & Therapeut, San Francisco, CA USA. [Greenberg, Charles H.] Univ Calif San Francisco, Calif Inst Quantitat Biosci, San Francisco, CA USA. [Frosch, Matthew P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, CS Kubik Lab Neuropathol, Boston, MA USA. [Goldstein, Joshua N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Greenberg, SM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. EM sgreenberg@partners.org RI Goldstein, Joshua/H-8953-2016 FU National Institutes of Health [R01 AG026484]; National Science Foundation Graduate Research Fellowship [DGE-1144247] FX This work was supported by the National Institutes of Health (R01 AG026484), the National Science Foundation Graduate Research Fellowship under grant DGE-1144247. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 11 Z9 11 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 30 PY 2012 VL 7 IS 10 AR e48458 DI 10.1371/journal.pone.0048458 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HJ UT WOS:000310705600045 PM 23119028 ER PT J AU Peng, Q Yeh, HD Wei, LL Enjyoj, K Machaidze, Z Csizmad, E Schuetz, C Lee, KM Deng, SP Robson, SC Markmann, J Buhler, L AF Peng, Qiang Yeh, Heidi Wei, Lingling Enjyoj, Keiichi Machaidze, Zurab Csizmad, Eva Schuetz, Christian Lee, Kang Mi Deng, Shaoping Robson, Simon C. Markmann, James Buhler, Leo TI Mechanisms of Xenogeneic Baboon Platelet Aggregation and Phagocytosis by Porcine Liver Sinusoidal Endothelial Cells SO PLOS ONE LA English DT Article ID IN-VITRO; XENOTRANSPLANTATION; PIG; CLEARANCE; SURVIVAL; REJECTION; RECEPTORS AB Background: Baboons receiving xenogeneic livers from wild type and transgenic pigs survive less than 10 days. One of the major issues is the early development of profound thrombocytopenia that results in fatal hemorrhage. Histological examination of xenotransplanted livers has shown baboon platelet activation, phagocytosis and sequestration within the sinusoids. In order to study the mechanisms of platelet consumption in liver xenotransplantation, we have developed an in vitro system to examine the interaction between pig endothelial cells with baboon platelets and to thereby identify molecular mechanisms and therapies. Methods: Fresh pig hepatocytes, liver sinusoidal and aortic endothelial cells were isolated by collagenase digestion of livers and processing of aortae from GTKO and Gal+ MGH-miniature swine. These primary cell cultures were then tested for the differential ability to induce baboon or pig platelet aggregation. Phagocytosis was evaluated by direct observation of CFSE labeled-platelets, which are incubated with endothelial cells under confocal light microscopy. Aurintricarboxylic acid (GpIb antagonist blocking interactions with von Willebrand factor/vWF), eptifibatide (Gp IIb/IIIa antagonist), and anti-Mac-1 Ab (anti-alpha(M)beta(2) integrin Ab) were tested for the ability to inhibit phagocytosis. Results: None of the pig cells induced aggregation or phagocytosis of porcine platelets. However, pig hepatocytes, liver sinusoidal and aortic endothelial cells (GTKO and Gal+) all induced moderate aggregation of baboon platelets. Importantly, pig liver sinusoidal endothelial cells efficiently phagocytosed baboon platelets, while pig aortic endothelial cells and hepatocytes had minimal effects on platelet numbers. Anti-MAC-1 Ab, aurintricarboxylic acid or eptifibatide, significantly decreased baboon platelet phagocytosis by pig liver endothelial cells (P<0.01). Conclusions: Although pig hepatocytes and aortic endothelial cells directly caused aggregation of baboon platelets, only pig liver endothelial cells efficiently phagocytosed baboon platelets. Blocking vWF and integrin adhesion pathways prevented both aggregation and phagocytosis. C1 [Peng, Qiang; Yeh, Heidi; Wei, Lingling; Machaidze, Zurab; Schuetz, Christian; Lee, Kang Mi; Deng, Shaoping; Markmann, James; Buhler, Leo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Transplant Surg, Boston, MA 02115 USA. [Enjyoj, Keiichi; Csizmad, Eva; Robson, Simon C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Gastroenterol, Ctr Liver, Boston, MA 02215 USA. [Buhler, Leo] Univ Hosp Geneva, Dept Surg, Surg Res Unit, Geneva, Switzerland. RP Buhler, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Transplant Surg, Boston, MA 02115 USA. EM Leo.Buhler@hcuge.ch OI Schuetz, Christian/0000-0002-6828-4543 FU Department of Transplant Surgery, Massachusetts General Hospital; Department of Gastroenterology, Liver Center, Beth Israel Deaconess Medical Center (Harvard Medical School, Boston); foundation Insuleman (Switzerland); foundation Louis-Jeantet (Switzerland); National Institutes of Health [P01 AI045897-11A1 DHS/SCR]; Transplantation Biology Research Center, Massachusetts General Hospital FX This work was supported by the Department of Transplant Surgery, Massachusetts General Hospital and the Department of Gastroenterology, Liver Center, Beth Israel Deaconess Medical Center (Harvard Medical School, Boston), by the foundations Insuleman and Louis-Jeantet (Switzerland) and National Institutes of Health (P01 AI045897-11A1 DHS/SCR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We thank our colleagues at the Department of Transplant Surgery, Massachusetts General Hospital and the Transplantation Biology Research Center, Massachusetts General Hospital for their support. In particular, we thank David K. C. Cooper for his advice and support. NR 21 TC 10 Z9 11 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 30 PY 2012 VL 7 IS 10 AR e47273 DI 10.1371/journal.pone.0047273 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HJ UT WOS:000310705600010 PM 23118867 ER PT J AU Grossmann, TN Yeh, JTH Bowman, BR Chu, Q Moellering, RE Verdine, GL AF Grossmann, Tom N. Yeh, Johannes T. -H. Bowman, Brian R. Chu, Qian Moellering, Raymond E. Verdine, Gregory L. TI Inhibition of oncogenic Wnt signaling through direct targeting of beta-catenin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colorectal cancer; peptide engineering; targeted therapy ID STAPLED P53 PEPTIDE; CRYSTAL-STRUCTURE; COLORECTAL-CANCER; BH3 HELIX; IN-VIVO; COMPLEX; ACTIVATION; APOPTOSIS; TUMORIGENESIS; TRANSCRIPTION AB Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of beta-catenin by interfering with its constitutive degradation. beta-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein-protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein-protein interactions is a biologically compelling approach toward suppression of beta-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence beta-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets beta-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway. C1 [Grossmann, Tom N.; Yeh, Johannes T. -H.; Bowman, Brian R.; Chu, Qian; Moellering, Raymond E.; Verdine, Gregory L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Grossmann, Tom N.; Yeh, Johannes T. -H.; Bowman, Brian R.; Chu, Qian; Moellering, Raymond E.; Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Verdine, Gregory L.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. RP Verdine, GL (reprint author), Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. EM gregory_verdine@harvard.edu RI Grossmann, Tom/A-4175-2015 OI Grossmann, Tom/0000-0003-0179-4116 FU GlaxoSmithKline; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Deutsche Akademie der Naturforscher Leopoldina [LPDS 2009-2]; Susan G. Komen for the Cure [KG091054]; American Association for Cancer Research FX We thank M. Kolar and Y.-W. Kim for assistance with automated solid-phase peptide synthesis; the Broad Institute Chemical Biology Program for access to instrumentation; A. Koehler and C. Feau at the Broad Institute for their support of the Biacore experiments; C. Sevenich at Technical University Dortmund, Germany for performing high-resolution mass spectroscopy experiments; W. Xu at University of Washington, Seattle for kindly providing the beta-catenin expression construct; and H. Clevers at Hubrecht Institute, The Netherlands for kindly providing TOPflash reporter construct. This research was supported by GlaxoSmithKline. Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract DE-AC02-06CH11357. T.N.G. is the recipient of a fellowship (LPDS 2009-2) from Deutsche Akademie der Naturforscher Leopoldina. J.T-H.Y. was supported by a grant from Susan G. Komen for the Cure (KG091054). R.E.M was supported by an American Association for Cancer Research Centennial Pre-doctoral Research Fellowship. NR 35 TC 69 Z9 70 U1 2 U2 45 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 OCT 30 PY 2012 VL 109 IS 44 BP 17942 EP 17947 DI 10.1073/pnas.1208396109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900057 PM 23071338 ER PT J AU Bailey, ST Shin, HJ Westerling, T Liu, XS Brown, M AF Bailey, Shannon T. Shin, Hyunjin Westerling, Thomas Liu, Xiaole Shirley Brown, Myles TI Estrogen receptor prevents p53-dependent apoptosis in breast cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cistrome; DNA damage; nuclear receptor; nutlin; doxorubicin ID GENE-EXPRESSION; MOLECULAR SUBTYPES; CELLULAR-RESPONSE; MICROARRAY DATA; P53 PATHWAY; DNA-DAMAGE; ER-ALPHA; PROTEIN; SURVIVAL; BTG2 AB More than two-thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function, including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity, play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild-type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches, we have addressed the mechanism by which ER antagonizes the proapoptotic function of p53. Interestingly, both ER agonists such as estradiol and the selective ER modulator (SERM) tamoxifen promote p53 antagonism. In contrast, the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This inhibition works through a mechanism involving the modulation of a subset of p53 and ER target genes that can predict the relapse-free survival of patients with ER+ breast cancer. These findings suggest an improved strategy for the treatment of ER+ breast cancer using antagonists that completely block ER action together with drugs that activate p53-mediated cell death. C1 [Bailey, Shannon T.; Shin, Hyunjin; Westerling, Thomas; Liu, Xiaole Shirley; Brown, Myles] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Bailey, Shannon T.; Westerling, Thomas; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Bailey, Shannon T.; Westerling, Thomas; Brown, Myles] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Bailey, Shannon T.; Westerling, Thomas; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Shin, Hyunjin; Liu, Xiaole Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Shin, Hyunjin; Liu, Xiaole Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. RP Brown, M (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. EM myles_brown@dfci.harvard.edu RI Bailey, Shannon/B-8045-2014; OI Brown, Myles/0000-0002-8213-1658 FU Novartis; Pfizer; Terri Brodeur Breast Cancer Foundation; National Institutes of Health [P01 CA080111, R01 DK074967, R01 HG004069] FX M.B. serves as a consultant to Novartis and receives sponsored research support from Novartis and Pfizer.; This work was supported by a Terri Brodeur Breast Cancer Foundation fellowship (to S.T.B.) and National Institutes of Health Grants P01 CA080111 (to M.B.), R01 DK074967 (to M.B.), and R01 HG004069 (to X.S.L.). NR 57 TC 43 Z9 45 U1 1 U2 24 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 OCT 30 PY 2012 VL 109 IS 44 BP 18060 EP 18065 DI 10.1073/pnas.1018858109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900077 PM 23077249 ER PT J AU Hunzicker-Dunn, ME Lopez-Biladeau, B Law, NC Fiedler, SE Carr, DW Maizels, ET AF Hunzicker-Dunn, Mary E. Lopez-Biladeau, Blanca Law, Nathan C. Fiedler, Sarah E. Carr, Daniel W. Maizels, Evelyn T. TI PKA and GAB2 play central roles in the FSH signaling pathway to PI3K and AKT in ovarian granulosa cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; PROTEIN-KINASE-A; HISTONE H3 PHOSPHORYLATION; GROWTH-FACTOR RECEPTORS; ANCHORING PROTEINS; PHOSPHATIDYLINOSITOL 3-KINASE; REGULATORY SUBUNIT; ADAPTER PROTEINS; CYCLIC-AMP; ACTIVATION AB Controlled maturation of ovarian follicles is necessary for fertility. Follicles are restrained at an immature stage until stimulated by FSH secreted by pituitary gonadotropes. FSH acts on granulosa cells within the immature follicle to inhibit apoptosis, promote proliferation, stimulate production of steroid and protein hormones, and induce ligand receptors and signaling intermediates. The phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway is a pivotal signaling corridor necessary for transducing the FSH signal. We report that protein kinase A (PKA) mediates the actions of FSH by signaling through multiple targets to activate PI3K/AKT. PKA uses a route that promotes phosphorylation of insulin receptor substrate-1 (IRS-1) on Tyr(989), a canonical binding site for the 85-kDa regulatory subunit of PI3K that allosterically activates the catalytic subunit. PI3K activation leads to activation of AKT through phosphorylation of AKT on Thr(308) and Ser(473). The adaptor growth factor receptor bound protein 2-associated binding protein 2 (GAB2) is present in a preformed complex with PI3K heterodimer and IRS-1, it is an A-kinase anchoring protein that binds the type I regulatory subunit of PKA, and it is phosphorylated by PKA on Ser(159). Overexpression of GAB2 enhances FSH-stimulated AKT phosphorylation. GAB2, thus, seems to coordinate signals from the FSH-stimulated rise in cAMP that leads to activation of PI3K/AKT. The ability of PKA to commandeer IRS-1 and GAB2, adaptors that normally integrate receptor/nonreceptor tyrosine kinase signaling into PI3K/AKT, reveals a previously unrecognized route for PKA to activate a pathway that promotes proliferation, inhibits apoptosis, enhances translation, and initiates differentiation of granulosa cells. C1 [Hunzicker-Dunn, Mary E.; Lopez-Biladeau, Blanca; Law, Nathan C.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Fiedler, Sarah E.; Carr, Daniel W.] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97239 USA. [Maizels, Evelyn T.] Northwestern Univ, Dept Cell & Mol Biol, Feinberg Sch Med, Chicago, IL 60611 USA. RP Hunzicker-Dunn, ME (reprint author), Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. EM mehd@wsu.edu FU National Institutes of Health [R01HD062053, R03HD068668]; Department of Veterans Affairs FX We thank additional members of the Hunzicker-Dunn laboratory for their technical and intellectual contributions. We thank John Nilson for his critical reading of the manuscript. This work was supported by National Institutes of Health Grants R01HD062053 (to M.E.H.-D.) and R03HD068668 (to D. W. C.) and a Merit Award from the Department of Veterans Affairs (to D.W.C.). NR 56 TC 37 Z9 39 U1 3 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 30 PY 2012 VL 109 IS 44 BP E2979 EP E2988 DI 10.1073/pnas.1205661109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038BJ UT WOS:000311149900007 PM 23045700 ER PT J AU Adachi, MS Taylor, AB Hart, PJ Fitzpatrick, PF AF Adachi, Mariya S. Taylor, Alexander B. Hart, P. John Fitzpatrick, Paul F. TI Mechanistic and Structural Analyses of the Roles of Active Site Residues in Yeast Polyamine Oxidase Fms1: Characterization of the N195A and D94N Enzymes SO BIOCHEMISTRY LA English DT Article ID AMINO-ACID OXIDASE; MONOAMINE-OXIDASE; KINETIC MECHANISM; PH-DEPENDENCE; SUBSTRATE-SPECIFICITY; OXYGEN ACTIVATION; FLAVOPROTEIN; OXIDATION; METABOLISM; SPERMINE AB Flavoprotein Fms1 from Saccharomyces cerevisiae catalyzes the oxidation of spermine in the biosynthetic pathway for pantothenic acid. The same reaction is catalyzed by the mammalian polyamine and spermine oxidases. The active site of Fms1 contains three amino acid residues positioned to interact with the polyamine substrate, His67, Asn195, and Asp94. These three residues form a hydrogen bonding triad with Asn195 being the central residue. Previous studies of the effects of mutating His67 are consistent with that residue being important both for interacting with the substrate and for maintaining the hydrogen bonds in the triad [Adachi, M. S., Taylor, A. B., Hart, P. J., and Fitzpatrick, P. F. (2012) Biochemistry Si, 4888-4897]. The N195A and D94N enzymes have now been characterized to evaluate their roles in catalysis. Both mutations primarily affect the reductive half-reaction. With N-1-acetylspermine as the substrate, the rate constant for flavin reduction decreases similar to 450-fold for both mutations; the effects with spermine as the substrate are smaller, 20-40-fold. The k(cat)/K-amine- and k(cat)-pH profiles with N-1-acetylspermine are only slightly changed from the profiles for the wild-type enzyme, consistent with the pK(a) values arising from the amine substrate or product and not from active site residues. The structure of the N195A enzyme was determined at a resolution of 2.0 angstrom. The structure shows a molecule of tetraethylene glycol in the active site and establishes that the mutation has no effect on the protein structure. Overall, the results are consistent with the role of Asn195 and Asp94 being to properly position the polyamine substrate for oxidation. C1 [Adachi, Mariya S.; Taylor, Alexander B.; Hart, P. John; Fitzpatrick, Paul F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Audie Murphy Div, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Fitzpatrick, PF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM fitzpatrick@biochem.uthscsa.edu FU National Institutes of Health Grant [R01 GM058698]; Welch Foundation [AQ-1399, AQ1245]; National Center for Research Resources [5P41RR015301-10]; National Institute of General Medical Sciences from the National Institutes of Health [(8 P41 GM103403-10]; U.S. DOE [DE-AC02-06CH11357]; Department of Veterans Affairs, Veterans Health Administration, Office of Research Development, Biomedical Laboratory Research and Development FX This work was supported in part by National Institutes of Health Grant R01 GM058698 (to P.F.F.) and The Welch Foundation Grants AQ-1399 (to R.J.H.) and AQ1245 (to P.F.F.). This work is based upon research conducted at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines, which are supported by grants from the National Center for Research Resources (5P41RR015301-10) and the National Institute of General Medical Sciences (8 P41 GM103403-10) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE), Office of Science, by Argonne National Laboratory, was supported by the U.S. DOE under Contract DE-AC02-06CH11357.; This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research Development, Biomedical Laboratory Research and Development. Support for the X-ray Crystallography Core Laboratory by the University of Texas Health Science Center at San Antonio Executive Research Committee and the Cancer Therapy Research Center is gratefully acknowledged. NR 35 TC 2 Z9 2 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 30 PY 2012 VL 51 IS 43 BP 8690 EP 8697 DI 10.1021/bi3011434 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 029GX UT WOS:000310483900020 PM 23034052 ER PT J AU Anderson, ML Peterson, ED Brennan, JM Rao, SV Dai, D Anstrom, KJ Piana, R Popescu, A Sedrakyan, A Messenger, JC Douglas, PS AF Anderson, Monique L. Peterson, Eric D. Brennan, J. Matthew Rao, Sunil V. Dai, David Anstrom, Kevin J. Piana, Robert Popescu, Andra Sedrakyan, Art Messenger, John C. Douglas, Pamela S. TI Short- and Long-Term Outcomes of Coronary Stenting in Women Versus Men Results From the National Cardiovascular Data Registry Centers for Medicare & Medicaid Services Cohort SO CIRCULATION LA English DT Article DE coronary disease; bare metal stents; drug-eluting stents; proportional hazards models; sex factors ID DRUG-ELUTING STENTS; ACUTE MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; IN-HOSPITAL OUTCOMES; BARE-METAL STENTS; GENDER-DIFFERENCES; ARTERY-DISEASE; ELDERLY-PATIENTS; INTERVENTION; SEX AB Background-Conflicting evidence exists on sex-based outcomes after coronary stenting. Methods and Results-Data on 426 996 patients >= 65 years old (42.3% women) from the National Cardiovascular Data Registry CathPCI Registry (2004-2008) were linked to Medicare inpatient claims to compare in-hospital outcomes by sex and long-term outcomes by sex and stent type. In-hospital complications were more frequent in women than in men: death (3869 [2.2%] versus 3737 [1.6%]; adjusted odds ratio, 1.41; 95% confidence interval [CI], 1.33-1.49), myocardial infarction (2365 [1.3%] versus 2858 [1.2%]; odds ratio, 1.19; 95% CI, 1.11-1.27), bleeding (7860 [4.4%] versus 5627 [2.3%]; odds ratio, 1.86; 95% CI, 1.79-1.93), and vascular complications (2381 [1.3%] versus 1648 [0.7%]; odds ratio, 1.85; 95% CI, 1.73-1.99). At 20.4 months, women had a lower adjusted risk of death (hazard ratio [HR], 0.92; 95% CI, 0.90-0.94) but similar rates of myocardial infarction, revascularization, and bleeding. Relative to bare metal stent use, drug-eluting stent use was associated with similar improved long-term outcomes in both sexes: death (women: adjusted HR, 0.78; 95% CI, 0.76-0.81; men: HR, 0.77; 95% CI, 0.74-0.79), myocardial infarction (women: HR, 0.79; 95% CI, 0.74-0.84; men: HR, 0.81; 95% CI, 0.77-0.85), and revascularization (women: HR, 0.93; 95% CI, 0.90-0.97; men: HR, 0.91; 95% CI, 0.88-0.94). There was no interaction between sex and stent type for long-term outcomes. Conclusions-In contemporary coronary stenting, women have a slightly higher procedural risk than men but have better long-term survival. In both sexes, use of a drug-eluting stent is associated with lower long-term likelihood for death, myocardial infarction, and revascularization. (Circulation. 2012; 126: 2190-2199.) C1 [Anderson, Monique L.; Peterson, Eric D.; Brennan, J. Matthew; Rao, Sunil V.; Dai, David; Anstrom, Kevin J.; Douglas, Pamela S.] Duke Univ, Duke Clin Res Inst, Med Ctr, Durham, NC USA. [Piana, Robert] Vanderbilt Heart Inst, Nashville, TN USA. [Popescu, Andra] Christiana Care Hlth Syst, Newark, DE USA. [Sedrakyan, Art] Weill Cornell Med Coll, New York, NY USA. [Messenger, John C.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Anderson, ML (reprint author), 7022 N Pavil DUMC,POB 17969, Durham, NC 27715 USA. EM monique.anderson@duke.edu FU Agency for Healthcare Research and Quality, US Department of Health and Human Services, Rockville, MD, as part of the Cardiovascular Consortium [24-EHC-1, HHSAA290-2005-0032-TO4-WA2]; Alexion; AstraZeneca; Bristol Myers Squibb; Lilly; Innocoll Pharmaceuticals; Medtronic; Pfizer; Proctor Gamble; Cordis FX This project was sponsored by the Agency for Healthcare Research and Quality, US Department of Health and Human Services, Rockville, MD, as part of the Cardiovascular Consortium and funded under project 24-EHC-1 and work assignment number HHSAA290-2005-0032-TO4-WA2 as part of the Developing Evidence to Inform Decisions About Effectiveness (DEcIDE) program. The authors are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services. Additional support was obtained from the National Cardiovascular Data Registry, American College of Cardiology, Washington, DC. The funding organization had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.; Dr Anstrom has received research and salary support from Alexion, AstraZeneca, Bristol Myers Squibb, Lilly, Innocoll Pharmaceuticals, Medtronic, Pfizer, and Proctor & Gamble; has served on data safety monitoring boards for Pfizer and Vertex; and has provided consulting services for Pacific Therapeutics, Bristol Myers Squibb, and AstraZeneca. Dr Rao has received research funding from Cordis. Dr Messenger has served as the site principal investigator for the Resolute Study and EDUCATE study (Medtronic, Inc). The other authors report no conflicts. NR 44 TC 21 Z9 22 U1 3 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 30 PY 2012 VL 126 IS 18 BP 2190 EP + DI 10.1161/CIRCULATIONAHA.112.111369 PG 19 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 028PU UT WOS:000310435400011 PM 22988009 ER PT J AU Piccini, JP Sinner, MF Greiner, MA Hammill, BG Fontes, JD Daubert, JP Ellinor, PT Hernandez, AF Walkey, AJ Heckbert, SR Benjamin, EJ Curtis, LH AF Piccini, Jonathan P. Sinner, Moritz F. Greiner, Melissa A. Hammill, Bradley G. Fontes, Joao D. Daubert, James P. Ellinor, Patrick T. Hernandez, Adrian F. Walkey, Allan J. Heckbert, Susan R. Benjamin, Emelia J. Curtis, Lesley H. TI Outcomes of Medicare Beneficiaries Undergoing Catheter Ablation for Atrial Fibrillation SO CIRCULATION LA English DT Article DE atrial fibrillation; catheter ablation; Medicare; outcome assessment (health care) ID CONGESTIVE-HEART-FAILURE; TERM CLINICAL-EFFICACY; UNITED-STATES; ANTIARRHYTHMIC-DRUG; ADMINISTRATIVE DATA; LIFETIME RISK; STROKE RISK; COMPLICATIONS; REHOSPITALIZATIONS; PREVALENCE AB Background-Atrial fibrillation is common among older persons. Catheter ablation is increasingly used in patients for whom medical therapy has failed. Methods and Results-We conducted a retrospective cohort study of all fee-for-service Medicare beneficiaries >= 65 years of age who underwent catheter ablation for atrial fibrillation between July 1, 2007, and December 31, 2009. The main outcome measures were major complications within 30 days and mortality, heart failure, stroke, hospitalization, and repeat ablation within 1 year. A total of 15 423 patients underwent catheter ablation for atrial fibrillation. Mean age was 72 years; 41% were women; and >95% were white. For every 1000 procedures, there were 17 cases of hemopericardium requiring intervention, 8 cases of stroke, and 8 deaths within 30 days. More than 40% of patients required hospitalization within 1 year; however, atrial fibrillation or flutter was the primary discharge diagnosis in only 38.4% of cases. Eleven percent of patients underwent repeat ablation within 1 year. Renal impairment (hazard ratio, 2.07; 95% confidence interval, 1.66-2.58), age >= 80 years (hazard ratio, 3.09; 95% confidence interval, 2.32-4.11), and heart failure (hazard ratio, 2.54; 95% confidence interval, 2.07-3.13) were major risk factors for 1-year mortality. Advanced age was a major risk factor for all adverse outcomes. Conclusions-Major complications after catheter ablation for atrial fibrillation were associated with advanced age but were fairly infrequent. Few patients underwent repeat ablation. Randomized trials are needed to inform risk-benefit calculations for older persons with drug-refractory, symptomatic atrial fibrillation. (Circulation. 2012;126:2200-2207.) C1 [Piccini, Jonathan P.; Greiner, Melissa A.; Hammill, Bradley G.; Daubert, James P.; Hernandez, Adrian F.; Curtis, Lesley H.] Duke Univ, Duke Clin Res Inst, Sch Med, Durham, NC 27715 USA. [Piccini, Jonathan P.; Daubert, James P.; Hernandez, Adrian F.; Curtis, Lesley H.] Duke Univ, Dept Med, Sch Med, Durham, NC 27715 USA. [Sinner, Moritz F.; Benjamin, Emelia J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Sinner, Moritz F.] Univ Munich, Dept Med 1, Univ Hosp Grosshadern, Munich, Germany. [Fontes, Joao D.; Walkey, Allan J.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. RP Curtis, LH (reprint author), Duke Univ, Duke Clin Res Inst, Sch Med, POB 17969, Durham, NC 27715 USA. EM lesley.curtis@duke.edu RI Hernandez, Adrian F./A-7818-2016; OI Walkey, Allan/0000-0003-4685-6894; Hernandez, Adrian F./0000-0003-3387-9616; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute [R01HL102214, R01HL068986, R01HL092577, R01HL104156, K24HL105780, RC1HL101056]; National Institute on Drug Abuse [R21DA027021]; Janssen Pharmaceuticals; Biosense Webster; Biotronik; Gilead; Medtronic; Johnson Johnson FX This work was supported by grants R01HL102214, R01HL068986, R01HL092577, R01HL104156, K24HL105780, and RC1HL101056 from the National Heart, Lung, and Blood Institute and grant R21DA027021 from the National Institute on Drug Abuse. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Heart, Lung, and Blood Institute; the National Institute on Drug Abuse; or the National Institutes of Health.; Dr Piccini reports receiving research grant funding from Janssen Pharmaceuticals and consultant/advisory board income from Forest Laboratories, Johnson & Johnson, Medtronic, and Titan Pharmaceuticals. Dr Daubert reports receiving research grant funding from Biosense Webster, Biotronik, Gilead, and Medtronic; receiving honoraria from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude; serving as an expert witness for a patient with sudden cardiac death resulting from coronary artery disease; having ownership interest in Biosense Webster inherited by his wife/children in a generation-skipping trust for the children; and receiving consultant/ advisory board income from Premier, Inc. Dr Hernandez reports receiving research grant funding from Johnson & Johnson. Dr Curtis reports receiving research grant funding from Johnson & Johnson. Drs Piccini, Hernandez, and Curtis have made available online detailed listings of financial disclosures (http://www.dcri.duke.edu/about-us/conflict-of-interest/). The other authors reported no conflicts. NR 37 TC 37 Z9 39 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 30 PY 2012 VL 126 IS 18 BP 2200 EP + DI 10.1161/CIRCULATIONAHA.112.109330 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 028PU UT WOS:000310435400012 PM 23019293 ER PT J AU Das, S Aiba, T Rosenberg, M Hessler, K Xiao, CY Quintero, PA Ottaviano, FG Knight, AC Graham, EL Bostrom, P Morissette, MR del Monte, F Begley, MJ Cantley, LC Ellinor, PT Tomaselli, GF Rosenzweig, A AF Das, Saumya Aiba, Takeshi Rosenberg, Michael Hessler, Katherine Xiao, Chunyang Quintero, Pablo A. Ottaviano, Filomena G. Knight, Ashley C. Graham, Evan L. Bostroem, Pontus Morissette, Michael R. del Monte, Federica Begley, Michael J. Cantley, Lewis C. Ellinor, Patrick T. Tomaselli, Gordon F. Rosenzweig, Anthony TI Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling SO CIRCULATION LA English DT Article DE arrhythmia; heart failure; ion channels or ion channel; signal transduction ID LATE SODIUM CURRENT; CARDIAC NA+ CHANNELS; LONG-QT SYNDROME; HEART-FAILURE; AKT ACTIVATION; IN-VIVO; PROTEIN; RANOLAZINE; MODULATION; SGK AB Background-Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum-and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications. Methods and Results-We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. Conclusions-SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease. (Circulation. 2012;126:2208-2219.) C1 [Rosenzweig, Anthony] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Ctr Life Sci, Cardiovasc Inst, Boston, MA 02215 USA. [Begley, Michael J.; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct Unit, Boston, MA 02215 USA. [Begley, Michael J.; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Ctr Canc, Boston, MA 02215 USA. [Aiba, Takeshi; Tomaselli, Gordon F.] Johns Hopkins Univ, Div Cardiol, Sch Med, Baltimore, MD USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Morissette, Michael R.] W Virginia Univ, Morgantown, WV 26506 USA. [Bostroem, Pontus] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Bostroem, Pontus] Dana Farber Canc Inst, Boston, MA USA. RP Rosenzweig, A (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiovasc, Ctr Life Sci, Cardiovasc Inst, 3 Blackfan Cir, Boston, MA 02215 USA. EM arosenzw@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU Leducq Foundation Network of Research Excellence; National Institutes of Health [R01HL094677, R21HL104370, KO8HL089319, R01HL050411] FX This research was supported by a Leducq Foundation Network of Research Excellence (to Dr Rosenzweig) and the National Institutes of Health (grants R01HL094677 and R21HL104370 to Dr Rosenzweig, KO8HL089319 to Dr Das, and R01HL050411 to Dr Tomaselli). Dr Rosenzweig also gratefully acknowledges support from Judith and David Ganz. He is a principal faculty member of the Harvard Stem Cell Institute and an Associate Member of the Broad Institute. NR 43 TC 34 Z9 35 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 30 PY 2012 VL 126 IS 18 BP 2208 EP + DI 10.1161/CIRCULATIONAHA.112.115592 PG 29 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 028PU UT WOS:000310435400013 PM 23019294 ER PT J AU Shah, RV Goldfine, AB AF Shah, Ravi V. Goldfine, Allison B. TI Statins and Risk of New-Onset Diabetes Mellitus SO CIRCULATION LA English DT Editorial Material ID RANDOMIZED-TRIALS; ROSUVASTATIN; METAANALYSIS; CHOLESTEROL; THERAPY; PEOPLE C1 [Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Goldfine, Allison B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Shah, Ravi V.] Harvard Univ, Div Cardiol, Dept Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Goldfine, AB (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02115 USA. EM allison.goldfine@joslin.harvard.edu NR 7 TC 29 Z9 29 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 30 PY 2012 VL 126 IS 18 BP E282 EP E284 DI 10.1161/CIRCULATIONAHA.112.122135 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 028PU UT WOS:000310435400002 PM 23109518 ER PT J AU Ma, YB Sun, CP Haake, DA Churchill, BM Ho, CM AF Ma, Yanbao Sun, Chien-Pin Haake, David A. Churchill, Bernard M. Ho, Chih-Ming TI A high-order alternating direction implicit method for the unsteady convection-dominated diffusion problem SO INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN FLUIDS LA English DT Article DE high-order method; unsteady convection-dominated diffusion equation; ADI method; finite difference ID FINITE-DIFFERENCE APPROXIMATIONS; ADI METHOD; COMPACT SCHEME; NUMERICAL-SOLUTION; STABILITY ANALYSIS; EQUATION; COEFFICIENTS AB A high-order alternating direction implicit (ADI) method for solving the unsteady convection-dominated diffusion equation is developed. The fourth-order Pade scheme is used for the discretization of the convection terms, while the second-order Pade scheme is used for the diffusion terms. The CrankNicolson scheme and ADI factorization are applied for time integration. After ADI factorization, the two-dimensional problem becomes a sequence of one-dimensional problems. The solution procedure consists of multiple use of a one-dimensional tridiagonal matrix algorithm that produces a computationally cost-effective solver. Von Neumann stability analysis is performed to show that the method is unconditionally stable. An unsteady two-dimensional problem concerning convection-dominated propagation of a Gaussian pulse is studied to test its numerical accuracy and compare it to other high-order ADI methods. The results show that the overall numerical accuracy can reach third or fourth order for the convection-dominated diffusion equation depending on the magnitude of diffusivity, while the computational cost is much lower than other high-order numerical methods. Copyright (c) 2011 John Wiley & Sons, Ltd. C1 [Ma, Yanbao] Univ Calif Merced, Sch Engn, Merced, CA 95343 USA. [Sun, Chien-Pin; Ho, Chih-Ming] Univ Calif Los Angeles, Dept Mech & Aerosp Engn, Los Angeles, CA 90095 USA. [Haake, David A.; Churchill, Bernard M.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. [Haake, David A.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Ma, YB (reprint author), Univ Calif Merced, Sch Engn, Merced, CA 95343 USA. EM yma5@ucmerced.edu FU National Institute of Biomedical Imaging and Bioengineering, NIH [EB00127]; National Institute of Health [1R33DK070328] FX The authors gratefully acknowledge the reviewers and editor for their precious suggestions and comments. This work was supported in part by Bioengineering Research Partnership grant EB00127 (to B. M. C.) from the National Institute of Biomedical Imaging and Bioengineering, NIH, and in part by grant 1R33DK070328 (to JL) from the National Institute of Health. The authors also thank Drs Donghyun You, Samir Karaa, and Jun Zhang for great help in implementation of boundary conditions. NR 25 TC 5 Z9 5 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-2091 J9 INT J NUMER METH FL JI Int. J. Numer. Methods Fluids PD OCT 30 PY 2012 VL 70 IS 6 BP 703 EP 712 DI 10.1002/fld.2707 PG 10 WC Computer Science, Interdisciplinary Applications; Mathematics, Interdisciplinary Applications; Mechanics; Physics, Fluids & Plasmas SC Computer Science; Mathematics; Mechanics; Physics GA 008PE UT WOS:000308968200003 ER PT J AU Ames, NJ Sulima, P Ngo, T Barb, J Munson, PJ Paster, BJ Hart, TC AF Ames, Nancy J. Sulima, Pawel Ngo, Thoi Barb, Jennifer Munson, Peter J. Paster, Bruce J. Hart, Thomas C. TI A Characterization of the Oral Microbiome in Allogeneic Stem Cell Transplant Patients SO PLOS ONE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; INTENSIVE-CARE-UNIT; DENTAL PLAQUE; RESPIRATORY PATHOGENS; INFECTIOUS COMPLICATIONS; NOSOCOMIAL INFECTIONS; HOST DISEASE; COLONIZATION; MICROARRAY; PNEUMONIA AB Background: The mouth is a complex biological structure inhabited by diverse bacterial communities. The purpose of this study is to describe the effects of allogeneic stem cell transplantation on the oral microbiota and to examine differences among those patients who acquired respiratory complications after transplantation. Methodology/Principal Findings: All patients were consented at the National Institutes of Health, Clinical Center. Bacterial DNA was analyzed from patients' oral specimens using the Human Oral Microbe Identification Microarray. The specimens were collected from four oral sites in 45 allogeneic transplantation patients. Specimens were collected at baseline prior to transplantation, after transplantation at the nadir of the neutrophil count and after myeloid engraftment. If respiratory signs and symptoms developed, additional specimens were obtained. Patients were followed for 100 days post transplantation. Eleven patients' specimens were subjected to further statistical analysis. Many common bacterial genera, such as Streptococcus, Veillonella, Gemella, Granulicatella and Camplyobacter were identified as being present before and after transplantation. Five of 11 patients developed respiratory complications following transplantation and there was preliminary evidence that the oral microbiome changed in their oral specimens. Cluster analysis and principal component analysis revealed this change in the oral microbiota. Conclusions/Significance: After allogeneic transplantation, the oral bacterial community's response to a new immune system was not apparent and many of the most common core oral taxa remained unaffected. However, the oral microbiome was affected in patients who developed respiratory signs and symptoms after transplantation. The association related to the change in the oral microbiota and respiratory complications after transplantation will be validated by future studies using high throughput molecular methods. C1 [Ames, Nancy J.; Ngo, Thoi] NIH, Ctr Clin, Nursing Serv, Bethesda, MD 20892 USA. [Ames, Nancy J.; Ngo, Thoi] NIH, Ctr Clin, Patient Care Serv, Bethesda, MD 20892 USA. [Sulima, Pawel; Hart, Thomas C.] Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. [Barb, Jennifer; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Paster, Bruce J.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Paster, Bruce J.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Ames, NJ (reprint author), NIH, Ctr Clin, Nursing Serv, Bethesda, MD 20892 USA. EM names@nih.gov FU National Institute of Dental and Craniofacial Research of the National Institutes of Health, Bethesda, MD; Clinical Center Nursing and Patient Care Services of the National Institutes of Health, Bethesda, MD FX The authors acknowledge support from the Intramural Program of the National Institute of Dental and Craniofacial Research and the Clinical Center Nursing and Patient Care Services of the National Institutes of Health, Bethesda, MD. NR 45 TC 6 Z9 6 U1 0 U2 13 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 OCT 29 PY 2012 VL 7 IS 10 AR e47628 DI 10.1371/journal.pone.0047628 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300015 PM 23144704 ER PT J AU Tacutu, R Shore, DE Budovsky, A de Magalhaes, JP Ruvkun, G Fraifeld, VE Curran, SP AF Tacutu, Robi Shore, David E. Budovsky, Arie de Magalhaes, Joao Pedro Ruvkun, Gary Fraifeld, Vadim E. Curran, Sean P. TI Prediction of C. elegans Longevity Genes by Human and Worm Longevity Networks SO PLOS ONE LA English DT Article ID EXTENDS LIFE-SPAN; NEMATODE CAENORHABDITIS-ELEGANS; DIETARY RESTRICTION; MESSENGER-RNA; STRESS; DISEASE; INHIBITION; SENESCENCE; RESISTANCE; MUTATIONS AB Intricate and interconnected pathways modulate longevity, but screens to identify the components of these pathways have not been saturating. Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans. We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes. We have used C. elegans to determine whether post-developmental inactivation of these essential genes modulates lifespan. Our results suggest that the worm and human longevity networks are functionally relevant and possess a high predictive power for identifying new longevity regulators. C1 [Tacutu, Robi; Budovsky, Arie; Fraifeld, Vadim E.] Ben Gurion Univ Negev, Shraga Segal Dept Microbiol Immunol & Genet, Ctr Multidisciplinary Res Aging, IL-84105 Beer Sheva, Israel. [Shore, David E.; Ruvkun, Gary] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Shore, David E.; Ruvkun, Gary] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [de Magalhaes, Joao Pedro] Univ Liverpool, Inst Integrat Biol, Integrat Genom Ageing Grp, Liverpool L69 3BX, Merseyside, England. [Curran, Sean P.] Univ So Calif, Div Biogerontol, Davis Sch Gerontol, Los Angeles, CA USA. [Curran, Sean P.] Univ So Calif, Dept Mol & Computat Biol, Dornsife Coll Letters Arts & Sci, Los Angeles, CA USA. [Curran, Sean P.] Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. RP Fraifeld, VE (reprint author), Ben Gurion Univ Negev, Shraga Segal Dept Microbiol Immunol & Genet, Ctr Multidisciplinary Res Aging, IL-84105 Beer Sheva, Israel. EM vadim.fraifeld@gmail.com; spcurran@usc.edu RI de Magalhaes, Joao Pedro/B-4741-2010 OI de Magalhaes, Joao Pedro/0000-0002-6363-2465 FU NIH [AG032308, AG16636]; Wellcome Trust [ME050495MES]; Marie Curie International Reintegration Grant within EC-FP7; European Commission [HEALTH-F4-2008-202047] FX The research in this study was supported by NIH AG032308 to SPC and AG16636 (NIA NIH HHS/United State) to GR. JPM is grateful for support from the Wellcome Trust (ME050495MES) and from a Marie Curie International Reintegration Grant within EC-FP7. VM was partly funded by the European Commission FP7 Health Research Grant number HEALTH-F4-2008-202047. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 10 Z9 10 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 29 PY 2012 VL 7 IS 10 AR e48282 DI 10.1371/journal.pone.0048282 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300057 PM 23144747 ER PT J AU Taylor, JA Richter, CA Suzuki, A Watanabe, H Iguchi, T Coser, KR Shioda, T vom Saal, FS AF Taylor, Julia A. Richter, Catherine A. Suzuki, Atsuko Watanabe, Hajime Iguchi, Taisen Coser, Kathryn R. Shioda, Toshihiro vom Saal, Frederick S. TI Dose-Related Estrogen Effects on Gene Expression in Fetal Mouse Prostate Mesenchymal Cells SO PLOS ONE LA English DT Article ID UROGENITAL SINUS MESENCHYME; CHAIN-REACTION ASSAYS; ANDROGEN RECEPTOR; REPRODUCTIVE-ORGANS; SIGNALING PATHWAYS; RAT PROSTATE; CANCER CELLS; MALE-MICE; EXPOSURE; GROWTH AB Developmental exposure of mouse fetuses to estrogens results in dose-dependent permanent effects on prostate morphology and function. Fetal prostatic mesenchyme cells express estrogen receptor alpha (ER alpha) and androgen receptors and convert stimuli from circulating estrogens and androgens into paracrine signaling to regulate epithelial cell proliferation and differentiation. To obtain mechanistic insight into the role of different doses of estradiol (E2) in regulating mesenchymal cells, we examined E2-induced transcriptomal changes in primary cultures of fetal mouse prostate mesenchymal cells. Urogenital sinus mesenchyme cells were obtained from male mouse fetuses at gestation day 17 and exposed to 10 pM, 100 pM or 100 nM E2 in the presence of a physiological concentration of dihydrotestosterone (0.69 nM) for four days. Gene ontology studies suggested that low doses of E2 (10 pM and 100 pM) induce genes involved in morphological tissue development and sterol biosynthesis but suppress genes involved in growth factor signaling. Genes involved in cell adhesion were enriched among both up-regulated and down-regulated genes. Genes showing inverted-U-shape dose responses (enhanced by E2 at 10 pM E2 but suppressed at 100 pM) were enriched in the glycolytic pathway. At the highest dose (100 nM), E2 induced genes enriched for cell adhesion, steroid hormone signaling and metabolism, cytokines and their receptors, cell-to-cell communication, Wnt signaling, and TGF-beta signaling. These results suggest that prostate mesenchymal cells may regulate epithelial cells through direct cell contacts when estrogen level is low whereas secreted growth factors and cytokines might play significant roles when estrogen level is high. C1 [Taylor, Julia A.; Richter, Catherine A.; vom Saal, Frederick S.] Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. [Suzuki, Atsuko; Watanabe, Hajime; Iguchi, Taisen] Grad Univ Adv Studies SOKENDAI, Dept Basic Biol, Sokendai, Aichi, Japan. [Suzuki, Atsuko; Watanabe, Hajime; Iguchi, Taisen] Grad Univ Adv Studies SOKENDAI, Natl Inst Nat Sci, Natl Inst Basic Biol, Okazaki Inst Integrat Biosci, Sokendai, Aichi, Japan. [Coser, Kathryn R.; Shioda, Toshihiro] Massachusetts Gen Hosp, Ctr Canc, Mol Profiling Lab, Charlestown, MA USA. [Coser, Kathryn R.; Shioda, Toshihiro] Harvard Univ, Sch Med, Charlestown, MA USA. RP Taylor, JA (reprint author), Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. EM taylorja@missouri.edu OI Richter, Catherine/0000-0001-7322-4206 FU National Institute of Environmental Health Sciences (NIEHS) [ES11283, ES018764, 1F32ES11549]; Ministry of Education, Culture, Sports, Science and Technology; Ministry of Health Labor and Welfare, Japan; Susan G. Komen for Cure [FAS0703860, KG090515] FX This work was supported by grants from the National Institute of Environmental Health Sciences (NIEHS) (www.niehs.nih.gov/) to FVS (ES11283; ES018764) and to CR (1F32ES11549); a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (B) (http://www.mext.go.jp/english/) and a grant from the Ministry of Health Labor and Welfare, Japan (www.mhlw.go.jp/english/) to TI, and grants from Susan G. Komen for Cure (http://ww5.komen.org/researchgrants/researchandgrants.html) (FAS0703860 and KG090515) to TS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 3 Z9 3 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 29 PY 2012 VL 7 IS 10 AR e48311 DI 10.1371/journal.pone.0048311 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 032HH UT WOS:000310705300061 PM 23144751 ER PT J AU Bhatt, DL AF Bhatt, Deepak L. TI EXAMINATION of new drug-eluting stents-top of the class! SO LANCET LA English DT Editorial Material ID METAL CORONARY STENTS; RANDOMIZED-TRIALS; LATE THROMBOSIS; FOLLOW-UP; RESTENOSIS; METAANALYSIS; OUTCOMES; THERAPY C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02132 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA 02132 USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02132 USA. EM dlbhattmd@post.harvard.edu NR 13 TC 14 Z9 15 U1 0 U2 2 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 OCT 27 PY 2012 VL 380 IS 9852 BP 1453 EP 1455 DI 10.1016/S0140-6736(12)61021-6 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 026JJ UT WOS:000310272000007 PM 22951304 ER PT J AU Kamran, SC Shinagare, AB Howard, SA Hornick, JL Ramaiya, NH AF Kamran, S. C. Shinagare, A. B. Howard, S. A. Hornick, J. L. Ramaiya, N. H. TI A-Z of malignant peripheral nerve sheath tumors SO CANCER IMAGING LA English DT Review DE Malignant peripheral nerve sheath tumor; neurofibromatosis; malignant triton tumor; MRI; PET/CT ID RADIOLOGIC-PATHOLOGICAL CORRELATION; TRITON TUMORS; DIFFERENTIATION; NEUROFIBROMATOSIS; SURVIVAL; BENIGN AB This article reviews the typical and atypical locations, imaging findings, local recurrence, and metastatic pattern of malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are rare soft tissue sarcomas, commonly occur in extremities, and are often associated with neurofibromatosis. Distinction between benign and malignant tumors can be challenging on imaging. MPNSTs have a poor prognosis; however, rhabdomyoblastic differentiation (malignant triton tumor), which has imaging features similar to MPNSTs, is associated with even more aggressive behavior. C1 [Kamran, S. C.; Shinagare, A. B.; Howard, S. A.; Ramaiya, N. H.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Kamran, S. C.; Shinagare, A. B.; Howard, S. A.; Ramaiya, N. H.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Hornick, J. L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kamran, S. C.; Shinagare, A. B.; Howard, S. A.; Hornick, J. L.; Ramaiya, N. H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Shinagare, AB (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02115 USA. EM ashinagare@partners.org OI Kamran, Sophia/0000-0001-9283-6515 NR 16 TC 6 Z9 7 U1 0 U2 2 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD OCT 26 PY 2012 VL 12 IS 3 BP 475 EP 483 DI 10.1102/1470-7330.2012.0043 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 172LG UT WOS:000321004100003 PM 23108260 ER PT J AU Hull, RL Peters, MJ Perigo, SP Chan, CK Wight, TN Kinsella, MG AF Hull, Rebecca L. Peters, Michael J. Perigo, Susan Potter Chan, Christina K. Wight, Thomas N. Kinsella, Michael G. TI Overall Sulfation of Heparan Sulfate from Pancreatic Islet beta-TC3 Cells Increases Maximal Fibril Formation but Does Not Determine Binding to the Amyloidogenic Peptide Islet Amyloid Polypeptide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; FORMATION IN-VITRO; TRANSFORMING GROWTH-FACTOR-BETA-1; ALZHEIMERS-DISEASE; DIABETES-MELLITUS; FORMATION RATHER; MOUSE MODEL; PROTEOGLYCAN; PROTEINS AB Islet amyloid, a pathologic feature of type 2 diabetes, contains the islet beta-cell peptide islet amyloid polypeptide (IAPP) as its unique amyloidogenic component. Islet amyloid also contains heparan sulfate proteoglycans (HSPGs) that may contribute to amyloid formation by binding IAPP via their heparan sulfate (HS) chains. We hypothesized that beta-cells produce HS that bind IAPP via regions of highly sulfated disaccharides. Unexpectedly, HS from the beta-cell line beta-TC3 contained fewer regions of highly sulfated disaccharides compared with control normal murine mammary gland (NMuMG) cells. The proportion of HS that bound IAPP was similar in both cell lines ( 65%). The sulfation pattern of IAPP-bound versus non-bound HS from beta-TC3 cells was similar. In contrast, IAPP-bound HS from NMuMG cells contained frequent highly sulfated regions, whereas the nonbound material demonstrated fewer sulfated regions. Fibril formation from IAPP was stimulated equally by IAPP-bound beta-TC3 HS, non-bound beta-TC3 HS, and non-bound NMuMG HS but was stimulated to a greater extent by the highly sulfated IAPP-bound NMuMG HS. Desulfation of HS decreased the ability of both beta-TC3 and NMuMG HS to stimulate IAPP maximal fibril formation, but desulfated HS from both cell types still accelerated fibril formation relative to IAPP alone. In summary, neither binding to nor acceleration of fibril formation from the amyloidogenic peptide IAPP is dependent on overall sulfation in HS synthesized by beta-TC3 cells. This information will be important in determining approaches to reduce HS-IAPP interactions and ultimately prevent islet amyloid formation and its toxic effects in type 2 diabetes. C1 [Hull, Rebecca L.; Peters, Michael J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Hull, Rebecca L.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Wight, Thomas N.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Perigo, Susan Potter; Chan, Christina K.; Wight, Thomas N.; Kinsella, Michael G.] Benaroya Res Inst Virginia Mason, Hope Heart Matrix Biol Program, Seattle, WA 98101 USA. RP Hull, RL (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM rhull@u.washington.edu OI Hull, Rebecca/0000-0001-9690-4087 FU Department of Veterans Affairs, Veterans Affairs Puget Sound Health Care System (Seattle, WA); National Institutes of Health [DK74404, HL18645, HL92969, DK17047] FX This work was supported by the Department of Veterans Affairs, Veterans Affairs Puget Sound Health Care System (Seattle, WA) and National Institutes of Health Grants DK74404 (to R. L. H.), HL18645 and HL92969 (to T. N. W.), and DK17047 (to the University of Washington Diabetes Research Center). NR 38 TC 3 Z9 3 U1 0 U2 7 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 OCT 26 PY 2012 VL 287 IS 44 BP 37154 EP 37164 DI 10.1074/jbc.M112.409847 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 030RT UT WOS:000310588500049 PM 22936797 ER PT J AU Massengale, M Lu, B Pan, JJ Katz, JN Solomon, DH AF Massengale, Mei Lu, Bing Pan, John J. Katz, Jeffrey N. Solomon, Daniel H. TI Adipokine Hormones and Hand Osteoarthritis: Radiographic Severity and Pain SO PLOS ONE LA English DT Article ID KNEE; PROGRESSION; BIOMARKERS; OBESITY; LEPTIN; HIP AB Introduction: Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain. Methods: In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain. Results: The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m(2) for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R-2 = 0.00-0.04 unadjusted analysis, all p-values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R-2 = 0.36 unadjusted analysis, p-values <= 0.04). Conclusion: In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain. C1 [Massengale, Mei; Lu, Bing; Katz, Jeffrey N.; Solomon, Daniel H.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Solomon, Daniel H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Orthopaed & Arthrit Ctr Outcomes Res, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Massengale, Mei; Lu, Bing; Katz, Jeffrey N.; Solomon, Daniel H.] Harvard Univ, Sch Med, Boston, MA USA. [Pan, John J.] Brigham & Womens Hosp, Dept Radiol, Div Musculoskeletal Radiol, Boston, MA 02115 USA. [Massengale, Mei] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Massengale, M (reprint author), Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, 75 Francis St, Boston, MA 02115 USA. EM hmei@partners.org FU Harvard Catalyst; Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 RR 025758]; Harvard University; NIH [T32 AR 055885, K24 AR 055989, P60 AR 47782]; Harvard Catalyst Institutional Award FX Authors gratefully acknowledge the support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Institutes of Health Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health (NIH). MM was supported by NIH T32 AR 055885 and Harvard Catalyst Institutional Award. DHS's effort on this project was supported by the NIH (K24 AR 055989). DHS and NKK were supported by NIH P60 AR 47782. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 24 Z9 24 U1 0 U2 6 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 OCT 26 PY 2012 VL 7 IS 10 AR e47860 DI 10.1371/journal.pone.0047860 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026GL UT WOS:000310262500022 PM 23110114 ER PT J AU Rana, S Cerdeira, AS Wenger, J Salahuddin, S Lim, KH Ralston, SJ Thadhani, RI Karumanchi, SA AF Rana, Sarosh Cerdeira, Ana Sofia Wenger, Julia Salahuddin, Saira Lim, Kee-Hak Ralston, Steven J. Thadhani, Ravi I. Karumanchi, S. Ananth TI Plasma Concentrations of Soluble Endoglin versus Standard Evaluation in Patients with Suspected Preeclampsia SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANTI-ANGIOGENIC FACTORS; TYROSINE KINASE 1; MATERNAL PLASMA; ANTIANGIOGENIC FACTORS; PREGNANCY; RISK; HYPERTENSION; COMPLICATIONS; PROTEINURIA AB Background: The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks. Methods and Findings: Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009-October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25-75th centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73225.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = 20.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74). Conclusions: In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia. C1 [Rana, Sarosh; Ralston, Steven J.; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Boston, MA 02215 USA. [Rana, Sarosh; Cerdeira, Ana Sofia; Wenger, Julia; Salahuddin, Saira; Lim, Kee-Hak; Ralston, Steven J.; Thadhani, Ravi I.; Karumanchi, S. Ananth] Harvard Univ, Sch Med, Boston, MA USA. [Rana, Sarosh; Salahuddin, Saira; Lim, Kee-Hak; Ralston, Steven J.; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Cerdeira, Ana Sofia; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Cerdeira, Ana Sofia] Gulbenkian Programme Adv Med Educ, Lisbon, Portugal. [Wenger, Julia; Thadhani, Ravi I.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. [Lim, Kee-Hak] Boston Maternal Fetal Med Grp, Boston, MA USA. [Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Rana, S (reprint author), Beth Israel Deaconess Med Ctr, Div Maternal Fetal Med, Boston, MA 02215 USA. EM srana1@bidmc.harvard.edu FU National Institutes of Health/National Institute of Child Health and Human Development (NIH/NICHD); Burroughs Wellcome Fund Clinical Scientist Award; Howard Hughes Medical Institute; Aggamin LLC FX This work was supported by a KO8 award from National Institutes of Health/National Institute of Child Health and Human Development (NIH/NICHD) (to SR), a Burroughs Wellcome Fund Clinical Scientist Award (to SAK) and the Howard Hughes Medical Institute (to SAK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have read the journal's policy and have the following conflicts: Dr. Karumanchi is co-inventor on multiple patents (USPTO #7,740,849, #7,407,658, #7,335,362, #7,344,892) related to the use of angiogenic markers for the diagnosis, prediction and therapy of preeclampsia). Dr. Karumanchi reports having served as a consultant to Roche and Beckman Coulter and has financial interest in Aggamin LLC. Dr. Thadhani is a co-inventor on a patent (USPTO #7,344,892) related to the use of angiogenic proteins for the prediction of preeclampsia and has financial interest in Aggamin LLC. NR 29 TC 20 Z9 20 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 OCT 26 PY 2012 VL 7 IS 10 AR e48259 DI 10.1371/journal.pone.0048259 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026GL UT WOS:000310262500054 PM 23110221 ER PT J AU Treister, N Duncan, C Cutler, C Lehmann, L AF Treister, Nathaniel Duncan, Christine Cutler, Corey Lehmann, Leslie TI How we treat oral chronic graft-versus-host disease SO BLOOD LA English DT Review ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; WORKING GROUP-REPORT; PILOCARPINE HYDROCHLORIDE; TOPICAL TACROLIMUS; CLINICAL-TRIALS; CHRONIC GVHD; RANDOMIZED TRIAL; DENDRITIC CELLS AB Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation that is associated with a diminished quality of life. The oral cavity is frequently affected, with a wide variety of signs and symptoms that can result in significant short-and long-term complications ranging from mucosal sensitivity and limited oral intake to secondary malignancy and early death. This article provides a comprehensive approach to the diagnosis and clinical management of patients with oral cGVHD, with particular attention to differential diagnosis, control of symptoms, and prevention of and screening for secondary complications. The clinical considerations and recommendations presented are intended to be practical and relevant for all clinicians involved in the care of patients with oral cGVHD, with the ultimate goal of improving care and outcomes. (Blood. 2012;120(17):3407-3418) C1 [Treister, Nathaniel] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02120 USA. [Treister, Nathaniel] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Duncan, Christine; Lehmann, Leslie] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Duncan, Christine; Cutler, Corey; Lehmann, Leslie] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Cutler, Corey] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Treister, N (reprint author), Brigham & Womens Hosp, Div Oral Med & Dent, 1620 Tremont St,3rd Fl, Boston, MA 02120 USA. EM ntreister@partners.org NR 76 TC 19 Z9 19 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 25 PY 2012 VL 120 IS 17 BP 3407 EP 3418 DI 10.1182/blood-2012-05-393389 PG 12 WC Hematology SC Hematology GA 044MN UT WOS:000311623800007 PM 22898605 ER PT J AU Davids, MS Deng, J Wiestner, A Lannutti, BJ Wang, LL Wu, CJ Wilson, WH Brown, JR Letai, A AF Davids, Matthew S. Deng, Jing Wiestner, Adrian Lannutti, Brian J. Wang, Lili Wu, Catherine J. Wilson, Wyndham H. Brown, Jennifer R. Letai, Anthony TI Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia SO BLOOD LA English DT Article ID B-CELLS; CHEMOKINE RECEPTORS; EXPRESSION; INHIBITOR; CAL-101; DISEASE; SIGNALS; MECHANISMS; SURVIVAL; CXCR4 AB Stroma induces treatment resistance in chronic lymphocytic leukemia (CLL), possibly because of alterations in the BCL-2 family of proteins, which are key regulators of apoptosis. We previously developed BH3 profiling, a functional assay that assesses mitochondrial depolarization in response to BH3-only peptides, to measure "apoptotic priming," the proximity of a cell to the apoptotic threshold. In the present study, we use BH3 profiling to show that CLL cells from the PB are highly primed. Increased priming is associated with improved clinical response and, unexpectedly, with unmutated IGHV status. Coculturing CLL cells in vitro with stroma decreases priming. Using matched PB, BM, and lymph node compartment samples, we found in vivo that BM-derived CLL cells are the least primed. CLL cells cocultured with stroma were treated with the PI3K delta-isoform inhibitor CAL-101 (GS1101). CAL-101 caused CLL cell de-adhesion, leading to increased CLL cell priming. Stimulation of CLL cells with anti-IgM or CXCL12 caused decreased priming that could be reversed by CAL-101. Our results show that inhibition of stromal interactions leading to displacement of CLL cells into the blood by CAL-101 in vivo may increase CLL cell priming, suggesting a mechanism by which agents inducing lymphocyte redistribution might facilitate improved clinical response when used in combination with other therapies. (Blood. 2012;120(17):3501-3509) C1 [Davids, Matthew S.; Deng, Jing; Wang, Lili; Wu, Catherine J.; Brown, Jennifer R.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Wiestner, Adrian] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lannutti, Brian J.] Gilead Sci Inc, Seattle, WA USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM anthony_letai@dfci.harvard.edu FU FLAMES Fund of the Pan-Mass Challenge; National Institutes of Health [RO1CA129974]; Ruth L. Kirschstein National Research Service Award T32 National Cancer Institute grant; Friends of the Dana-Farber Cancer Institute; National Institutes of Health; National Heart, Lung, and Blood Institute; National Cancer Institute; American Association of Cancer Research/Stand Up To Cancer Innovative Research Grant; Gilead Sciences FX This work was funded by the FLAMES Fund of the Pan-Mass Challenge, the National Institutes of Health (RO1CA129974), a Ruth L. Kirschstein National Research Service Award T32 National Cancer Institute grant, and the Friends of the Dana-Farber Cancer Institute. M. S. D. is a Leukemia & Lymphoma Society Special Fellow in Clinical Research and a recipient of an National Institutes of Health Loan Repayment Program award. A. W. and W. H. W. are supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the National Cancer Institute, respectively. C. J. W. is a Damon Runyon Cancer Research Foundation Clinical Investigator and a recipient of an American Association of Cancer Research/Stand Up To Cancer Innovative Research Grant. J. R. B. is a Leukemia & Lymphoma Society Scholar in Clinical Research and a Scholar of the American Society of Hematology. A. L. is a Leukemia & Lymphoma Society Scholar and a Scholar of the American Society of Hematology.; B.J.L. is an employee of Gilead Sciences. J.R.B. was a paid consultant for Calistoga Pharmaceuticals before its acquisition by Gilead Sciences. A. L. is a cofounder of, and formerly a paid advisor to, Eutropics Pharmaceuticals, which has purchased a license to BH3 profiling from Dana-Farber Cancer Institute. A. L. and the Dana-Farber Cancer Institute have a patent relating to the use of BH3 profiling in predicting chemosensitivity. The remaining authors declare no competing financial interests. NR 28 TC 51 Z9 51 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 25 PY 2012 VL 120 IS 17 BP 3501 EP 3509 DI 10.1182/blood-2012-02-414060 PG 9 WC Hematology SC Hematology GA 044MN UT WOS:000311623800017 PM 22955911 ER PT J AU Cea, M Cagnetta, A Fulciniti, M Tai, YT Hideshima, T Chauhan, D Roccaro, A Sacco, A Calimeri, T Cottini, F Jakubikova, J Kong, SY Patrone, F Nencioni, A Gobbi, M Richardson, P Munshi, N Anderson, KC AF Cea, Michele Cagnetta, Antonia Fulciniti, Mariateresa Tai, Yu-Tzu Hideshima, Teru Chauhan, Dharminder Roccaro, Aldo Sacco, Antonio Calimeri, Teresa Cottini, Francesca Jakubikova, Jana Kong, Sun-Young Patrone, Franco Nencioni, Alessio Gobbi, Marco Richardson, Paul Munshi, Nikhil Anderson, Kenneth C. TI Targeting NAD(+) salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition SO BLOOD LA English DT Article ID NICOTINAMIDE ADENINE-DINUCLEOTIDE; ANTITUMOR-ACTIVITY; MOLECULAR-MECHANISMS; MAMMALIAN TARGET; BONE-MARROW; CANCER; NAMPT; METABOLISM; DEPLETION; RAPAMYCIN AB Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach. (Blood. 2012;120(17):3519-3529) C1 [Cea, Michele; Cagnetta, Antonia; Fulciniti, Mariateresa; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Roccaro, Aldo; Sacco, Antonio; Calimeri, Teresa; Cottini, Francesca; Jakubikova, Jana; Kong, Sun-Young; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Univ, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Sch Med, Boston, MA 02115 USA. [Cea, Michele; Cagnetta, Antonia; Fulciniti, Mariateresa; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Roccaro, Aldo; Sacco, Antonio; Calimeri, Teresa; Cottini, Francesca; Jakubikova, Jana; Kong, Sun-Young; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Univ, Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Sch Med, Boston, MA 02115 USA. [Cea, Michele; Patrone, Franco; Nencioni, Alessio] Azienda Osped Univ San Martino IST, Ist Ricovero & Cura Carattere Sci, Dept Internal Med, Genoa, Italy. [Cagnetta, Antonia; Gobbi, Marco] Azienda Osped Univ San Martino IST, Ist Ricovero & Cura Carattere Sci, Dept Hematol & Oncol, Genoa, Italy. [Kong, Sun-Young] Natl Canc Ctr, Res Inst & Hosp, Goyang, South Korea. RP Cea, M (reprint author), Harvard Univ, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Sch Med, M551,450 Brookline Ave, Boston, MA 02115 USA. EM michele_cea@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu RI Sacco, Antonio/K-4681-2016; OI Sacco, Antonio/0000-0003-2945-9416; Roccaro, Aldo/0000-0002-1872-5128 FU National Institutes of Health [RO-1 50947, RO-1 73878]; DF/HCC SPORE in Multiple Myeloma [P-50100707]; American Italian Cancer Foundation; International Multiple Myeloma Foundation; Associazione Cristina Bassi; Associazione Italiana per la Ricerca sul Cancro [START-UP P-6108] FX This work was supported by National Institutes of Health (grants RO-1 50947, RO-1 73878), DF/HCC SPORE in Multiple Myeloma (P-50100707); American Italian Cancer Foundation (M. C.); International Multiple Myeloma Foundation and Associazione Cristina Bassi (A. C.); and Associazione Italiana per la Ricerca sul Cancro (START-UP P-6108 A. N.). K. C. A. is an American Cancer Society Clinical Research Professor. NR 45 TC 59 Z9 62 U1 2 U2 13 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 OCT 25 PY 2012 VL 120 IS 17 BP 3519 EP 3529 DI 10.1182/blood-2012-03-416776 PG 11 WC Hematology SC Hematology GA 044MN UT WOS:000311623800019 PM 22955917 ER PT J AU Kumar, S Xu, JY Perkins, C Guo, FK Snapper, S Finkelman, FD Zheng, Y Filippi, MD AF Kumar, Sachin Xu, Juying Perkins, Charles Guo, Fukun Snapper, Scott Finkelman, Fred D. Zheng, Yi Filippi, Marie-Dominique TI Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules SO BLOOD LA English DT Article ID SRC FAMILY KINASES; SIGNAL-TRANSDUCTION; CELL-MIGRATION; LEADING-EDGE; POLARITY; ACTIVATION; CHEMOTAXIS; POLARIZATION; ADHESION; DEFICIENCY AB Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. Our study reveals a new function for WASp in the control of neutrophil polarity via crosstalk between CD11b and microtubules. (Blood. 2012;120(17):3563-3574) C1 [Kumar, Sachin; Xu, Juying; Guo, Fukun; Zheng, Yi; Filippi, Marie-Dominique] Cincinnati Childrens Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Perkins, Charles; Finkelman, Fred D.] Univ Cincinnati, Coll Med, Dept Internal Med, Cincinnati, OH USA. [Perkins, Charles; Finkelman, Fred D.] Cincinnati Childrens Res Fdn, Div Immunobiol, Cincinnati, OH 45229 USA. [Perkins, Charles; Finkelman, Fred D.] Cincinnati Vet Affairs Med Ctr, Dept Med, Cincinnati, OH USA. [Snapper, Scott] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Gastrointestinal Unit, Boston, MA 02114 USA. [Snapper, Scott] Harvard Univ, Sch Med, Boston, MA USA. RP Filippi, MD (reprint author), Cincinnati Childrens Res Fdn, Div Expt Hematol & Canc Biol, S7-605,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM marie-dominique.filippi@cchmc.org RI Zheng, Yi/J-7235-2015 OI Zheng, Yi/0000-0001-7089-6074 FU NIH [HL090676-MDF, 5P01 HL059561-11-SS] FX The work was supported by NIH (HL090676-MDF; 5P01 HL059561-11-SS). NR 50 TC 25 Z9 26 U1 6 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 25 PY 2012 VL 120 IS 17 BP 3563 EP 3574 DI 10.1182/blood-2012-04-426981 PG 12 WC Hematology SC Hematology GA 044MN UT WOS:000311623800023 PM 22932798 ER PT J AU Halloran, J Hussong, SA Burbank, R Podlutskaya, N Fischer, KE Sloane, LB Austad, SN Strong, R Richardson, A Hart, MJ Galvan, V AF Halloran, J. Hussong, S. A. Burbank, R. Podlutskaya, N. Fischer, K. E. Sloane, L. B. Austad, S. N. Strong, R. Richardson, A. Hart, M. J. Galvan, V. TI CHRONIC INHIBITION OF MAMMALIAN TARGET OF RAPAMYCIN BY RAPAMYCIN MODULATES COGNITIVE AND NON-COGNITIVE COMPONENTS OF BEHAVIOR THROUGHOUT LIFESPAN IN MICE SO NEUROSCIENCE LA English DT Article DE mammalian target of rapamycin; memory; depression; anxiety; brain aging; monoamines ID CALORIC RESTRICTION; ALZHEIMERS-DISEASE; AMYLOID-BETA; MOUSE MODEL; MTOR; ANXIETY; MEMORY; SEROTONIN; MIDBRAIN; DEFICITS AB Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Halloran, J.; Hussong, S. A.; Burbank, R.; Podlutskaya, N.; Fischer, K. E.; Sloane, L. B.; Austad, S. N.; Strong, R.; Richardson, A.; Hart, M. J.; Galvan, V.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst, San Antonio, TX 78245 USA. [Halloran, J.; Hussong, S. A.; Burbank, R.; Fischer, K. E.; Galvan, V.] Dept Physiol, San Antonio, TX 78229 USA. [Hussong, S. A.; Podlutskaya, N.; Austad, S. N.; Richardson, A.] Dept Cell & Struct Biol, San Antonio, TX 78229 USA. [Strong, R.] Dept Pharmacol, San Antonio, TX 78229 USA. [Hart, M. J.] Dept Mol Med, San Antonio, TX 78245 USA. [Strong, R.; Richardson, A.] Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. [Strong, R.; Richardson, A.] Audie L Murphy Div, S Texas Vet Hlth Care Network, Res Serv, San Antonio, TX 78229 USA. RP Galvan, V (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, MSC 7755,15355 Lambda Dr, San Antonio, TX 78245 USA. EM galvanv@uthscsa.edu FU Alzheimer's Association [NIRG 04-1054]; New Scholar Award in Aging from the Ellison Medical Foundation [AG-NS-0726-10]; University Research Council Award from UTHSCSA; San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging; NIH Recovery Act Grand Opportunities "GO" Grant [RC2AG036613]; [T32AG21890] FX This work was supported by NIRG 04-1054 from the Alzheimer's Association, AG-NS-0726-10 New Scholar Award in Aging from the Ellison Medical Foundation, and a University Research Council Award from UTHSCSA to VG, the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging to AR and RS, the RC2AG036613 NIH Recovery Act Grand Opportunities "GO" Grant to AR, and T32AG21890 to SAH.; The authors thank Ms. Katrine Krueger for excellent administrative assistance. We are also grateful to Dr. Elisabeth Fernandez and to Ms. Xiang Bai for their help with monoamine measurements, and to Ms. Vanessa Soto and Mr. John Ramos and to the South Texas Center for Biology in Medicine Animal Facility staff for excellent animal care. This work was supported in part by the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging (AR and RS), RC2AG036613 NIH Recovery Act Grand Opportunities "GO" Grant to AR, and by NIRG 04-1054 from the Alzheimer's Association, AG-NS-0726-10 New Scholar Award in Aging from the Ellison Medical Foundation, and a University Research Council Award from UTHSCSA to VG. NR 55 TC 80 Z9 84 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 25 PY 2012 VL 223 BP 102 EP 113 DI 10.1016/j.neuroscience.2012.06.054 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 018VM UT WOS:000309694700011 PM 22750207 ER PT J AU Bonab, AA Fricchione, JG Gorantla, S Vitalo, AG Auster, ME Levine, SJ Scichilone, JM Hegde, M Foote, W Fricchione, GL Denninger, JW Yarmush, DM Fischman, AJ Yarmush, ML Levine, JB AF Bonab, A. A. Fricchione, J. G. Gorantla, S. Vitalo, A. G. Auster, M. E. Levine, S. J. Scichilone, J. M. Hegde, M. Foote, W. Fricchione, G. L. Denninger, J. W. Yarmush, D. M. Fischman, A. J. Yarmush, M. L. Levine, J. B. TI ISOLATION REARING SIGNIFICANTLY PERTURBS BRAIN METABOLISM IN THE THALAMUS AND HIPPOCAMPUS SO NEUROSCIENCE LA English DT Article DE PET; FDG; IEG; brain; isolation rearing; childhood adversity; biomarker; stress ID MEDIAL PREFRONTAL CORTEX; ISOLATION-REARED RATS; POSTWEANING SOCIAL-ISOLATION; EARLY GENE-EXPRESSION; SIZED SPINY NEURONS; PREPULSE INHIBITION; ENVIRONMENTAL ENRICHMENT; ACOUSTIC STARTLE; DEFICITS; EXTINCTION AB Psychosocial neglect during childhood severely impairs both behavioral and physical health. The isolation rearing model in rodents has been employed by our group and others to study this clinical problem at a basic level. We previously showed that immediate early gene (IEG) expression in the hippocampus and medial prefrontal cortex (mPFC) is decreased in isolation-reared (IR) compared to group-reared (OR) rats. In the current study, we sought to evaluate: (1) whether these changes in IEG expression would be detected by the measurement of brain glucose metabolism using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and (2) whether PET FDG could illuminate other brain regions with different glucose metabolism in IR compared to GR rats. We found that there were significant differences in FDG uptake in the hippocampus that were consistent with our findings for IEG expression (decreased mean FDG uptake in IR rats). In contrast, in the mPFC, the FDG uptake between IR and OR rats did not differ. Finally, we found decreased mean FDG uptake in the thalamus of the IR rats, a region we had not previously examined. The results suggest that PET FOG has the potential to be utilized as a biomarker of molecular changes in the hippocampus. Further, the differences found in thalamic brain FDG uptake suggest that further investigation of this region at the molecular and cellular levels may provide an important insight into the neurobiological basis of the adverse clinical outcomes found in children exposed to psychosocial deprivation. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Levine, J. B.] Shriners Hosp Children, Ctr Engn & Med, Boston, MA 02114 USA. [Fricchione, J. G.; Gorantla, S.; Vitalo, A. G.; Auster, M. E.; Levine, S. J.; Scichilone, J. M.; Foote, W.; Fricchione, G. L.; Denninger, J. W.; Levine, J. B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Hegde, M.; Yarmush, D. M.; Yarmush, M. L.; Levine, J. B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Bonab, A. A.] Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. [Fricchione, J. G.; Gorantla, S.; Vitalo, A. G.; Auster, M. E.; Levine, S. J.; Scichilone, J. M.; Foote, W.; Fricchione, G. L.; Denninger, J. W.; Levine, J. B.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. [Fricchione, J. G.; Gorantla, S.; Vitalo, A. G.; Auster, M. E.; Levine, S. J.; Scichilone, J. M.; Hegde, M.; Yarmush, D. M.; Yarmush, M. L.; Levine, J. B.] Massachusetts Gen Hosp, Ctr Engn & Med, Boston, MA 02114 USA. [Bonab, A. A.; Hegde, M.; Foote, W.; Fricchione, G. L.; Denninger, J. W.; Yarmush, D. M.; Fischman, A. J.; Yarmush, M. L.; Levine, J. B.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Yarmush, M. L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08855 USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, Ctr Engn & Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org; jblevine@partners.org RI Hegde, Manjunath/M-3038-2014 OI Hegde, Manjunath/0000-0002-5396-2241 FU John Henry Foundation; Benson-Henry Institute (BHI) for Mind Body Medicine at Massachusetts General Hospital; Medical Research Programs of Shriners Burns Hospital for Children (Boston) FX The John Henry Foundation and The Benson-Henry Institute (BHI) for Mind Body Medicine at Massachusetts General Hospital; The Medical Research Programs of Shriners Burns Hospital for Children (Boston). The John Henry Foundation provides research funding to the BHI. The John Henry Foundation itself had no role in study design, data collection, analysis, or decision to publish, or in the preparation of the manuscript. NR 57 TC 2 Z9 2 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD OCT 25 PY 2012 VL 223 BP 457 EP 464 DI 10.1016/j.neuroscience.2012.07.032 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 018VM UT WOS:000309694700044 PM 22835621 ER PT J AU Liao, XY Lochhead, P Nishihara, R Morikawa, T Kuchiba, A Yamauchi, M Imamura, Y Qian, ZR Baba, Y Shima, K Sun, RF Nosho, K Meyerhardt, JA Giovannucci, E Fuchs, CS Chan, AT Ogino, S AF Liao, Xiaoyun Lochhead, Paul Nishihara, Reiko Morikawa, Teppei Kuchiba, Aya Yamauchi, Mai Imamura, Yu Qian, Zhi Rong Baba, Yoshifumi Shima, Kaori Sun, Ruifang Nosho, Katsuhiko Meyerhardt, Jeffrey A. Giovannucci, Edward Fuchs, Charles S. Chan, Andrew T. Ogino, Shuji TI Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; MICROSATELLITE INSTABILITY; COLON-CANCER; PERSONALIZED MEDICINE; RANDOMIZED-TRIALS; BRAF MUTATION; RISK; METASTASIS; INHIBITION AB BACKGROUND Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers. METHODS We obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1. RESULTS Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P = 0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P = 0.76 by the log-rank test; P = 0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P = 0.96 by the log-rank test; P = 0.07 for interaction). CONCLUSIONS Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.) C1 [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Liao, Xiaoyun; Lochhead, Paul; Nishihara, Reiko; Kuchiba, Aya; Yamauchi, Mai; Imamura, Yu; Qian, Zhi Rong; Sun, Ruifang; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Liao, Xiaoyun; Lochhead, Paul; Nishihara, Reiko; Kuchiba, Aya; Yamauchi, Mai; Imamura, Yu; Qian, Zhi Rong; Sun, Ruifang; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Chan, Andrew T.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Giovannucci, Edward; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Fuchs, Charles S.; Chan, Andrew T.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Morikawa, Teppei] Tokyo Univ Hosp, Dept Pathol, Tokyo 113, Japan. [Baba, Yoshifumi] Kumamoto Univ, Dept Surg Gastroenterol, Kumamoto, Japan. [Shima, Kaori] Kagoshima Univ, Dept Oral Pathol, Kagoshima 890, Japan. [Nosho, Katsuhiko] Sapporo Med Univ, Dept Internal Med 1, Sapporo, Hokkaido, Japan. RP Chan, AT (reprint author), Massachusetts Gen Hosp, Div Gastroenterol, 55 Fruit St, Boston, MA 02115 USA. EM achan@partners.org; shuji_ogino@dfci.harvard.edu OI Qian, Zhi rong/0000-0003-1633-4120 FU National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, R01 CA149222, R01 CA137178, R01 CA151993]; Bennett Family Fund; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Frank Knox Memorial Fellowship at Harvard University; Chief Scientist Office, Scotland; Damon Runyon Clinical Investigator Award FX Supported by grants from the National Institutes of Health (P01 CA87969 and P01 CA55075; P50 CA127003, to Dr. Fuchs; R01 CA149222, to Dr. Meyerhardt; R01 CA137178, to Dr. Chan; and R01 CA151993, to Dr. Ogino), the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; by the Frank Knox Memorial Fellowship at Harvard University and a fellowship from the Chief Scientist Office, Scotland (to Dr. Lochhead); and by a Damon Runyon Clinical Investigator Award (to Dr. Chan). NR 40 TC 320 Z9 333 U1 5 U2 41 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 25 PY 2012 VL 367 IS 17 BP 1596 EP 1606 DI 10.1056/NEJMoa1207756 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 024TO UT WOS:000310131700006 PM 23094721 ER PT J AU Weeks, JC Catalano, PJ Cronin, A Finkelman, MD Mack, JW Keating, NL Schrag, D AF Weeks, Jane C. Catalano, Paul J. Cronin, Angel Finkelman, Matthew D. Mack, Jennifer W. Keating, Nancy L. Schrag, Deborah TI Patients' Expectations about Effects of Chemotherapy for Advanced Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CELL LUNG-CANCER; ADVANCED COLORECTAL-CANCER; CARE OUTCOMES RESEARCH; QUALITY-OF-LIFE; SURVEILLANCE CONSORTIUM; MULTIPLE IMPUTATION; RANDOMIZED-TRIAL; PALLIATIVE CARE; SUPPORTIVE CARE; TREATMENT GOALS AB Background Chemotherapy for metastatic lung or colorectal cancer can prolong life by weeks or months and may provide palliation, but it is not curative. Methods We studied 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study (a national, prospective, observational cohort study) who were alive 4 months after diagnosis and received chemotherapy for newly diagnosed metastatic (stage IV) lung or colorectal cancer. We sought to characterize the prevalence of the expectation that chemotherapy might be curative and to identify the clinical, sociodemographic, and health-system factors associated with this expectation. Data were obtained from a patient survey by professional interviewers in addition to a comprehensive review of medical records. Results Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer. In multivariable logistic regression, the risk of reporting inaccurate beliefs about chemotherapy was higher among patients with colorectal cancer, as compared with those with lung cancer (odds ratio, 1.75; 95% confidence interval [CI], 1.29 to 2.37); among nonwhite and Hispanic patients, as compared with non-Hispanic white patients (odds ratio for Hispanic patients, 2.82; 95% CI, 1.51 to 5.27; odds ratio for black patients, 2.93; 95% CI, 1.80 to 4.78); and among patients who rated their communication with their physician very favorably, as compared with less favorably (odds ratio for highest third vs. lowest third, 1.90; 95% CI, 1.33 to 2.72). Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy. Conclusions Many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative, which could compromise their ability to make informed treatment decisions that are consonant with their preferences. Physicians may be able to improve patients' understanding, but this may come at the cost of patients' satisfaction with them. (Funded by the National Cancer Institute and others.) C1 [Weeks, Jane C.; Cronin, Angel; Schrag, Deborah] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Catalano, Paul J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Mack, Jennifer W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Finkelman, Matthew D.] Tufts Univ, Sch Dent Med, Dept Publ Hlth & Community Serv, Boston, MA 02111 USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Weeks, JC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM jane_weeks@dfci.harvard.edu FU National Cancer Institute (NCI) [U01 CA093344]; NCI; Dana-Farber Cancer Institute/Cancer Research Network [U01 CA093332]; Harvard Medical School/Northern California Cancer Center [U01 CA093324, RAND/UCLA U01 CA093348]; University of Alabama at Birmingham [U01 CA093329]; University of Iowa [U01 CA093339]; University of North Carolina [U01 CA093326]; Department of Veterans Affairs [CRS 02-164] FX Supported by grants from the National Cancer Institute (NCI) to the Statistical Coordinating Center (U01 CA093344) and the NCI-supported Primary Data Collection and Research Centers, Dana-Farber Cancer Institute/Cancer Research Network (U01 CA093332), Harvard Medical School/Northern California Cancer Center (U01 CA093324, RAND/UCLA U01 CA093348), University of Alabama at Birmingham (U01 CA093329), University of Iowa (U01 CA093339), and University of North Carolina (U01 CA093326); and by a Department of Veterans Affairs grant to the Durham Veterans Affairs Medical Center (CRS 02-164). NR 39 TC 295 Z9 297 U1 9 U2 54 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 25 PY 2012 VL 367 IS 17 BP 1616 EP 1625 DI 10.1056/NEJMoa1204410 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 024TO UT WOS:000310131700008 PM 23094723 ER PT J AU Pallais, JC Blake, MA Deshpande, V AF Pallais, J. Carl Blake, Michael A. Deshpande, Vikram TI Case 33-2012: A 34-Year-Old Woman with Episodic Paresthesias and Altered Mental Status after Childbirth Pancreatic neuroendocrine neoplasm, grade 1 (insulinoma) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PERIPHERAL GLUCOSE-UPTAKE; HYPOGLYCEMIC DISORDERS; MANAGEMENT; DIAGNOSIS; TUMORS; UNAWARENESS; MECHANISMS; PHYSIOLOGY; PREGNANCY; WOMEN C1 [Pallais, J. Carl] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Pallais, J. Carl] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Blake, Michael A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Pallais, JC (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 35 TC 1 Z9 1 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 25 PY 2012 VL 367 IS 17 BP 1637 EP 1646 DI 10.1056/NEJMcpc1114037 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 024TO UT WOS:000310131700012 PM 23094726 ER PT J AU Hoffmann, U Peacock, WF Udelson, JE AF Hoffmann, Udo Peacock, W. Frank Udelson, James E. TI Coronary CT Angiography for Acute Chest Pain REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Peacock, W. Frank] Baylor Coll Med, Houston, TX 77030 USA. [Udelson, James E.] Tufts Med Ctr, Boston, MA USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM uhoffmann@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 25 PY 2012 VL 367 IS 17 BP 1666 EP 1666 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 024TO UT WOS:000310131700025 ER PT J AU Gala, MK AF Gala, Manish K. TI Case 23-2012: A Man with Abdominal Pain and Weight Loss Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gala, MK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 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 OCT 25 PY 2012 VL 367 IS 17 BP 1671 EP 1672 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 024TO UT WOS:000310131700035 ER PT J AU Ugai, H Dobbins, GC Wang, MH Le, LP Matthews, DA Curiel, DT AF Ugai, Hideyo Dobbins, George C. Wang, Minghui Le, Long P. Matthews, David A. Curiel, David T. TI Adenoviral protein V promotes a process of viral assembly through nucleophosmin 1 SO VIROLOGY LA English DT Article DE Adenovirus; Adenoviral assembly; Cancer gene therapy; Nucleophosmin 1; Protein V ID NUCLEOLAR PROTEIN; NUCLEAR-MATRIX; DNA-REPLICATION; GENE-EXPRESSION; NUCLEOPROTEIN CORES; ATM ACTIVATION; INFECTED-CELLS; RIBOSOMAL-RNA; MINUTE VIRUS; IN-VIVO AB Adenoviral infection induces nucleoplasmic redistribution of a nucleolar nucleophosmin 1/NPM1/B23.1. NPM1 is preferentially localized in the nucleoli of normal cells, whereas it is also present at the nuclear matrix in cancer cells. However, the biological roles of NPM1 during infection are unknown. Here, by analyzing a pV-deletion mutant, Ad5-dV/TSB, we demonstrate that pV promotes the NPM1 translocation from the nucleoli to the nucleoplasm in normal cells, and the NPM1 translocation is correlated with adenoviral replication. Lack of pV causes a dramatic reduction of adenoviral replication in normal cells, but not cancer cells, and Ad5-dV/TSB was defective in viral assembly in normal cells. NPM1 knockdown inhibits adenoviral replication, suggesting an involvement of NPM1 in adenoviral biology. Further, we show that NPM1 interacts with empty adenovirus particles which are an intermediate during virion maturation by immunoelectron microscopy. Collectively, these data implicate that pV participates in a process of viral assembly through NPM1. (C) 2012 Elsevier Inc. All rights reserved. C1 [Ugai, Hideyo; Dobbins, George C.; Wang, Minghui; Curiel, David T.] Univ Alabama Birmingham, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Dobbins, George C.; Wang, Minghui; Curiel, David T.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Dobbins, George C.; Wang, Minghui; Curiel, David T.] Univ Alabama Birmingham, Dept Pathol, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Ugai, Hideyo; Dobbins, George C.; Wang, Minghui; Curiel, David T.] Univ Alabama Birmingham, Dept Surg, Div Human Gene Therapy, Birmingham, AL 35294 USA. [Curiel, David T.] Univ Alabama Birmingham, Gene Therapy Ctr, Birmingham, AL 35294 USA. [Le, Long P.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Matthews, David A.] Sch Cellular & Mol Med, Bristol BS8 1TD, Avon, England. RP Curiel, DT (reprint author), Washington Univ, Sch Med, Dept Radiat Oncol, Div Canc Biol, St Louis, MO 63108 USA. EM dcuriel@radonc.wustl.edu OI Matthews, David/0000-0003-4611-8795 FU Susan G. Komen for the Cure [PDF0707736, KG100194]; Wellcome Trust [083604]; National Institutes of Health [T32-NS048039, R01CA121187] FX We thank Dr. Roger Y. Tsien (University of California at San Diego) for providing the mRFP1 construct, and Drs A. J. Levine (The Cancer Institute of New Jersey), W. S. M. Wold (St. Louis University), T. Shenk (Princeton University) for providing antibodies against adenoviral proteins. We are also grateful to Drs. Melissa F. Chimento and Olga Borkhsenious for technical support with transmission electron microscopy at the High Resolution Imaging Facility in University of Alabama at Birmingham and School of Veterinary Medicine Microscopy Center in Louisiana State University, respectively. This work was supported by grants from Susan G. Komen for the Cure PDF0707736 (Dr. Hideyo Ugai), Susan G. Komen for the Cure KG100194 (Drs. David T. Curiel and Hideyo Ugai), Grant number 083604 from the Wellcome Trust (Dr. David A Matthews), grant T32-NS048039 from the National Institutes of Health (Dr. George C Dobbins), and grant R01CA121187 from the National Institutes of Health (Dr. David T. Curiel). NR 77 TC 10 Z9 11 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 25 PY 2012 VL 432 IS 2 BP 283 EP 295 DI 10.1016/j.virol.2012.05.028 PG 13 WC Virology SC Virology GA 996UZ UT WOS:000308121600006 PM 22717133 ER PT J AU Gebregziabher, M Egede, L Gilbert, GE Hunt, K Nietert, PJ Mauldin, P AF Gebregziabher, Mulugeta Egede, Leonard Gilbert, Gregory E. Hunt, Kelly Nietert, Paul J. Mauldin, Patrick TI Fitting parametric random effects models in very large data sets with application to VHA national data SO BMC MEDICAL RESEARCH METHODOLOGY LA English DT Article DE Generalized linear mixed model; Homogeneity; Random effect meta regression; Longitudinal data; Very large dataset ID LINEAR MIXED MODELS; METAANALYSIS; REGRESSION; INFERENCE; TRIALS AB Background: With the current focus on personalized medicine, patient/subject level inference is often of key interest in translational research. As a result, random effects models (REM) are becoming popular for patient level inference. However, for very large data sets that are characterized by large sample size, it can be difficult to fit REM using commonly available statistical software such as SAS since they require inordinate amounts of computer time and memory allocations beyond what are available preventing model convergence. For example, in a retrospective cohort study of over 800,000 Veterans with type 2 diabetes with longitudinal data over 5 years, fitting REM via generalized linear mixed modeling using currently available standard procedures in SAS (e. g. PROC GLIMMIX) was very difficult and same problems exist in Stata's gllamm or R's lme packages. Thus, this study proposes and assesses the performance of a meta regression approach and makes comparison with methods based on sampling of the full data. Data: We use both simulated and real data from a national cohort of Veterans with type 2 diabetes (n=890,394) which was created by linking multiple patient and administrative files resulting in a cohort with longitudinal data collected over 5 years. Methods and results: The outcome of interest was mean annual HbA1c measured over a 5 years period. Using this outcome, we compared parameter estimates from the proposed random effects meta regression (REMR) with estimates based on simple random sampling and VISN (Veterans Integrated Service Networks) based stratified sampling of the full data. Our results indicate that REMR provides parameter estimates that are less likely to be biased with tighter confidence intervals when the VISN level estimates are homogenous. Conclusion: When the interest is to fit REM in repeated measures data with very large sample size, REMR can be used as a good alternative. It leads to reasonable inference for both Gaussian and non-Gaussian responses if parameter estimates are homogeneous across VISNs. C1 [Gebregziabher, Mulugeta; Egede, Leonard; Gilbert, Gregory E.; Hunt, Kelly; Mauldin, Patrick] Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. [Gebregziabher, Mulugeta; Hunt, Kelly; Nietert, Paul J.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. [Egede, Leonard] Med Univ S Carolina, Ctr Hlth Dispar Res, Div Gen Internal Med, Charleston, SC 29425 USA. [Mauldin, Patrick] Med Univ S Carolina, Dept Clin Pharm & Outcome Sci, Charleston, SC 29425 USA. RP Gebregziabher, M (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. EM gebregz@musc.edu RI Gilbert, Gregory/C-7735-2016; OI Gilbert, Gregory/0000-0003-0879-5496; Nietert, Paul/0000-0002-3933-4986; Gebregziabher, Mulugeta/0000-0002-4826-481X FU Veterans Health Administration Health Services Research and Development (HSRD) program [REA 08-261] FX This work was supported, by the Veterans Health Administration Health Services Research and Development (HSR&D) program [grant #REA 08-261, Center for Disease Prevention and Health Interventions for Diverse Populations]. The funding agency did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. NR 51 TC 2 Z9 2 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2288 J9 BMC MED RES METHODOL JI BMC Med. Res. Methodol. PD OCT 24 PY 2012 VL 12 AR 163 DI 10.1186/1471-2288-12-163 PG 14 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 071GG UT WOS:000313577700001 PM 23095325 ER PT J AU Nasr, S Tootell, RBH AF Nasr, Shahin Tootell, Roger B. H. TI A Cardinal Orientation Bias in Scene-Selective Visual Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PERCEPTION; PARAHIPPOCAMPAL; DISCRIMINATION; ROLES AB It has long been known that human vision is more sensitive to contours at cardinal (horizontal and vertical) orientations, compared with oblique orientations; this is the "oblique effect." However, the real-world relevance of the oblique effect is not well understood. Experiments here suggest that this effect is linked to scene perception, via a common bias in the image statistics of scenes. This statistical bias for cardinal orientations is found in many "carpentered environments" such as buildings and indoor scenes, and some natural scenes. In Experiment 1, we confirmed the presence of a perceptual oblique effect in a specific set of scene stimuli. Using those scenes, we found that a well known "scene-selective" visual cortical area (the parahippocampal place area; PPA) showed distinctively higher functional magnetic resonance imaging (fMRI) activity to cardinal versus oblique orientations. This fMRI-based oblique effect was not observed in other cortical areas (including scene-selective areas transverse occipital sulcus and retrosplenial cortex), although all three scene-selective areas showed the expected inversion effect to scenes. Experiments 2 and 3 tested for an analogous selectivity for cardinal orientations using computer-generated arrays of simple squares and line segments, respectively. The results confirmed the preference for cardinal orientations in PPA, thus demonstrating that the oblique effect can also be produced in PPA by simple geometrical images, with statistics similar to those in scenes. Thus, PPA shows distinctive fMRI selectivity for cardinal orientations across a broad range of stimuli, which may reflect a perceptual oblique effect. C1 [Nasr, Shahin; Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinioula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Tootell, Roger B. H.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Tootell, Roger B. H.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Nasr, S (reprint author), Massachusetts Gen Hosp, Athinioula A Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. EM shahin@nmr.mgh.harvard.edu FU NIH [R01 MH67529, R01 EY017081]; Martinos Center for Biomedical Imaging; National Center for Research Resources; MIND Institute; NIMH Intramural Research Program FX This study was supported by NIH Grants R01 MH67529 and R01 EY017081 to R. B. H. T., the Martinos Center for Biomedical Imaging, the National Center for Research Resources, the MIND Institute, and the NIMH Intramural Research Program. We thank Ali Amin-Mansour for help with data collection, and Dr. Dara Manoach for support measuring eye movements. NR 25 TC 27 Z9 27 U1 4 U2 17 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 OCT 24 PY 2012 VL 32 IS 43 BP 14921 EP 14926 DI 10.1523/JNEUROSCI.2036-12.2012 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 029VD UT WOS:000310523900009 PM 23100415 ER PT J AU Hashimoto, T Serrano-Pozo, A Hori, Y Adams, KW Takeda, S Banerji, AO Mitani, A Joyner, D Thyssen, DH Bacskai, BJ Frosch, MP Spires-Jones, TL Finn, MB Holtzman, DM Hyman, BT AF Hashimoto, Tadafumi Serrano-Pozo, Alberto Hori, Yukiko Adams, Kenneth W. Takeda, Shuko Banerji, Adrian Olaf Mitani, Akinori Joyner, Daniel Thyssen, Diana H. Bacskai, Brian J. Frosch, Matthew P. Spires-Jones, Tara L. Finn, Mary Beth Holtzman, David M. Hyman, Bradley T. TI Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid beta Peptide SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FAMILIAL ALZHEIMER-DISEASE; GENOME-WIDE ASSOCIATION; A-BETA; MOUSE MODEL; SYNAPTIC PLASTICITY; IDENTIFIES VARIANTS; FIBRIL FORMATION; PLAQUE-FORMATION; TYPE-4 ALLELE; APOE AB Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid beta peptide (A beta) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of A beta have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE epsilon 4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of A beta oligomerization. Here, we found that the level of A beta oligomers in APOE epsilon 4/epsilon 4AD patient brains is 2.7 times higher than those in APOE epsilon 3/epsilon 3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of A beta oligomers. To test this hypothesis, we examined the effect of apoE on A beta oligomer formation. Using both synthetic A beta and a split-luciferase method for monitoring A beta oligomers, we observed that apoE increased the level of A beta oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of A beta oligomers. Together, these data show that lipidated apoE, especially apoE4, increases A beta oligomers in the brain. Higher levels of A beta oligomers in the brains of APOE epsilon 4/epsilon 4 carriers compared with APOE epsilon 3/epsilon 3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD. C1 [Hashimoto, Tadafumi; Serrano-Pozo, Alberto; Hori, Yukiko; Adams, Kenneth W.; Takeda, Shuko; Banerji, Adrian Olaf; Mitani, Akinori; Joyner, Daniel; Thyssen, Diana H.; Bacskai, Brian J.; Frosch, Matthew P.; Spires-Jones, Tara L.; Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Charlestown, MA 02129 USA. [Finn, Mary Beth; Holtzman, David M.] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, Hope Ctr Neurol Disorders,Dept Neurol, St Louis, MO 63110 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Bldg 114,16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org RI Hashimoto, Tadafumi/A-7723-2013; SERRANO-POZO, ALBERTO/F-5119-2013 FU NIH [AG12406, AG13956, AG033670]; Ellison Medical Foundation/AFAR [2009A059868]; Fundacion Alfonso Martin Escudero; Massachusetts Alzheimer's Disease Research Center [P50 AG005134] FX This work was supported by NIH Grants AG12406 (B. T. H.), AG13956 (D. M. H.), and AG033670 (T.L.S.-J.), Ellison Medical Foundation/AFAR Grant 2009A059868 (T. H.), Fundacion Alfonso Martin Escudero (A. S.-P.), and P50 AG005134 (Massachusetts Alzheimer's Disease Research Center). We thank Drs. Zhanyun Fan and Pamela J. McLean for the construction of split-luciferase-tagged A beta cDNA plasmids. We also thank Dr. Eloise Hudry and Dr. Robert M. Koffie for valuable discussion. NR 43 TC 63 Z9 65 U1 0 U2 35 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 OCT 24 PY 2012 VL 32 IS 43 BP 15181 EP 15192 DI 10.1523/JNEUROSCI.1542-12.2012 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 029VD UT WOS:000310523900033 PM 23100439 ER PT J AU Lee, E Hooker, JM Ritter, T AF Lee, Eunsung Hooker, Jacob M. Ritter, Tobias TI Nickel-Mediated Oxidative Fluorination for PET with Aqueous [F-18] Fluoride SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY AB A one-step oxidative fluorination for carbon-fluorine bond formation from well-defined nickel complexes with oxidant and aqueous fluoride is presented, which enables a straightforward and practical F-18 late-stage fluorination of complex small molecules with potential for PET imaging. C1 [Lee, Eunsung; Ritter, Tobias] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Hooker, Jacob M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hooker, Jacob M.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Hooker, Jacob M.; Ritter, Tobias] Massachusetts Gen Hosp, Dept Radiol, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. RP Ritter, T (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. EM ritter@chemistry.harvard.edu RI Lee, Eunsung/F-5308-2013; OI Hooker, Jacob/0000-0002-9394-7708 FU NIH-NIGMS [GM088237]; NIH-NIBIB [EB013042]; [S10RR017208] FX Funding was provided by NIH-NIGMS (GM088237) and NIH-NIBIB (EB013042), as well as for a shared instrument grant (S10RR017208). We thank Dr. A. Kamlet for the synthesis of material used to prepare [18F]2h. We thank S.-L. Zheng (Harvard) for X-ray crystallographic analysis. We thank S. Carlin (Massachusetts General Hospital) for technical assistance with [18F]fluoride. TR is a Sloan fellow, a Lilly Grantee, an Amgen Young Investigator, a Camille Dreyfus Teacher-Scholar, and an AstraZeneca Awardee. NR 23 TC 125 Z9 125 U1 6 U2 118 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 OCT 24 PY 2012 VL 134 IS 42 BP 17456 EP 17458 DI 10.1021/ja3084797 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 024IV UT WOS:000310103800032 PM 23061667 ER PT J AU He, CW Qu, XY Wan, JB Rong, R Huang, LL Cai, C Zhou, KY Gu, Y Qian, SY Kang, JX AF He, Chengwei Qu, Xiying Wan, Jianbo Rong, Rong Huang, Lili Cai, Chun Zhou, Keyuan Gu, Yan Qian, Steven Y. Kang, Jing X. TI Inhibiting Delta-6 Desaturase Activity Suppresses Tumor Growth in Mice SO PLOS ONE LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; PROSTATE-CANCER; TRANSGENIC MICE; CHRONIC DISEASES; LIPID MEDIATORS; GENE-EXPRESSION; FAT-1 MICE; IN-VIVO; ANGIOGENESIS; ACTIVATION AB Recent studies have shown that a tumor-supportive microenvironment is characterized by high levels of pro-inflammatory and pro-angiogenic eicosanoids derived from omega-6 (n-6) arachidonic acid (AA). Although the metabolic pathways (COX, LOX, and P450) that generate these n-6 AA eicosanoids have been targeted, the role of endogenous AA production in tumorigenesis remains unexplored. Delta-6 desaturase (D6D) is the rate-limiting enzyme responsible for the synthesis of n-6 AA and increased D6D activity can lead to enhanced n-6 AA production. Here, we show that D6D activity is upregulated during melanoma and lung tumor growth and that suppressing D6D activity, either by RNAi knockdown or a specific D6D inhibitor, dramatically reduces tumor growth. Accordingly, the content of AA and AA-derived tumor-promoting metabolites is significantly decreased. Angiogenesis and inflammatory status are also reduced. These results identify D6D as a key factor for tumor growth and as a potential target for cancer therapy and prevention. C1 [He, Chengwei; Qu, Xiying; Wan, Jianbo; Rong, Rong; Huang, Lili; Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. [He, Chengwei; Qu, Xiying; Wan, Jianbo; Rong, Rong; Huang, Lili; Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA USA. [Cai, Chun; Zhou, Keyuan; Kang, Jing X.] Guangdong Med Coll, Lab Genet Nutr & Hlth, Zhanjiang, Guangdong, Peoples R China. [Gu, Yan; Qian, Steven Y.] N Dakota State Univ, Dept Pharmaceut Sci, Fargo, ND 58105 USA. [He, Chengwei] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med UM, Taipa, Macao Sar, Peoples R China. RP Kang, JX (reprint author), Massachusetts Gen Hosp, Dept Med, Lab Lipid Med & Technol, Boston, MA 02114 USA. EM jxkang@partners.org RI Wan, Jian-Bo/D-8368-2014 OI Wan, Jian-Bo/0000-0002-6750-2617 FU National Institutes of Health [CA113605] FX This work was supported by National Institutes of Health grant CA113605 to JXK. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 14 Z9 15 U1 2 U2 18 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 OCT 24 PY 2012 VL 7 IS 10 AR e47567 DI 10.1371/journal.pone.0047567 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200052 PM 23112819 ER PT J AU Shah, SJ Krumholz, HM Reid, KJ Rathore, SS Mandawat, A Spertus, JA Ross, JS AF Shah, Sachin J. Krumholz, Harlan M. Reid, Kimberly J. Rathore, Saif S. Mandawat, Aditya Spertus, John A. Ross, Joseph S. TI Financial Stress and Outcomes after Acute Myocardial Infarction SO PLOS ONE LA English DT Article ID STABLE CORONARY-DISEASE; ARTERY-DISEASE; HEALTH-CARE; EVENTS; ANGINA; WOMEN; HEART; PCI AB Background: Little is known about the association between financial stress and health care outcomes. Our objective was to examine the association between self-reported financial stress during initial hospitalization and long-term outcomes after acute myocardial infarction (AMI). Materials and Methods: We used Prospective Registry Evaluating Myocardial Infarction: Event and Recovery (PREMIER) data, an observational, multicenter US study of AMI patients discharged between January 2003 and June 2004. Primary outcomes were disease-specific and generic health status outcomes at 1 year (symptoms, function, and quality of life (QoL)), assessed by the Seattle Angina Questionnaire [SAQ] and Short Form [SF]-12. Secondary outcomes included 1-year rehospitalization and 4-year mortality. Hierarchical regression models accounted for patient socio-demographic, clinical, and quality of care characteristics, and access and barriers to care. Results: Among 2344 AMI patients, 1241 (52.9%) reported no financial stress, 735 (31.4%) reported low financial stress, and 368 (15.7%) reported high financial stress. When comparing individuals reporting low financial stress to no financial stress, there were no significant differences in post-AMI outcomes. In contrast, individuals reporting high financial stress were more likely to have worse physical health (SF-12 PCS mean difference -3.24, 95% Confidence Interval [CI]: -4.82, -1.66), mental health (SF-12 MCS mean difference: -2.44, 95% CI: -3.83, -1.05), disease-specific QoL (SAQ QoL mean difference: -6.99, 95% CI: -9.59, -4.40), and be experiencing angina (SAQ Angina Relative Risk = 1.66, 95% CI: 1.19, 2.32) at 1 year post-AMI. While 1-year readmission rates were increased (Hazard Ratio = 1.50; 95% CI: 1.20, 1.86), 4-year mortality was no different. Conclusions: High financial stress is common and an important risk factor for worse long-term outcomes post-AMI, independent of access and barriers to care. C1 [Krumholz, Harlan M.; Ross, Joseph S.] Yale Univ, Sch Med, Dept Med, Robert Wood Johnson Fdn,Clin Scholars Program, New Haven, CT 06510 USA. [Shah, Sachin J.; Rathore, Saif S.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiovasc Med, New Haven, CT 06510 USA. [Reid, Kimberly J.; Spertus, John A.] St Lukes Hosp, Mid Amer Heart Inst, Dept Cardiol, Kansas City, MO 64111 USA. [Mandawat, Aditya] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Spertus, John A.] Univ Missouri, Dept Cardiol, Kansas City, MO 64110 USA. [Ross, Joseph S.] Yale Univ, Sch Med, Dept Med, Gen Internal Med Sect, New Haven, CT 06510 USA. [Krumholz, Harlan M.; Ross, Joseph S.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. RP Ross, JS (reprint author), Yale Univ, Sch Med, Dept Med, Robert Wood Johnson Fdn,Clin Scholars Program, New Haven, CT 06510 USA. EM joseph.ross@yale.edu FU Cardiovascular Therapeutics Inc, Palo Alto, Calif; Cardiovascular Outcomes Inc, Kansas City; National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center Award [1U01HL105270-01]; National Center for Research Resources [1UL1RR033179-01]; National Institute on Aging [K08 AG032886]; American Federation for Aging Research through the Paul B. Beeson Career Development Award Program; Medtronic, Inc. FX This work was funded by Cardiovascular Therapeutics Inc, Palo Alto, Calif., and Cardiovascular Outcomes Inc, Kansas City, Mo. Dr. Krumholz is supported by a National Heart, Lung, and Blood Institute Cardiovascular Outcomes Center Award (1U01HL105270-01). Dr. Spertus is supported by the National Center for Research Resources (1UL1RR033179-01). Dr. Ross is currently supported by the National Institute on Aging (K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors have read the journal's policy and have the following potential conflicts of interest to disclose. Dr. Spertus reported that he had a research grant from Cardiovascular Therapeutics Inc. to support PREMIER and both Drs. Krumholz and Spertus were consultants for that company at the time the PREMIER study was on-going. Drs. Krumholz and Ross currently receive grant support from Medtronic, Inc. for work unrelated to the PREMIER study. Dr. Krumholz reports that he chairs a scientific advisory board for UnitedHealthcare. Dr. Spertus reports that he owns the copyright to the Seattle Angina Questionnaire and is a member of a scientific advisory board for UnitedHealthcare. Dr. Ross is a member of a scientific advisory board for FAIR Health, Inc. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 23 TC 8 Z9 8 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 24 PY 2012 VL 7 IS 10 AR e47420 DI 10.1371/journal.pone.0047420 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 026VC UT WOS:000310310200038 PM 23112814 ER PT J AU Hansen, JE Chan, G Liu, YF Hegan, DC Dalal, S Dray, E Kwon, Y Xu, YY Xu, XH Peterson-Roth, E Geiger, E Liu, YL Gera, J Sweasy, JB Sung, P Rockwell, S Nishimura, RN Weisbart, RH Glazer, PM AF Hansen, James E. Chan, Grace Liu, Yanfeng Hegan, Denise C. Dalal, Shibani Dray, Eloise Kwon, Youngho Xu, Yuanyuan Xu, Xiaohua Peterson-Roth, Elizabeth Geiger, Erik Liu, Yilun Gera, Joseph Sweasy, Joann B. Sung, Patrick Rockwell, Sara Nishimura, Robert N. Weisbart, Richard H. Glazer, Peter M. TI Targeting Cancer with a Lupus Autoantibody SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID HOMOLOGY-DIRECTED REPAIR; DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE; MAMMALIAN-CELLS; PROTEIN THERAPY; ERYTHEMATOSUS; RAD51; BRCA2; INHIBITION; ANTIBODY AB Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell-penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair-deficient malignancies. We find that 3E10 preferentially binds DNA single-strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA-damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents. C1 [Hansen, James E.; Liu, Yanfeng; Hegan, Denise C.; Dalal, Shibani; Peterson-Roth, Elizabeth; Geiger, Erik; Sweasy, Joann B.; Sung, Patrick; Rockwell, Sara; Glazer, Peter M.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Hansen, James E.; Sweasy, Joann B.; Sung, Patrick; Rockwell, Sara; Glazer, Peter M.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. [Chan, Grace; Gera, Joseph; Nishimura, Robert N.; Weisbart, Richard H.] Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. [Dray, Eloise; Kwon, Youngho; Xu, Yuanyuan; Sung, Patrick] Yale Univ, Dept Mol Biophys & Biochem, Sch Med, New Haven, CT 06520 USA. [Xu, Xiaohua; Liu, Yilun] City Hope Natl Med Ctr, Beckman Res Inst, Div Radiat Biol, Duarte, CA 91010 USA. [Gera, Joseph] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Gera, Joseph] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. [Sweasy, Joann B.] Univ Vermont, Dept Microbiol & Mol Genet, Burlington, VT 05405 USA. [Sweasy, Joann B.; Glazer, Peter M.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Rockwell, Sara] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Nishimura, Robert N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. RP Hansen, JE (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, 333 Cedar St, New Haven, CT 06520 USA. EM james.e.hansen@yale.edu; peter.glazer@yale.edu RI Dray, Eloise/E-3938-2012; xu, xiaohua/D-1152-2011; OI Dray, Eloise/0000-0001-6793-9838 FU Radiological Society of North America [RR1108]; Kalimeris Fund through the Department of Therapeutic Radiology at Yale School of Medicine; Women's Health Research at Yale Pilot Grant; U.S. Public Health Service (USPHS) [1 RO1 NS066845-01, P01CA129186]; Veterans Affairs Merit Review grant FX This work was partially supported by Radiological Society of North America Research Resident grant RR1108 (J.E.H.), the Kalimeris Fund through the Department of Therapeutic Radiology at Yale School of Medicine (J.E.H. and P.M.G.), a Women's Health Research at Yale Pilot Grant (P.M.G.), U.S. Public Health Service (USPHS) grant 1 RO1 NS066845-01 (R.N.N.), a Veterans Affairs Merit Review grant (R.H.W.), and USPHS grant P01CA129186 (P.M.G., J.B.S., P.S., and S.R.). Author contributions: J.E.H. and P.M.G. conceived and designed the study, analyzed the data, and wrote the paper. J.E.H., G.C., Yanfeng Liu, D.C.H., S.D., E.D., Y.K., Y.X., X.X., E.P.-R., E.G., and R.H.W. performed the experiments and analyzed the data. Yilun Liu, J.B.S., and P.S. supervised the DNA binding and repair assays. J.G., S.R., and R.N.N. supervised the xenograft experiments. Competing interests: J.E.H., P.M.G., R.H. W., R.N.N., and G.C. are inventors on the patent application PCT/US2012/031860, "Cell-Penetrating Anti-DNA Antibodies and Uses Thereof to Inhibit DNA Repair." The other authors declare that they have no competing financial interests. The 3E10 antibody and the 3E10 single chain Fv fragment were obtained by Yale University under a material transfer agreement with the University of California, Los Angeles. NR 32 TC 16 Z9 16 U1 0 U2 12 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 OCT 24 PY 2012 VL 4 IS 157 AR 157ra142 DI 10.1126/scitranslmed.3004385 PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 028WM UT WOS:000310455500004 PM 23100628 ER PT J AU Carroll, AE Frakt, AB AF Carroll, Aaron E. Frakt, Austin B. TI The Health Policy Election SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Carroll, Aaron E.] Indiana Univ Sch Med, Childrens Hlth Serv Res, Indianapolis, IN 46202 USA. [Frakt, Austin B.] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA USA. [Frakt, Austin B.] Boston Univ, Boston, MA 02215 USA. RP Carroll, AE (reprint author), Indiana Univ Sch Med, Childrens Hlth Serv Res, 410W10th St,HITS Bldg,Ste 1020, Indianapolis, IN 46202 USA. EM aaecarro@iupui.edu NR 6 TC 1 Z9 1 U1 0 U2 0 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 OCT 24 PY 2012 VL 308 IS 16 BP 1633 EP 1634 DI 10.1001/jama.2012.13667 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 028PI UT WOS:000310434100014 PM 23060272 ER PT J AU Volpp, KG Loewenstein, G Asch, DA AF Volpp, Kevin G. Loewenstein, George Asch, David A. TI Choosing Wisely Low-Value Services, Utilization, and Patient Cost Sharing SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INSURANCE DESIGN; COVERAGE; CARE C1 [Volpp, Kevin G.; Asch, David A.] Univ Penn, Perelman Sch Med, Ctr Hlth Equity Res & Promot, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Loewenstein, George; Asch, David A.] Univ Penn, Perelman Sch Med, Leonard Davis Inst Ctr Hlth Incent & Behav Econ, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.] Univ Penn, Dept Hlth Care Management, Wharton Sch, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Asch, David A.] Penn Med Ctr Innovat, Philadelphia, PA USA. [Loewenstein, George] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. RP Volpp, KG (reprint author), Univ Penn, Perelman Sch Med, Ctr Hlth Equity Res & Promot, Philadelphia Vet Affairs Med Ctr, 1120 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM volpp70@wharton.upenn.edu OI Asch, David/0000-0002-7970-286X FU NIA NIH HHS [P30 AG034546, RC2 AG036592, RC4 AG039114] NR 7 TC 22 Z9 22 U1 0 U2 7 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 OCT 24 PY 2012 VL 308 IS 16 BP 1635 EP 1636 DI 10.1001/jama.2012.13616 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 028PI UT WOS:000310434100015 PM 23093160 ER PT J AU Armstrong, E Maddox, T Carey, E Grunwald, G Shunk, K AF Armstrong, Ehrin Maddox, Thomas Carey, Evan Grunwald, Gary Shunk, Kendrick TI Very Late Stent Thrombosis is Associated with Lower Mortality than Early Stent Thrombosis: A Report from the VHA CART Program SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Armstrong, Ehrin] Univ Calif Davis, Sacramento, CA USA. [Maddox, Thomas; Carey, Evan; Grunwald, Gary] Univ Colorado, Denver, CO 80202 USA. [Shunk, Kendrick] San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B186 EP B186 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101429 ER PT J AU Elmariah, S Inglessis, I Rengifo, P Margey, R Baron, S O'Callaghan, C Cruz-Gonzalez, I Demirjian, Z Buonanno, F Ning, MM Silverman, S Pomerantsev, E Schainfeld, R Dec, G Palacios, I AF Elmariah, Sammy Inglessis, Ignacio Rengifo, Pablo Margey, Ronan Baron, Suzanne O'Callaghan, Caitlin Cruz-Gonzalez, Ignacio Demirjian, Zareh Buonanno, Ferdinando Ning, MingMing Silverman, Scott Pomerantsev, Eugene Schainfeld, Robert Dec, G. Palacios, Igor TI Long-term Outcomes After Transcatheter Closure of Patent Foramen Ovale SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Elmariah, Sammy; Inglessis, Ignacio; Rengifo, Pablo; Margey, Ronan; O'Callaghan, Caitlin; Demirjian, Zareh; Buonanno, Ferdinando; Ning, MingMing; Silverman, Scott; Pomerantsev, Eugene; Schainfeld, Robert; Dec, G.; Palacios, Igor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Cruz-Gonzalez, Ignacio] Hosp Univ Salamanca, Salamanca, Castilla, Spain. [Cruz-Gonzalez, Ignacio] Hosp Univ Salamanca, Salamanca, Leon, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B226 EP B226 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101565 ER PT J AU Elmariah, S Passeri, J Hueter, I Margey, R Inglessis, I Baker, J Daher, M Kodali, S Mehrotra, P Leon, M Svensson, L Agnihotri, A Vlahakes, G Pibarot, P Douglas, P Palacios, I AF Elmariah, Sammy Passeri, Jonathan Hueter, Irene Margey, Ronan Inglessis, Ignacio Baker, Joshua Daher, Maureen Kodali, Susheel Mehrotra, Praveen Leon, Martin Svensson, Lars Agnihotri, Arvind Vlahakes, Gus Pibarot, Philippe Douglas, Pamela Palacios, Igor TI Relationship of Transcatheter and Surgical Aortic Valve Replacement with Left Ventricular Function in High-Risk Patients with Aortic Stenosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Elmariah, Sammy; Passeri, Jonathan; Margey, Ronan; Inglessis, Ignacio; Baker, Joshua; Daher, Maureen; Agnihotri, Arvind; Vlahakes, Gus; Palacios, Igor] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Hueter, Irene; Kodali, Susheel; Leon, Martin] Columbia Univ, New York, NY USA. [Svensson, Lars] Cleveland Clin, Cleveland, OH 44106 USA. [Pibarot, Philippe] Univ Laval, Quebec Lung & Heart Inst, Quebec City, PQ, Canada. [Douglas, Pamela] Duke Univ, Med Ctr, Durham, NC 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B29 EP B29 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210100093 ER PT J AU Herrero-Garibi, J Cruz-Gonzalez, I Rengifo, P Bounanno, F Sanchez-Ledesma, M Martin-Herrero, F Palacios, I AF Herrero-Garibi, Jesus Cruz-Gonzalez, Ignacio Rengifo, Pablo Bounanno, Ferdinando Sanchez-Ledesma, Maria Martin-Herrero, Francisco Palacios, Igor TI Efficacy And Safety Of Percutaneous Patent Foramen Ovale Closure In Patients With A Hypercoagulable Disorder SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Herrero-Garibi, Jesus] Univ Hosp Burgos, Burgos, Spain. [Cruz-Gonzalez, Ignacio; Sanchez-Ledesma, Maria; Martin-Herrero, Francisco] Univ Hosp Salamanca, Salamanca, Spain. [Rengifo, Pablo; Bounanno, Ferdinando] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Palacios, Igor] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B27 EP B27 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210100085 ER PT J AU Madder, R Madden, S Puri, R Hendricks, M Vanoosterhout, S Sum, S Kini, A Sharma, S Rizik, D Brilakis, E Shunk, K Goldstein, J Weisz, G Virmani, R Nicholls, S Maehara, A Mintz, G Stone, G Muller, J AF Madder, Ryan Madden, Sean Puri, Rishi Hendricks, Michael Vanoosterhout, Stacie Sum, Steve Kini, Annapoorna Sharma, Samin Rizik, David Brilakis, Emmanouil Shunk, Kendrick Goldstein, James Weisz, Giora Virmani, Renu Nicholls, Stephen Maehara, Akiko Mintz, Gary Stone, Gregg Muller, James TI Detection by Near-infrared Spectroscopy of Large Lipid Core Plaques at Culprit Sites in Patients with Acute ST-Segment Elevation Myocardial Infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Madder, Ryan; Vanoosterhout, Stacie] Frederik Meijer Heart & Vasc Inst Spectrum Hlth, Grand Rapids, MI USA. [Madden, Sean; Hendricks, Michael; Sum, Steve; Muller, James] Infraredx Inc, Burlington, MA USA. [Puri, Rishi; Nicholls, Stephen] Cleveland Clin, Cleveland, OH 44106 USA. [Kini, Annapoorna; Sharma, Samin] Mt Sinai Sch Med, New York, NY USA. [Rizik, David] Scottsdale Healthcare Hosp, Scottsdale, AZ USA. [Brilakis, Emmanouil] VA N Texas Healthcare Syst, Dallas, TX USA. [Brilakis, Emmanouil] UT SW Med Ctr, Dallas, TX USA. [Shunk, Kendrick] San Francisco VA Med Ctr, San Francisco, CA USA. [Goldstein, James] Beaumont Hosp, Royal Oak, MI USA. [Stone, Gregg] Columbia Univ, Med Ctr, New York, NY USA. [Virmani, Renu] CVPath Inc, Gaithersburg, MD USA. [Maehara, Akiko; Stone, Gregg] Cardiovasc Res Fdn, New York, NY USA. [Mintz, Gary] CRF, Washington, DC USA. NR 0 TC 2 Z9 2 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 OCT 23 PY 2012 VL 60 IS 17 SU S BP B7 EP B7 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210100023 ER PT J AU Margey, R Margey, R Elmariah, S Hynes, B Renfigo-Moreno, P Jaff, M Schainfeld, R Inglessis, I Palacios, I AF Margey, Ronan Margey, Ronan Elmariah, Sammy Hynes, Brian Renfigo-Moreno, Pablo Jaff, Michael Schainfeld, Robert Inglessis, Ignacio Palacios, Igor TI Non-Cerebrovascular Systemic Arterial Embolic Events from Paradoxical Embolization via Patent Foramen Ovale (PFO) SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Margey, Ronan; Margey, Ronan; Elmariah, Sammy; Hynes, Brian; Renfigo-Moreno, Pablo; Inglessis, Ignacio] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jaff, Michael; Palacios, Igor] Harvard Univ, Sch Med, Boston, MA USA. [Schainfeld, Robert] Harvard Univ, Sch Med, Newton, 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B226 EP B226 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101564 ER PT J AU Margey, R Ridgway, H Rullman, R Spencer, J Margey, R McNulty, I Mangla, A Polena, S Soffer, D Jang, IK AF Margey, Ronan Ridgway, Helen Rullman, Richard Spencer, Jeff Margey, Ronan McNulty, Iris Mangla, Aditya Polena, Sotir Soffer, Daniel Jang, Ik-Kyung TI Ecarin Clotting Time (ECT) more accurately reflects bivalirudin concentration than Activated Clotting Time (ACT) in patients undergoing Percutaneous Coronary Intervention using bivalirudin anticoagulation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Margey, Ronan; Margey, Ronan; McNulty, Iris] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ridgway, Helen; Rullman, Richard; Spencer, Jeff] Helena Labs, Beaumont, TX USA. [Mangla, Aditya; Soffer, Daniel] Lenox Hill Hosp, New York, NY 10021 USA. [Polena, Sotir] Huntington Hosp, New York, NY USA. [Jang, Ik-Kyung] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 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 OCT 23 PY 2012 VL 60 IS 17 SU S BP B219 EP B220 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101540 ER PT J AU Mauri, L Steg, G Matteau, A Camenzind, E Boersma, E Vranckx, P Serruys, P O'Neill, W Yeh, R Wijns, W AF Mauri, Laura Steg, Gabriel Matteau, Alexis Camenzind, Edoardo Boersma, Eric Vranckx, Pascal Serruys, Patrick O'Neill, William Yeh, Robert Wijns, William TI Individual and Regional Variations in Dual Antiplatelet Therapy Dose and Duration in a Large, Randomized International Trial Comparing Two Drug-eluting Stents: Results From PROTECT SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Mauri, Laura; Matteau, Alexis] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mauri, Laura] Harvard Univ, Sch Med, Boston, MA USA. [Steg, Gabriel] Hop Bichat Claude Bernard, F-75877 Paris, France. [Camenzind, Edoardo] Univ Hosp Geneva, Geneva, Switzerland. [Boersma, Eric; Serruys, Patrick] Erasmus MC, Thoraxctr, Rotterdam, Netherlands. [Vranckx, Pascal] Hartctr Hasselt, Hasselt, Belgium. [O'Neill, William] Leonard M Miller Sch Med, Miami, FL USA. [Yeh, Robert] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wijns, William] Cardiovasc Ctr Aalst, Aalst, Belgium. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B216 EP B217 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101530 ER PT J AU Reed, G Hoffman, E Kumar, A Maree, A McLean, D Buros, J Aranki, S Shekar, P Agnihotri, A Williams, L Rosenfeld, K Cannon, C AF Reed, Grant Hoffman, Elaine Kumar, Amit Maree, Andrew McLean, Dalton Buros, Jacki Aranki, Sary Shekar, Prem Agnihotri, Arvind Williams, Laura Rosenfeld, Kenneth Cannon, Christopher TI Platelet Function Testing Predicts Bleeding In Patients Exposed To Clopidogrel Undergoing Coronary Artery Bypass Grafting SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Reed, Grant; Hoffman, Elaine; Buros, Jacki; Aranki, Sary; Shekar, Prem; Williams, Laura; Cannon, Christopher] Brigham & Womens Hosp, Boston, MA 02115 USA. [Kumar, Amit; Agnihotri, Arvind; Rosenfeld, Kenneth] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Maree, Andrew] Waterford Reg Hosp, Waterford City, Ireland. [McLean, Dalton] LeBauer Hlth Care, Greensboro, NC USA. NR 0 TC 1 Z9 2 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 OCT 23 PY 2012 VL 60 IS 17 SU S BP B210 EP B211 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101510 ER PT J AU Schlett, C Maurovich-Horvat, P Bamberg, F Warger, W Nakano, M Tanaka, A Vorpahl, M Seifarth, H Ferencik, M Virmani, R Tearney, G Hoffmann, U AF Schlett, Christopher Maurovich-Horvat, Pal Bamberg, Fabian Warger, William Nakano, Masataka Tanaka, Atsushi Vorpahl, Marc Seifarth, Harald Ferencik, Maros Virmani, Renu Tearney, Guillermo Hoffmann, Udo TI Value of Optical Coherence Tomography beyond the Napkin-Ring Sign in CT Angiography for Detecting Coronary Lipid-Core Plaques as Determined by Histology: A Multimodality Imaging Study in Human Donor Hearts SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Schlett, Christopher; Maurovich-Horvat, Pal; Warger, William; Tanaka, Atsushi; Seifarth, Harald; Ferencik, Maros; Tearney, Guillermo; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Bamberg, Fabian] Univ Munich, Hosp Grosshadern, Munich, Germany. [Nakano, Masataka; Virmani, Renu] CVPath Inc, Gaithersburg, MD USA. [Vorpahl, Marc] Univ Witten Herdecke, Helius Clin Wuppertal, Wuppertal, Germany. 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B69 EP B69 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101043 ER PT J AU Scirica, B Murphy, S Karwatowska-Prokopczuk, E Walker, G Belardinelli, L Ben-Yehuda, O Morrow, D AF Scirica, Benjamin Murphy, Sabina Karwatowska-Prokopczuk, Ewa Walker, Gennyne Belardinelli, Luiz Ben-Yehuda, Ori Morrow, David TI Effects of ranolazine in patients with acute coronary syndrome and stable angina according to whether they undergo percutaneous coronary intervention: Observations from the MERLIN-TIMI 36 Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Scirica, Benjamin; Murphy, Sabina; Morrow, David] Brigham & Womens Hospita, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA USA. [Karwatowska-Prokopczuk, Ewa; Walker, Gennyne; Belardinelli, Luiz; Ben-Yehuda, Ori] Gilead Sci Inc, Forest City, CA USA. NR 0 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B210 EP B210 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101507 ER PT J AU Zeglin-Sawczuk, M Jang, IK Ashikaga, T Kato, K Yonetsu, T Choi, SY Kim, SJ Kratlian, C Lee, H Dauerman, H AF Zeglin-Sawczuk, Magdalena Jang, Ik-Kyung Ashikaga, Taka Kato, Koji Yonetsu, Taishi Choi, So-Yeon Kim, Soo Joong Kratlian, Christina Lee, Hang Dauerman, Harold TI Incidence and Characterization of Stent Dissections in Women Versus Men: A Report from the Massachusetts General Hospital Optical Coherence Tomography Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT Transcatheter Cardiovascular Therapeutics (TCT) Symposium CY OCT 22-26, 2012 CL Miami, FL SP ACC C1 [Zeglin-Sawczuk, Magdalena; Ashikaga, Taka; Dauerman, Harold] Univ Vermont, Burlington, VT USA. [Jang, Ik-Kyung] Harvard Univ, Sch Med, Boston, MA USA. [Kato, Koji; Yonetsu, Taishi; Choi, So-Yeon; Kim, Soo Joong; Kratlian, Christina; Lee, Hang] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 SU S BP B71 EP B71 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025RM UT WOS:000310210101049 ER PT J AU El-Haibi, CP Bell, GW Zhang, JW Collmann, AY Wood, D Scherber, CM Csizmadia, E Mariani, O Zhu, CH Campagne, A Toner, M Bhatia, SN Irimia, D Vincent-Salomon, A Karnoub, AE AF El-Haibi, Christelle P. Bell, George W. Zhang, Jiangwen Collmann, Anthony Y. Wood, David Scherber, Cally M. Csizmadia, Eva Mariani, Odette Zhu, Cuihua Campagne, Antoine Toner, Mehmet Bhatia, Sangeeta N. Irimia, Daniel Vincent-Salomon, Anne Karnoub, Antoine E. TI Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSITION; METASTASIS; TUMORS; BONE; HYALURONAN; GENERATION; CARCINOMA; CD44 AB Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells. C1 [El-Haibi, Christelle P.; Collmann, Anthony Y.; Zhu, Cuihua; Campagne, Antoine; Karnoub, Antoine E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol, Sch Med, Boston, MA 02215 USA. [Bell, George W.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Zhang, Jiangwen] Harvard Univ, Fac Arts & Sci, Ctr Syst Biol, Cambridge, MA 02138 USA. [Wood, David; Bhatia, Sangeeta N.] Harvard Massachusetts Inst Technol, Div Hlth Sci & Technol, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Scherber, Cally M.; Toner, Mehmet; Irimia, Daniel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, BioMEMS Resource Ctr,Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Csizmadia, Eva] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Mariani, Odette; Campagne, Antoine; Vincent-Salomon, Anne] Inst Curie, Dept Pathol, F-75248 Paris 05, France. RP Karnoub, AE (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol, Sch Med, Boston, MA 02215 USA. EM akarnoub@bidmc.harvard.edu RI Wood, David/P-1998-2015; OI Wood, David/0000-0001-5225-2144; Irimia, Daniel/0000-0001-7347-2082 FU Texas A&M Health Science Center through National Institutes of Health [P40RR017447]; Packard Foundation; National Institutes of Health [R21CA135601]; Beth Israel Deaconess Medical Center; Sidney Kimmel Cancer Research Foundation; Prostate and Breast Cancer Program of BIDMC; Susan G. Komen for the Cure FX We thank T. Chavarria, F. Reinhardt, and S. Malstrom for assistance in animal studies; D. Louvard for helpful discussions; and R. Weinberg for critical reading of the manuscript. BM-MSCs were provided by the Texas A&M Health Science Center through National Institutes of Health Grant P40RR017447. This work was supported by the Packard Foundation (S.N.B.), National Institutes of Health Grant R21CA135601 (D. I.), Beth Israel Deaconess Medical Center (A. E. K.), and the Sidney Kimmel Cancer Research Foundation (A. E. K.). A. E. K. is a Kimmel Scholar, a recipient of a Career Development Award from the Prostate and Breast Cancer Program of BIDMC, and of a Career Catalyst Research Award from Susan G. Komen for the Cure. NR 38 TC 70 Z9 71 U1 0 U2 24 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 OCT 23 PY 2012 VL 109 IS 43 BP 17460 EP 17465 DI 10.1073/pnas.1206653109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800036 PM 23033492 ER PT J AU Kleinnijenhuis, J Quintin, J Preijers, F Joosten, LAB Ifrim, DC Saeed, S Jacobs, C van Loenhout, J de Jong, D Stunnenberg, HG Xavier, RJ van der Meer, JWM van Crevel, R Netea, MG AF Kleinnijenhuis, Johanneke Quintin, Jessica Preijers, Frank Joosten, Leo A. B. Ifrim, Daniela C. Saeed, Sadia Jacobs, Cor van Loenhout, Joke de Jong, Dirk Stunnenberg, Hendrik G. Xavier, Ramnik J. van der Meer, Jos W. M. van Crevel, Reinout Netea, Mihai G. TI Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mycobacterium tuberculosis vaccine; innate immune memory ID NATURAL-KILLER-CELLS; BCG VACCINATION; MYCOBACTERIUM-TUBERCULOSIS; INFLAMMATORY RESPONSE; IMMUNE-RESPONSE; CHILD SURVIVAL; WEST-AFRICA; BOVIS BCG; MICE; MEMORY AB Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guerin (BCG) vaccination in healthy volunteers led not only to a four-to sevenfold increase in the production of IFN-gamma, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1 beta, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T-and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells. C1 [Kleinnijenhuis, Johanneke; Quintin, Jessica; Joosten, Leo A. B.; Ifrim, Daniela C.; Jacobs, Cor; van der Meer, Jos W. M.; van Crevel, Reinout; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. [Kleinnijenhuis, Johanneke; Quintin, Jessica; Joosten, Leo A. B.; Ifrim, Daniela C.; Jacobs, Cor; van der Meer, Jos W. M.; van Crevel, Reinout; Netea, Mihai G.] Radboud Univ Nijmegen, Med Ctr, Nijmegen Inst Infect Inflammat & Immun N4i, NL-6525 GA Nijmegen, Netherlands. [Preijers, Frank] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Hematol Lab, NL-6525 GA Nijmegen, Netherlands. [Saeed, Sadia; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Fac Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [Saeed, Sadia; Stunnenberg, Hendrik G.] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, Fac Med, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. [van Loenhout, Joke] Publ Hlth Off GGD, Nijmegen, Netherlands. [de Jong, Dirk] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol, NL-6525 GA Nijmegen, Netherlands. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA. RP Netea, MG (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Med, NL-6525 GA Nijmegen, Netherlands. EM M.Netea@aig.umcn.nl RI van der Meer, Jos/C-8521-2013; Rivet, Catherine/M-7978-2014; Stunnenberg, Hendrik/D-6875-2012; van Crevel, reinout/A-6636-2010; Joosten, Leo/H-3138-2015; Netea, Mihai/N-5155-2014; Kleinnijenhuis, Johanneke/P-6309-2015; Preijers, F.W.M.B./L-4586-2015; kleinnijenhuis, johanneke/G-7978-2016 OI van der Meer, Jos/0000-0001-5120-3690; FU Vici Grant from the Netherlands Organization for Scientific Research; Vidi Grant from the Netherlands Organization for Scientific Research; Higher Education Commission of Pakistan; European Seventh Framework Programme ALLFun Project; US National Institutes of Health [AI 062773, DK 043351, DK 83756]; Helmsley Trust FX J.Q. and M.G.N. were supported by a Vici Grant from the Netherlands Organization for Scientific Research (to M.G.N.). R. v. C. was supported by a Vidi Grant from the Netherlands Organization for Scientific Research. S. S. was supported by the Higher Education Commission of Pakistan. D. C. I. was supported by the European Seventh Framework Programme ALLFun Project. R.J.X. was supported by US National Institutes of Health Grants AI 062773, DK 043351, and DK 83756 and the Helmsley Trust. NR 35 TC 208 Z9 208 U1 5 U2 20 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 OCT 23 PY 2012 VL 109 IS 43 BP 17537 EP 17542 DI 10.1073/pnas.1202870109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800049 PM 22988082 ER PT J AU Huang, YH Yuan, JP Righi, E Kamoun, WS Ancukiewicz, M Nezivar, J Santosuosso, M Martin, JD Martin, MR Vianello, F Leblanc, P Munn, LL Huang, P Duda, DG Fukumura, D Jain, RK Poznansky, MC AF Huang, Yuhui Yuan, Jianping Righi, Elda Kamoun, Walid S. Ancukiewicz, Marek Nezivar, Jean Santosuosso, Michael Martin, John D. Martin, Margaret R. Vianello, Fabrizio Leblanc, Pierre Munn, Lance L. Huang, Peigen Duda, Dan G. Fukumura, Dai Jain, Rakesh K. Poznansky, Mark C. TI Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vascular normalization; hypoxia; myeloid-derived suppressor cell; tumor tissue vaccine ID THERAPEUTIC CANCER VACCINES; METASTATIC BREAST-CANCER; REGULATORY T-CELLS; BEVACIZUMAB; PROGRESSION; GROWTH; SURVIVAL; MOUSE; BLOOD; ANGIOGENESIS AB The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatoryM1-like phenotype and in facilitating CD4(+) and CD8(+) T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8(+) T-cell-dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies. C1 [Huang, Yuhui; Kamoun, Walid S.; Ancukiewicz, Marek; Martin, John D.; Martin, Margaret R.; Munn, Lance L.; Huang, Peigen; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Yuan, Jianping; Righi, Elda; Nezivar, Jean; Santosuosso, Michael; Vianello, Fabrizio; Leblanc, Pierre; Poznansky, Mark C.] Massachusetts Gen Hosp, Vaccine & Immunotherapy Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016; Martin, John/L-6892-2016; Vianello, Fabrizio/M-5211-2016; OI Munn, Lance/0000-0003-0698-7232; Martin, John/0000-0002-9828-8203; Vianello, Fabrizio/0000-0002-7174-4651; Huang, Yuhui/0000-0003-1985-3575 FU Dyax; MedImmune; Roche; Enlight; Noxxon; SynDevRx; National Institutes of Health [R01-CA115767, R01-CA126642, R01-CA096915, R21-CA139168, R01-CA159258]; National Cancer Institutes Federal Share grant; Department of Defense (DoD) Breast Cancer Innovator Award [W81XWH-10-1-0016]; DoD Research Fellowship [W81XWH-11-1-0619]; Marsha Rivkin Foundation; Friends of the Vaccine and Immunotherapy Center; Frank Lynch Jr. Cancer Research Fund FX R.K.J. received research grants from Dyax, MedImmune, and Roche; consultant fees from Dyax, Enlight, Noxxon, and SynDevRx; owns equity in Enlight, SynDevRx, and XTuit; and serves on the Board of Directors of XTuit and Boards of Trustees of H&Q Healthcare Investors and H&Q Life Sciences Investors. M.C.P. serves as a scientific adviser to Evaxion-Biotech and owns equity in Celtaxsys. No reagents or funding from these companies was used in this study. Therefore, there is no significant financial or other competing interest in the work.; We thank ImClone/Lilly for their gift of DC101; Glenn Dranoff for advice on cancer vaccine preparation; Sylvie Roberge, Julia Kahn, Carolyn Smith, Ned Kirkpatrick, Ramone Williams, Madzia Kowalski, Rachel Ingraham, and Amy Yang for technical assistance; and Shom Goel, Vikash Chauhan, Eleanor Ager, and Sergey Kozin for their helpful scientific input. This work was supported by National Institutes of Health Grants R01-CA115767 and R01-CA126642 (to R.K.J.), R01-CA096915 (to D.F.), and R21-CA139168 and R01-CA159258 (to D.G.D.); a National Cancer Institutes Federal Share grant (to M.C.P. and J.Y.); Department of Defense (DoD) Breast Cancer Innovator Award W81XWH-10-1-0016 (to R.K.J.); DoD Research Fellowship W81XWH-11-1-0619 (to Y.H.). This work was also supported by the Marsha Rivkin Foundation (E.R. and M.C.P.), Friends of the Vaccine and Immunotherapy Center, and the Frank Lynch Jr. Cancer Research Fund (J.Y. and M.C.P.). NR 38 TC 164 Z9 168 U1 2 U2 43 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 OCT 23 PY 2012 VL 109 IS 43 BP 17561 EP 17566 DI 10.1073/pnas.1215397109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800053 PM 23045683 ER PT J AU MacLean, GA Menne, TF Guo, GJ Sanchez, DJ Park, IH Daley, GQ Orkin, SH AF MacLean, Glenn A. Menne, Tobias F. Guo, Guoji Sanchez, Danielle J. Park, In-Hyun Daley, George Q. Orkin, Stuart H. TI Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOWN-SYNDROME; STEM-CELLS; MEGAKARYOBLASTIC LEUKEMIA; TRANSIENT LEUKEMIA; MOUSE MODEL; HUMAN ES; GATA1; GENERATION; MUTATIONS; LEUKEMOGENESIS AB Trisomy 21 is associated with hematopoietic abnormalities in the fetal liver, a preleukemic condition termed transient myeloproliferative disorder, and increased incidence of acute megakaryoblastic leukemia. Human trisomy 21 pluripotent cells of various origins, human embryionic stem (hES), and induced pluripotent stem (iPS) cells, were differentiated in vitro as a model to recapitulate the effects of trisomy on hematopoiesis. To mitigate clonal variation, we isolated disomic and trisomic subclones from the same parental iPS line, thereby generating subclones isogenic except for chromosome 21. Under differentiation conditions favoring development of fetal liver-like, gamma-globin expressing, definitive hematopoiesis, we found that trisomic cells of hES, iPS, or isogenic origins exhibited a two-to fivefold increase in a population of CD43(+)(Leukosialin)/CD235(+)(Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony-forming assays. These findings establish an intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage. C1 [MacLean, Glenn A.; Menne, Tobias F.; Guo, Guoji; Sanchez, Danielle J.; Daley, George Q.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [MacLean, Glenn A.; Menne, Tobias F.; Guo, Guoji; Sanchez, Danielle J.; Daley, George Q.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Daley, George Q.; Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Daley, George Q.; Orkin, Stuart H.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Park, In-Hyun] Yale Univ, Sch Med, Dept Genet, Yale Stem Cell Ctr, New Haven, CT 06520 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU National Institutes of Health as part of the Progenitor Cell Biology Consortium of the National Heart, Lung and Blood Institute [U01 HL 10001]; Harvard Stem Cell Institute; Howard Hughes Medical Institute; Lady Tata Memorial Trust fellowship; Leukemia and Lymphoma Research Fund fellowship; Kay Kendal Leukemia Fund fellowship FX This work was funded by National Institutes of Health Grant U01 HL 10001 as part of the Progenitor Cell Biology Consortium of the National Heart, Lung and Blood Institute; a seed grant of the Harvard Stem Cell Institute and the Howard Hughes Medical Institute; a Lady Tata Memorial Trust fellowship (to G.M.); and Leukemia and Lymphoma Research and Kay Kendal Leukemia Fund fellowships (to T.F.M.). NR 34 TC 51 Z9 51 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 23 PY 2012 VL 109 IS 43 BP 17567 EP 17572 DI 10.1073/pnas.1215468109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800054 PM 23045682 ER PT J AU McAuliffe, SM Morgan, SL Wyant, GA Tran, LT Muto, KW Chen, YS Chin, KT Partridge, JC Poole, BB Cheng, KH Daggett, J Cullen, K Kantoff, E Hasselbatt, K Berkowitz, J Muto, MG Berkowitz, RS Aster, JC Matulonis, UA Dinulescu, DM AF McAuliffe, Shannon M. Morgan, Stefanie L. Wyant, Gregory A. Tran, Lieu T. Muto, Katherine W. Chen, Yu Sarah Chin, Kenneth T. Partridge, Justin C. Poole, Barish B. Cheng, Kuang-Hung Daggett, John, Jr. Cullen, Kristen Kantoff, Emily Hasselbatt, Kathleen Berkowitz, Julia Muto, Michael G. Berkowitz, Ross S. Aster, Jon C. Matulonis, Ursula A. Dinulescu, Daniela M. TI Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor models; Notch3 expression patterns; isobologram and combination index analysis; platinum-induced DNA damage response; synergistic cytotoxic effects for GSI/cisplatin combination therapy ID MULLERIAN-INHIBITING SUBSTANCE; GYNECOLOGIC-ONCOLOGY-GROUP; SIDE POPULATION; STAGE-III; CISPLATIN; HETEROGENEITY; CARBOPLATIN; PACLITAXEL; PHASE; RESISTANCE AB Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, gamma-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/Mcell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant. C1 [McAuliffe, Shannon M.; Morgan, Stefanie L.; Wyant, Gregory A.; Tran, Lieu T.; Muto, Katherine W.; Chen, Yu Sarah; Chin, Kenneth T.; Partridge, Justin C.; Poole, Barish B.; Cheng, Kuang-Hung; Daggett, John, Jr.; Berkowitz, Julia; Aster, Jon C.; Dinulescu, Daniela M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hasselbatt, Kathleen; Muto, Michael G.; Berkowitz, Ross S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Cullen, Kristen] Cell Signaling Technol, Danvers, MA 01923 USA. [Kantoff, Emily; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Dinulescu, DM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM DDinulescu@rics.bwh.harvard.edu FU Department of Defense Ovarian Cancer Research Program Award [W81XWH-10-1-0263]; V Foundation Scholar Award; Ovarian Cancer Research Fund Liz Tilberis Award; Burroughs Wellcome; Mary Kay Ash; Rivkin Foundations FX This work was supported by Department of Defense Ovarian Cancer Research Program Award W81XWH-10-1-0263 (D. M. D.), a V Foundation Scholar Award (D. M. D.), an Ovarian Cancer Research Fund Liz Tilberis Award (D. M. D.), by Burroughs Wellcome (D. M. D.), by the Mary Kay Ash (D. M. D.) and Rivkin Foundations (D. M. D.), and by a generous contribution from the Mildred Moorman Ovarian Cancer Research Fund (D.M.D.). NR 35 TC 109 Z9 113 U1 3 U2 33 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 OCT 23 PY 2012 VL 109 IS 43 BP E2939 EP E2948 DI 10.1073/pnas.1206400109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AO UT WOS:000311147800007 PM 23019585 ER PT J AU Hall, KT Lembo, AJ Kirsch, I Ziogas, DC Douaiher, J Jensen, KB Conboy, LA Kelley, JM Kokkotou, E Kaptchuk, TJ AF Hall, Kathryn T. Lembo, Anthony J. Kirsch, Irving Ziogas, Dimitrios C. Douaiher, Jeffrey Jensen, Karin B. Conboy, Lisa A. Kelley, John M. Kokkotou, Efi Kaptchuk, Ted J. TI Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome SO PLOS ONE LA English DT Article ID COMT VAL(158)MET POLYMORPHISM; PREFRONTAL CORTEX; INDIVIDUAL-DIFFERENCES; CLINICAL-TRIALS; END-POINT; GENOTYPE; DOPAMINE; METAANALYSIS; IMPROVEMENT; RESPONSES AB Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response. C1 [Hall, Kathryn T.; Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Hall, Kathryn T.; Lembo, Anthony J.; Kirsch, Irving; Jensen, Karin B.; Conboy, Lisa A.; Kelley, John M.; Kokkotou, Efi; Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Program Placebo Studies, Boston, MA 02215 USA. [Lembo, Anthony J.; Kokkotou, Efi] Beth Israel Deaconess Med Ctr, Dept Gastroenterol, Boston, MA 02215 USA. [Kirsch, Irving] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Ziogas, Dimitrios C.] Univ Athens, Dept Internal Med, Athens, Greece. [Douaiher, Jeffrey] Dept Surg, Baltimore, MD USA. [Jensen, Karin B.; Kelley, John M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Kelley, John M.] Endicott Coll, Beverly, MA USA. RP Hall, KT (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. EM kthall@bidmc.harvard.edu OI Jensen, Karin/0000-0003-2521-3160 FU NCCAM-NIH [R01 AT004662, K24 AT004095, 3R01AT004662-02S1, T32 AT000051, R21 AT002860] FX The funding received for this study came from NCCAM-NIH grants # R01 AT004662, K24 AT004095, 3R01AT004662-02S1, T32 AT000051 and R21 AT002860. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 56 Z9 57 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 23 PY 2012 VL 7 IS 10 AR e48135 DI 10.1371/journal.pone.0048135 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025MO UT WOS:000310193600048 PM 23110189 ER PT J AU Angin, M King, M Altfeld, M Walker, BD Wucherpfennig, KW Addo, MM AF Angin, Mathieu King, Melanie Altfeld, Marcus Walker, Bruce D. Wucherpfennig, Kai W. Addo, Marylyn M. TI Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers SO AIDS LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HIV-1 INFECTION; REPLICATION; SUPPRESSION; ACTIVATION; EXPANSION; BLOOD AB Regulatory T cells (Tregs) are potent immune modulators, but their precise role in HIV pathogenesis remains incompletely understood. Most studies to date have focused on frequencies or phenotypes of 'bulk' Treg populations. However, although antigen-specific Tregs have been reported in other diseases, HIV-1 epitope-specific Tregs have not been described to date. We here report the first identification of functional HIV-1-Gag-specific regulatory T cells using human leukocyte antigen class II tetramer staining in HIV-1-infected individuals. C1 [Angin, Mathieu; King, Melanie; Altfeld, Marcus; Walker, Bruce D.; Addo, Marylyn M.] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Wucherpfennig, Kai W.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Addo, Marylyn M.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Addo, MM (reprint author), Harvard & MIT, Ragon Inst MCH, 149 13th St,6th Floor,Suite 6620, Charlestown, MA 02129 USA. EM maddo@partners.org OI Angin, Mathieu/0000-0002-6867-4680 FU Elisabeth Glaser Pediatric AIDS Foundation [MV-00-9-900-1429-0-00]; MGH/ECOR; NIH NIAID [KO8 AI074405, AI074405-03S1]; Bill & Melinda Gates Foundation; Terry and Susan Ragon Foundation; Harvard University Center for AIDS Research (CFAR), an NIH [P30 AI060354]; NIH NIAID; NIH NCI; NIH NICHD; NIH NHLBI; NIH NIDA; NIH NCCAM; NIH FIC; NIH OAR; NIH NIMH; NIH NIA FX This work was supported in part by research funding from the Elisabeth Glaser Pediatric AIDS Foundation (Pediatric HIV Vaccine Program Award MV-00-9-900-1429-0-00 to M.M.A.), MGH/ECOR (Physician Scientist Development Award to M.M.A.), NIH NIAID (KO8 AI074405 and AI074405-03S1 to M.M.A.). These studies were furthermore supported by the Bill & Melinda Gates Foundation and the Terry and Susan Ragon Foundation. This publication resulted in part from research supported by the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NCCAM, FIC, and OAR. NR 19 TC 17 Z9 17 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD OCT 23 PY 2012 VL 26 IS 16 BP 2112 EP 2115 DI 10.1097/QAD.0b013e328358cc75 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 021OB UT WOS:000309894000015 PM 22874519 ER PT J AU Hawkins, BM Kennedy, KF Giri, J Saltzman, AJ Rosenfield, K Drachman, DE White, CJ Spertus, JA Yeh, RW AF Hawkins, Beau M. Kennedy, Kevin F. Giri, Jay Saltzman, Adam J. Rosenfield, Kenneth Drachman, Douglas E. White, Christopher J. Spertus, John A. Yeh, Robert W. TI Pre-procedural Risk Quantification for Carotid Stenting Using the CAS Score A Report From the NCDR CARE Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE carotid stenosis; carotid stenting; risk score ID ARTERY STENOSIS; MEDICARE BENEFICIARIES; ENDARTERECTOMY; OUTCOMES; RECLASSIFICATION AB Objectives We developed and internally validated a risk score to predict in-hospital stroke or death after carotid artery stenting (CAS). Background A tool that accurately assesses CAS risk could aid clinical decision making and improve patient selection. Methods Patients undergoing CAS without acute evolving stroke from April 2005 through June 2011 as part of the NCDR Carotid Artery Revascularization and Endarterectomy (CARE) Registry were included. In-hospital stroke or death was modeled using logistic regression with 35 candidate variables. Internal validation was achieved with boot-strapping, and model discrimination and calibration were assessed. Results A total of 271 (2.4%) primary endpoint events occurred during 11,122 procedures. Independent predictors of stroke or death included impending major surgery, previous stroke, age, symptomatic lesion, atrial fibrillation, and absence of previous ipsilateral carotid endarterectomy. The model was well calibrated with moderate discriminatory ability (C-statistic: 0.71) overall, and within symptomatic (C-statistic: 0.68) and asymptomatic (C-statistic: 0.72) subgroups. The inclusion of available angiographic variables did not improve model performance (C-statistic: 0.72, integrated discrimination improvement 0.001; p = 0.21). The NCDR CAS score was developed to support prospective risk quantification. Conclusions The NCDR CAS score, comprising 6 clinical variables, predicts in-hospital S/D after CAS. This tool may be useful to assist clinicians in evaluating optimal management, share more accurate pre-procedural risks with patients, and improve patient selection for CAS. (J Am Coll Cardiol 2012;60:1617-22) (c) 2012 by the American College of Cardiology Foundation C1 [Hawkins, Beau M.; Giri, Jay; Saltzman, Adam J.; Rosenfield, Kenneth; Drachman, Douglas E.; Yeh, Robert W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Kennedy, Kevin F.; Spertus, John A.] Univ Missouri, St Lukes Mid Amer Heart Inst, Kansas City, MO 64110 USA. [White, Christopher J.] Ochsner Med Ctr, John Ochsner Heart & Vasc Inst, New Orleans, LA USA. RP Yeh, RW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, GRB 8-843,55 Fruit St, Boston, MA 02114 USA. EM ryeh@partners.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 FU American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR); Abbott Vascular; Bard Peripheral Vascular; Medtronic/Invatec; Atrium; Boston Scientific Corp.; Complete Conference Management; Harvard Clinical Research Institute; Contego; Micell; Becker Ventures; iDev Technologies, Inc.; Lutonix/Bard FX From the *Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; dagger St. Luke's Mid-America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri; and the double dagger John Ochsner Heart and Vascular Institute, Ochsner Medical Center, New Orleans, Louisiana. This research was supported by the American College of Cardiology Foundation's National Cardiovascular Data Registry (NCDR). The views expressed in this manuscript represent those of the author(s), and do not necessarily represent the official views of the NCDR or its associated professional societies identified at www.ncdr.com. The CARE Registry is an initiative of the American College of Cardiology Foundation, The Society for Cardiovascular Angiography and Interventions, the Society of Interventional Radiology, the American Academy of Neurology, the American Association of Neurological Surgeons/Congress of Neurological Surgeons, the Society for Vascular Medicine, and the Society of Vascular and Interventional Neurology. Dr. Yeh is an investigator at the Harvard Clinical Research Institute and has served as a consultant for the Kaiser Permanente Division of Research. Dr. Spertus has an ACCF contract to serve as an analytic center for the CARE registry. Dr. White is an investigator for the CABANA trial from Boston Scientific Corp. Dr. Rosenfield has received research grants from Abbott Vascular, Bard Peripheral Vascular, Medtronic/Invatec, and Atrium; has received consulting/advisory board fees from Abbott Vascular, Boston Scientific Corp., Complete Conference Management, Harvard Clinical Research Institute, Contego, Micell, and Becker Ventures; has equity in Lumen Biomedical, Medical Stimulation Corp., Angioguard (Cordis), and Micell; and has served on the board of directors for VIVA Physicians (501C3). Dr. Drachman has received research grant support from iDev Technologies, Inc. and Lutonix/Bard; is member of the clinical events committee of PLC Medical Systems, Inc.; and is a member of the Data and Safety Monitoring Board of Prarie Education & Research Cooperative. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 30 TC 14 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 23 PY 2012 VL 60 IS 17 BP 1617 EP 1622 DI 10.1016/j.jacc.2012.07.026 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025OH UT WOS:000310199700005 PM 22999733 ER PT J AU Varenhorst, C Alstrom, U Scirica, BM Hogue, CW Asenblad, N Storey, RF Steg, G Horrow, J Mahaffey, KW Becker, RC James, S Cannon, CP Brandrup-Wognsen, G Wallentin, L Held, C AF Varenhorst, Christoph Alstrom, Ulrica Scirica, Benjamin M. Hogue, Charles W. Asenblad, Nils Storey, Robert F. Steg, Gabriel Horrow, Jay Mahaffey, Kenneth W. Becker, Richard C. James, Stefan Cannon, Christopher P. Brandrup-Wognsen, Gunnar Wallentin, Lars Held, Claes TI Factors Contributing to the Lower Mortality With Ticagrelor Compared With Clopidogrel in Patients Undergoing Coronary Artery Bypass Surgery SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE bypass; clopidogrel; myocardial infarction; surgery; ticagrelor ID PLATELET INHIBITION; PRACTICE GUIDELINES; ASPIRIN; ANTIPLATELET; ANTAGONIST; MANAGEMENT; PRASUGREL; UPDATE; SAFETY; TRIAL AB Objectives This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial. Background In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality. Methods In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death. Results Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively). Conclusions The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872) (J Am Coll Cardiol 2012;60:1623-30) (c) 2012 by the American College of Cardiology Foundation C1 [Varenhorst, Christoph; Asenblad, Nils; James, Stefan; Wallentin, Lars; Held, Claes] Uppsala Univ, Uppsala Clin Res Ctr, MTC, Uppsala 75237, Sweden. [Varenhorst, Christoph; Asenblad, Nils; James, Stefan; Wallentin, Lars; Held, Claes] Uppsala Univ, Dept Med Sci, Uppsala 75237, Sweden. [Alstrom, Ulrica] Uppsala Univ, Dept Cardiothorac Surg & Anesthesiol, Uppsala 75237, Sweden. [Scirica, Benjamin M.; Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Hogue, Charles W.] Johns Hopkins Univ, Sch Med, Dept Anaesthesiol & Crit Care Med, Baltimore, MD USA. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Steg, Gabriel] Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France. [Steg, Gabriel] Univ Paris Diderot, U698, INSERM, Paris, France. [Horrow, Jay] AstraZeneca LP, Wilmington, DE USA. [Mahaffey, Kenneth W.; Becker, Richard C.] Duke Clin Res Inst, Durham, NC USA. [Brandrup-Wognsen, Gunnar] AstraZeneca, Molndal, Sweden. RP Varenhorst, C (reprint author), Uppsala Univ, Uppsala Clin Res Ctr, MTC, Dag Hammar Skjolds Vag,14B,1Tr,Sci Pk, Uppsala 75237, Sweden. EM christoph.varenhorst@ucr.uu.se OI Varenhorst, Christoph/0000-0002-8378-3869; Held, Claes/0000-0001-9402-7404 FU AstraZeneca; Merck; Johnson Johnson; Bayer; Daiichi Sankyo; Bristol-Myers Squibb; Gilead Sciences; Novartis; Covidien; Boehringer-Ingelheim; Eli Lilly Company; GlaxoSmithKline; Pozen; Regado Biotechnologies; Sanofi Aventis; Schering Plough; Medicines Company; Regado; MSD; Accumetrics; Essentialis; Regeneron; Takeda; Merck/Schering-Plough; Bristol-Myers Squibb/Pfizer; Schering-Plough/Merck; Roche FX From the *Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; dagger Department of Cardiothoracic Surgery and Anesthesiology, Uppsala University, Uppsala, Sweden; double dagger TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts; Department of Anesthesiology & Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; parallel to Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom; Hopital Bichat, Assistance Publique-Hopitaux de Paris, Paris, France; #INSERM U-698, Universite Paris-Diderot, Paris, France; **AstraZeneca LP, Wilmington, Delaware; dagger dagger Duke Clinical Research Institute, Durham, North Carolina; and double dagger double dagger AstraZeneca, Molndal, Sweden. This study was supported by AstraZeneca. Dr. Varenhorst has received a research grant from AstraZeneca to perform this research; and is a member of the Speakers' Bureaus for AstraZeneca, Eli Lilly & Company, and The Medicines Company. Dr. Scirica has received research grants from Merck, AstraZeneca, Johnson & Johnson, Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Gilead Sciences, and Novartis; and is a consultant to Gilead Sciences, Arena, and Lexicon. Dr. Hogue has received research support from Covidien; and is a consultant to Covidien, Merck, and Ornim. Dr. Storey is a consultant to AstraZeneca, Accumetrics, Merck, Novartis, Eli Lilly & Company, Daiichi Sankyo, Eisai, Iroko, The Medicines Company, Sanofi Aventis, Bristol-Myers Squibb, and Medscape. Dr. Steg is a consultant to AstraZeneca, Amarin, Amgen, Astellas, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly & Company, Daiichi Sankyo, Eisai, GlaxoSmithKline, Medtronic, Merck, Novartis, Otsuka, Pfizer, Roche, The Medicines Company, Sanofi Aventis, and Servier; is a member of the Speakers' Bureaus for AstraZeneca, Bayer, Bristol-Myers Squibb, Pfizer, The Medicines Company, Sanofi Aventis, and Servier; and has received Data Safety Monitoring Board support from Ablynx. Dr. Horrow is the executive director of AstraZeneca LP, and has equity ownership in the company. Dr. Mahaffey has received grant support from AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Pozen, Regado Biotechnologies, Sanofi Aventis, Schering Plough, and The Medicines Company; and is a consultant to AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Polymedix, and Sanofi Aventis. Dr. Becker is a consultant to and receives support from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, The Medicines Company, Merck, and Regado. Dr. James has received institutional grants from AstraZeneca, Eli Lilly & Company, and MSD; and honoraria from AstraZeneca, Eli Lilly & Company, MSD, Merck, and The Medicines Company. Dr. Cannon has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi Aventis, and Takeda; is a member of the Advisory Boards for Alnylam, Bristol-Myers Squibb, and Pfizer; has received funds from these companies, which have been donated to charity; and is a clinical advisor to Automated Medical Systems with equity in the company. Dr. Wallentin is a consultant to Merck/Schering Plough, Regado Biosciences, Evolva, Portola, C.S.L.; Behring, Athera Biotechnologies, Boehringer-Ingelheim, AstraZeneca, GlaxoSmithKline, and Brisol-Myers Squibb/Pfizer; has received research grants from AstraZeneca, Merck/Schering-Plough, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; and lecture fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, and Schering-Plough/Merck. Dr. Held is on the Advisory Boards for AstraZeneca, Roche, and Pfizer; and has received institutional grants from Schering-Plough/Merck, GlaxoSmithKline, Bristol-Myers Squibb, and Roche. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 23 TC 39 Z9 45 U1 0 U2 7 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 OCT 23 PY 2012 VL 60 IS 17 BP 1623 EP 1630 DI 10.1016/j.jacc.2012.07.021 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025OH UT WOS:000310199700006 PM 23021325 ER PT J AU Kendall, EA Zaman, RU Naved, RT Rahman, MW Kadir, MA Arman, S Azziz-Baumgartner, E Gurley, ES AF Kendall, Emily A. Zaman, Rashid Uz Naved, Ruchira Tabassum Rahman, Muhammad Waliur Kadir, Mohammad Abdul Arman, Shaila Azziz-Baumgartner, Eduardo Gurley, Emily S. TI Medically unexplained illness and the diagnosis of hysterical conversion reaction (HCR) in women's medicine wards of Bangladeshi hospitals: a record review and qualitative study SO BMC WOMENS HEALTH LA English DT Review DE Women's health services; Mental health; Somatoform disorders; Conversion disorder; Diagnosis; Physician's practice patterns; Health services needs and demand; Bangladesh ID PRIMARY-CARE; PSYCHIATRIC-DISORDERS; SOMATOFORM DISORDERS; INCOME COUNTRIES; SPOUSAL VIOLENCE; SOMATIC SYMPTOMS; FOLLOW-UP; SOMATIZATION; PREVALENCE; DISTRESS AB Background: Frequent reporting of cases of hysterical conversion reaction (HCR) among hospitalized female medical patients in Bangladesh's public hospital system led us to explore the prevalence of "HCR" diagnoses within hospitals and the manner in which physicians identify, manage, and perceive patients whom they diagnose with HCR. Methods: We reviewed admission records from women's general medicine wards in two public hospitals to determine how often and at what point during hospitalization patients received diagnoses of HCR. We also interviewed 13 physicians about their practices and perceptions related to HCR. Results: Of 2520 women admitted to the selected wards in 2008, 6% received diagnoses of HCR. HCR patients had wide-ranging symptoms including respiratory distress, headaches, chest pain, convulsions, and abdominal complaints. Most doctors diagnosed HCR in patients who had any medically-unexplained physical symptom. According to physician reports, women admitted to medical wards for HCR received brief diagnostic evaluations and initial treatment with short-acting tranquilizers or placebo agents. Some were referred to outpatient psychiatric treatment. Physicians reported that repeated admissions for HCR were common. Physicians noted various social factors associated with HCR, and they described failures of the current system to meet psychosocial needs of HCR patients. Conclusions: In these hospital settings, physicians assign HCR diagnoses frequently and based on vague criteria. We recommend providing education to increase general physicians' awareness, skill, and comfort level when encountering somatization and other common psychiatric issues. Given limited diagnostic capacity for all patients, we raise concern that when HCR is used as a "wastebasket" diagnosis for unexplained symptoms, patients with treatable medical conditions may go unrecognized. We also advocate introducing non-physician hospital personnel to address psychosocial needs of HCR patients, assist with triage in a system where both medical inpatient beds and psychiatric services are scarce commodities, and help ensure appropriate follow up. C1 [Kendall, Emily A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zaman, Rashid Uz] Oxford Policy Management, Oxford OX1 1BN, England. [Naved, Ruchira Tabassum] Icddr B, Ctr Equ & Hlth Syst, Dhaka 1000, Bangladesh. [Rahman, Muhammad Waliur; Arman, Shaila; Gurley, Emily S.] Icddr B, Ctr Communicable Dis, Dhaka 1000, Bangladesh. [Kadir, Mohammad Abdul] Univ Queensland, Hlth Communities Res Ctr, Ipswich, Qld 4305, Australia. [Azziz-Baumgartner, Eduardo] US Ctr Dis Control & Prevent, Epidemiol & Prevent Branch, Atlanta, GA 30075 USA. RP Kendall, EA (reprint author), Massachusetts Gen Hosp, Dept Med, Bigelow 740,55 Fruit St, Boston, MA 02114 USA. EM ekendall1@partners.org RI Gurley, Emily/B-7903-2010; OI Gurley, Emily/0000-0002-8648-9403; Kendall, Emily/0000-0002-0083-422X FU Centers for Disease Control and Prevention (CDC), United States of America [U01/CI000298]; National Institutes of Health (NIH), Fogarty International Center [R24 TW007988] FX This study was funded by the Centers for Disease Control and Prevention (CDC), United States of America, under cooperative agreement U01/CI000298, and by the National Institutes of Health (NIH), Fogarty International Center grant R24 TW007988. icddr,b acknowledges with gratitude the commitment of the CDC and NIH to its research efforts. NR 36 TC 0 Z9 0 U1 4 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6874 J9 BMC WOMENS HEALTH JI BMC Womens Health PD OCT 22 PY 2012 VL 12 AR 38 DI 10.1186/1472-6874-12-38 PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology SC Public, Environmental & Occupational Health; Obstetrics & Gynecology GA 070LR UT WOS:000313508100001 PM 23088583 ER PT J AU Lambert, B Vandeputte, J Remacle, S Bergiers, I Simonis, N Twizere, JC Vidal, M Rezsohazy, R AF Lambert, Barbara Vandeputte, Julie Remacle, Sophie Bergiers, Isabelle Simonis, Nicolas Twizere, Jean-Claude Vidal, Marc Rezsohazy, Rene TI Protein interactions of the transcription factor Hoxa1 SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article DE Hox; Hoxa1; ORFeome; Interactome ID RECEPTOR DOWN-REGULATION; BINDING PROTEIN; DNA-BINDING; SPROUTY PROTEINS; AXIAL SKELETON; HOMEOBOX GENES; CELL ADHESIONS; ALIX; ACTIVATION; HINDBRAIN AB Background: Hox proteins are transcription factors involved in crucial processes during animal development. Their mode of action remains scantily documented. While other families of transcription factors, like Smad or Stat, are known cell signaling transducers, such a function has never been squarely addressed for Hox proteins. Results: To investigate the mode of action of mammalian Hoxa1, we characterized its interactome by a systematic yeast two-hybrid screening against similar to 12,200 ORF-derived polypeptides. Fifty nine interactors were identified of which 45 could be confirmed by affinity co-purification in animal cell lines. Many Hoxa1 interactors are proteins involved in cell-signaling transduction, cell adhesion and vesicular trafficking. Forty-one interactions were detectable in live cells by Bimolecular Fluorescence Complementation which revealed distinctive intracellular patterns for these interactions consistent with the selective recruitment of Hoxa1 by subgroups of partner proteins at vesicular, cytoplasmic or nuclear compartments. Conclusions: The characterization of the Hoxa1 interactome presented here suggests unexplored roles for Hox proteins in cell-to-cell communication and cell physiology. C1 [Lambert, Barbara; Vandeputte, Julie; Remacle, Sophie; Bergiers, Isabelle; Rezsohazy, Rene] Catholic Univ Louvain, Life Sci Inst ISV, Mol & Cellular Anim Embryol Grp, B-1348 Louvain, Belgium. [Simonis, Nicolas] Univ Libre Brussels, Brussels, Belgium. [Twizere, Jean-Claude] Univ Liege, GIGA R & Gembloux Agro Biotech, B-4000 Liege, Belgium. [Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Rezsohazy, R (reprint author), Catholic Univ Louvain, Life Sci Inst ISV, Mol & Cellular Anim Embryol Grp, B-1348 Louvain, Belgium. EM rene.rezsohazy@uclouvain.be OI Bergiers, Isabelle/0000-0001-9622-7960 FU Belgian Fund for Scientific Research (FNRS, FRSM) [3.4.536.06F]; Direction Generale des Technologies, de la Recherche et de l'Energie" of the Walloon Region (WALEOII) [516054]; Fonds Speciaux de Recherche (FSR) of the Universite catholique de Louvain (UCL); US National Human Genome Research Institute [R01-HG001715]; Belgian Fund for Scientific Research; FSR grant from UCL; Belspo (Belgian Federal Government) FX We are grateful to Michael Cusick and Matija Dreze for helpful comments on the manuscript. We are also grateful to Abdelmounaim Errachid (IMABIOL imaging platform) for technical assistance in confocal microscopy. We thank Samir Merabet for providing us with plasmids coding for the VENUS VN173 and VC155 moieties and for helping us in setting up the BiFC assay. This work was supported by the Belgian Fund for Scientific Research (FNRS, FRSM grant 3.4.536.06F), the "Direction Generale des Technologies, de la Recherche et de l'Energie" of the Walloon Region (WALEOII grant no516054), the Fonds Speciaux de Recherche (FSR) of the Universite catholique de Louvain (UCL), and by US National Human Genome Research Institute grant R01-HG001715 to MV. BL and IB held a FRIA fellowship from the Belgian Fund for Scientific Research and a FSR grant from UCL. NS is supported by a return grant from Belspo (Belgian Federal Government). MV is a Chercheur Qualifie Honoraire of the Belgian Fund for Scientific Research. NR 61 TC 15 Z9 16 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD OCT 22 PY 2012 VL 12 AR 29 DI 10.1186/1471-213X-12-29 PG 17 WC Developmental Biology SC Developmental Biology GA 051LG UT WOS:000312127700001 PM 23088713 ER PT J AU Schnell, E Bensen, AL Washburn, EK Westbrook, GL AF Schnell, Eric Bensen, AeSoon L. Washburn, Eric K. Westbrook, Gary L. TI Neuroligin-1 Overexpression in Newborn Granule Cells In Vivo SO PLOS ONE LA English DT Article ID NEWLY GENERATED NEURONS; TRAUMATIC BRAIN-INJURY; INHIBITORY SYNAPSE FORMATION; DENTATE GYRUS; PARKINSONS-DISEASE; EXCITATORY SYNAPSES; ADULT HIPPOCAMPUS; ADHESION MOLECULE; NEUROGENESIS; PLASTICITY AB Adult-born dentate granule cells integrate into the hippocampal network, extend neurites and form synapses in otherwise mature tissue. Excitatory and inhibitory inputs innervate these new granule cells in a stereotyped, temporally segregated manner, which presents a unique opportunity to study synapse development in the adult brain. To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1-overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse-inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1-overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons. C1 [Schnell, Eric] Portland VA Med Ctr, Portland, OR USA. [Schnell, Eric] OHSU Dept Anesthesiol & Perioperat Med, Portland, OR USA. [Bensen, AeSoon L.; Washburn, Eric K.; Westbrook, Gary L.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA. RP Schnell, E (reprint author), Portland VA Med Ctr, Portland, OR USA. EM schneler@ohsu.edu OI Schnell, Eric/0000-0002-5623-5015 FU Oregon Medical Research Foundation; Department of Veteran's Affairs Career Development Award; National Institute of Mental Health [R01MH46613]; NIH [P30 NS06180] FX This work was supported by the Oregon Medical Research Foundation (ES), a Department of Veteran's Affairs Career Development Award (ES), the National Institute of Mental Health (R01MH46613; GLW), and the Jungers Center Light Microscopy Image Core that is supported in part by NIH P30 NS06180. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 22 PY 2012 VL 7 IS 10 AR e48045 DI 10.1371/journal.pone.0048045 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 025MM UT WOS:000310193400031 PM 23110172 ER PT J AU Croci, DO Salatino, M Rubinstein, N Cerliani, JP Cavallin, LE Leung, HJ Ouyang, J Ilarregui, JM Toscano, MA Domaica, CI Croci, MC Shipp, MA Mesri, EA Albini, A Rabinovich, GA AF Croci, Diego O. Salatino, Mariana Rubinstein, Natalia Cerliani, Juan P. Cavallin, Lucas E. Leung, Howard J. Ouyang, Jing Ilarregui, Juan M. Toscano, Marta A. Domaica, Carolina I. Croci, Maria C. Shipp, Margaret A. Mesri, Enrique A. Albini, Adriana Rabinovich, Gabriel A. TI Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; TUMOR-IMMUNE PRIVILEGE; T-CELL APOPTOSIS; GENE-EXPRESSION; PARACRINE NEOPLASIA; HERPESVIRUS VGPCR; ENDOTHELIAL-CELLS; CANCER CELLS; INDUCTION; KSHV AB Kaposi's sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1. and HIF-2. but involved reactive oxygen species-dependent activation of the transcription factor nuclear factor. B. Targeted disruption of Gal-1-N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-1-specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but also for understanding and managing a variety of solid tumors. C1 [Croci, Diego O.; Salatino, Mariana; Cerliani, Juan P.; Ilarregui, Juan M.; Toscano, Marta A.; Domaica, Carolina I.; Rabinovich, Gabriel A.] Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Lab Inmunopatol, RA-1428 Buenos Aires, DF, Argentina. [Croci, Diego O.; Salatino, Mariana; Rubinstein, Natalia; Ilarregui, Juan M.; Toscano, Marta A.; Domaica, Carolina I.; Rabinovich, Gabriel A.] Univ Buenos Aires, Hosp Clin Jose de San Martin, Div Inmunogenet, RA-1120 Buenos Aires, DF, Argentina. [Cavallin, Lucas E.; Leung, Howard J.; Mesri, Enrique A.] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Viral Oncol Program,Miami Ctr AIDS Res,Dept Micro, Miami, FL 33136 USA. [Ouyang, Jing; Shipp, Margaret A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Croci, Maria C.] Univ Nacl Comahue, Fac Ciencias Med, Lab Patol, RA-8324 Cipolletti, Argentina. [Albini, Adriana] Ist Ricovero & Cura Carattere Sci MultiMed, I-20138 Milan, Italy. [Rabinovich, Gabriel A.] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, RA-1428 Buenos Aires, DF, Argentina. RP Rabinovich, GA (reprint author), Consejo Nacl Invest Cient & Tecn, Inst Biol & Med Expt, Lab Inmunopatol, RA-1428 Buenos Aires, DF, Argentina. EM gabyrabi@gmail.com OI Albini, Adriana/0000-0002-9624-5103; Ilarregui, Juan Martin/0000-0002-6871-6764; Domaica, Carolina Ines/0000-0001-9596-4889 FU Cancer Research Institute; Mizutani Foundation for Glycoscience; Fundacion Sales; Agencia Nacional de Promocion Cientifica y Tecnologica [PICT 2010-870]; University of Buenos Aires; Consejo Nacional de Investigaciones Cientificas y Tecnicas; Associazione Italiana per la Ricerca sul Cancro; National Institutes of Health (NIH), National Cancer Institute (NCI) [CA136387]; NCI/OHAM supplements to the Developmental Center for AIDS Research [5P30AI073961]; Leukemia and Lymphoma Society SCOR grant [7009-12] FX This work was supported by grants from the Cancer Research Institute (G.A. Rabinovich), Mizutani Foundation for Glycoscience (G.A. Rabinovich), Fundacion Sales (G.A. Rabinovich), Agencia Nacional de Promocion Cientifica y Tecnologica (G.A. Rabinovich; PICT 2010-870), University of Buenos Aires (G.A. Rabinovich), Consejo Nacional de Investigaciones Cientificas y Tecnicas (M. Salatino and G.A. Rabinovich), the Associazione Italiana per la Ricerca sul Cancro (A. Albini), National Institutes of Health (NIH), National Cancer Institute (NCI; CA136387), and NCI/OHAM supplements to the Developmental Center for AIDS Research (E.A. Mesri; 5P30AI073961), and a Leukemia and Lymphoma Society SCOR grant (M.A. Shipp; # 7009-12). We are grateful to Ferioli and Ostry families for generous donations. NR 63 TC 60 Z9 60 U1 1 U2 12 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 OCT 22 PY 2012 VL 209 IS 11 BP 1985 EP 2000 DI 10.1084/jem.20111665 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 027QT UT WOS:000310368800007 PM 23027923 ER PT J AU Kaji, T Ishige, A Hikida, M Taka, J Hijikata, A Kubo, M Nagashima, T Takahashi, Y Kurosaki, T Okada, M Ohara, O Rajewsky, K Takemori, T AF Kaji, Tomohiro Ishige, Akiko Hikida, Masaki Taka, Junko Hijikata, Atsushi Kubo, Masato Nagashima, Takeshi Takahashi, Yoshimasa Kurosaki, Tomohiro Okada, Mariko Ohara, Osamu Rajewsky, Klaus Takemori, Toshitada TI Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GERMINAL-CENTER FORMATION; PRIMARY IMMUNE-RESPONSE; LIVED PLASMA-CELLS; B-CELLS; AFFINITY MATURATION; CLONAL SELECTION; PRIMARY IMMUNIZATION; GENE-EXPRESSION; MURINE MEMORY; T-CELLS AB One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell-dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell-dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen. C1 [Kaji, Tomohiro; Ishige, Akiko; Taka, Junko; Takemori, Toshitada] RIKEN Res Ctr Allergy & Immunol, Lab Immunol Memory, Yokohama, Kanagawa 2300045, Japan. [Kubo, Masato] RIKEN Res Ctr Allergy & Immunol, Signal Network, Yokohama, Kanagawa 2300045, Japan. [Hikida, Masaki] Kyoto Univ, Grad Sch Med, Ctr Immunoregulat Technol & Therapeut, Sakyo Ku, Kyoto 6068501, Japan. [Takahashi, Yoshimasa] Natl Inst Infect Dis, Dept Immunol, Shinjyuku Ku, Tokyo 1628640, Japan. [Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Rajewsky, Klaus] Harvard Univ, Program Cellular & Mol Med, Childrens Hosp, Sch Med, Boston, MA 02115 USA. [Rajewsky, Klaus] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. RP Takemori, T (reprint author), RIKEN Res Ctr Allergy & Immunol, Lab Immunol Memory, Yokohama, Kanagawa 2300045, Japan. EM klaus.rajewsky@mdc-berlin.de; mttoshi@rcai.riken.jp RI Takemori, Toshitada/A-5909-2016; Ohara, Osamu/G-5448-2015; Kurosaki, Tomohiro/D-1306-2009; Okada, Mariko/N-6933-2015 OI Ohara, Osamu/0000-0002-3328-9571; Kurosaki, Tomohiro/0000-0002-6352-304X; FU National Institutes of Health of the USA FX We are grateful to Atsushi Miyawaki and Asako Sakaue-Sawano for Fucci-expressing transgenic mice, Michael Reth for mb1-cre mice, Michel Nussenzweig for B1-8hi mice, Garnett Kelsoe for anti-CD40L mAb, and Yuichi Aiba for discussion. K. Rajewsky is supported by the National Institutes of Health of the USA. NR 60 TC 75 Z9 77 U1 3 U2 16 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 OCT 22 PY 2012 VL 209 IS 11 BP 2079 EP 2097 DI 10.1084/jem.20120127 PG 19 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 027QT UT WOS:000310368800013 PM 23027924 ER PT J AU Vickers, AJ Cronin, AM Maschino, AC Lewith, G MacPherson, H Foster, NE Sherman, KJ Witt, CM Linde, K AF Vickers, Andrew J. Cronin, Angel M. Maschino, Alexandra C. Lewith, George MacPherson, Hugh Foster, Nadine E. Sherman, Karen J. Witt, Claudia M. Linde, Klaus CA Acupuncture Trialists' TI Acupuncture for Chronic Pain Individual Patient Data Meta-analysis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Review ID LOW-BACK-PAIN; RANDOMIZED CONTROLLED-TRIAL; CHRONIC NECK PAIN; TENSION-TYPE HEADACHE; CONTROLLED CLINICAL-TRIAL; ELECTRICAL NERVE-STIMULATION; STUDY COMPARING ACUPUNCTURE; TRIGGER POINT ACUPUNCTURE; ANTI-INFLAMMATORY THERAPY; ROTATOR CUFF TENDINITIS AB Background: Although acupuncture is widely used for chronic pain, there remains considerable controversy as to its value. We aimed to determine the effect size of acupuncture for 4 chronic pain conditions: back and neck pain, osteoarthritis, chronic headache, and shoulder pain. Methods: We conducted a systematic review to identify randomized controlled trials (RCTs) of acupuncture for chronic pain in which allocation concealment was determined unambiguously to be adequate. Individual patient data meta-analyses were conducted using data from 29 of 31 eligible RCTs, with a total of 17 922 patients analyzed. Results: In the primary analysis, including all eligible RCTs, acupuncture was superior to both sham and no-acupuncture control for each pain condition (P<.001 for all comparisons). After exclusion of an outlying set of RCTs that strongly favored acupuncture, the effect sizes were similar across pain conditions. Patients receiving acupuncture had less pain, with scores that were 0.23 (95% CI, 0.13-0.33), 0.16 (95% CI, 0.07-0.25), and 0.15 (95% CI, 0.07-0.24) SDs lower than sham controls for back and neck pain, osteoarthritis, and chronic headache, respectively; the effect sizes in comparison to no-acupuncture controls were 0.55 (95% CI, 0.51-0.58), 0.57 (95% CI, 0.50-0.64), and 0.42 (95% CI, 0.37-0.46) SDs. These results were robust to a variety of sensitivity analyses, including those related to publication bias. Conclusions: Acupuncture is effective for the treatment of chronic pain and is therefore a reasonable referral option. Significant differences between true and sham acupuncture indicate that acupuncture is more than a placebo. However, these differences are relatively modest, suggesting that factors in addition to the specific effects of needling are important contributors to the therapeutic effects of acupuncture. C1 [Vickers, Andrew J.; Maschino, Alexandra C.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol, New York, NY 10065 USA. [Vickers, Andrew J.; Maschino, Alexandra C.] Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10065 USA. [Cronin, Angel M.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. [Lewith, George] Univ Southampton, Complementary & Integrated Medline Res Unit, Southampton, Hants, England. [MacPherson, Hugh] Univ York, Dept Hlth Sci, York YO10 5DD, N Yorkshire, England. [Foster, Nadine E.] Keele Univ, Arthrit Res UK Primary Care Ctr, Newcastle Under Lyme, Staffs, England. [Sherman, Karen J.] Grp Hlth Res Inst, Seattle, WA USA. [Witt, Claudia M.] Inst Social Med Epidemiol & Hlth Econ, Berlin, Germany. [Linde, Klaus] Tech Univ Munich, Inst Gen Practice, Munich, Germany. RP Vickers, AJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 307 E 63rd St, New York, NY 10065 USA. EM vickersa@mskcc.org RI Vas, Jorge/B-1138-2012; OI Vas, Jorge/0000-0003-1326-856X; Lewith, George/0000-0002-2364-3960; MacPherson, Hugh/0000-0003-4255-4768; Vickers, Andrew/0000-0003-1525-6503 FU National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) [R21 (AT004189I)]; Samueli Institute; UK National Institute for Health Research (NIHR) [RP-PG-0707-10186] FX The Acupuncture Trialists' Collaboration is funded by an R21 (AT004189I from the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) to Dr Vickers) and by a grant from the Samueli Institute. Dr MacPherson's work has been supported in part by the UK National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10186). The views expressed in this publication are those of the author(s) and not necessarily those of the NCCAM NHS, the NIHR, or the Department of Health in England. NR 113 TC 273 Z9 286 U1 20 U2 107 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 22 PY 2012 VL 172 IS 19 BP 1444 EP 1453 DI 10.1001/archinternmed.2012.3654 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 023XG UT WOS:000310070200003 PM 22965186 ER PT J AU Zhang, YT Steinman, MA Kaplan, CM AF Zhang, Yuting Steinman, Michael A. Kaplan, Cameron M. TI Geographic Variation in Outpatient Antibiotic Prescribing Among Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RESPIRATORY-TRACT INFECTIONS; ADVERSE-REACTIONS; PRIMARY-CARE; QUALITY AB Background: Consequences of antibiotic overuse are substantial, especially among older adults, who are more susceptible to adverse reactions. Findings about variation in antibiotic prescribing can target policy efforts to focused areas; however, little is known about these patterns among older adults. Methods: Using Medicare Part D data from January 1, 2007, through December 31, 2009 (comprising 1.0-1.1 million patients per year), we examined geographic variation in antibiotic use among older adults in 306 Dartmouth Atlas of Health Care hospital referral regions, 50 states and the District of Columbia, and 4 national regions (South, West, Midwest, and Northeast). In addition, we examined the quarterly change in antibiotic use across the 4 regions. Differences in patient demographics, insurance status, and clinical characteristics were adjusted for across regions. Results: Substantial geographic and quarterly variation in outpatient antibiotic prescribing existed across regions after adjusting for population characteristics. This variation could not be explained by differences in the prevalences of the underlying conditions. For example, the ratios of the 75th percentile to the 25th percentile of adjusted annual antibiotic spending were 1.31 across states and 1.32 across regions. The highest antibiotic use was in the South, where 21.4% of patients per quarter used an antibiotic, whereas the lowest antibiotic use was in the West, where 17.4% of patients per quarter used an antibiotic (P < .01). Regardless of region, the rate of antibiotic use was highest in the first quarter (20.9% in January through March) and was lowest in the third quarter (16.9% in July through September) (P < .01). Conclusions: Areas with high rates of antibiotic use may benefit from targeted programs to reduce unnecessary prescription. Quality improvement programs can set attainable targets using the low-prescribing areas as a reference, particularly targeting older adults. C1 [Zhang, Yuting; Kaplan, Cameron M.] Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Steinman, Michael A.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, Hlth Serv Res & Dev Serv Res Enhancement Award Pr, San Francisco, CA USA. RP Zhang, YT (reprint author), Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, 130 De Soto St,Crabtree Hall,Room A664, Pittsburgh, PA 15261 USA. EM ytzhang@pitt.edu OI Zhang, Yuting/0000-0002-6460-6779 FU Centers for Medicare & Medicaid Services and the Institute of Medicine from the National Institute of Mental Health [HHSP22320042509XI, RC1 MH088510]; Agency for Healthcare Research and Quality [R01 HS018657]; National Institute on Aging [1K23-AG030999]; American Federation for Aging Research FX This study was supported in part by grants HHSP22320042509XI from the Centers for Medicare & Medicaid Services and the Institute of Medicine, RC1 MH088510 from the National Institute of Mental Health, and R01 HS018657 from the Agency for Healthcare Research and Quality (Dr Zhang) and by grant 1K23-AG030999 from the National Institute on Aging and the American Federation for Aging Research (Dr Steinman). NR 19 TC 30 Z9 30 U1 0 U2 10 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 OCT 22 PY 2012 VL 172 IS 19 BP 1465 EP 1471 DI 10.1001/archinternmed.2012.3717 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 023XG UT WOS:000310070200007 PM 23007171 ER PT J AU Ngwa, W Makrigiorgos, GM Berbeco, RI AF Ngwa, Wilfred Makrigiorgos, G. Mike Berbeco, Ross I. TI Gold nanoparticle enhancement of stereotactic radiosurgery for neovascular age-related macular degeneration SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID X-RAY-IRRADIATION; AMD 6-MONTH SAFETY; ANTI-VEGF AGENTS; PHOTODYNAMIC THERAPY; RANIBIZUMAB THERAPY; FUNCTIONAL OUTCOMES; RADIATION TREATMENT; DOSE ENHANCEMENT; ENERGY; RADIOTHERAPY AB Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries for people over the age of 50. In this work, the dosimetric feasibility of using gold nanoparticles (AuNP) as radiosensitizers to enhance kilovoltage stereotactic radiosurgery for neovascular AMD is investigated. Microdosimetry calculations at the sub-cellular level were carried out to estimate the radiation dose enhancement to individual nuclei in neovascular AMD endothelial cells (nDEF) due to photon-induced photo-/Auger electrons from x-ray-irradiated AuNP. The nDEF represents the ratio of radiation doses to the endothelial cell nuclei with and without AuNP. The calculations were carried out for a range of feasible AuNP local concentrations using the clinically applicable 100 kVp x-ray beam parameters employed by a commercially available x-ray therapy system. The results revealed nDEF values of 1.30-3.26 for the investigated concentration range of 1-7 mg g(-1), respectively. In comparison, for the same concentration range, nDEF values of 1.32-3.40, 1.31-3.33, 1.29-3.19, 1.28-3.12 were calculated for 80, 90, 110 and 120 kVp x-rays, respectively. Meanwhile, calculations as a function of distance from the AuNP showed that the dose enhancement, for 100 kVp, is markedly confined to the targeted neovascular AMD endothelial cells where AuNP are localized. These findings provide impetus for considering the application of AuNP to enhance therapeutic efficacy during stereotactic radiosurgery for neovascular AMD. C1 [Ngwa, Wilfred] Brigham & Womens Hosp, Div Med Phys & Biophys, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ngwa, W (reprint author), Brigham & Womens Hosp, Div Med Phys & Biophys, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM wngwa@lroc.harvard.edu NR 45 TC 15 Z9 16 U1 1 U2 29 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2012 VL 57 IS 20 BP 6371 EP 6380 DI 10.1088/0031-9155/57/20/6371 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 016WD UT WOS:000309549600005 PM 22995994 ER PT J AU Titt, U Bednarz, B Paganetti, H AF Titt, U. Bednarz, B. Paganetti, H. TI Comparison of MCNPX and Geant4 proton energy deposition predictions for clinical use SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MONTE-CARLO SIMULATIONS; DOSE DISTRIBUTIONS; TREATMENT UNCERTAINTIES; THERAPY; NOZZLE; IMPT; SENSITIVITY; TOOLKIT; BEAMS; MODEL AB Several different Monte Carlo codes are currently being used at proton therapy centers to improve upon dose predictions over standard methods using analytical or semi-empirical dose algorithms. There is a need to better ascertain the differences between proton dose predictions from different available Monte Carlo codes. In this investigation Geant4 and MCNPX, the two most-utilized Monte Carlo codes for proton therapy applications, were used to predict energy deposition distributions in a variety of geometries, comprising simple water phantoms, water phantoms with complex inserts and in a voxelized geometry based on clinical CT data. The Gamma analysis was used to evaluate the differences of the predictions between the codes. The results show that in all the cases the agreement was better than clinical acceptance criteria. C1 [Titt, U.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bednarz, B.] Univ Wisconsin, Dept Med Phys, Madison, WI 53705 USA. [Bednarz, B.; Paganetti, H.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Bednarz, B.; Paganetti, H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Titt, U (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd,Unit 94, Houston, TX 77030 USA. EM utitt@mdanderson.org FU National Cancer Institute [P01CA021239] FX This project is supported by P01CA021239 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. NR 26 TC 12 Z9 12 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2012 VL 57 IS 20 BP 6381 EP 6393 DI 10.1088/0031-9155/57/20/6381 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 016WD UT WOS:000309549600006 PM 22996039 ER PT J AU Mallas, G Brooks, DH Rosenthal, A Nudelman, RN Mauskapf, A Jaffer, FA Ntziachristos, V AF Mallas, Georgios Brooks, Dana H. Rosenthal, Amir Nudelman, R. Nika Mauskapf, Adam Jaffer, Farouc A. Ntziachristos, Vasilis TI Improving quantification of intravascular fluorescence imaging using structural information SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; RAY COMPUTED-TOMOGRAPHY; IN-VIVO; CARDIOVASCULAR-DISEASE; ULTRASOUND IMAGES; CONTRAST AGENT; ATHEROSCLEROSIS; SEGMENTATION; INFLAMMATION; SYSTEM AB Intravascular near-infrared fluorescence (iNIRF) imaging can enable the in vivo visualization of biomarkers of vascular pathology, including high-risk plaques. The technique resolves the bio-distribution of systemically administered fluorescent probes with molecular specificity in the vessel wall. However, the geometrical variations that may occur in the distance between fibre-tip and vessel wall can lead to signal intensity variations and challenge quantification. Herein we examined whether the use of anatomical information of the cross-section vessel morphology, obtained from co-registered intravascular ultrasound (IVUS), can lead to quantification improvements when fibre-tip and vessel wall distance variations are present. The algorithm developed employs a photon propagation model derived from phantom experiments that is used to calculate the relative attenuation of fluorescence signals as they are collected over 360. along the vessel wall, and utilizes it to restore accurate fluorescence readings. The findings herein point to quantification improvements when employing hybrid iNIRF, with possible implications to the clinical detection of high-risk plaques or blood vessel theranostics. C1 [Mallas, Georgios; Brooks, Dana H.] Northeastern Univ, Dept Elect & Comp Engn, Commun & Digital Signal Proc Res Ctr, Boston, MA 02115 USA. [Mallas, Georgios; Rosenthal, Amir; Mauskapf, Adam; Jaffer, Farouc A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Cardiovasc Res Ctr, Boston, MA USA. [Rosenthal, Amir; Nudelman, R. Nika; Ntziachristos, Vasilis] Tech Univ Munich, IBMI, Munich, Germany. [Rosenthal, Amir; Nudelman, R. Nika; Ntziachristos, Vasilis] Helmholtz Zentrum Munchen, Munich, Germany. RP Mallas, G (reprint author), Northeastern Univ, Dept Elect & Comp Engn, Commun & Digital Signal Proc Res Ctr, 409 Dana Bldg,360 Huntington Ave, Boston, MA 02115 USA. EM mallasgeo@gmail.com RI Rosenthal, Amir/C-8650-2014; OI Jaffer, Farouc/0000-0001-7980-384X FU National Institute of Health [1R01EB004382-01A2, R01 HL 108229]; European Community [235689]; Broadview Ventures FX This work was supported by National Institute of Health grant no 1R01EB004382-01A2 (GM, DHB, VN), European Community's Seventh Framework Programme (FP7/2007-2013 under grant agreement no 235689 (AR)), National Institutes of Health grant no R01 HL 108229 (FAJ.), Broadview Ventures (FAJ, VN). NR 30 TC 4 Z9 4 U1 0 U2 10 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2012 VL 57 IS 20 BP 6395 EP 6406 DI 10.1088/0031-9155/57/20/6395 PG 12 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 016WD UT WOS:000309549600007 PM 22996051 ER PT J AU Tichauer, KM Samkoe, KS Klubben, WS Hasan, T Pogue, BW AF Tichauer, K. M. Samkoe, K. S. Klubben, W. S. Hasan, T. Pogue, B. W. TI Advantages of a dual-tracer model over reference tissue models for binding potential measurement in tumors SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; RECEPTOR-BINDING; CARCINOEMBRYONIC ANTIGEN; COMPARTMENTAL MODEL; HUMAN BRAIN; EXPRESSION; KINETICS; TIME; RADIOIMMUNODETECTION AB The quantification of tumor molecular expression in vivo could have a significant impact for informing and monitoring emerging targeted therapies in oncology. Molecular imaging of targeted tracers can be used to quantify receptor expression in the form of a binding potential (BP) if the arterial input curve or a surrogate of it is also measured. However, the assumptions of the most common approaches (reference tissue models) may not be valid for use in tumors. In this study, the validity of reference tissue models is investigated for use in tumors experimentally and in simulations. Three different tumor lines were grown subcutaneously in athymic mice and the mice were injected with a mixture of an epidermal growth factor receptor-targeted fluorescent tracer and an untargeted fluorescent tracer. A one-compartment plasma input model demonstrated that the transport kinetics of both tracers was significantly different between tumors and all potential reference tissues, and using the reference tissue model resulted in a theoretical underestimation in BP of 50% +/- 37%. On the other hand, the targeted and untargeted tracers demonstrated similar transport kinetics, allowing a dual-tracer approach to be employed to accurately estimate BP (with a theoretical error of 0.23% +/- 9.07%). These findings highlight the potential for using a dual-tracer approach to quantify receptor expression in tumors with abnormal hemodynamics, possibly to inform the choice or progress of molecular cancer therapies. C1 [Tichauer, K. M.; Samkoe, K. S.; Klubben, W. S.; Pogue, B. W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Samkoe, K. S.; Pogue, B. W.] Dartmouth Med Sch, Dept Surg, Hanover, NH 03755 USA. [Pogue, B. W.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Tichauer, KM (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM kenneth.tichauer@dartmouth.edu; brian.w.pogue@dartmouth.edu OI Tichauer, Kenneth/0000-0003-1667-3026 FU NIH [P01CA84201, R01CA156177, U54CA151662]; CIHR FX This research was funded by NIH grants P01CA84201, R01CA156177 and U54CA151662. KMT acknowledges funding from the CIHR postdoctoral fellowship program. We would also like to thank Kristian J Sexton and Harold H Yang for their assistance with running the animal experiments, and Robert W Holt for his input on data presentation. NR 37 TC 12 Z9 12 U1 1 U2 9 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2012 VL 57 IS 20 BP 6647 EP 6659 DI 10.1088/0031-9155/57/20/6647 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 016WD UT WOS:000309549600021 PM 23022732 ER PT J AU Butterworth, KT McGarry, CK Clasie, B Carabe-Fernandez, A Schuemann, J Depauw, N Tang, SK McMahon, SJ Schettino, G O'Sullivan, JM Lu, HM Kooy, H Paganetti, H Hounsell, AR Held, KD Prise, KM AF Butterworth, Karl T. McGarry, Conor K. Clasie, Ben Carabe-Fernandez, Alejandro Schuemann, Jan Depauw, Nicolas Tang, Shikui McMahon, Stephen J. Schettino, Giuseppe O'Sullivan, Joe M. Lu, Hsaio-Ming Kooy, Hanne Paganetti, Harald Hounsell, Alan R. Held, Kathryn D. Prise, Kevin M. TI Relative biological effectiveness (RBE) and out-of-field cell survival responses to passive scattering and pencil beam scanning proton beam deliveries SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MODULATED RADIATION-FIELDS; THERAPY; CANCER; RADIOTHERAPY; EXPOSURE; IMRT AB The relative biological effectiveness (RBE) of passive scattered (PS) and pencil beam scanned (PBS) proton beam delivery techniques for uniform beam configurations was determined by clonogenic survival. The radiobiological impact of modulated beam configurations on cell survival occurring in- or out-of-field for both delivery techniques was determined with intercellular communication intact or physically inhibited. Cell survival responses were compared to those observed using a 6 MV photon beam produced with a linear accelerator. DU-145 cells showed no significant difference in survival response to proton beams delivered by PS and PBS or 6 MV photons taking into account a RBE of 1.1 for protons at the centre of the spread out Bragg peak. Significant out-of-field effects similar to those observed for 6 MV photons were observed for both PS and PBS proton deliveries with cell survival decreasing to 50-60% survival for scattered doses of 0.05 and 0.03 Gy for passive scattered and pencil beam scanned beams respectively. The observed out-of-field responses were shown to be dependent on intercellular communication between the in-and out-of-field cell populations. These data demonstrate, for the first time, a similar RBE between passive and actively scanned proton beams and confirm that out-of-field effects may be important determinants of cell survival following exposure to modulated photon and proton fields C1 [Butterworth, Karl T.; McGarry, Conor K.; McMahon, Stephen J.; Schettino, Giuseppe; Hounsell, Alan R.; Prise, Kevin M.] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland. [McGarry, Conor K.; O'Sullivan, Joe M.; Hounsell, Alan R.] Belfast Hlth & Social Care Trust, No Ireland Canc Ctr, Belfast, Antrim, North Ireland. [Clasie, Ben; Carabe-Fernandez, Alejandro; Schuemann, Jan; Depauw, Nicolas; Tang, Shikui; Lu, Hsaio-Ming; Kooy, Hanne; Paganetti, Harald; Held, Kathryn D.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Depauw, Nicolas] Univ Wollongong, Ctr Med Phys, Wollongong, NSW 2522, Australia. RP Butterworth, KT (reprint author), Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland. EM k.butterworth@qub.ac.uk RI Prise, Kevin/N-7872-2015; OI Prise, Kevin/0000-0001-6134-7946; Schettino, Giuseppe/0000-0003-3284-3953; McMahon, Stephen/0000-0001-5980-6728; McGarry, Conor/0000-0001-6396-2184 FU MGH [C06 CA059267]; Cancer Research UK [C1513/A7047, C212/A11342]; Health and Social Care Research and Development Office of the Public Health Agency FX The authors wish to acknowledge equal contributions to this work by KTB and CKM, who should be considered as joint first authors. This project was funded by MGH Federal Share of Program Income under C06 CA059267 to KDH and by Cancer Research UK (grant no. C1513/A7047 to KMP and grant no. C212/A11342 for ARH and SJM). CKM is supported by a training fellowship award from the Health and Social Care Research and Development Office of the Public Health Agency. NR 21 TC 5 Z9 5 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2012 VL 57 IS 20 BP 6671 EP 6680 DI 10.1088/0031-9155/57/20/6671 PG 10 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 016WD UT WOS:000309549600023 PM 23022765 ER PT J AU Ligibel, J AF Ligibel, Jennifer TI Lifestyle Factors in Cancer Survivorship SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID BODY-MASS INDEX; STAGE BREAST-CANCER; III COLON-CANCER; GROWTH-FACTOR-I; PHYSICAL-ACTIVITY; PROSTATE-CANCER; WEIGHT-GAIN; COLORECTAL-CANCER; SURVIVAL; RISK AB Lifestyle factors have been linked to the risk of developing many common malignancies and, increasingly, to prognosis. Observational evidence has shown a relationship between so-called energy balance factors (ie, diet, physical activity, and body weight) and risk of cancer recurrence and mortality in cancers of the breast, prostate, colon and, perhaps, other cancers. Interventional work has shown that individuals who make favorable changes in these lifestyle factors after cancer diagnosis feel better, experience less fatigue, and may possibly even decrease risk of cancer recurrence. Other lifestyle behaviors, such as smoking and alcohol consumption, have also been linked to the development of common cancers and may have important health consequences for cancer survivors. This article reviews the evidence that links lifestyle factors to cancer outcomes, provides clinical recommendations for cancer survivors, and describes future directions for lifestyle research in cancer survivors. C1 Dana Farber Canc Inst, Boston, MA 02215 USA. RP Ligibel, J (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. EM jligibel@partners.org NR 85 TC 48 Z9 48 U1 1 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 OCT 20 PY 2012 VL 30 IS 30 BP 3697 EP 3704 DI 10.1200/JCO.2012.42.0638 PG 8 WC Oncology SC Oncology GA 027LI UT WOS:000310353400006 PM 23008316 ER PT J AU Ruddy, KJ Partridge, AH AF Ruddy, Kathryn J. Partridge, Ann H. TI Fertility (male and female) and Menopause SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID BREAST-CANCER SURVIVORS; QUALITY-OF-LIFE; TESTICULAR SPERM EXTRACTION; YOUNG-WOMEN; POSTMENOPAUSAL WOMEN; OVARIAN STIMULATION; VASOMOTOR SYMPTOMS; HOT FLASHES; EMBRYO CRYOPRESERVATION; ADJUVANT TREATMENT AB The impact of oncologic treatments on fertility and menopausal symptoms is often significant for patients with cancer. Surgery, radiation, and chemotherapy can all damage the reproductive organs or the hypothalamic pituitary axis that controls them, impairing fertility and causing hormonally mediated symptoms such as hot flashes. Understanding these risks and strategies to mitigate them may substantially improve cancer survivorship care. For both female and male patients who desire a future biologic child, there are a variety of fertility preservation techniques that should be considered. For cancer survivors who experience menopausal symptoms, lifestyle changes may be beneficial, and hormonal and nonhormonal pharmacologic agents are well proven to reduce symptom burden. C1 [Ruddy, Kathryn J.; Partridge, Ann H.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02215 USA. [Ruddy, Kathryn J.; Partridge, Ann H.] Harvard Univ, Sch Med, Boston, MA USA. RP Partridge, AH (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ahpartridge@partners.org NR 74 TC 22 Z9 22 U1 1 U2 16 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 OCT 20 PY 2012 VL 30 IS 30 BP 3705 EP 3711 DI 10.1200/JCO.2012.42.1966 PG 7 WC Oncology SC Oncology GA 027LI UT WOS:000310353400007 PM 23008319 ER PT J AU Bober, SL Varela, VS AF Bober, Sharon L. Varela, Veronica Sanchez TI Sexuality in Adult Cancer Survivors: Challenges and Intervention SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID QUALITY-OF-LIFE; LOCALIZED PROSTATE-CANCER; RADICAL RETROPUBIC PROSTATECTOMIES; ANDROGEN DEPRIVATION THERAPY; BONE-MARROW-TRANSPLANTATION; CASE-MATCHED CONTROLS; VERSUS-HOST-DISEASE; LONG-TERM SURVIVORS; BREAST-CANCER; ERECTILE DYSFUNCTION AB Sexual dysfunction is one of the most common and distressing consequences of cancer treatment. Although some treatment-related sexual adverse effects are short-term, many survivors face long-term effects such as treatment-induced menopause, altered gonadal function, and significant surgical disfigurement. Profound sexual dysfunction has been shown to have a significant negative effect on quality of life. Although these problems have been well documented and there are a range of intervention strategies that can help patients cope with treatment-related sexual problems, many survivors do not feel prepared for potential sexual changes and often do not receive adequate support to manage sexual dysfunction. Numerous barriers contribute to this underprovided aspect of survivorship care, including lack of provider training and access to readily available resources. In addition, psychological, relational, and cultural factors significantly influence sexuality but are often not taken into consideration in research and clinical practice. By taking an integrative approach and providing survivors with appropriate screening, information, and support, sexual dysfunction and accompanying distress can be significantly alleviated. In this article, we aim to provide a concise review of the most common sexual problems experienced by survivors and highlight some of the most promising evidence-based practices for assessment and intervention. We also address limitations encountered in research and practice and explore future directions, including suggestions for adopting an integrative treatment model to address sexual dysfunction in a cancer survivorship treatment setting. C1 [Bober, Sharon L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Sexual Hlth Program, Boston, MA 02215 USA. [Varela, Veronica Sanchez] Perini Family Survivors Ctr, Dana Farber Canc Inst, Boston, MA USA. RP Bober, SL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Sexual Hlth Program, 450 Brookline Ave,D321, Boston, MA 02215 USA. EM sharon_bober@dfci.harvard.edu NR 109 TC 60 Z9 60 U1 0 U2 24 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 OCT 20 PY 2012 VL 30 IS 30 BP 3712 EP 3719 DI 10.1200/JCO.2012.41.7915 PG 8 WC Oncology SC Oncology GA 027LI UT WOS:000310353400008 PM 23008322 ER PT J AU Wood, ME Vogel, V Ng, A Foxhall, L Goodwin, P Travis, LB AF Wood, Marie E. Vogel, Victor Ng, Andrea Foxhall, Lewis Goodwin, Pamela Travis, Lois B. TI Second Malignant Neoplasms: Assessment and Strategies for Risk Reduction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CHILDHOOD-CANCER SURVIVOR; LONG-TERM SURVIVORS; CONTRALATERAL BREAST-CANCER; LI-FRAUMENI-SYNDROME; THERAPY-RELATED LEUKEMIA; SQUAMOUS-CELL CARCINOMA; ACUTE MYELOID-LEUKEMIA; RANDOMIZED CONTROLLED-TRIAL; SURGICAL ADJUVANT BREAST; BRCA2 MUTATION CARRIERS AB Improvements in early detection, supportive care, and treatment have resulted in an increasing number of cancer survivors, with a current 5-year relative survival rate for all cancers combined of approximately 66.1%. For some patients, these survival advances have been offset by the long-term late effects of cancer and its treatment, with second malignant neoplasms (SMNs) comprising one of the most potentially life-threatening sequelae. The number of patients with SMNs is growing, with new SMNs now representing about one in six of all cancers reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. SMNs reflect not only the late effects of therapy but also the influence of shared etiologic factors (in particular, tobacco and excessive alcohol intake), genetic susceptibility, environmental exposures, host effects, and combinations of factors, including gene-environment interactions. For selected SMNs, risk is also modified by age at exposure and attained age. SMNs can be categorized into three major groups according to the predominant etiologic factor(s): (1) treatment-related, (2) syndromic, and (3) those due to shared etiologic exposures, although the nonexclusivity of these groups should be underscored. Here we provide an overview of SMNs in survivors of adult-onset cancer, summarizing the current, albeit limited, clinical evidence with regard to screening and prevention, with a focus on the provision of guidance for health care providers. The growing number of patients with second (and higher-order) cancers mandates that we also further probe etiologic influences and genetic variants that heighten risk, and that we better define high-risk groups for targeted preventive and interventional clinical strategies. C1 [Wood, Marie E.] Univ Vermont, Div Hematol Oncol, Burlington, VT 05405 USA. Geisinger Hlth Syst, Danville, PA USA. [Ng, Andrea] Dana Farber Canc Inst, Boston, MA 02115 USA. [Foxhall, Lewis] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Goodwin, Pamela] Univ Toronto, Toronto, ON, Canada. [Travis, Lois B.] Univ Rochester, Med Ctr, Rochester, NY USA. RP Wood, ME (reprint author), Univ Vermont, Div Hematol Oncol, 89 Beaumont Ave,Given E214, Burlington, VT 05405 USA. EM marie.wood@uvm.edu RI Goodwin, Pamela/K-1477-2013 NR 148 TC 55 Z9 55 U1 1 U2 13 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 OCT 20 PY 2012 VL 30 IS 30 BP 3734 EP 3745 DI 10.1200/JCO.2012.41.8681 PG 12 WC Oncology SC Oncology GA 027LI UT WOS:000310353400011 PM 23008293 ER PT J AU Goldkorn, A Vogelzang, NJ Fink, LM Ely, B Quinn, DI Tangen, CM Tai, YC Twardowski, P Van Veldhuizen, PJ Agarwal, N Carducci, MA Monk, JP Garzotto, M Mack, PC Lara, P Higano, CS Hussain, M Cote, RJ Thompson, IM AF Goldkorn, Amir Vogelzang, Nicholas J. Fink, Louis M. Ely, Benjamin Quinn, David I. Tangen, Catherine M. Tai, Yu-Chong Twardowski, Przemyslaw Van Veldhuizen, Peter J. Agarwal, Neeraj Carducci, Michael Anthony Monk, J. P. Garzotto, Mark Mack, Philip C. Lara, Primo Higano, Celestia S. Hussain, Maha Cote, Richard J. Thompson, Ian Murchie CA Southwest Oncology Grp TI Circulating tumor cell (CTC) counts and CTC telomerase activity (TA) as prognotic markers of overall survival (OS) in SWOG S0421: Docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer (mCRPC). SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract C1 Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. US Oncol Res LLC, McKesson Specialty Hlth, The Woodlands, TX USA. Comprehens Canc Ctr Nevada, Las Vegas, NV USA. Nevada Canc Inst, Las Vegas, NV USA. SWOG Stat Ctr, Seattle, WA USA. CALTECH, Pasadena, CA 91125 USA. City Hope Natl Med Ctr, Duarte, CA USA. Univ Kansas, Ctr Canc, Westwood, KS USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Ohio State Univ, Columbus, OH 43210 USA. Portland VA Med Ctr, Portland, OR USA. Univ Calif Davis, Sacramento, CA 95817 USA. Univ Washington, Seattle Canc Care Alliance, Puget Sound Oncol Consortium, Seattle, WA 98195 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 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 OCT 20 PY 2012 VL 30 IS 30 SU S PG 1 WC Oncology SC Oncology GA V31YY UT WOS:000208920100002 ER PT J AU Wedick, NM Mantzoros, CS Ding, EL Brennan, AM Rosner, B Rimm, EB Hu, FB van Dam, RM AF Wedick, Nicole M. Mantzoros, Christos S. Ding, Eric L. Brennan, Aoife M. Rosner, Bernard Rimm, Eric B. Hu, Frank B. van Dam, Rob M. TI The effects of caffeinated and decaffeinated coffee on sex hormone-binding globulin and endogenous sex hormone levels: a randomized controlled trial SO NUTRITION JOURNAL LA English DT Article DE Coffee; Sex hormones; Randomized trial ID POSTMENOPAUSAL WOMEN; RISK; PREMENOPAUSAL; CONSUMPTION; ESTRADIOL; ALCOHOL; MEN AB Background: Findings from observational studies suggest that sex hormone-binding globulin (SHBG) and endogenous sex hormones may be mediators of the putative relation between coffee consumption and lower risk of type 2 diabetes. The objective of this study was to evaluate the effects of caffeinated and decaffeinated coffee on SHBG and sex hormone levels. Findings: After a two-week run-in phase with caffeine abstention, we conducted an 8-week parallel-arm randomized controlled trial. Healthy adults (n = 42) were recruited from the Boston community who were regular coffee consumers, nonsmokers, and overweight. Participants were randomized to five 6-ounce cups of caffeinated or decaffeinated instant coffee or water (control group) per day consumed with each meal, mid-morning, and mid-afternoon. The main outcome measures were SHBG and sex hormones [i.e., testosterone, estradiol, dehydroepiandrosterone sulfate]. No significant differences were found between treatment groups for any of the studied outcomes at week 8. At 4 weeks, decaffeinated coffee was associated with a borderline significant increase in SHBG in women, but not in men. At week 4, we also observed several differences in hormone concentrations between the treatment groups. Among men, consumption of caffeinated coffee increased total testosterone and decreased total and free estradiol. Among women, decaffeinated coffee decreased total and free testosterone and caffeinated coffee decreased total testosterone. Conclusions: Our data do not indicate a consistent effect of caffeinated coffee consumption on SHBG in men or women, however results should be interpreted with caution given the small sample size. This is the first randomized trial investigating the effects of caffeinated and decaffeinated coffee on SHBG and sex hormones and our findings necessitate further examination in a larger intervention trial. C1 [Wedick, Nicole M.; Ding, Eric L.; Rimm, Eric B.; Hu, Frank B.; van Dam, Rob M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Mantzoros, Christos S.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Endocrinol Sect, Boston, MA 02115 USA. [Mantzoros, Christos S.; Brennan, Aoife M.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Ding, Eric L.; Rosner, Bernard; Rimm, Eric B.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Rimm, Eric B.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [van Dam, Rob M.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore. [van Dam, Rob M.] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore. RP Wedick, NM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM nwedick@hsph.harvard.edu RI van Dam, Rob/F-9674-2010; OI van Dam, Rob/0000-0002-7354-8734; Ding, Eric/0000-0002-5881-8097 FU Harvard Catalyst Human Research Center Laboratory Support Award; Boston Obesity Nutrition Research Center pilot and feasibility grant [2005-P-000377/2]; National Institutes of Health - National Center for Research Resources [M01-RR-01032]; National Institute of Diabetes and Digestive and Kidney Diseases [58785, 79929, 81913, AG032030]; [UL1 RR025758] FX We gratefully thank the participants of the Coffee Trial for their participation. We also thank the General Clinical Research Center (GCRC) nurses at Beth Israel Deaconess Medical Center for assistance with collection of the samples for this research, and the GCRC nutritionists for conducting the dietary assessments, body composition measurements, and dispensing of treatment. We thank the Harvard Catalyst Human Research Center Laboratory for the timely and careful measurement of the sex hormones used for this analysis. The research for this study was financially supported by a Harvard Catalyst Human Research Center Laboratory Support Award, a Boston Obesity Nutrition Research Center pilot and feasibility grant (grant#: 2005-P-000377/2), and a National Institutes of Health - National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center) and grant number UL1 RR025758. The Mantzoros Lab is also supported by the National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929 and 81913, and AG032030. NR 13 TC 8 Z9 8 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2891 J9 NUTR J JI Nutr. J. PD OCT 19 PY 2012 VL 11 AR 86 DI 10.1186/1475-2891-11-86 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 041VF UT WOS:000311428600001 PM 23078574 ER PT J AU Oyoshi, MK He, R Li, YT Mondal, S Yoon, J Afshar, R Chen, M Lee, DM Luo, HBR Luster, AD Cho, JS Miller, LS Larson, A Murphy, GF Geha, RS AF Oyoshi, Michiko K. He, Rui Li, Yitang Mondal, Subhanjan Yoon, Juhan Afshar, Roshi Chen, Mei Lee, David M. Luo, Hongbo R. Luster, Andrew D. Cho, John S. Miller, Lloyd S. Larson, Allison Murphy, George F. Geha, Raif S. TI Leukotriene B4-Driven Neutrophil Recruitment to the Skin Is Essential for Allergic Skin Inflammation SO IMMUNITY LA English DT Article ID INFL AMMATORY ARTHRITIS; T-CELL RECRUITMENT; ATOPIC-DERMATITIS; AIRWAY HYPERRESPONSIVENESS; A(4) HYDROLASE; RECEPTOR BLT1; MURINE MODEL; B-4; MICE; 5-LIPOXYGENASE AB Scratching triggers skin flares in atopic dermatitis. We demonstrate that scratching of human skin and tape stripping of mouse skin cause neutrophil influx. In mice, this influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation. C1 [Oyoshi, Michiko K.; He, Rui; Yoon, Juhan; Geha, Raif S.] Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Li, Yitang; Mondal, Subhanjan; Luo, Hongbo R.] Boston Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Afshar, Roshi; Luster, Andrew D.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Chen, Mei; Lee, David M.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Larson, Allison; Murphy, George F.] Brigham & Womens Hosp, Dermatopathol Program, Boston, MA 02115 USA. [Cho, John S.; Miller, Lloyd S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Dermatol, Los Angeles, CA 90095 USA. [Oyoshi, Michiko K.; He, Rui; Li, Yitang; Mondal, Subhanjan; Yoon, Juhan; Afshar, Roshi; Chen, Mei; Lee, David M.; Luo, Hongbo R.; Luster, Andrew D.; Larson, Allison; Murphy, George F.; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Oyoshi, Michiko K.; He, Rui; Li, Yitang; Mondal, Subhanjan; Yoon, Juhan; Afshar, Roshi; Chen, Mei; Lee, David M.; Luo, Hongbo R.; Luster, Andrew D.; Larson, Allison; Murphy, George F.; Geha, Raif S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Oyoshi, Michiko K.; He, Rui; Li, Yitang; Mondal, Subhanjan; Yoon, Juhan; Afshar, Roshi; Chen, Mei; Lee, David M.; Luo, Hongbo R.; Luster, Andrew D.; Larson, Allison; Murphy, George F.; Geha, Raif S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Oyoshi, MK (reprint author), Boston Childrens Hosp, Div Immunol, Boston, MA 02115 USA. EM michiko.oyoshi@childrens.harvard.edu; raif.geha@childrens.harvard.edu RI Larson, Allison/N-4263-2015; OI Larson, Allison/0000-0001-8534-7078; Miller, Lloyd/0000-0002-8332-2210 FU Atopic Dermatitis Research Network National Institutes of Health/National Institute of Allergy and Infectious Diseases [HHSN272201000020C]; U.S. Public Health Service [AR-047417, AI 065858-03, HL-085100, AI-076471, HL-092020, GM-076084]; American Cancer Society [AI-050892, AI-040618, R01 AI078910, T32 AR058921, R24 CA92865]; Boston Children's Hospital Faculty Career Development Fellowship FX This work was supported by the Atopic Dermatitis Research Network National Institutes of Health/National Institute of Allergy and Infectious Diseases contract HHSN272201000020C (R.S.G.); U.S. Public Health Service grants AR-047417 (R.S.G.), AI 065858-03 (D.M.L.) HL-085100, AI-076471, and HL-092020, GM-076084; a Research Scholar Grant from the American Cancer Society (H.R.L.); and AI-050892 and AI-040618 (A.D.L.), R01 AI078910 (L.S.M.), T32 AR058921 (J.S.C.), R24 CA92865 (UCLA Small Animal Imaging Resource Program); and the Boston Children's Hospital Faculty Career Development Fellowship (M.K.O.). D.M.L. is currently an employee of Novartis Pharma AG and owns stock and/or options >$10,000 and has ownership and consulting income >$10,000 from Synovex. M.C. is currently an employee of Pfizer. We thank M.J. Massaad and H.C. Oettgen for reading the manuscript. We also thank J. Beaupre for her technical assistance. NR 39 TC 44 Z9 47 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD OCT 19 PY 2012 VL 37 IS 4 BP 747 EP 758 DI 10.1016/j.immuni.2012.06.018 PG 12 WC Immunology SC Immunology GA 025JQ UT WOS:000310185400018 PM 23063331 ER PT J AU Wang, XF Wang, SZ Lu, YB Gibson, MP Liu, Y Yuan, BZ Feng, JQ Qin, CL AF Wang, Xiaofang Wang, Suzhen Lu, Yongbo Gibson, Monica P. Liu, Ying Yuan, Baozhi Feng, Jian Q. Qin, Chunlin TI FAM20C Plays an Essential Role in the Formation of Murine Teeth SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENTIN MATRIX PROTEIN-1; AMELOGENESIS IMPERFECTA PHENOTYPE; TOOTH ROOT DEVELOPMENT; MICE DISPLAY; ODONTOBLAST DIFFERENTIATION; ENAMEL DEFECTS; SIALOPHOSPHOPROTEIN; EXPRESSION; MOUSE; LEADS AB FAM20Cis highly expressed in bone and tooth. Previously, we showed that Fam20C conditional knock-out (KO) mice manifest hypophosphatemic rickets, which highlights the crucial roles of this molecule in promoting bone formation and mediating phosphate homeostasis. In this study, we characterized the dentin, enamel, and cementum of Sox2-Cre-mediated Fam20C KO mice. The KO mice exhibited small malformed teeth, severe enamel defects, very thin dentin, less cementum than normal, and overall hypomineralization in the dental mineralized tissues. In situ hybridization and immunohistochemistry analyses revealed remarkable down-regulation of dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein in odontoblasts, along with a sharply reduced expression of ameloblastin and amelotin in ameloblasts. Collectively, these data indicate that FAM20Cis essential to the differentiation and mineralization of dental tissues through the regulation of molecules critical to the differentiation of tooth-formative cells. C1 [Wang, Xiaofang; Wang, Suzhen; Lu, Yongbo; Gibson, Monica P.; Liu, Ying; Feng, Jian Q.; Qin, Chunlin] Texas A&M Hlth Sci Ctr Baylor Coll Dent, Dept Biomed Sci, Dallas, TX 75246 USA. [Yuan, Baozhi] Univ Wisconsin, Dept Med, Madison, WI 53705 USA. [Yuan, Baozhi] William S Middleton Mem Vet Adm Med Ctr, Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. RP Qin, CL (reprint author), Texas A&M Hlth Sci Ctr Baylor Coll Dent, Dept Biomed Sci, 3302 Gaston Ave, Dallas, TX 75246 USA. EM cqin@bcd.tamhsc.edu FU National Institutes of Health [DE005092] FX This work was supported, in whole or in part, by National Institutes of Health Grant DE005092 (to C. Q.). NR 37 TC 27 Z9 27 U1 0 U2 4 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 OCT 19 PY 2012 VL 287 IS 43 BP 35934 EP 35942 DI 10.1074/jbc.M112.386862 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000015 PM 22936805 ER PT J AU Liu, YY Kogai, T Schultz, JJ Mody, K Brent, GA AF Liu, Yan-Yun Kogai, Takahiko Schultz, James J. Mody, Kaizeen Brent, Gregory A. TI Thyroid Hormone Receptor Isoform-specific Modification by Small Ubiquitin-like Modifier (SUMO) Modulates Thyroid Hormone-dependent Gene Regulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTIONAL ACTIVITY; BRAIN-DEVELOPMENT; RESPONSE ELEMENT; BETA; SUMOYLATION; MICE; BINDING; REPRESSOR; PROTEIN; ALPHA AB Thyroid hormone receptor (TR) alpha and beta mediate thyroid hormone action at target tissues. TR isoforms have specific roles in development and in adult tissues. The mechanisms underlying TR isoform-specific action, however, are not well understood. We demonstrate that posttranslational modification of TR by conjugation of smallSUMOtoTR alpha and TR beta plays an important role in triiodothyronine (T3) action and TR isoform specificity. TR alpha was sumoylated at lysines 283 and 389, and TR beta at lysines 50, 146, and 443. Sumoylation of TR beta was ligand-dependent, and sumoylation of TR alpha was ligand-independent. TR alpha-SUMO conjugation utilized the E3 ligase PIASx beta and TR beta-SUMO conjugation utilized predominantly PIAS1. SUMO1 and SUMO3 conjugation to TR was important for T3-dependent gene regulation, as demonstrated in transient transfection assay and studies of endogenous gene regulation. The functional role of SUMO1 and SUMO3 in T3 induction in transient expression assays was closely matched to the pattern of TR and cofactor recruitment to thyroid hormone response elements (TREs) as determined by ChIP assays. SUMO1 was required for the T3-induced recruitment of the co-activator CREB-binding protein (CBP) and release of nuclear receptor co-repressor (NCoR) on a TRE but had no significant effect on TR DNA binding. SUMO1 was required for T3-mediated recruitment of NCoR and release of CBP from the TSH beta-negative TRE. SUMO3 was required for T3-stimulated TR binding to the TSH beta-negative TRE and recruitment of NCoR. These findings demonstrate that conjugation of SUMO to TR has a TR-isoform preference and is important for T3-dependent gene induction and repression. C1 [Liu, Yan-Yun] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, Dept Med, Los Angeles, CA 90073 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, Dept Physiol, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90073 USA. RP Liu, YY (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, Dept Med, Bldg 114,Rm 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM yyl@ucla.edu; gbrent@ucla.edu FU Veterans Affairs Merit Review Funds FX This work was supported by Veterans Affairs Merit Review Funds. NR 35 TC 10 Z9 10 U1 2 U2 9 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 OCT 19 PY 2012 VL 287 IS 43 BP 36499 EP 36508 DI 10.1074/jbc.M112.344317 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 027PA UT WOS:000310364000069 PM 22930759 ER PT J AU Matthews, PC Listgarten, J Carlson, JM Payne, R Huang, KHG Frater, J Goedhals, D Steyn, D van Vuuren, C Paioni, P Jooste, P Ogwu, A Shapiro, R Mncube, Z Ndung'u, T Walker, BD Heckerman, D Goulder, PJR AF Matthews, Philippa C. Listgarten, Jennifer Carlson, Jonathan M. Payne, Rebecca Huang, Kuan-Hsiang Gary Frater, John Goedhals, Dominique Steyn, Dewald van Vuuren, Cloete Paioni, Paolo Jooste, Pieter Ogwu, Anthony Shapiro, Roger Mncube, Zenele Ndung'u, Thumbi Walker, Bruce D. Heckerman, David Goulder, Philip J. R. TI Co-Operative Additive Effects between HLA Alleles in Control of HIV-1 SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; DISEASE PROGRESSION; IMMUNE CONTROL; SELECTION PRESSURE; VIRAL LOAD; NK CELLS; INFECTION; VIREMIA; ASSOCIATION AB Background: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. Methodology/Principal Findings: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate 'co-operative additive' effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel 'sharing score' to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). Conclusions/Significance: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect. C1 [Matthews, Philippa C.; Payne, Rebecca; Paioni, Paolo; Goulder, Philip J. R.] Univ Oxford, Dept Paediat, Oxford, England. [Listgarten, Jennifer; Carlson, Jonathan M.; Heckerman, David] Microsoft Res, ESci Grp, Los Angeles, CA USA. [Huang, Kuan-Hsiang Gary; Frater, John] Univ Oxford, Nuffield Dept Med, Oxford, England. [Goedhals, Dominique] Univ Orange Free State, Dept Med Microbiol & Virol, Natl Hlth Lab Serv, Bloemfontein, South Africa. [Steyn, Dewald; van Vuuren, Cloete] Univ Orange Free State, Dept Internal Med, Bloemfontein, South Africa. [Jooste, Pieter] Univ Orange Free State, Kimberley Hosp, Dept Paediat, Kimberley, Northern Cape, South Africa. [Ogwu, Anthony; Shapiro, Roger] Botswana Harvard AIDS Inst Partnership, Gaborone, Botswana. [Shapiro, Roger] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Mncube, Zenele; Ndung'u, Thumbi; Walker, Bruce D.; Goulder, Philip J. R.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Ndung'u, Thumbi; Walker, Bruce D.] Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. RP Matthews, PC (reprint author), Univ Oxford, Dept Paediat, Oxford, England. EM p.matthews@doctors.org.uk OI Matthews, Philippa/0000-0002-4036-4269; Ndung'u, Thumbi/0000-0003-2962-3992 FU UK Medical Research Council; Oxford Radcliffe Hospitals Medical Research Fund; Wellcome Trust; National Institutes of Health; Bill and Melinda Gates Foundation; South African AIDS Vaccine Initiative FX PM was funded by the UK Medical Research Council and Oxford Radcliffe Hospitals Medical Research Fund. PG was funded by Wellcome Trust and is an Elizabeth Glaser Paediatric AIDS Foundation Scientist. TN holds the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS. The Durban cohort was funded by grants from the Wellcome Trust, The National Institutes of Health, The Bill and Melinda Gates Foundation and the South African AIDS Vaccine Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 14 Z9 14 U1 0 U2 1 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 OCT 19 PY 2012 VL 7 IS 10 AR e47799 DI 10.1371/journal.pone.0047799 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 023QT UT WOS:000310050200047 PM 23094091 ER PT J AU Tan, KL Scott, DW Hong, FX Kahl, BS Fisher, RI Bartlett, NL Advani, RH Buckstein, R Rimsza, LM Connors, JM Steidl, C Gordon, LI Horning, SJ Gascoyne, RD AF Tan, King L. Scott, David W. Hong, Fangxin Kahl, Brad S. Fisher, Richard I. Bartlett, Nancy L. Advani, Ranjana H. Buckstein, Rena Rimsza, Lisa M. Connors, Joseph M. Steidl, Christian Gordon, Leo I. Horning, Sandra J. Gascoyne, Randy D. TI Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial SO BLOOD LA English DT Article ID INTERNATIONAL PROGNOSTIC SCORE; MICROENVIRONMENT; MARKERS; SURVIVAL; SERIES; CD163 AB Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial. (Blood. 2012;120(16):3280-3287) C1 [Tan, King L.; Scott, David W.; Connors, Joseph M.; Steidl, Christian; Gascoyne, Randy D.] British Columbia Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada. [Tan, King L.; Scott, David W.; Connors, Joseph M.; Steidl, Christian; Gascoyne, Randy D.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Hong, Fangxin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Kahl, Brad S.] Univ Wisconsin, Dept Med Hematol Oncol, Madison, WI USA. [Fisher, Richard I.] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. [Bartlett, Nancy L.] Washington Univ, Sch Med, St Louis, MO USA. [Advani, Ranjana H.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Buckstein, Rena] Sunnybrook Med Ctr, Odette Canc Ctr, Toronto, ON, Canada. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Gordon, Leo I.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Gordon, Leo I.] Northwestern Univ, Feinberg Sch Med, Div Hematol Oncol, Chicago, IL 60611 USA. [Horning, Sandra J.] Genentech Inc, San Francisco, CA 94080 USA. RP Gascoyne, RD (reprint author), British Columbia Canc Agcy, Ctr Lymphoid Canc, 675 W 10th Ave,Room 5-113, Vancouver, BC V5Z 1L3, Canada. EM rgascoyn@bccancer.bc.ca OI Gordon, Leo/0000-0003-1666-7064 FU Public Health Service [CA21115, CA23318, CA66636, CA17145, CA11083, CA32102, CA38926, CA77202, CA21076, CA77470]; National Cancer Institute, National Institutes of Health; Department of Health and Human Services; Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at Canadian Institutes of Health Research [TGT-53912]; Cancer Research Society; Michael Smith Foundation for Health Research FX This work was coordinated by the Eastern Cooperative Oncology Group (Dr Robert L. Comis, Chair) and supported in part by Public Health Service (grants CA21115, CA23318, CA66636, CA17145, CA11083, CA32102, CA38926, CA77202, CA21076, and CA77470), the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Biospecimens were provided by the ECOG Pathology Coordinating Office and Reference Laboratory. K. L. T and D. W. S were supported by the Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at Canadian Institutes of Health Research (postdoctoral fellowships grant TGT-53912). C. S. was supported by postdoctoral fellowships of the Cancer Research Society (Steven E. Drabin Fellowship) and the Michael Smith Foundation for Health Research. NR 36 TC 82 Z9 84 U1 0 U2 7 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 OCT 18 PY 2012 VL 120 IS 16 BP 3280 EP 3287 DI 10.1182/blood-2012-04-421057 PG 8 WC Hematology SC Hematology GA 044KX UT WOS:000311619200019 PM 22948049 ER PT J AU Oubaha, M Lin, MI Margaron, Y Filion, D Price, EN Zon, LI Cote, JF Gratton, JP AF Oubaha, Malika Lin, Michelle I. Margaron, Yoran Filion, Dominic Price, Emily N. Zon, Leonard I. Cote, Jean-Francois Gratton, Jean-Philippe TI Formation of a PKC zeta/beta-catenin complex in endothelial cells promotes angiopoietin-1-induced collective directional migration and angiogenic sprouting SO BLOOD LA English DT Article ID VE-CADHERIN; IN-VIVO; TIP CELLS; POLARITY; MORPHOGENESIS; CDC42; TIE2; PERMEABILITY; ACTIVATION; JUNCTIONS AB Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-zeta and beta-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKC zeta and beta-catenin at leading edge along with PKC zeta-dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKC zeta in endothelial cells alters Ang-1-induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKC zeta and beta-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis. (Blood. 2012;120(16):3371-3381) C1 [Oubaha, Malika; Filion, Dominic; Gratton, Jean-Philippe] Univ Montreal, Inst Rech Clin Montreal, Lab Endothelial Cell Biol, Montreal, PQ H2W 1R7, Canada. [Lin, Michelle I.; Price, Emily N.; Zon, Leonard I.] Harvard Univ, Sch Med, Stem Cell Program, Div Hematol Oncol,Childrens Hosp Boston, Boston, MA USA. [Lin, Michelle I.; Price, Emily N.; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Margaron, Yoran; Cote, Jean-Francois] Univ Montreal, IRCM, Lab Cytoskeletal Org & Cell Migrat, Montreal, PQ H2W 1R7, Canada. RP Gratton, JP (reprint author), Univ Montreal, Inst Rech Clin Montreal, Lab Endothelial Cell Biol, 110 Pins Ave W, Montreal, PQ H2W 1R7, Canada. EM jean-philippe.gratton@ircm.qc.ca FU Canadian Institutes of Health Research [MOP-86464, MOP-111031]; Canadian Cancer Society Research Institute [CCSRI-019104]; American Heart Association postdoctoral fellowship; Fonds de la Recherche en Sante du Quebec postdoctoral fellowship; National Institutes of Health [5PO1HL32262-29, 5R01HL048801-18]; FRSQ Junior 2 career award FX This work was supported by grants from the Canadian Institutes of Health Research to J.-P.G. (MOP-86464 and MOP-111031); Canadian Cancer Society Research Institute to J.-F.C. (CCSRI-019104); American Heart Association postdoctoral fellowship to M.I.L.; Fonds de la Recherche en Sante du Quebec postdoctoral fellowship to Y.M.; and the National Institutes of Health to L.I.Z. (5PO1HL32262-29 and 5R01HL048801-18). J.-F.C. holds a FRSQ Junior 2 career award. J.-P.G. holds a Tier 2 Canada Research Chair in Endothelial Cell Signaling and Angiogenesis. NR 50 TC 9 Z9 9 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 18 PY 2012 VL 120 IS 16 BP 3371 EP 3381 DI 10.1182/blood-2012-03-419721 PG 11 WC Hematology SC Hematology GA 044KX UT WOS:000311619200029 PM 22936663 ER PT J AU Burton, DR Ahmed, R Barouch, DH Butera, ST Crotty, S Godzik, A Kaufmann, DE McElrath, MJ Nussenzweig, MC Pulendran, B Scanlan, CN Schief, WR Silvestri, G Streeck, H Walker, BD Walker, LM Ward, AB Wilson, IA Wyatt, R AF Burton, Dennis R. Ahmed, Rafi Barouch, Dan H. Butera, Salvatore T. Crotty, Shane Godzik, Adam Kaufmann, Daniel E. McElrath, M. Juliana Nussenzweig, Michel C. Pulendran, Bali Scanlan, Chris N. Schief, William R. Silvestri, Guido Streeck, Hendrik Walker, Bruce D. Walker, Laura M. Ward, Andrew B. Wilson, Ian A. Wyatt, Richard TI A Blueprint for HIV Vaccine Discovery SO CELL HOST & MICROBE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; T FOLLICULAR HELPER; AUTOLOGOUS NEUTRALIZING ANTIBODY; RESPIRATORY SYNCYTIAL VIRUS; HUMAN MONOCLONAL-ANTIBODIES; VESICULAR STOMATITIS-VIRUS; SITE-SPECIFIC ANALYSIS; CD4 BINDING-SITE; ENVELOPE GLYCOPROTEINS; B-CELLS AB Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine. C1 [Burton, Dennis R.; Butera, Salvatore T.; Schief, William R.; Walker, Laura M.; Wyatt, Richard] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.; Schief, William R.; Wyatt, Richard] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Ward, Andrew B.; Wilson, Ian A.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. [Ahmed, Rafi; Pulendran, Bali; Silvestri, Guido] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. [Crotty, Shane] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA. [Godzik, Adam] Sanford Burnham Med Res Inst, Grad Sch Biomed Sci, La Jolla, CA 92037 USA. [McElrath, M. Juliana] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scanlan, Chris N.] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. [Burton, Dennis R.; Barouch, Dan H.; Kaufmann, Daniel E.; Streeck, Hendrik; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Burton, Dennis R.; Barouch, Dan H.; Kaufmann, Daniel E.; Streeck, Hendrik; Walker, Bruce D.] Harvard Univ, Boston, MA 02114 USA. [Silvestri, Guido] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Burton, Dennis R.; Ahmed, Rafi; Barouch, Dan H.; Butera, Salvatore T.; Crotty, Shane; Godzik, Adam; Kaufmann, Daniel E.; McElrath, M. Juliana; Nussenzweig, Michel C.; Pulendran, Bali; Scanlan, Chris N.; Schief, William R.; Silvestri, Guido; Walker, Bruce D.; Ward, Andrew B.; Wilson, Ian A.; Wyatt, Richard] Scripps Res Inst, Scripps Ctr HIV AIDS Vaccine Immunol & Immunogen, La Jolla, CA 92037 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu RI Godzik, Adam/A-7279-2009; Ward, Andrew/F-9203-2014 OI Godzik, Adam/0000-0002-2425-852X; Ward, Andrew/0000-0001-7153-3769 FU Howard Hughes Medical Institute; NIAID NIH HHS [UM1 AI100663, R01 AI084817]; NIDDK NIH HHS [R37 DK057665] NR 148 TC 190 Z9 195 U1 6 U2 79 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT 18 PY 2012 VL 12 IS 4 SI SI BP 396 EP 407 DI 10.1016/j.chom.2012.09.008 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 032LI UT WOS:000310719700004 PM 23084910 ER PT J AU Chakkalakal, JV Jones, KM Basson, MA Brack, AS AF Chakkalakal, Joe V. Jones, Kieran M. Basson, M. Albert Brack, Andrew S. TI The aged niche disrupts muscle stem cell quiescence SO NATURE LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; SKELETAL-MUSCLE; SELF-RENEWAL; SATELLITE CELLS; ADULT MUSCLE; PROGENITOR CELLS; IN-VIVO; REGENERATION; MYOGENESIS; FIBERS AB The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function. C1 [Chakkalakal, Joe V.; Brack, Andrew S.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Jones, Kieran M.; Basson, M. Albert] Kings Coll London, Dept Craniofacial Dev & Stem Cell Biol, London SE1 9RT, England. [Brack, Andrew S.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Brack, Andrew S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Brack, AS (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM Brack.Andrew@mgh.harvard.edu OI Basson, M. Albert/0000-0001-9834-7528; Chakkalakal, Joe/0000-0002-8440-7312 FU MGH; Harvard Stem Cell Institute; NIH [R01 AR060868, R01 AR061002]; Wellcome Trust [WT091475]; MGH ECOR Postdoctoral Fellow Award; BBSRC Doctoral Training Award [BB/F017626/1] FX We thank H. Hock, K. Hochedlinger and R. Friesel for the generous provision of reagents, and G. Estrada for technical assistance. We are also grateful to L. Prickett-Rice, K. Folz-Donahue and M. Weglarz for cell sorting. This work was supported by MGH start-up funds, Harvard Stem Cell Institute grants and NIH grants (R01 AR060868, R01 AR061002) (A. S. B.); a Wellcome Trust grant (WT091475) (M. A. B.); and an MGH ECOR Postdoctoral Fellow Award (J.V.C.) and a BBSRC Doctoral Training Award (BB/F017626/1) (K.M.J.). NR 55 TC 190 Z9 197 U1 3 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 18 PY 2012 VL 490 IS 7420 BP 355 EP + DI 10.1038/nature11438 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 021XI UT WOS:000309918500036 PM 23023126 ER PT J AU Jensen, JK Medina, HM Norgaard, BL Ovrehus, KA Jensen, JM Nielsen, LH Maurovich-Horvat, P Engel, LC Januzzi, JL Hoffmann, U Truong, QA AF Jensen, Jesper K. Medina, Hector M. Norgaard, Bjarne L. Ovrehus, Kristian A. Jensen, Jesper M. Nielsen, Lene H. Maurovich-Horvat, Pal Engel, Leif-Christopher Januzzi, James L. Hoffmann, Udo Truong, Quynh A. TI Association of ischemic stroke to coronary artery disease using computed tomography coronary angiography SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Acute ischemic stroke; Coronary atherosclerosis; Coronary CT angiography ID HEALTH-CARE PROFESSIONALS; ATHEROSCLEROTIC PLAQUE; CARDIOVASCULAR-DISEASE; CEREBRAL INFARCTION; GUIDELINES; CALCIFICATION; INDIVIDUALS; PREVALENCE; STATEMENT; STENOSIS AB Background: While patients with coronary artery disease (CAD) and cerebrovascular disease share similar risk factor profiles, data on whether IS can be considered a "CAD equivalent" are limited. We aimed to determine whether ischemic stroke is an independent predictor of CAD by using cardiac computed tomography angiography (CTA). Methods: We analyzed the CTA in 392 patients with no history of CAD (24 patients with acute IS and 368 patients with acute chest pain). Extent of plaque burden was additionally dichotomized into 0-4 versus >4 segments. Results: Patients with IS had a near 5-fold increase odds of having coronary artery plaque (odds ratio [OR] 4.9, P<0.01) as compared to those without IS. After adjustment for age, gender, and traditional cardiac risk factors, there remained a near 4-fold increase odds for coronary plaque (adjusted OR 3.7, P=0.04). When stratified by extent of plaque, patients with IS had over 18-fold increase odds of having >4 segments of plaque than 0-4 segments as compared to patients without stroke (OR 18.3, P<0.01), which remained significantly associated in adjusted analysis (adjusted OR 12.1, P<0.001). Conclusion: Acute IS is independently associated with higher risk and greater extent of CAD compared to patients with acute chest pain at low-to-intermediate risk for acute coronary syndrome. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Jensen, Jesper K.; Norgaard, Bjarne L.; Ovrehus, Kristian A.; Jensen, Jesper M.; Nielsen, Lene H.] Vejle Hosp, Dept Cardiol, Vejle, Denmark. [Medina, Hector M.; Maurovich-Horvat, Pal; Engel, Leif-Christopher; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Dept Radiol, Cambridge, MA 02138 USA. [Januzzi, James L.; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Cambridge, MA 02138 USA. RP Jensen, JK (reprint author), Odense Univ Hosp, Dept Cardiol, DK-5000 Odense C, Denmark. EM jesperkjensen@dadlnet.dk OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU P.A Messerschmidt Foundation, Copenhagen; Familien Hede Nielsens Foundation, Horsens; Danish Medical Association, Copenhagen; Kirsten Anthonius Foundation, Aarhus FX We are greatly indebted to Jens O. Kjaersgaard for helping with the clinical evaluation of the patients. This project was supported with grants from P.A Messerschmidt Foundation, Copenhagen, Familien Hede Nielsens Foundation, Horsens, The Danish Medical Association, Copenhagen and Kirsten Anthonius Foundation, Aarhus. NR 29 TC 6 Z9 7 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 EI 1874-1754 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 18 PY 2012 VL 160 IS 3 BP 171 EP 174 DI 10.1016/j.ijcard.2011.04.006 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 017LZ UT WOS:000309592700013 PM 21543126 ER PT J AU Pascual-Figal, DA Bonaque, JC Manzano-Fernandez, S Fernandez, A Garrido, IP Pastor-Perez, F Lax, A Valdes, M Januzzi, JL AF Pascual-Figal, Domingo A. Bonaque, Juan C. Manzano-Fernandez, Sergio Fernandez, Asuncion Garrido, Iris P. Pastor-Perez, Francisco Lax, Antonio Valdes, M. Januzzi, James L. TI Red blood cell distribution width predicts new-onset anemia in heart failure patients SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Red blood cell distribution width; Anemia; Heart failure; Hemoglobin ID IRON-DEFICIENCY; PROGNOSTIC MARKER; DARBEPOETIN-ALPHA; DOUBLE-BLIND; MORTALITY; MECHANISMS; DISEASE; COHORT; ERYTHROPOIESIS; HEMOGLOBIN AB Background: Hematologic abnormalities such as elevated red blood cell distribution width (RDW) as well as anemia are prognostically meaningful among heart failure (HF) patients. The inter-relationship between these hematologic abnormalities in HF is unclear, however. We therefore aimed to assess whether RDW is predicting changes in hemoglobin concentrations as well as onset of anemia. Methods: 268 consecutive non-anemic patients with acutely decompensated HF (ADHF) were enrolled at hospital discharge and RDW was measured. At 6 month follow-up, change in hemoglobin as well as new-onset anemia was studied as a function of RDW at discharge. Results: RDW at discharge correlated negatively with hemoglobin values at 6 months (r = -0.220; p<0.001); a greater decrease in hemoglobin concentration occurred in those with higher values of RDW at discharge (p=0.004), independently of baseline hemoglobin concentration and other risk factors. At 6 months, 54 patients (20%) developed new-onset anemia. RDW values at discharge were significantly higher among patients who developed new-onset anemia (15.1 +/- 2.2 vs. 14.2 +/- 1.4, p=0.005). In integrated discrimination improvement analyses, the addition of RDW measurement improved the ability to predict new-onset anemia (IDI 0.0531, p<0.001), beyond known risk factors as hemoglobin, renal function, age, diabetes mellitus, sex and HF symptom severity. In adjusted analyses, patients with RDW>15% (derived from receiver operating characteristic analysis) had a tripling of the risk of new-onset anemia (OR=3.1, 95% CI 1.5-5.1, p=0.002). Conclusion: Among non-anemic patients with ADHF, RDW measurement at the time of hospital discharge independently predicts lower hemoglobin concentrations and new-onset anemia over a 6-month follow up period. (C) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Pascual-Figal, Domingo A.; Bonaque, Juan C.; Manzano-Fernandez, Sergio; Fernandez, Asuncion; Garrido, Iris P.; Pastor-Perez, Francisco; Lax, Antonio; Valdes, M.] Univ Murcia, Sch Med, Serv Cardiol, Virgen de la Arrixaca Hosp, Murcia, Spain. [Januzzi, James L.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Pascual-Figal, DA (reprint author), Univ Hosp Virgen de la Arrixaca, Dept Cardiol, Heart Failure Unit, Ctra Madrid Cartagena S-N, Murcia 30120, Spain. EM dapascual@servicam.com RI Pascual Figal, Domingo /B-3794-2008 OI Pascual Figal, Domingo /0000-0002-4993-9540 FU national network of investigation on heart failure "REDINSCOR": Instituto de Salud Carlos III, Ministry of Health, Madrid, Spain [RD06/0003/0013]; Balson Clinical Scholar fund FX This study was supported by the national network of investigation on heart failure "REDINSCOR": Grant RD06/0003/0013, Instituto de Salud Carlos III, Ministry of Health, Madrid, Spain. Dr. Januzzi is supported in part by the Balson Clinical Scholar fund. NR 29 TC 18 Z9 18 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD OCT 18 PY 2012 VL 160 IS 3 BP 196 EP 200 DI 10.1016/j.ijcard.2011.04.018 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 017LZ UT WOS:000309592700018 PM 21555160 ER PT J AU Dienstag, JL Cosimi, AB AF Dienstag, Jules L. Cosimi, A. Benedict TI Liver Transplantation - A Vision Realized SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Dienstag, Jules L.] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. [Cosimi, A. Benedict] Harvard Univ, Sch Med, Boston, MA USA. RP Dienstag, JL (reprint author), Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. NR 6 TC 24 Z9 26 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 18 PY 2012 VL 367 IS 16 BP 1483 EP 1485 DI 10.1056/NEJMp1210159 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500005 PM 22992048 ER PT J AU Anasetti, C Logan, BR Lee, SJ Waller, EK Weisdorf, DJ Wingard, JR Cutler, CS Westervelt, P Woolfrey, A Couban, S Ehninger, G Johnston, L Maziarz, RT Pulsipher, MA Porter, DL Mineishi, S McCarty, JM Khan, SP Anderlini, P Bensinger, WI Leitman, SF Rowley, SD Bredeson, C Carter, SL Horowitz, MM Confer, DL AF Anasetti, Claudio Logan, Brent R. Lee, Stephanie J. Waller, Edmund K. Weisdorf, Daniel J. Wingard, John R. Cutler, Corey S. Westervelt, Peter Woolfrey, Ann Couban, Stephen Ehninger, Gerhard Johnston, Laura Maziarz, Richard T. Pulsipher, Michael A. Porter, David L. Mineishi, Shin McCarty, John M. Khan, Shakila P. Anderlini, Paolo Bensinger, William I. Leitman, Susan F. Rowley, Scott D. Bredeson, Christopher Carter, Shelly L. Horowitz, Mary M. Confer, Dennis L. CA Blood And Marrow Transplant Clinic TI Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VERSUS-HOST-DISEASE; COLONY-STIMULATING FACTOR; TERM-FOLLOW-UP; RANDOMIZED-TRIAL; CHRONIC GRAFT; PROGENITOR CELLS; ALLOGENEIC TRANSPLANTATION; LEUKEMIA; RECIPIENTS; MALIGNANCIES AB BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1: 1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.) C1 [Anasetti, Claudio] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Logan, Brent R.; Horowitz, Mary M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Lee, Stephanie J.; Woolfrey, Ann; Bensinger, William I.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Waller, Edmund K.] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Khan, Shakila P.] Mayo Clin, Rochester, MN USA. [Confer, Dennis L.] Natl Marrow Donor Program, Minneapolis, MN USA. [Cutler, Corey S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Westervelt, Peter] Washington Univ, Siteman Canc Ctr, St Louis, MO USA. [Couban, Stephen] Dalhousie Univ, Halifax, NS, Canada. [Bredeson, Christopher] Ottawa Hosp, Ottawa, ON, Canada. [Ehninger, Gerhard] Univ Hosp Dresden, Dresden, Germany. [Johnston, Laura] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Maziarz, Richard T.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Pulsipher, Michael A.] Univ Utah, Primary Childrens Med Ctr, Salt Lake City, UT USA. [Porter, David L.] Univ Penn, Philadelphia, PA 19104 USA. [Mineishi, Shin] Univ Michigan, Ann Arbor, MI 48109 USA. [McCarty, John M.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23284 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Leitman, Susan F.] NIH, Bethesda, MD 20892 USA. [Carter, Shelly L.] EMMES Corp, Rockville, MD USA. [Rowley, Scott D.] Hackensack Univ, John Theurer Canc Ctr, Hackensack, NJ USA. [Wingard, John R.] Univ Florida, Shands Canc Ctr, Gainesville, FL USA. RP Anasetti, C (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. EM claudio.anasetti@moffitt.org FU National Heart, Lung, and Blood Institute-National Cancer Institute; National Heart, Lung, and Blood Institute; National Cancer Institute [U10HL069294]; Office of Naval Research; National Marrow Donor Program FX Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.; Supported by a grant from the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294), by the Office of Naval Research, and by the National Marrow Donor Program. NR 29 TC 212 Z9 216 U1 1 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 18 PY 2012 VL 367 IS 16 BP 1487 EP 1496 DI 10.1056/NEJMoa1203517 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500006 PM 23075175 ER PT J AU Devanand, DP Mintzer, J Schultz, SK Andrews, HF Sultzer, DL de la Pena, D Gupta, S Colon, S Schimming, C Pelton, GH Levin, B AF Devanand, D. P. Mintzer, Jacobo Schultz, Susan K. Andrews, Howard F. Sultzer, David L. de la Pena, Danilo Gupta, Sanjay Colon, Sylvia Schimming, Corbett Pelton, Gregory H. Levin, Bruce TI Relapse Risk after Discontinuation of Risperidone in Alzheimer's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ATYPICAL ANTIPSYCHOTIC MEDICATIONS; PLACEBO-CONTROLLED TRIALS; NURSING-HOME RESIDENTS; DOUBLE-BLIND; CATIE-AD; NEUROPSYCHIATRIC INVENTORY; COGNITIVE DECLINE; RANDOMIZED TRIAL; ELDERLY-PATIENTS; DEMENTIA AB BACKGROUND Among patients with Alzheimer's disease who have had a response to antipsychotic medication for psychosis or agitation-aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established. METHODS Patients with Alzheimer's disease and psychosis or agitation-aggression received open-label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). The primary outcome was the time to relapse of psychosis or agitation. RESULTS A total of 180 patients received open-label risperidone (mean dose, 0.97 mg daily). The severity of psychosis and agitation were reduced, although there was a mild increase in extrapyramidal signs; 112 patients met the criteria for response to treatment, of whom 110 underwent randomization. In the first 16 weeks after randomization, the rate of relapse was higher in the group that received placebo than in the groups that received risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P = 0.004; hazard ratio with placebo, 1.94; 95% confidence interval [CI], 1.09 to 3.45; P = 0.02). During the next 16 weeks, the rate of relapse was higher in the group that was switched from risperidone to placebo than in the group that continued to receive risperidone (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P = 0.02; hazard ratio, 4.88; 95% CI, 1.08 to 21.98; P = 0.02). The rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks. CONCLUSIONS In patients with Alzheimer's disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00417482.) C1 [Devanand, D. P.; Pelton, Gregory H.] Columbia Univ, New York State Psychiat Inst, Div Geriatr Psychiat, New York, NY 10032 USA. [Devanand, D. P.; Andrews, Howard F.; Pelton, Gregory H.] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10032 USA. [Devanand, D. P.; Andrews, Howard F.; Pelton, Gregory H.] Columbia Univ, Dept Neurol, New York, NY 10032 USA. [Devanand, D. P.; Andrews, Howard F.; Pelton, Gregory H.] Columbia Univ, Coll Physicians & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA. [Andrews, Howard F.; Levin, Bruce] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY 10032 USA. [Gupta, Sanjay] Global Res & Consulting, Buffalo, NY USA. [Schimming, Corbett] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Mintzer, Jacobo] Med Univ S Carolina, Dept Neurosci, Div Translat Res, Charleston, SC USA. [Mintzer, Jacobo] Ralph H Johnson Vet Affairs VA Med Ctr, Charleston, SC USA. [Schultz, Susan K.] Univ Iowa, Carver Coll Med, Dept Psychiat, Iowa City, IA USA. [Sultzer, David L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Sultzer, David L.] VA Greater Angeles Hlth Syst, Los Angeles, CA USA. [de la Pena, Danilo] Res Ctr Clin Studies, Norwalk, CT USA. [Colon, Sylvia] VA Med Ctr, Dept Psychiat, Tuscaloosa, AL USA. RP Devanand, DP (reprint author), Columbia Univ, New York State Psychiat Inst, Div Geriatr Psychiat, 1051 Riverside Dr,Unit 126, New York, NY 10032 USA. EM dpd3@columbia.edu FU National Institutes of Health [R01 AG021488, R01 AG17761]; Department of Veterans Affairs FX Supported by grants from the National Institutes of Health (R01 AG021488 and R01 AG17761) and the Department of Veterans Affairs. NR 39 TC 47 Z9 49 U1 1 U2 12 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 18 PY 2012 VL 367 IS 16 BP 1497 EP 1507 DI 10.1056/NEJMoa1114058 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500007 PM 23075176 ER PT J AU Glassock, RJ Khorashadi, L Kushner, YB AF Glassock, Richard J. Khorashadi, Leila Kushner, Yael B. TI Case 32-2012: A 35-Year-Old Man with Respiratory and Renal Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DIFFUSE ALVEOLAR HEMORRHAGE; PULMONARY CAPILLARITIS; LUNG HEMORRHAGE; VASCULITIS; NEPHRITIS; GLOMERULONEPHRITIS; ANTIBODIES C1 [Glassock, Richard J.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Khorashadi, Leila] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kushner, Yael B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Khorashadi, Leila] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kushner, Yael B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Glassock, RJ (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. FU Harvard Medical School Department of Continuing Education; QuestCor; BioMarin; Novartis; Eli Lilly; Bristol-Myers Squibb; Genentech; Vifor; Genzyme-Sanofi; American Renal Associates; Renal Ventures FX This case was presented at the Harvard Medical School postgraduate course MGH Nephrology Update (Directors, Drs. Mario F. Rubin, Hasan Bazari, and M. Amin Arnaout), sponsored by the Harvard Medical School Department of Continuing Education.; Dr. Glassock reports receiving consulting fees from QuestCor, BioMarin, Novartis, Eli Lilly, Bristol-Myers Squibb, Genentech, Vifor, Genzyme-Sanofi, and American Renal Associates; receiving fees for expert opinions for patients and caregivers in legal cases involving renal disease and for expert testimony for the defense in a lawsuit involving alleged renal injury from volatile hydrocarbons; receiving lecture fees from Renal Ventures and Genentech; receiving payment from Lighthouse Learning for the development of educational presentations; receiving editorial stipends from UpToDate; receiving royalties from Oxford Medical Publishers and UpToDate; owning stock or stock options in Reata and La Jolla Pharmaceuticals; and serving as an unpaid board member for LABioMed and UKRO. No other potential conflict of interest relevant to this article was reported. NR 30 TC 2 Z9 2 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 18 PY 2012 VL 367 IS 16 BP 1540 EP 1553 DI 10.1056/NEJMcpc1201412 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 021SA UT WOS:000309904500012 PM 23075181 ER PT J AU Martinez, HG Quinones, MP Jimenez, F Estrada, C Clark, KM Suzuki, K Miura, N Ohno, N Ahuja, SK Ahuja, SS AF Martinez, Hernan G. Quinones, Marlon P. Jimenez, Fabio Estrada, Carlos Clark, Kassandra M. Suzuki, Kazuo Miura, Noriko Ohno, Naohito Ahuja, Sunil K. Ahuja, Seema S. TI Important role of CCR2 in a murine model of coronary vasculitis SO BMC IMMUNOLOGY LA English DT Article DE CCR2; Coronary vasculitis; Treg; Treg/Th17 imbalance ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; PERIPHERAL-BLOOD MONOCYTES; ACUTE KAWASAKI-DISEASE; REGULATORY T-CELLS; INTRAVENOUS IMMUNOGLOBULIN; CANDIDA-ALBICANS; KNOCKOUT MICE; PROPAGERMANIUM; RECEPTOR; ATHEROSCLEROSIS AB Background: Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD). Results: Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2(+/+) mice, processes that were ameliorated following the genetic inactivation of CCR2. Conclusion: Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments. C1 [Martinez, Hernan G.; Jimenez, Fabio; Estrada, Carlos; Clark, Kassandra M.; Ahuja, Seema S.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med MC 7870, San Antonio, TX 78229 USA. [Martinez, Hernan G.; Jimenez, Fabio; Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. [Quinones, Marlon P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Suzuki, Kazuo] Chiba Univ, Grad Sch Med, Dept Immunol, Inflammat Program, Chiba 2608670, Japan. [Miura, Noriko; Ohno, Naohito] Tokyo Univ Pharm & Life Sci, Sch Pharm, Lab Immunopharmacol Microbial Prod, Hachioji, Tokyo 1920392, Japan. [Ahuja, Sunil K.] S Texas Vet Hlth Care Syst, Vet Adm Ctr Aids & HIV Infect 1, San Antonio, TX USA. RP Ahuja, SS (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med MC 7870, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ahuja@uthscsa.edu FU Veterans Administration [Merit Review]; National Institutes of Health [R01 AR 052755] FX This work was supported by the Veterans Administration [Merit Review] and National Institutes of Health [R01 AR 052755] to S.S.A. NR 42 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD OCT 17 PY 2012 VL 13 AR 56 DI 10.1186/1471-2172-13-56 PG 12 WC Immunology SC Immunology GA 053JU UT WOS:000312268400001 PM 23074996 ER PT J AU Makino, CL Wen, XH Olshevskaya, EV Peshenko, IV Savchenko, AB Dizhoor, AM AF Makino, Clint L. Wen, Xiao-Hong Olshevskaya, Elena V. Peshenko, Igor V. Savchenko, Andrey B. Dizhoor, Alexander M. TI Enzymatic Relay Mechanism Stimulates Cyclic GMP Synthesis in Rod Photoresponse: Biochemical and Physiological Study in Guanylyl Cyclase Activating Protein 1 Knockout Mice SO PLOS ONE LA English DT Article ID OUTER SEGMENTS; DIFFUSION-COEFFICIENT; IN-VIVO; PHOTORECEPTORS; CALCIUM; EXPRESSION; RETGC; GCAPS; PHOTOTRANSDUCTION; CLONING AB Regulation of cGMP synthesis by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) in rod and cone photoreceptors by calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) is one of the key molecular mechanisms affecting the response to light and is involved in congenital retinal diseases. The objective of this study was to identify the physiological sequence of events underlying RetGC activation in vivo, by studying the electrophysiological and biochemical properties of mouse rods in a new genetic model lacking GCAP1. The GCAP1(-/-) retinas expressed normal levels of RetGC isozymes and other phototransduction proteins, with the exception of GCAP2, whose expression was elevated in a compensatory fashion. RetGC activity in GCAP1(-/-) retinas became more sensitive to Ca2+ and slightly increased. The bright flash response in electroretinogram (ERG) recordings recovered quickly in GCAP1(-/-), as well as in RetGC1(-/-) GCAP1(-/-), and RetGC2(-/-) GCAP1(-/-) hybrid rods, indicating that GCAP2 activates both RetGC isozymes in vivo. Individual GCAP1(-/-) rod responses varied in size and shape, likely reflecting variable endogenous GCAP2 levels between different cells, but single-photon response (SPR) amplitude and time-to-peak were typically increased, while recovery kinetics remained faster than in wild type. Recovery from bright flashes in GCAP1(-/-) was prominently biphasic, because rare, aberrant SPRs producing the slower tail component were magnified. These data provide strong physiological evidence that rod photoresponse recovery is shaped by the sequential recruitment of RetGC isozyme activation by GCAPs according to the different GCAP sensitivities for Ca2+ and specificities toward RetGC isozymes. GCAP1 is the 'first-response' sensor protein that stimulates RetGC1 early in the response and thus limits the SPR amplitude, followed by activation of GCAP2 that adds stimulation of both RetGC1 and RetGC2 to speed-up photoreceptor recovery. C1 [Olshevskaya, Elena V.; Peshenko, Igor V.; Savchenko, Andrey B.; Dizhoor, Alexander M.] Salus Univ, Dept Basic Sci, Elkins Pk, PA USA. [Olshevskaya, Elena V.; Peshenko, Igor V.; Savchenko, Andrey B.; Dizhoor, Alexander M.] Salus Univ, Penn Coll Optometry, Elkins Pk, PA USA. [Makino, Clint L.; Wen, Xiao-Hong] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Makino, Clint L.; Wen, Xiao-Hong] Harvard Univ, Sch Med, Boston, MA USA. RP Dizhoor, AM (reprint author), Salus Univ, Dept Basic Sci, Elkins Pk, PA USA. EM adizhoor@salus.edu OI Makino, Clint/0000-0002-6005-9069 FU National Institutes of Health [EY11522, EY011358, EY014104]; Lion's of Massachusetts; Pennsylvania Department of Health Formula Grant FX This work was supported by National Institutes of Health grants EY11522 (AMD) and EY011358, EY014104 (CLM), Lion's of Massachusetts, and Pennsylvania Department of Health Formula Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 24 Z9 24 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2012 VL 7 IS 10 AR e47637 DI 10.1371/journal.pone.0047637 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900081 PM 23082185 ER PT J AU Soberman, RJ MacKay, CR Vaine, CA Ryan, GB Cerny, AM Thompson, MR Nikolic, B Primo, V Christmas, P Sheiffele, P Aronov, L Knipe, DM Kurt-Jones, EA AF Soberman, Roy J. MacKay, Christopher R. Vaine, Christine A. Ryan, Glennice Bowen Cerny, Anna M. Thompson, Mikayla R. Nikolic, Boris Primo, Valeria Christmas, Peter Sheiffele, Paul Aronov, Lisa Knipe, David M. Kurt-Jones, Evelyn A. TI CD200R1 Supports HSV-1 Viral Replication and Licenses Pro-Inflammatory Signaling Functions of TLR2 SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; CENTRAL-NERVOUS-SYSTEM; INHIBITORY LIGAND CD200; IMMUNE-RESPONSE; TYPE-1 INFECTION; DENDRITIC CELLS; INNATE IMMUNITY; KAPPA-B; RECEPTOR; HOST AB The CD200R1:CD200 axis is traditionally considered to limit tissue inflammation by down-regulating pro-inflammatory signaling in myeloid cells bearing the receptor. We generated CD200R1(-/-) mice and employed them to explore both the role of CD200R1 in regulating macrophage signaling via TLR2 as well as the host response to an in vivo, TLR2-dependent model, herpes simplex virus 1 (HSV-1) infection. CD200R1(-/-) peritoneal macrophages demonstrated a 70-75% decrease in the generation of IL-6 and CCL5 (Rantes) in response to the TLR2 agonist Pam(2)CSK(4) and to HSV-1. CD200R1(-/-) macrophages could neither up-regulate the expression of TLR2, nor assemble a functional inflammasome in response to HSV-1. CD200R1(-/-) mice were protected from HSV-1 infection and exhibited dysfunctional TLR2 signaling. Finally, both CD200R1(-/-) mice and CD200R1(-/-) fibroblasts and macrophages showed a markedly reduced ability to support HSV-1 replication. In summary, our data demonstrate an unanticipated and novel requirement for CD200R1 in "licensing'' pro-inflammatory functions of TLR2 and in limiting viral replication that are supported by ex vivo and in vivo evidence. C1 [Soberman, Roy J.; Vaine, Christine A.; Nikolic, Boris; Primo, Valeria; Christmas, Peter] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit,Dept Med, Charlestown, MA USA. [MacKay, Christopher R.; Ryan, Glennice Bowen; Cerny, Anna M.; Thompson, Mikayla R.; Kurt-Jones, Evelyn A.] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Sheiffele, Paul; Aronov, Lisa] InGenious Targeting Lab Inc, Stony Brook, NY USA. [Knipe, David M.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. RP Soberman, RJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit,Dept Med, Charlestown, MA USA. EM Soberman@helix.mgh.harvard.edu; evelyn.kurt-jones@umassmed.edu RI Mackay, Charles/A-9673-2008; OI Mackay, Charles/0000-0002-6338-7340; Vaine, Christine/0000-0003-2645-8223 FU National Institutes of Health [R01AI068871, R01AI068871-S4, P01 AI083215-01]; Diabetes Endocrinology Research Center [DK32520]; UMass CFAR from the National Institutes of Health [5P30 AI-42845] FX This work was supported by grants R01AI068871 (RJS), R01AI068871-S4 (RJS and CV), P01 AI083215-01 (EAK-J and DMK) and UMass CFAR Grant 5P30 AI-42845 (EAK-J) from the National Institutes of Health. Core resources supported by the Diabetes Endocrinology Research Center grant DK32520 were also used. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 7 Z9 7 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 OCT 17 PY 2012 VL 7 IS 10 AR e47740 DI 10.1371/journal.pone.0047740 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900101 PM 23082204 ER PT J AU Zhao, W Zheng, XF Liu, YY Yang, WL Amirbekian, V Diaz, LE Huang, XD AF Zhao, Wen Zheng, Xiaofeng Liu, Yuying Yang, Wenlu Amirbekian, Vardan Diaz, Luis E. Huang, Xudong TI An MRI Study of Symptomatic Adhesive Capsulitis SO PLOS ONE LA English DT Article ID ROTATOR INTERVAL LESIONS; FROZEN SHOULDER; CORACOHUMERAL LIGAMENT; ARTHROGRAPHY; DIAGNOSIS; ANATOMY; PATHOLOGY; RELEASE; MOTION AB Background: Appilication of MR imaging to diagnose Adhesive Capsulitis (AC) has previously been described. However, there is insufficient information available for the MRI analysis of AC. This study is to describe and evaluate the pathomorphology of the shoulder in Asian patients with AC compared to healthy volunteers. Methodology/Principal Findings: 60 Asian patients with clinically diagnosed AC and 60 healthy volunteers without frozen shoulder underwent MRI of the shoulder joint. All subjects who were age- and sex-matched control ones underwent routine MRI scans of the affected shoulder, including axial, oblique coronal, oblique sagittal T1WI SE and coronal oblique T2WI FSE sequences. Significant abnormal findings were observed on MRI, especially at the rotator cuff interval. The coracohumeral ligament (CHL), articular capsule thickness in the rotator cuff interval as well as the fat space under coracoid process were evaluated. MRI showed that patients with adhesive capsulitis had a significantly thickened coracohumeral ligament and articular capsule in the rotator cuff interval compared to the control subjects (4.2 vs. 2.4 mm, 7.2 vs. 4.4 mm; p<0.05). Partial or complete obliteration of the subcoracoid fat triangle was significantly more frequent in patients with adhesive capsulitis compared with control subjects (73% vs. 13%, 26% vs. 1.6%; p<0.001). Synovitis-like abnormality around the long biceps tendon was significantly more common in patients with adhesive capsulitis than in control subjects. With regards to the inter-observer variability, two MR radiologists had an excellent kappa value of 0.86. Conclusions/Significance: MRI can be used to show characteristic findings in diagnosing AC. Thickening of the CHL and the capsule at the rotator cuff interval and complete obliteration of the fat triangle under the coracoid process have been shown to be the most characteristic MR findings seen with AC. C1 [Huang, Xudong] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Huang, Xudong] Harvard Univ, Sch Med, Charlestown, MA USA. [Zhao, Wen] Beijing Aerosp Gen Hosp, Dept Orthoped, Beijing, Peoples R China. [Zheng, Xiaofeng] Beijing Aerosp Gen Hosp, Dept Radiol, Beijing, Peoples R China. [Liu, Yuying] Med Univ S Carolina, Dept Cell & Mol Pharmacol & Expt Therapeut, Charleston, SC 29425 USA. [Yang, Wenlu] Shanghai Maritime Univ, Informat Engn Coll, Dept Elect Engn, Shanghai, Peoples R China. [Amirbekian, Vardan] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Amirbekian, Vardan] Harvard Univ, Sch Med, Boston, MA USA. [Diaz, Luis E.] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Diaz, Luis E.] VA Boston Healthcare Syst, Boston, MA USA. RP Huang, XD (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. EM xhuang3@partners.org FU Beijing General Aerospace Hospital; Radiology Department of Brigham and Women's Hospital (BWH) FX This study was supported by research funds from the Beijing General Aerospace Hospital. XH is partially supported by the Radiology Department of Brigham and Women's Hospital (BWH). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 10 Z9 10 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2012 VL 7 IS 10 AR e47277 DI 10.1371/journal.pone.0047277 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 038AF UT WOS:000311146900048 PM 23082152 ER PT J AU Katz, JN Wright, EA Wright, J Malchau, H Mahomed, NN Stedman, M Baron, JA Losina, E AF Katz, Jeffrey N. Wright, Elizabeth A. Wright, John Malchau, Henrik Mahomed, Nizar N. Stedman, Margaret Baron, John A. Losina, Elena TI Twelve-Year Risk of Revision After Primary Total Hip Replacement in the US Medicare Population SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID NORWEGIAN ARTHROPLASTY REGISTER; PRIMARY OSTEOARTHRITIS; IMPLANTS; FAILURE; INDEX; OLDER AB Background: There is limited population-based literature on rates and risk factors for revision following primary total hip replacement. Methods: We performed a retrospective cohort study of Medicare beneficiaries who had elective total hip replacement for osteoarthritis between July 1, 1995, and June 30, 1996. Patients were followed with use of Medicare claims through 2008. The primary end point was revision total hip replacement as indicated by hospital discharge codes according to the International Classification of Diseases, Ninth Revision. We used the Kaplan-Meier method to plot the risks of revision and of death over a twelve-year follow-up period. We used Cox proportional hazard regression models to identify preoperative risk factors for revision of primary total hip replacement. We conducted sensitivity analyses to account for competing risks of major comorbid conditions. Results: The risk of revision total hip replacement for patients remaining alive was approximately 2% per year for the first eighteen months and then 1% per year for the remainder of the follow-up period. The absolute risk of death over the twelve-year follow-up period exceeded the risk of revision total hip replacement by a factor of ten (59% vs. 5.7%) in patients older than seventy-five years at the time of primary total hip replacement and by a factor of three (29% vs. 9.4%) in patients sixty-five to seventy-five years old at the time of surgery. In multivariate Cox proportional hazard models, the relative risk of revision was higher in men than in women (hazard ratio [HR], 1.23; 95% confidence interval [95% CI], 1.15, 1.31) and in patients sixty-five to seventy-five years of age at the time of primary total hip replacement than in those over seventy-five years (HR, 1.47; 95% CI, 1.37, 1.58). Patients of surgeons who performed fewer than six total hip replacements annually in the Medicare population had a higher risk of revision than those whose surgeons performed more than twelve per year (HR, 1.21; 95% CI, 1.12, 1.32). Conclusions: Efforts to reduce the number of revision hip arthroplasties should be targeted at revisions occurring in the first eighteen months following the index arthroplasty, when revision risk is higher, and at younger patients, who are more likely to survive long enough to require revision. C1 [Katz, Jeffrey N.] Brigham & Womens Hosp, Orthoped & Arthrit Ctr Outcomes Res, Dept Orthoped Surg, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02114 USA. Univ Toronto, Dept Orthoped Surg, Univ Hlth Network, Toronto, ON M5T 2S8, Canada. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. RP Katz, JN (reprint author), Brigham & Womens Hosp, Orthoped & Arthrit Ctr Outcomes Res, Dept Orthoped Surg, 75 Francis St,OBC 4-016, Boston, MA 02115 USA. EM jnkatz@partners.org OI Stedman, Margaret/0000-0001-9271-8332; Malchau, Henrik/0000-0002-4291-2441 FU National Institutes of Health (NIH) FX This study was funded by the National Institutes of Health (NIH). The NIH played no role in our investigation beyond providing the funding. NR 20 TC 29 Z9 30 U1 0 U2 8 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 17 PY 2012 VL 94A IS 20 BP 1825 EP 1832 DI 10.2106/JBJS.K.00569 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 028IT UT WOS:000310416700001 PM 23079874 ER PT J AU Schwab, JH Springfield, DS Raskin, KA Mankin, HJ Hornicek, FJ AF Schwab, Joseph H. Springfield, Dempsey S. Raskin, Kevin A. Mankin, Henry J. Hornicek, Francis J. TI What's New in Primary Bone Tumors SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Reprint ID GIANT-CELL TUMOR; EWINGS-SARCOMA; ZOLEDRONIC ACID; OSTEOSARCOMA; CHONDROSARCOMA; EXPRESSION; RECEPTOR; GROWTH; CHORDOMA; OUTCOMES RP Schwab, JH (reprint author), Massachusetts Gen Hosp, Orthopaed Oncol Serv, 55 Fruit St, Boston, MA 02114 USA. EM jhschwab@partners.org NR 55 TC 17 Z9 18 U1 0 U2 8 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD OCT 17 PY 2012 VL 94A IS 20 BP 1913 EP 1919 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 028IT UT WOS:000310416700012 PM 23079883 ER PT J AU Teo, AKK Kulkarni, RN AF Teo, Adrian Kee Keong Kulkarni, Rohit N. TI Setting sail for glucose homeostasis with the AKAP150-PP2B-anchor SO EMBO JOURNAL LA English DT Editorial Material ID PROTEIN-KINASE-A; INSULIN-SECRETION; PHOSPHORYLATION AB Glucose-stimulated insulin secretion, controlled by multiple protein phosphorylation events, is critical for the regulation of glucose homeostasis. Protein kinase A (PKA) is known to play a role in beta cell physiology, but the role of its anchoring protein is not fully understood. Hinke et al (2012) illustrate the significance of A-kinase anchoring protein 150 in tethering protein phosphatase 2B to mediate nutrient-stimulated insulin secretion and thus modulate glucose homeostasis. C1 [Kulkarni, Rohit N.] Harvard Univ, Brigham & Womens Hosp, Sect Islet Cell Biol & Regenerat Med, Joslin Diabet Ctr,Sch Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Kulkarni, RN (reprint author), Harvard Univ, Brigham & Womens Hosp, Sect Islet Cell Biol & Regenerat Med, Joslin Diabet Ctr,Sch Med, Boston, MA 02115 USA. EM rohit.kulkarni@joslin.harvard.edu RI Teo, Adrian/A-4009-2013 OI Teo, Adrian/0000-0001-5901-7075 FU NIDDK NIH HHS [R01 DK 55523, R01 DK055523, R01 DK 67536, R01 DK067536] NR 10 TC 1 Z9 1 U1 0 U2 4 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 OCT 17 PY 2012 VL 31 IS 20 BP 3956 EP 3957 DI 10.1038/emboj.2012.265 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 023SJ UT WOS:000310055400003 PM 22983555 ER PT J AU Hayes, SM Salat, DH Verfaellie, M AF Hayes, Scott M. Salat, David H. Verfaellie, Mieke TI Default Network Connectivity in Medial Temporal Lobe Amnesia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FUNCTIONAL CONNECTIVITY; RESTING-STATE; HIPPOCAMPAL DAMAGE; ALZHEIMERS-DISEASE; EPISODIC MEMORY; CORPUS-CALLOSUM; CEREBRAL-CORTEX; WORKING-MEMORY; MODE NETWORK; HUMAN BRAIN AB There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans, the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting fMRI was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex were observed in amnesic patients. In contrast, somatomotor network connectivity was intact in amnesic patients, indicating that bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia. C1 [Hayes, Scott M.; Verfaellie, Mieke] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02130 USA. [Hayes, Scott M.; Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02130 USA. [Hayes, Scott M.; Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA 02130 USA. [Salat, David H.] MGH Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Hayes, SM (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr 151A, 150 S Huntington Ave, Boston, MA 02130 USA. EM smhayes@bu.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU Department of Veterans Affairs Rehabilitation Research and Development Service [e7822w]; Clinical Science Research and Development Service; National Institutes of Health [R01 MH093431] FX This work was supported by the Department of Veterans Affairs Rehabilitation Research and Development Service (Career Development Award e7822w to S. M. H.), Clinical Science Research and Development Service (to M. V.), and the National Institutes of Health (Grant R01 MH093431). We thank Amanda Mikedis for assistance with MRI data collection, Dr. Ginette Lafleche for clinical neuropsychological assessment, and Dr. Margaret Keane for helpful comments and discussion. NR 46 TC 14 Z9 14 U1 0 U2 11 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 OCT 17 PY 2012 VL 32 IS 42 BP 14622 EP 14630 DI 10.1523/JNEUROSCI.0700-12.2012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 023RY UT WOS:000310054000016 PM 23077048 ER PT J AU Bickart, KC Hollenbeck, MC Barrett, LF Dickerson, BC AF Bickart, Kevin C. Hollenbeck, Mark C. Barrett, Lisa Feldman Dickerson, Bradford C. TI Intrinsic Amygdala-Cortical Functional Connectivity Predicts Social Network Size in Humans SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MEDIAL PREFRONTAL CORTEX; MACAQUE MONKEYS; RHESUS-MONKEY; INDIVIDUAL-DIFFERENCES; NEURAL BASIS; DIFFERENTIAL CONNECTIONS; CHARITABLE DONATION; FACIAL EXPRESSIONS; DECISION-MAKING; HUMAN BRAIN AB Using resting-state functional magnetic resonance imaging data from two independent samples of healthy adults, we parsed the amygdala's intrinsic connectivity into three partially distinct large-scale networks that strongly resemble the known anatomical organization of amygdala connectivity in rodents and monkeys. Moreover, in a third independent sample, we discovered that people who fostered and maintained larger and more complex social networks not only had larger amygdala volumes, but also amygdalae with stronger intrinsic connectivity within two of these networks: one putatively subserving perceptual abilities and one subserving affiliative behaviors. Our findings were anatomically specific to amygdalar circuitry in that individual differences in social network size and complexity could not be explained by the strength of intrinsic connectivity between nodes within two networks that do not typically involve the amygdala(i.e., the mentalizing and mirror networks), and were behaviorally specific in that amygdala connectivity did not correlate with other self-report measures of sociality. C1 [Bickart, Kevin C.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Hollenbeck, Mark C.; Barrett, Lisa Feldman; Dickerson, Bradford C.] Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hollenbeck, Mark C.; Barrett, Lisa Feldman; Dickerson, Bradford C.] Psychiat Neuroimaging Res Program, Charlestown, MA 02129 USA. [Barrett, Lisa Feldman] Northwestern Univ, Dept Psychol, Boston, MA 02115 USA. [Hollenbeck, Mark C.; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Frontotemporal Disorders Unit, Charlestown, MA 02129 USA. [Hollenbeck, Mark C.; Dickerson, Bradford C.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Dickerson, BC (reprint author), MGH Frontotemporal Disorders Unit, 149 13th St,Suite 2691, Charlestown, MA 02129 USA. EM bradd@nmr.mgh.harvard.edu FU U.S. National Institutes of Health [DP1OD003312]; U.S. National Institute on Aging [R01-AG030311, R01-AG029411, P50-AG005134] FX This study was supported by grants from the U.S. National Institutes of Health Director's Pioneer Award (DP1OD003312) and the U.S. National Institute on Aging (R01-AG030311, R01-AG029411 and P50-AG005134). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Institute on Aging. We thank Randy Buckner for providing the data used in the analysis of the discovery sample and the tools used for fcMRI preprocessing and Rebecca Dautoff for assistance. NR 102 TC 64 Z9 65 U1 5 U2 31 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 OCT 17 PY 2012 VL 32 IS 42 BP 14729 EP 14741 DI 10.1523/JNEUROSCI.1599-12.2012 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 023RY UT WOS:000310054000026 PM 23077058 ER PT J AU Rigotti, NA AF Rigotti, Nancy A. TI Strategies to Help a Smoker Who Is Struggling to Quit SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NICOTINE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; SMOKING-CESSATION PHARMACOTHERAPIES; SUSTAINED-RELEASE BUPROPION; RECEPTOR PARTIAL AGONIST; OPEN-LABEL TRIAL; TOBACCO DEPENDENCE; CHRONIC DISEASE; ADVERSE EVENTS; UNITED-STATES AB Tobacco use is the leading preventable cause of death worldwide. Stopping tobacco use benefits virtually every smoker. Most of the 19% of US residents who smoke want to quit and have tried to do so. Most individual quit attempts fail, but two-thirds of smokers use no treatment when trying to quit. Treating tobacco dependence is one of the most cost-effective actions in health care. With a brief intervention, physicians can prompt smokers to attempt to quit and connect them to evidence-based treatment that includes pharmacotherapy and behavioral support (ie, counseling). Physicians can link smokers to effective counseling support offered by a free national network of telephone quit lines. Smokers who use nicotine replacement therapy (NRT), bupropion, or varenicline when trying to quit double their odds of success. The most effective way to use NRT is to combine the long-acting nicotine patch with a shorter-acting product (lozenge, gum, inhaler, or nasal spray) and extend treatment beyond 12 weeks. Observational studies have not confirmed case reports of behavior changes associated with varenicline and bupropion, and these drugs' benefits outweigh potential risks. A chronic disease management model is effective for treating tobacco dependence, which deserves as high a priority in health care systems as treating other chronic diseases like diabetes and hypertension. JAMA. 2012;308(15):1573-1580 www.jama.com C1 [Rigotti, Nancy A.] Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Dept Med,Med Sch, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Gen Med, Dept Med,Med Sch, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM nrigotti@partners.org FU Nabi Biopharmaceuticals Inc; Pfizer Inc.; National Institutes of Health, National Heart, Lung, and Blood Institute [5K24HL4440-10] FX The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported that she has received royalties from UpToDate Inc and research grants to her institution from Nabi Biopharmaceuticals Inc, and Pfizer Inc. She also reported that she has served as an unpaid consultant for Pfizer Inc and Alere Wellbeing Inc.; This was supported by grant 5K24HL4440-10, a Mid-Career Investigator Award in Patient-Oriented Research from the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 65 TC 45 Z9 45 U1 1 U2 23 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 OCT 17 PY 2012 VL 308 IS 15 BP 1573 EP 1580 DI 10.1001/jama.2012.13043 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 021AQ UT WOS:000309858100024 PM 23073954 ER PT J AU Kostis, WJ AF Kostis, William J. TI Absolute Risk Reduction Due to Statin Use According to Sex SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Kostis, WJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB800, Boston, MA 02114 USA. EM wkostis@partners.org NR 2 TC 4 Z9 4 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 OCT 16 PY 2012 VL 60 IS 16 BP 1580 EP 1580 DI 10.1016/j.jacc.2012.03.081 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 025OB UT WOS:000310198200022 PM 23058318 ER PT J AU Wong, EB Omar, T Setlhako, GJ Osih, R Feldman, C Murdoch, DM Martinson, NA Bangsberg, DR Venter, WDF AF Wong, Emily B. Omar, Tanvier Setlhako, Gosetsemang J. Osih, Regina Feldman, Charles Murdoch, David M. Martinson, Neil A. Bangsberg, David R. Venter, W. D. F. TI Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa SO PLOS ONE LA English DT Article ID RECONSTITUTION INFLAMMATORY SYNDROME; HIV-POSITIVE PATIENTS; SUB-SAHARAN AFRICA; EARLY MORTALITY; AUTOPSY; TUBERCULOSIS; DISEASE; ADULTS; PATHOLOGY; COHORT AB Background: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. Methods: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. Results: Thirty-nine adults were enrolled: 1 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. Conclusions: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge. C1 [Wong, Emily B.; Setlhako, Gosetsemang J.; Osih, Regina; Venter, W. D. F.] Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. [Wong, Emily B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Wong, Emily B.] Univ KwaZulu Natal, KwaZulu Natal Res Inst TB & HIV, Durban, South Africa. [Omar, Tanvier] Univ Witwatersrand, Fac Hlth Sci, Sch Pathol, Johannesburg, South Africa. [Setlhako, Gosetsemang J.; Feldman, Charles] Univ Witwatersrand, Charlotte Maxeke Johannesburg Acad Hosp, Dept Internal Med, Johannesburg, South Africa. [Murdoch, David M.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Martinson, Neil A.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Martinson, Neil A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Ragon Inst MGH MIT & Harvard, Massachusetts Gen Hosp,Ctr Global Hlth, Boston, MA 02115 USA. RP Wong, EB (reprint author), Univ Witwatersrand, Wits Reprod Hlth & HIV Inst, Johannesburg, South Africa. EM emily.wong@k-rith.org FU Fogarty International Center at the National Institutes of Health [R24TW007988, RTW007373/0, D43TW000010-21S1]; President's Emergency Plan for AIDS Relief [674-A-00-08-00005-00]; National Research Foundation of South Africa FX This work was supported by the Fogarty International Center at the National Institutes of Health (www.fic.nih.gov, R24TW007988 supported and provided research training to E. B. W. and G.J.S.; RTW007373/0 supported N.M. and provided research training to W. D. F. V.; and D43TW000010-21S1 provided research training to T.O.), the President's Emergency Plan for AIDS Relief (www.pepfar.gov, 674-A-00-08-00005-00 supported R.O., G.J.S, W. D. F. V.), and the National Research Foundation of South Africa (www.nrf.ac.za, supported C. F.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 54 Z9 54 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 16 PY 2012 VL 7 IS 10 AR e47542 DI 10.1371/journal.pone.0047542 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 024UX UT WOS:000310135800054 PM 23094059 ER PT J AU Clark, K MacKenzie, KF Petkevicius, K Kristariyanto, Y Zhang, JZ Choi, HG Peggie, M Plater, L Pedrioli, PGA McIver, E Gray, NS Arthur, JSC Cohen, P AF Clark, Kristopher MacKenzie, Kirsty F. Petkevicius, Kasparas Kristariyanto, Yosua Zhang, Jiazhen Choi, Hwan Geun Peggie, Mark Plater, Lorna Pedrioli, Patrick G. A. McIver, Ed Gray, Nathanael S. Arthur, J. Simon C. Cohen, Philip TI Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Toll-like receptor; AMPK-related kinases; MRT67307; MRT199665; HG-9-91-01 ID INNATE IMMUNITY; CROSS-TALK; IN-VIVO; FAMILY; CREB; POLARIZATION; RECEPTORS; CYTOKINE; AMPK AB Macrophages acquire strikingly different properties that enable them to play key roles during the initiation, propagation, and resolution of inflammation. Classically activated (M1) macrophages produce proinflammatory mediators to combat invading pathogens and respond to tissue damage in the host, whereas regulatory macrophages (M2b) produce high levels of anti-inflammatory molecules, such as IL-10, and low levels of proinflammatory cytokines, like IL-12, and are important for the resolution of inflammatory responses. A central problem in this area is to understand how the formation of regulatory macrophages can be promoted at sites of inflammation to prevent and/or alleviate chronic inflammatory and autoimmune diseases. Here, we demonstrate that the salt-inducible kinases (SIKs) restrict the formation of regulatory macrophages and that their inhibition induces striking increases in many of the characteristic markers of regulatory macrophages, greatly stimulating the production of IL-10 and other anti-inflammatory molecules. We show that SIK inhibitors elevate IL-10 production by inducing the dephosphorylation of cAMP response element-binding protein (CREB)-regulated transcriptional coactivator (CRTC) 3, its dissociation from 14-3-3 proteins and its translocation to the nucleus where it enhances a gene transcription program controlled by CREB. Importantly, the effects of SIK inhibitors on IL-10 production are lost in macrophages that express a drug-resistant mutant of SIK2. These findings identify SIKs as a key molecular switch whose inhibition reprograms macrophages to an anti-inflammatory phenotype. The remarkable effects of SIK inhibitors on macrophage function suggest that drugs that target these protein kinases may have therapeutic potential for the treatment of inflammatory and autoimmune diseases. C1 [Clark, Kristopher; MacKenzie, Kirsty F.; Petkevicius, Kasparas; Kristariyanto, Yosua; Zhang, Jiazhen; Peggie, Mark; Plater, Lorna; Arthur, J. Simon C.; Cohen, Philip] Univ Dundee, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland. [Pedrioli, Patrick G. A.; Cohen, Philip] Univ Dundee, Scottish Inst Cell Signaling, Coll Life Sci, Sir James Black Ctr, Dundee DD1 5EH, Scotland. [Choi, Hwan Geun; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [McIver, Ed] Med Res Council Technol, London NW7 1AD, England. RP Cohen, P (reprint author), Univ Dundee, MRC, Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland. EM p.cohen@dundee.ac.uk RI Arthur, J. Simon/B-8058-2010 OI Arthur, J. Simon/0000-0002-8135-1958 FU UK Medical Research Council; AstraZeneca; Boehringer Ingelheim; GlaxoSmithKline; Janssen Pharmaceutica; Merck-Serono; Pfizer FX We thank Shizuo Akira (University of Osaka) for generously providing the TBK1/IKKe-/- MEFs; Tomi Makela (University of Helsinki) for the LKB1-/-MEFs; Alan Ashworth (Institute of Cancer Research) for the LKB1flox/flox mice; Denise Harding who synthesized MRT199665 under the supervision of E.M.; George Allen and Alan Prescott for help with light microscopy; Catherine Johnson for providing 14-3-3 reagents; Julia Carr and Gail Fraser for genotyping; the University of Dundee Resource Centre (coordinated by Don Tennant and Lorraine Malone) for housing the mice; the International Centre for Kinase Profiling (www.kinase-screen.mrc.ac.uk) for establishing the potency and selectivity of the inhibitors; and the Medical Research Council-Protein Phosphorylation Unit's DNA Sequencing Service (coordinated by Nicholas Helps) and the Antibody Production Team (coordinated by Hilary McLauchlan and James Hastie) for outstanding technical support. The work was supported by the UK Medical Research Council, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck-Serono, and Pfizer. NR 25 TC 61 Z9 63 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 16 PY 2012 VL 109 IS 42 BP 16986 EP 16991 DI 10.1073/pnas.1215450109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 029SK UT WOS:000310515800052 PM 23033494 ER PT J AU Choi, YJ Li, XY Hydbring, P Sanda, T Stefano, J Christie, AL Signoretti, S Look, AT Kung, AL von Boehmer, H Sicinski, P AF Choi, Yoon Jong Li, Xiaoyu Hydbring, Per Sanda, Takaomi Stefano, Joanna Christie, Amanda L. Signoretti, Sabina Look, A. Thomas Kung, Andrew L. von Boehmer, Harald Sicinski, Piotr TI The Requirement for Cyclin D Function in Tumor Maintenance SO CANCER CELL LA English DT Article ID TRANSGENIC MICE; CELLULAR SENESCENCE; OXIDATIVE STRESS; BREAST-CANCER; IN-VIVO; TUMORIGENESIS; CELLS; GENE; ONCOGENESIS; INHIBITION AB D-cyclins represent components of cell cycle machinery. To test the efficacy of targeting D-cyclins in cancer treatment, we engineered mouse strains that allow acute and global ablation of individual D-cyclins in a living animal. Ubiquitous shutdown of cyclin D1 or inhibition of cyclin D-associated kinase activity in mice bearing ErbB2-driven mammary carcinomas triggered tumor cell senescence, without compromising the animals' health. Ablation of cyclin D3 in mice bearing Notch 1-driven T cell acute lymphoblastic leukemias (T-ALL) triggered tumor cell apoptosis. Such selective killing of leukemic cells can also be achieved by inhibiting cyclin D associated kinase activity in mouse and human T-ALL models. Inhibition of cyclin D-kinase activity represents a highly-selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues. C1 [Choi, Yoon Jong; Hydbring, Per; Stefano, Joanna; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Sanda, Takaomi; Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Li, Xiaoyu; von Boehmer, Harald] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Christie, Amanda L.; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02215 USA. [Signoretti, Sabina] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Sanda, Takaomi; Look, A. Thomas] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Choi, Yoon Jong; Hydbring, Per; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Li, Xiaoyu; von Boehmer, Harald] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Sanda, Takaomi; Look, A. Thomas; Kung, Andrew L.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM peter_sicinski@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU Swedish Foundation; Wennergren Foundation; NIH [R01 CA083688, P01 CA080111, P01 CA109901]; Claudia Adams Barr grant; Novartis; National Cancer Institute [1K99CA157951]; William Lawrence and Blanche Hughes Foundation; Children's Leukemia Research Association; Japan Society for the Promotion of Science FX We thank Drs. K. Kozar for initial help with gene-targeting constructs; E. Sicinska, Y. Geng, L. Anders, and Q. Yu for reagents, advice, and expertise. P.H. was partly supported by a fellowship from the Swedish Wennergren Foundations. This work was supported by NIH Grants R01 CA083688 and P01 CA080111 to P.S., P01 CA109901 to A.T.L., H.v.B., and P.S., and Claudia Adams Barr grant to X.L. P.S. is a consultant and a recipient of a research grant from Novartis. T.S. is supported by grants from the National Cancer Institute (1K99CA157951), the William Lawrence and Blanche Hughes Foundation, the Children's Leukemia Research Association, and the Japan Society for the Promotion of Science. NR 51 TC 80 Z9 81 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD OCT 16 PY 2012 VL 22 IS 4 BP 438 EP 451 DI 10.1016/j.ccr.2012.09.015 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 024MS UT WOS:000310113900006 PM 23079655 ER PT J AU Zhang, XW Zhao, XH Fiskus, W Lin, JH Lwin, T Rao, R Zhang, YZ Chan, JC Fu, K Marquez, VE Chen-Kiang, S Moscinski, LC Seto, E Dalton, WS Wright, KL Sotomayor, E Bhalla, K Tao, JG AF Zhang, Xinwei Zhao, Xiaohong Fiskus, Warren Lin, Jianhong Lwin, Tint Rao, Rekha Zhang, Yizhuo Chan, John C. Fu, Kai Marquez, Victor E. Chen-Kiang, Selina Moscinski, Lynn C. Seto, Edward Dalton, William S. Wright, Kenneth L. Sotomayor, Eduardo Bhalla, Kapil Tao, Jianguo TI Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas SO CANCER CELL LA English DT Article ID MANTLE-CELL; EXPRESSION; CANCER; DEACETYLASE; REPRESSION; TUMORIGENESIS; RECRUITMENT; LEUKEMIA; MODEL AB We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies. C1 [Zhang, Xinwei; Zhao, Xiaohong; Lwin, Tint; Moscinski, Lynn C.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA. [Zhang, Xinwei; Zhao, Xiaohong; Lwin, Tint; Moscinski, Lynn C.; Dalton, William S.; Sotomayor, Eduardo; Tao, Jianguo] H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33613 USA. [Seto, Edward] H Lee Moffitt Canc Ctr & Res Inst, Mol Oncol Program, Tampa, FL 33613 USA. [Wright, Kenneth L.] H Lee Moffitt Canc Ctr & Res Inst, Immunol Program, Tampa, FL 33613 USA. [Zhang, Xinwei; Zhang, Yizhuo] Tianjin Canc Hosp, Dept Immunol & Malignant Hematol, Tianjin 300060, Peoples R China. [Fiskus, Warren; Rao, Rekha; Bhalla, Kapil] Univ Kansas, Ctr Canc, Kansas City, KS 66160 USA. [Lin, Jianhong] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chan, John C.; Fu, Kai] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE 68198 USA. [Marquez, Victor E.] NCI, Chem Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Chen-Kiang, Selina] Weill Cornell Med Coll, Dept Pathol, New York, NY 10065 USA. RP Tao, JG (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA. EM jianguo.tao@moffitt.org FU National Cancer Institute [R01 CA137123]; Maher Fund; Susan and John Sykes Lymphoma Research Fund; Lymphoma Research Foundation FX We are grateful to the Tissue Procurement and Molecular Core Laboratory at Moffitt Cancer Center for providing specimens and molecular analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institute (Grant R01 CA137123 to J.T.), the Maher Fund (to J.T.), the Susan and John Sykes Lymphoma Research Fund (to J.T.) and the Lymphoma Research Foundation (to J.T.). NR 21 TC 109 Z9 114 U1 2 U2 25 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 OCT 16 PY 2012 VL 22 IS 4 BP 506 EP 523 DI 10.1016/j.ccr.2012.09.003 PG 18 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 024MS UT WOS:000310113900011 PM 23079660 ER PT J AU Caro, P Kishan, AU Norberg, E Stanley, IA Chapuy, B Ficarro, SB Polak, K Tondera, D Gounarides, J Yin, H Zhou, F Green, MR Chen, LF Monti, S Marto, JA Shipp, MA Danial, NN AF Caro, Pilar Kishan, Amar U. Norberg, Erik Stanley, Illana A. Chapuy, Bjoern Ficarro, Scott B. Polak, Klaudia Tondera, Daniel Gounarides, John Yin, Hong Zhou, Feng Green, Michael R. Chen, Linfeng Monti, Stefano Marto, Jarrod A. Shipp, Margaret A. Danial, Nika N. TI Metabolic Signatures Uncover Distinct Targets in Molecular Subsets of Diffuse Large B Cell Lymphoma SO CANCER CELL LA English DT Article ID FATTY-ACID OXIDATION; ACTIVATED RECEPTOR-GAMMA; GLUTAMINE-METABOLISM; CANCER-CELLS; EXPRESSION; PATHWAYS; TUMOR; GROWTH; TISSUE; PROLIFERATION AB Molecular signatures have identified several subsets of diffuse large B cell lymphoma (DLBCL) and rational targets within the B cell receptor (BCR) signaling axis. The OxPhos-DLBCL subset, which harbors the signature of genes involved in mitochondrial metabolism, is insensitive to inhibition of BCR survival signaling but is functionally undefined. We show that, compared with BCR-DLBCLs, OxPhos-DLBCLs display enhanced mitochondrial energy transduction, greater incorporation of nutrient-derived carbons into the tricarboxylic acid cycle, and increased glutathione levels. Moreover, perturbation of the fatty acid oxidation program and glutathione synthesis proved selectively toxic to this tumor subset. Our analysis provides evidence for distinct metabolic fingerprints and associated survival mechanisms in DLBCL and may have therapeutic implications. C1 [Caro, Pilar; Kishan, Amar U.; Norberg, Erik; Stanley, Illana A.; Ficarro, Scott B.; Polak, Klaudia; Tondera, Daniel; Zhou, Feng; Marto, Jarrod A.; Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Chapuy, Bjoern; Green, Michael R.; Chen, Linfeng; Shipp, Margaret A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ficarro, Scott B.; Zhou, Feng; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Kishan, Amar U.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Norberg, Erik; Stanley, Illana A.; Danial, Nika N.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Zhou, Feng; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Gounarides, John; Yin, Hong] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Monti, Stefano] Broad Inst, Cambridge, MA 02142 USA. [Monti, Stefano] Boston Univ, Sch Med, Sect Computat Biomed, Boston, MA 02218 USA. RP Danial, NN (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM nika_danial@dfci.harvard.edu RI Green, Michael/F-3482-2013; OI Green, Michael/0000-0001-6309-9472; Monti, Stefano/0000-0002-9376-0660 FU Alexandra Jane Miliotis Fellowship in Pediatric Oncology; Harvard-MIT Division of Health Sciences and Technology; Howard Hughes Medical Institute; Swedish Research Council; Novartis Institutes for Biomedical Research; National Institutes of Health [PO1 CA092625]; German Research Foundation DFG [Ch 735/1-1]; Burroughs Welcome Fund FX We thank Eric Smith for manuscript preparation. We gratefully acknowledge George Rogers, Martin Brand, David Ferrick, Min Wu, and Orian Shirihai for advice on respirometry; Wei Jiang and Frank Cook for assistance with LC-MS/MS and GC/MS; and Georg Lenz and Frank Stegmeier for HBL-1 and U2932 DLBCL cell lines. A.U.K. was supported by the Alexandra Jane Miliotis Fellowship in Pediatric Oncology, the IDEA2 Program Grant from the Harvard-MIT Division of Health Sciences and Technology, and a Medical Student Research Training Fellowship from the Howard Hughes Medical Institute. E.N. was supported by a postdoctoral fellowship from the Swedish Research Council. This work was supported in part by funding from the Novartis Institutes for Biomedical Research (N.N.D.), National Institutes of Health Grant PO1 CA092625 (M.A.S.), and the German Research Foundation DFG Ch 735/1-1 (B.C.). The authors acknowledge generous support provided through the Dana-Farber Cancer Institute Strategic Research Initiative (to JAM.). N.N.D. is a recipient of the Burroughs Welcome Fund Career Award in Biomedical Sciences and a consultant for the Novartis Institutes for Biomedical Research. NR 41 TC 89 Z9 92 U1 4 U2 31 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 OCT 16 PY 2012 VL 22 IS 4 BP 547 EP 560 DI 10.1016/j.ccr.2012.08.014 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 024MS UT WOS:000310113900014 PM 23079663 ER PT J AU Shahian, DM O'Brien, SM Sheng, SB DeLong, ER Peterson, ED Grau-Sepulveda, MV Grover, FL Mayer, JE Jacobs, JP Weiss, JM Weintraub, WS Klein, LW Shaw, RE Garratt, K Moussa, I Shewan, CM Dangas, GD Edwards, FH AF Shahian, David M. O'Brien, Sean M. Sheng, Shubin DeLong, Elizabeth R. Peterson, Eric D. Grau-Sepulveda, Maria V. Grover, Frederick L. Mayer, John E. Jacobs, Jeffrey P. Weiss, Jocelyn M. Weintraub, William S. Klein, Lloyd W. Shaw, Richard E. Garratt, Kirk Moussa, Issam Shewan, Cynthia M. Dangas, George D. Edwards, Fred H. TI Response to Letter Regarding Article, "Predictors of Long-Term Survival After Coronary Artery Bypass Grafting Surgery: Results From the Society of Thoracic Surgeons Adult Cardiac Surgery Database (the ASCERT Study)" SO CIRCULATION LA English DT Letter C1 [Shahian, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Brien, Sean M.; Sheng, Shubin; DeLong, Elizabeth R.; Peterson, Eric D.; Grau-Sepulveda, Maria V.] Duke Clin Res Inst, Durham, NC USA. [Grover, Frederick L.] Univ Colorado, Sch Med, Denver, CO USA. [Mayer, John E.] Childrens Hosp, Boston, MA 02115 USA. [Jacobs, Jeffrey P.] Congenital Heart Inst Florida, St Petersburg, FL USA. [Weiss, Jocelyn M.] Amer Coll Cardiol, Washington, DC USA. [Weintraub, William S.] Christiana Care Ctr Outcomes Res, Newark, DE USA. [Klein, Lloyd W.] Gottlieb Mem Hosp, Melrose Pk, IL USA. [Shaw, Richard E.] Calif Pacific Med Ctr, San Francisco, CA USA. [Garratt, Kirk] Lenox Hill Heart & Vasc Inst New York, New York, NY USA. [Moussa, Issam] Mayo Clin, Jacksonville, FL 32224 USA. [Shewan, Cynthia M.] Soc Thorac Surg, Chicago, IL USA. [Dangas, George D.] Columbia Univ, Med Ctr, New York, NY USA. [Edwards, Fred H.] Univ Florida Shands Jacksonville, Jacksonville, FL USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. RI O'Brien, Sean/H-6268-2013 NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2012 VL 126 IS 16 BP E259 EP E259 DI 10.1161/CIRCULATIONAHA.112.130989 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 022PX UT WOS:000309973700005 ER PT J AU Xu, J Shao, Z Glass, K Bauer, DE Pinello, L Van Handel, B Hou, S Stamatoyannopoulos, JA Mikkola, HKA Yuan, GC Orkin, SH AF Xu, Jian Shao, Zhen Glass, Kimberly Bauer, Daniel E. Pinello, Luca Van Handel, Ben Hou, Serena Stamatoyannopoulos, John A. Mikkola, Hanna K. A. Yuan, Guo-Cheng Orkin, Stuart H. TI Combinatorial Assembly of Developmental Stage-Specific Enhancers Controls Gene Expression Programs during Human Erythropoiesis SO DEVELOPMENTAL CELL LA English DT Article ID EMBRYONIC STEM-CELLS; INTERFERON REGULATORY FACTOR-2; FETAL-HEMOGLOBIN EXPRESSION; GENOME-WIDE ANALYSIS; ERYTHROID-CELLS; HISTONE MODIFICATIONS; CHROMATIN OCCUPANCY; C-MYB; IDENTIFICATION; DIFFERENTIATION AB Gene-distal enhancers are critical for tissue-specific gene expression, but their genomic determinants within a specific lineage at different stages of development are unknown. Here we profile chromatin state maps, transcription factor occupancy, and gene expression profiles during human erythroid development at fetal and adult stages. Comparative analyses of human erythropoiesis identify developmental stage-specific enhancers as primary determinants of stage-specific gene expression programs. We find that erythroid master regulators GATA1 and TAL1 act cooperatively within active enhancers but confer little predictive value for stage specificity. Instead, a set of stage-specific coregulators collaborates with master regulators and contributes to differential gene expression. We further identify and validate IRF2, IRF6, and MYB as effectors of an adult-stage expression program. Thus, the combinatorial assembly of lineage-specific master regulators and transcriptional coregulators within developmental stage-specific enhancers determines gene expression programs and temporal regulation of transcriptional networks in a mammalian genome. C1 [Glass, Kimberly; Pinello, Luca; Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Xu, Jian; Shao, Zhen; Bauer, Daniel E.; Hou, Serena; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Hematol Oncol, Boston, MA 02115 USA. [Xu, Jian; Shao, Zhen; Bauer, Daniel E.; Hou, Serena; Orkin, Stuart H.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Van Handel, Ben; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Stamatoyannopoulos, John A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Yuan, GC (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM gcyuan@jimmy.harvard.edu; stuart_orkin@dfci.harvard.edu RI cheng, yong/I-4270-2012 FU National Institutes of Health (NIH); NIH ARRA grant [RCHL101553]; NIDDK Career Development Award [K01DK093543] FX We thank V.G. Sankaran, D. Higgs, D.A. Williams, L.I. Zon, E.H. Bresnick, and members of the Orkin laboratory for discussions. We thank Z. Herbert for assistance with Helicos sequencing, F. Abderazzaq and R. Rubio at the Center for Cancer Computational Biology sequencing facility at Dana-Farber Cancer Institute (DFCI) for assistance with Illumina HiSeq2000, E. Fox at Microarray Core at DFCI for microarray analyses, and R. Tomaino and S. Gygi at the Taplin Mass Spectrometry Facility for assistance with protein identification. This work was supported by funding from the National Institutes of Health (NIH) (to S.H.O., G.-C.Y., J.A.S., and H.K.A.M.) and NIH ARRA grant RCHL101553 (to S.H.O.). S.H.O. is an Investigator of the Howard Hughes Medical Institute (HHMI). J.X. is an HHMI-Helen Hay Whitney Foundation fellow and is supported by a NIDDK Career Development Award K01DK093543. NR 54 TC 65 Z9 65 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD OCT 16 PY 2012 VL 23 IS 4 BP 796 EP 811 DI 10.1016/j.devcel.2012.09.003 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 023LR UT WOS:000310036200015 PM 23041383 ER PT J AU Grosse-Sundrup, M Henneman, JP Sandberg, WS Bateman, BT Uribe, JV Nguyen, NT Ehrenfeld, JM Martinez, EA Kurth, T Eikermann, M AF Grosse-Sundrup, Martina Henneman, Justin P. Sandberg, Warren S. Bateman, Brian T. Uribe, Jose Villa Nicole Thuy Nguyen Ehrenfeld, Jesse M. Martinez, Elizabeth A. Kurth, Tobias Eikermann, Matthias TI Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID POSTANESTHESIA CARE-UNIT; TRACHEAL INTUBATION; PULMONARY COMPLICATIONS; NONCARDIAC SURGERY; CONTROLLED-TRIAL; MUSCLE-ACTIVITY; BLOCKADE; ANESTHESIA; MORBIDITY; REVERSAL AB Objective To determine whether use of intermediate acting neuromuscular blocking agents during general anesthesia increases the incidence of postoperative respiratory complications. Design Prospective, propensity score matched cohort study. Setting General teaching hospital in Boston, Massachusetts, United States, 2006-10. Participants 18 579 surgical patients who received intermediate acting neuromuscular blocking agents during surgery were matched by propensity score to 18 579 reference patients who did not receive such agents. Main outcome measures The main outcome measures were oxygen desaturation after extubation (hemoglobin oxygen saturation <90% with a decrease in oxygen saturation after extubation of >3%) and reintubations requiring unplanned admission to an intensive care unit within seven days of surgery. We also evaluated effects on these outcome variables of qualitative monitoring of neuromuscular transmission (train-of-four ratio) and reversal of neuromuscular blockade with neostigmine to prevent residual postoperative neuromuscular blockade. Results The use of intermediate acting neuromuscular blocking agents was associated with an increased risk of postoperative desaturation less than 90% after extubation (odds ratio 1.36, 95% confidence interval 1.23 to 1.51) and reintubation requiring unplanned admission to an intensive care unit (1.40, 1.09 to 1.80). Qualitative monitoring of neuromuscular transmission did not decrease this risk and neostigmine reversal increased the risk of postoperative desaturation less than 90% (1.32, 1.20 to 1.46) and reintubation (1.76, 1.38 to 2.26). Conclusion The use of intermediate acting neuromuscular blocking agents during anesthesia was associated with an increased risk of clinically meaningful respiratory complications. Our data suggest that the strategies used in our trial to prevent residual postoperative neuromuscular blockade should be revisited. C1 [Grosse-Sundrup, Martina; Henneman, Justin P.; Bateman, Brian T.; Uribe, Jose Villa; Nicole Thuy Nguyen; Martinez, Elizabeth A.; Eikermann, Matthias] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anaesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Sandberg, Warren S.; Ehrenfeld, Jesse M.] Vanderbilt Univ, Sch Med, Dept Anaesthesiol, Nashville, TN 37212 USA. [Bateman, Brian T.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02114 USA. [Kurth, Tobias] INSERM, Unit Neuroepidemio 708, Bordeaux, France. [Kurth, Tobias] Univ Bordeaux, Bordeaux, France. [Kurth, Tobias] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02114 USA. [Eikermann, Matthias] Univ Klinikum Essen, Klin Anaesthesie & Intens Med, Essen, Germany. RP Eikermann, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anaesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org OI Ehrenfeld, Jesse/0000-0003-3427-0140; Kurth, Tobias/0000-0001-7169-2620 FU Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, United States; French National Research Agency; US National Institutes of Health; Migraine Research Foundation; Parkinson's Disease Foundation; Merck; Pfizer; ResMed Foundation; Department of Anesthesia; Critical Care and Pain Medicine of the Massachusetts General Hospital FX This study was funded by the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, United States.; All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: that this study has been funded only by academic research funds; TK has received investigator initiated research funding from the French National Research Agency, the US National Institutes of Health, the Migraine Research Foundation, and the Parkinson's Disease Foundation. He has received honorariums from Allergan, the American Academy of Neurology, and Merck for educational lectures, from the BMJ for editorial services, and from MAP Pharmaceutical for contributing to a scientific advisory panel. ME has received investigator initiated research funding from Merck, Pfizer, and the ResMed Foundation, as well as the Department of Anesthesia and Critical Care and Pain Medicine of the Massachusetts General Hospital. He has received honorariums from Hill-Rom for giving advise, and from the American Thoracic Society, Brown University, Michigan University, and Vanderbilt University for educational lectures, and from the Journal Anesthesiology for editorial services; the authors have no financial relationships with any organisation or company that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work. NR 47 TC 65 Z9 67 U1 0 U2 10 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD OCT 16 PY 2012 VL 345 AR e6329 DI 10.1136/bmj.e6329 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 024WG UT WOS:000310140600001 PM 23077290 ER PT J AU Buttery, SM Kono, K Stokasimov, E Pellman, D AF Buttery, Shawnna M. Kono, Keiko Stokasimov, Ema Pellman, David TI Regulation of the formin Bnr1 by septins and a MARK/Par1-family septin-associated kinase SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MITOTIC SIGNALING NETWORK; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; ACTIN NUCLEATION; CELL-CYCLE; POLARIZED GROWTH; PROTEIN-KINASE; GIN4 KINASE; CYTOSKELETON; BNI1P AB Formin-family proteins promote the assembly of linear actin filaments and are required to generate cellular actin structures, such as actin stress fibers and the cytokinetic actomyosin contractile ring. Many formin proteins are regulated by an autoinhibition mechanism involving intramolecular binding of a Diaphanous inhibitory domain and a Diaphanous autoregulatory domain. However, the activation mechanism for these Diaphanous-related formins (DRFs) is not completely understood. Although small GTPases play an important role in relieving autoinhibition, other factors likely contribute. Here we describe a requirement for the septin Shs1 and the septin-associated kinase Gin4 for the localization and in vivo activity of the budding yeast DRF Bnr1. In budding yeast strains in which the other formin, Bni1, is conditionally inactivated, the loss of Gin4 or Shs1 results in the loss of actin cables and cell death, similar to the loss of Bnr1. The defects in these strains can be suppressed by constitutive activation of Bnr1. Gin4 is involved in both the localization and activation of Bnr1, whereas the septin Shs1 is required for Bnr1 activation but not its localization. Gin4 promotes the activity of Bnr1 independently of the Gin4 kinase activity, and Gin4 lacking its kinase domain binds to the critical localization region of Bnr1. These data reveal novel regulatory links between the actin and septin cytoskeletons. C1 [Pellman, David] Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. RP Pellman, D (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM david_pellman@dfci.harvard.edu FU National Institutes of Health National Research Service Award [F32 GM076895]; National Institutes of Health [GM61345] FX We thank A. Bretscher, B. Goode, J. Thorner, and M. Iwase for strains and/or plasmids. We thank D. Kellogg for plasmids and the Gin4 antibody. We are grateful to Chiwa Kuroda for technical support. We acknowledge members of the Pellman lab for helpful discussions. S.M.B. was supported by National Institutes of Health National Research Service Award F32 GM076895. D.P. was supported by National Institutes of Health Grant GM61345. NR 69 TC 12 Z9 12 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT 15 PY 2012 VL 23 IS 20 BP 4041 EP 4053 DI 10.1091/mbc.E12-05-0395 PG 13 WC Cell Biology SC Cell Biology GA 052UU UT WOS:000312224800013 PM 22918953 ER PT J AU Cai, A Keskin, DB DeLuca, DS Alonso, A Zhang, WD Zhang, GL Hammond, NN Nardi, V Stone, RM Neuberg, D Sidney, J Brusic, V Wu, CJ AF Cai, Ann Keskin, Derin B. DeLuca, David S. Alonso, Anselmo Zhang, Wandi Zhang, Guang Lan Hammond, Naa Norkor Nardi, Valentina Stone, Richard M. Neuberg, Donna Sidney, John Brusic, Vladimir Wu, Catherine J. TI Mutated BCR-ABL Generates Immunogenic T-cell Epitopes in CML Patients SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; MHC CLASS-I; SELECTIVE INHIBITOR; IMATINIB-RESISTANT; ACCELERATED-PHASE; IMMUNE-RESPONSES; TYROSINE KINASE; FOLLOW-UP AB Purpose: Characterization of an approach to identify leukemia neoantigens arising in the context of drug resistance. Experimental Design: We assessed whether leukemia neoantigens could be generated from drug-resistant mutations in BCR-ABL after imatinib relapse in patients with chronic myelogenous leukemia (CML). Results: We computationally predicted that approximately 70 peptides derived from 26 BCR-ABL mutations would bind eight common alleles of MHC class I (IC50 < 1,000 nmol/L). Seven of nine imatinib-resistant CML patients were predicted to generate at least 1 peptide that binds autologous HLA alleles. We predicted and confirmed that an E255K mutation-derived peptide would bind HLA-A3 with high affinity (IC50 28 nmol/L), and showed that this peptide is endogenously processed and presented. Polyfunctional E255K-specific CD8+ T cells were detected in two imatinib-resistant HLA-A3+ CML patients concurrent with an effective anti-CML response to further therapy. Conclusions: Our in vitro studies support the hypothesis that leukemia-driven genetic alterations are targeted by the immune system in association with a clinical response, and suggest the possibility of immunizing relapsed patients with CML against newly acquired tumor neoantigens. Clin Cancer Res; 18(20); 5761-72. (C) 2012 AACR. C1 [Wu, Catherine J.] Massachusetts Gen Hosp, Harvard Inst Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Cai, Ann] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Zhang, Guang Lan; Stone, Richard M.; Brusic, Vladimir; Wu, Catherine J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Cai, Ann; Keskin, Derin B.; DeLuca, David S.; Alonso, Anselmo; Zhang, Wandi; Zhang, Guang Lan; Hammond, Naa Norkor; Brusic, Vladimir; Wu, Catherine J.] Massachusetts Gen Hosp, Canc Vaccine Ctr, Boston, MA 02114 USA. [Neuberg, Donna] Massachusetts Gen Hosp, Dept Biostat & Computat Biol, Boston, MA 02114 USA. [Nardi, Valentina] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sidney, John] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. RP Wu, CJ (reprint author), Massachusetts Gen Hosp, Harvard Inst Med, Dana Farber Canc Inst, Room 418,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cwu@partners.org FU Howard Hughes Medical Institute; Department of Defense [W81XWH-07-1-0080]; Claudia Adams Barr Program Award; NCI [5R21CA115043-2]; Damon-Runyon Cancer Research Foundation [CI-38-07] FX A. Cai is supported by a grant from the Howard Hughes Medical Institute. C. J. Wu is supported by a grant from the Department of Defense (W81XWH-07-1-0080), the Claudia Adams Barr Program Award, the Miles and Eleanor Shore Award, NCI (5R21CA115043-2), the Early Career Physician-Scientist Award of the Howard Hughes Medical Institute, and is a Damon-Runyon Clinical Investigator supported in part by the Damon-Runyon Cancer Research Foundation (CI-38-07). NR 50 TC 16 Z9 17 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 OCT 15 PY 2012 VL 18 IS 20 BP 5761 EP 5772 DI 10.1158/1078-0432.CCR-12-1182 PG 12 WC Oncology SC Oncology GA 048JW UT WOS:000311908500027 PM 22912393 ER PT J AU Bauer, DE Mitchell, CM Strait, KM Lathan, CS Stelow, EB Luer, SC Muhammed, S Evans, AG Sholl, LM Rosai, J Giraldi, E Oakley, RP Rodriguez-Galindo, C London, WB Sallan, SE Bradner, JE French, CA AF Bauer, Daniel E. Mitchell, Chelsey M. Strait, Kelly M. Lathan, Christopher S. Stelow, Edward B. Lueer, Sonja C. Muhammed, Somala Evans, Andrew G. Sholl, Lynette M. Rosai, Juan Giraldi, Eugenia Oakley, Richard P. Rodriguez-Galindo, Carlos London, Wendy B. Sallan, Stephen E. Bradner, James E. French, Christopher A. TI Clinicopathologic Features and Long-term Outcomes of NUT Midline Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID UPPER AERODIGESTIVE TRACT; BRD4-NUT FUSION ONCOGENE; AGGRESSIVE CARCINOMA; THYMIC CARCINOMA; YOUNG-PATIENTS; TRANSLOCATION; REARRANGEMENT; DIFFERENTIATION; T(15/19); CHILDREN AB Purpose: NUT midline carcinoma (NMC) is a poorly differentiated squamous cancer characterized by rearrangement of the NUT gene. Research advances have provided opportunities for targeted therapy in NMC, yet the clinical features of this rare disease have not been systematically characterized. We report on a large population of such patients to identify the disease characteristics and treatments, correlate them with outcome, and to consider clinical recommendations. Experimental Design: A clinical database was established using retrospective demographic and outcomes data available on all known cases of NMC. Questionnaires were completed by treating physicians. Pathologic, demographic, and clinical variables were assessed for 63 patients, the largest cohort of patients with NMC studied to date. Outcome data from 54 patients were available for survival analyses. Results: The diagnosis of NMC has increased annually since 2007. Since 2009, there has been an observed increase in the age at diagnosis (P < 0.05). Geographic distribution of patients with NMC has been concentrated in the United States (n = 41, 65%). The median overall survival for patients with NMC was 6.7 months. The 2-year progression-free survival (PFS) was 9% with a 95% confidence interval (CI) of 1% to 17% [1-year PFS 15% (5-24%) and 2-year overall survival (OS) was 19% with a 95% CI of 7%-31% (1-year OS: 30% (27-34%)]. Multivariate analysis suggested that extent of surgical resection and initial radiotherapy were independent predictors of PFS and OS. Notably, no chemotherapeutic regimen was associated with improved outcome. Conclusions: NMC portends a poor prognosis among all squamous cell neoplasms and seems to be frequently unrecognized. The finding that conventional chemotherapy has been inadequate indicates a pressing need for the development of targeted therapeutics. Intensive local therapies such as gross total resection and radiotherapy might be associated with enhanced survival. Clin Cancer Res; 18(20); 5773-9. (C) 2012 AACR. C1 [Mitchell, Chelsey M.; Evans, Andrew G.; Sholl, Lynette M.; French, Christopher A.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Bauer, Daniel E.; Strait, Kelly M.; Muhammed, Somala; Rodriguez-Galindo, Carlos; London, Wendy B.; Sallan, Stephen E.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bauer, Daniel E.; Strait, Kelly M.; Muhammed, Somala; Rodriguez-Galindo, Carlos; London, Wendy B.; Sallan, Stephen E.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston, Boston, MA 02115 USA. [Lathan, Christopher S.; Oakley, Richard P.; Bradner, James E.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Stelow, Edward B.] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. [Lueer, Sonja C.] Univ Bern, Inselspital, Univ Childrens Hosp Bern, Dept Pediat Hematol Oncol, CH-3010 Bern, Switzerland. [Rosai, Juan] Italiano Int Ctr Oncol Pathol Consultat, Ctr Diagnost, Milan, Italy. [Giraldi, Eugenia] Osped Riuniti Bergamo, Dept Pediat, I-24100 Bergamo, Italy. RP French, CA (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, 75 Francis St, Boston, MA 02115 USA. EM james_bradner@dfci.harvard.edu FU Adolescent and Young Adult Gap Fund; Smith Family Foundation; NIH [3K01CA124581-03S1, 1R01CA124633, 3R01CA124633-04S1] FX This work was supported by the Adolescent and Young Adult Gap Fund (to J. E. Bradner and C. A. French), the Smith Family Foundation (to J. E. Bradner) and the NIH grants 3K01CA124581-03S1 (to C. S. Lathan), 1R01CA124633, and 3R01CA124633-04S1 (to C. A. French). NR 25 TC 57 Z9 59 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 15 PY 2012 VL 18 IS 20 BP 5773 EP 5779 DI 10.1158/1078-0432.CCR-12-1153 PG 7 WC Oncology SC Oncology GA 048JW UT WOS:000311908500028 PM 22896655 ER PT J AU Wang, ZGC Birkbak, NJ Culhane, AC Drapkin, R Fatima, A Tian, RY Schwede, M Alsop, K Daniels, KE Piao, HY Liu, J Etemadmoghadam, D Miron, A Salvesen, HB Mitchell, G DeFazio, A Quackenbush, J Berkowitz, RS Iglehart, JD Bowtell, DDL Matulonis, UA AF Wang, Zhigang C. Birkbak, Nicolai Juul Culhane, Aedin C. Drapkin, Ronny Fatima, Aquila Tian, Ruiyang Schwede, Matthew Alsop, Kathryn Daniels, Kathryn E. Piao, Huiying Liu, Joyce Etemadmoghadam, Dariush Miron, Alexander Salvesen, Helga B. Mitchell, Gillian DeFazio, Anna Quackenbush, John Berkowitz, Ross S. Iglehart, J. Dirk Bowtell, David D. L. Matulonis, Ursula A. CA Australian Ovarian Canc Study Grp TI Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome SO CLINICAL CANCER RESEARCH LA English DT Article ID NEGATIVE BREAST-CANCER; LOSS-OF-HETEROZYGOSITY; POLY(ADP-RIBOSE) POLYMERASE; HOMOLOGOUS RECOMBINATION; CISPLATIN RESISTANCE; EXPRESSION PROFILES; BRCA1 MUTATIONS; SNP ARRAYS; CARCINOMA; TUMORS AB Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design: We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions: Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 5806-15. (C) 2012 AACR. C1 [Wang, Zhigang C.; Birkbak, Nicolai Juul; Fatima, Aquila; Tian, Ruiyang; Miron, Alexander; Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Culhane, Aedin C.; Schwede, Matthew; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Drapkin, Ronny; Daniels, Kathryn E.; Piao, Huiying; Liu, Joyce; Matulonis, Ursula A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Drapkin, Ronny; Piao, Huiying] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Berkowitz, Ross S.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02115 USA. [Birkbak, Nicolai Juul] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Peter MacCallum Canc Ctr, Canc Genom Program, Melbourne, Vic, Australia. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Peter MacCallum Canc Ctr, Dept Biochem, Melbourne, Vic, Australia. [Etemadmoghadam, Dariush; Bowtell, David D. L.] Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic, Australia. [Alsop, Kathryn; Mitchell, Gillian] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia. [Alsop, Kathryn; Mitchell, Gillian] Univ Melbourne, Melbourne, Vic, Australia. [DeFazio, Anna] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Dept Gynaecol Oncol, Westmead, NSW 2145, Australia. [DeFazio, Anna] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Westmead Inst Canc Res, Westmead, NSW 2145, Australia. [Salvesen, Helga B.] Haukeland Hosp, Dept Obstet & Gynecol, Bergen, Norway. [Salvesen, Helga B.] Univ Bergen, Dept Clin Med, Bergen, Norway. RP Iglehart, JD (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM jiglehart@partners.org; umatulonis@partners.org RI deFazio, Anna/D-3939-2013; Drapkin, Ronny/E-9944-2016; Bowtell, David/H-1007-2016; salvesen, Helga/C-1187-2017 OI deFazio, Anna/0000-0003-0057-4744; Drapkin, Ronny/0000-0002-6912-6977; Bowtell, David/0000-0001-9089-7525; salvesen, Helga/0000-0002-4438-8831 FU Breast Cancer Research Foundation, New York, NY; Susan F. Smith Center for Women's Cancers Program at Dana-Farber Cancer Institute; Danish Council for Independent Research-Medical Sciences (FSS); Ovarian Cancer SPORE [P50 CA105009]; Ovarian Cancer Research Fund; Robert and Deborah First Fund; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; US Department of Defense [W81XWH-08-1-0684, W81XWH-08-1-0685]; Cancer Australia; National Breast Cancer Foundation [509303]; Peter MacCallum Cancer Centre Foundation; Cancer Council Victoria; Queensland Cancer Fund; Cancer Council New South Wales; Cancer Council South Australia; Cancer Foundation of Western Australia; Cancer Council Tasmania; National Health and Medical Research Council of Australia (NHMRC); NHMRC; The Norwegian Cancer Society; The Research Council of Norway FX This study was funded by the Breast Cancer Research Foundation, New York, NY. Funds from the Susan F. Smith Center for Women's Cancers Program at Dana-Farber Cancer Institute partially supported the genomic studies. N. J. Birkbak was funded by the Danish Council for Independent Research-Medical Sciences (FSS). R. Drapkin was supported by Ovarian Cancer SPORE P50 CA105009, Ovarian Cancer Research Fund, and Robert and Deborah First Fund. The Australian Ovarian Cancer Study was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), the US Department of Defense (W81XWH-08-1-0684 and W81XWH-08-1-0685), Cancer Australia and National Breast Cancer Foundation (509303), the Peter MacCallum Cancer Centre Foundation, Cancer Council Victoria, Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, Cancer Foundation of Western Australia, Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, is also funded by NHMRC. H. B. Salvesen was supported by funds from The Norwegian Cancer Society and The Research Council of Norway. NR 48 TC 60 Z9 61 U1 1 U2 15 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 OCT 15 PY 2012 VL 18 IS 20 BP 5806 EP 5815 DI 10.1158/1078-0432.CCR-12-0857 PG 10 WC Oncology SC Oncology GA 048JW UT WOS:000311908500032 PM 22912389 ER PT J AU Tateno, M Park, TW Kato, TA Umene-Nakano, W Saito, T AF Tateno, Masaru Park, Tae Woo Kato, Takahiro A. Umene-Nakano, Wakako Saito, Toshikazu TI Hikikomori as a possible clinical term in psychiatry: a questionnaire survey SO BMC PSYCHIATRY LA English DT Article DE Hikikomori; Social withdrawal; School refusal; Psychiatric diagnosis; Developmental disorders ID CULTURE-BOUND SYNDROME; SOCIAL WITHDRAWAL; AUTISM-SPECTRUM; COMMUNITY POPULATION; YOUNG-PEOPLE; JAPAN; DEPRESSION; PREVALENCE; DISORDERS AB Background: The word hikikomori, the abnormal avoidance of social contact, has become increasingly well-known. However, a definition of this phenomenon has not been discussed thoroughly. The aim of this study is to gain a better understanding of the perception of hikikomori amongst health-related students and professionals and to explore possible psychiatric conditions underlying hikikomori. Methods: A total of 1,038 subjects were requested to complete a questionnaire regarding hikikomori phenomenon. Results: While some differences in the perception of hikikomori do exist, all subjects tended to disagree with the statement, "hikikomori is NOT a disorder". Regarding the underlying psychiatric disorders of hikikomori, approximately 30% of psychiatrists chose schizophrenia as the most applicable ICD-10 diagnosis for hikikomori, whereas 50% of pediatricians chose neurotic or stress-related disorders. Conclusions: An argument still exists regarding the relationship between hikikomori and psychiatric disorders. We propose that the term hikikomori could be used to describe severe social withdrawal in the setting of a number of psychiatric disorders. C1 [Tateno, Masaru; Saito, Toshikazu] Sapporo Med Univ, Sch Med, Dept Neuropsychiat, Chuo Ku, Sapporo, Hokkaido 0608543, Japan. [Park, Tae Woo] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Park, Tae Woo] VA Boston Healthcare Syst, Boston, MA 02114 USA. [Kato, Takahiro A.] Kyushu Univ, Grad Sch Med Sci, Dept Neuropsychiat, Higashi Ku, Fukuoka 8128582, Japan. [Umene-Nakano, Wakako] Univ Occupat & Environm Hlth, Sch Med, Dept Psychiat, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. RP Tateno, M (reprint author), Sapporo Med Univ, Sch Med, Dept Neuropsychiat, Chuo Ku, South 1,West 16, Sapporo, Hokkaido 0608543, Japan. EM tatema@sapmed.ac.jp FU World Psychiatric Association (WPA) FX The authors thank Yasuyo Suzuki, Kiyoji Matsuyama (Sapporo Medical University), Takeshi Ujiie (Hokkaido Ujiie Clinic for Psychosomatic Children) for their contributions for data collection, and Ryuji Sasaki (Sapporo Medical University) for his technical assistance for on-line questionnaire. This study was partially supported by the World Psychiatric Association (WPA) Research Fund 2010 to TAK. NR 35 TC 13 Z9 13 U1 2 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD OCT 15 PY 2012 VL 12 AR 169 DI 10.1186/1471-244X-12-169 PG 7 WC Psychiatry SC Psychiatry GA 044RJ UT WOS:000311640400001 PM 23061675 ER PT J AU Strange, A Riley, BP Spencer, CCA Morris, DW Pirinen, M O'Dushlaine, CT Su, Z Maher, BS Freeman, C Cormican, P Bellenguez, C Kenny, EM Band, G Wormley, B Donohoe, G Dilthey, A Moutsianas, L Quinn, E Edkins, S Judge, R Coleman, K Hunt, S Tropea, D Roche, S Cummings, L Kelleher, E McKeon, P Dinan, T McDonald, C Murphy, KC O'Callaghan, E O'Neill, FA Waddington, JL Walsh, D Giannoulatou, E Langford, C Deloukas, P Gray, E Dronov, S Potter, S Pearson, R Vukcevic, D Tashakkori-Ghanbaria, A Blackwell, JM Bramon, E Brown, MA Casas, JP Duncanson, A Jankowski, J Markus, HS Mathew, CG Palmer, CNA Plomin, R Rautanen, A Sawcer, SJ Trembath, RC Viswanathan, AC Wood, NW Stone, J Scolnick, E Purcell, S Sklar, P Ripke, S Walters, J Owen, MJ O'Donovan, MC Peltonen, L McVean, G Kendler, KS Gill, M Donnelly, P Corvin, A AF Strange, Amy Riley, Brien P. Spencer, Chris C. A. Morris, Derek W. Pirinen, Matti O'Dushlaine, Colm T. Su, Zhan Maher, Brion S. Freeman, Colin Cormican, Paul Bellenguez, Celine Kenny, Elaine M. Band, Gavin Wormley, Brandon Donohoe, Gary Dilthey, Alexander Moutsianas, Loukas Quinn, Emma Edkins, Sarah Judge, Roisin Coleman, Kim Hunt, Sarah Tropea, Daniela Roche, Siobhan Cummings, Liz Kelleher, Eric McKeon, Patrick Dinan, Ted McDonald, Colm Murphy, Kieran C. O'Callaghan, Eadbhard O'Neill, Francis A. Waddington, John L. Walsh, Dermot Giannoulatou, Eleni Langford, Cordelia Deloukas, Panos Gray, Emma Dronov, Serge Potter, Simon Pearson, Richard Vukcevic, Damjan Tashakkori-Ghanbaria, Avazeh Blackwell, Jenefer M. Bramon, Elvira Brown, Matthew A. Casas, Juan P. Duncanson, Audrey Jankowski, Janusz Markus, Hugh S. Mathew, Christopher G. Palmer, Colin N. A. Plomin, Robert Rautanen, Anna Sawcer, Stephen J. Trembath, Richard C. Viswanathan, Ananth C. Wood, Nicholas W. Stone, Jennifer Scolnick, Ed Purcell, Shaun Sklar, Pamela Ripke, Stephan Walters, James Owen, Michael J. O'Donovan, Michael C. Peltonen, Leena McVean, Gil Kendler, Ken S. Gill, Michael Donnelly, Peter Corvin, Aiden CA Irish Schizophrenia Genomics Conso SGENE Consortium Schizophrenia Working Grp Psychiat Wellcome Trust Case Control Consor TI Genome-Wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE CACNA1I; genetics; genome-wide association study; HLAC; major histocompatibility complex; polygene score; schizophrenia ID CLASSICAL HLA ALLELES; TOURETTE-SYNDROME; DISRUPTION; BREAKPOINT; DELETIONS; IMMP2L; GENE AB Background: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. Methods: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. Results: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 x 10(-9) and in combined samples (rs2523722 p combined = 2.88 x 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. Conclusions: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci. C1 [Strange, Amy; Spencer, Chris C. A.; Pirinen, Matti; Su, Zhan; Freeman, Colin; Bellenguez, Celine; Band, Gavin; Moutsianas, Loukas; Giannoulatou, Eleni; Pearson, Richard; Vukcevic, Damjan; Rautanen, Anna; Donnelly, Peter] Wellcome Trust Ctr Human Genet, Oxford, England. [Riley, Brien P.; Maher, Brion S.; Wormley, Brandon; Kendler, Ken S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA. [Riley, Brien P.; Maher, Brion S.; Wormley, Brandon; Kendler, Ken S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Human Genet, Richmond, VA USA. [Morris, Derek W.; O'Dushlaine, Colm T.; Cormican, Paul; Kenny, Elaine M.; Donohoe, Gary; Quinn, Emma; Judge, Roisin; Coleman, Kim; Tropea, Daniela; Cummings, Liz; Kelleher, Eric; Gill, Michael; Corvin, Aiden] Trinity Coll Dublin, Inst Mol Med, Dept Psychiat, Dublin, Ireland. [Dilthey, Alexander; Moutsianas, Loukas; McVean, Gil] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Edkins, Sarah; Hunt, Sarah; Langford, Cordelia; Deloukas, Panos; Gray, Emma; Dronov, Serge; Potter, Simon; Tashakkori-Ghanbaria, Avazeh; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge, England. [Roche, Siobhan; McKeon, Patrick] St Patricks Univ Hosp, Dublin, Ireland. [Dinan, Ted] Natl Univ Ireland Univ Coll Cork, Dept Psychiat, Cork, Ireland. [McDonald, Colm] Natl Univ Ireland, Dept Psychiat, Galway, Ireland. [Murphy, Kieran C.] Beaumont Hosp, RCSI Educ & Res Ctr, Dept Psychiat, Dublin 9, Ireland. [O'Callaghan, Eadbhard] Dun Laoghaire Co, DETECT Early Intervent Psychosis Serv, Dublin, Ireland. [O'Neill, Francis A.] Queens Univ Belfast, Dept Psychiat, Belfast, Antrim, North Ireland. [O'Neill, Francis A.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Waddington, John L.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [Walsh, Dermot] Hlth Res Board, Dublin 2, Ireland. [Blackwell, Jenefer M.] Univ Western Australia, Ctr Child Hlth Res, Telethon Inst Child Hlth Res, Subiaco, WA, Australia. [Blackwell, Jenefer M.] Univ Cambridge, Cambridge Inst Med Res, Sch Clin Med, Cambridge, England. [Bramon, Elvira] Kings Coll London, NIHR Biomed Res Ctr Mental Hlth, Inst Psychiat, Dept Psychosis Studies, London WC2R 2LS, England. [Bramon, Elvira] S London & Maudsley NHS Fdn Trust, London, England. [Brown, Matthew A.] Univ Queensland, Princess Alexandra Hosp, Univ Queensland 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. [Duncanson, Audrey] Wellcome Trust Res Labs, London, England. [Jankowski, Janusz] Queen Mary Univ London, Ctr Digest Dis, London, England. [Jankowski, Janusz] Leicester Royal Infirm, Ctr Digest Dis, Leicester, Leics, England. [Jankowski, Janusz] Univ Oxford, Dept Clin Pharmacol, Oxford, England. [Markus, Hugh S.] St Georges Univ London, London, England. [Mathew, Christopher G.; Trembath, Richard C.] Guys Hosp, Kings Coll London, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland. [Plomin, Robert] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London, England. [Sawcer, Stephen J.] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England. [Viswanathan, Ananth C.] Moorfields Eye Hosp NHS Fdn Trust, NIHR Biomed Res Ctr Ophthalmol, London, England. [Viswanathan, Ananth C.] UCL Inst Ophthalmol, London, England. [Wood, Nicholas W.] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela] Massachusetts Gen Hosp, Broad Inst, Boston, MA 02114 USA. [Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ripke, Stephan; Walters, James; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, MRC Ctr Neuropsychiat Genet &Genom, Sch Med, Cardiff, S Glam, Wales. [Morris, Derek W.; O'Dushlaine, Colm T.; Cormican, Paul; Kenny, Elaine M.; Donohoe, Gary; Quinn, Emma; Judge, Roisin; Coleman, Kim; Tropea, Daniela; Cummings, Liz; Gill, Michael; Corvin, Aiden] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Grp, Dublin, Ireland. RP Corvin, A (reprint author), St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. EM acorvin@tcd.ie RI Palmer, Colin/C-7053-2008; Deloukas, Panos/B-2922-2013; Maher, Brion/F-9185-2010; McDonald, Colm/C-1430-2009; Wood, Nicholas/C-2505-2009; Jankowski, Janusz/H-2706-2012; Blackwell, Jenefer/H-3015-2015; OI Donohoe, Gary/0000-0003-3037-7426; Tropea, Daniela/0000-0001-9730-6636; Pirinen, Matti/0000-0002-1664-1350; Palmer, Colin/0000-0002-6415-6560; Deloukas, Panos/0000-0001-9251-070X; Wood, Nicholas/0000-0002-9500-3348; Jankowski, Janusz/0000-0003-2130-9181; Corvin, Aiden/0000-0001-6717-4089; Giannoulatou, Eleni/0000-0002-7084-6736; Gillman, Matthew/0000-0002-2340-6930; Walters, James/0000-0002-6980-4053; Plomin, Robert/0000-0002-0756-3629 FU Wellcome Trust Case Control Consortium [085475/B/08/Z, 085475/Z/08/Z]; Wellcome Trust [072894/Z/03/Z, 090532/Z/09/Z, 075491/Z/04/B, 068545/Z/02]; NIMH [MH 41953, MH083094]; Science Foundation Ireland [08/IN.1/B1916]; Wolfson-Royal Society; Medical Research Council [G0000934] FX The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. We also thank S. Bertrand, J. Bryant, S. L. Clark, J. S. Conquer, T. Dibling, J. C. Eldred, S. Gamble, C. Hind, A. Wilk, C. R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We thank S. Leslie for support with the HLA imputation analysis. We acknowledge use of the Irish GeneBank sample, the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. NR 37 TC 44 Z9 45 U1 0 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2012 VL 72 IS 8 BP 620 EP 628 DI 10.1016/j.biopsych.2012.05.035 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 016UQ UT WOS:000309545400003 ER PT J AU Han, S Yang, BZ Kranzler, HR Oslin, D Anton, R Farrer, LA Gelernter, J AF Han, Shizhong Yang, Bao-Zhu Kranzler, Henry R. Oslin, David Anton, Raymond Farrer, Lindsay A. Gelernter, Joel TI Linkage Analysis Followed by Association Show NRG1 Associated with Cannabis Dependence in African Americans SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Association; candidate gene; cannabis dependence; linkage; NRG1; SNP ID GENOME-WIDE LINKAGE; HETEROZYGOUS NEUREGULIN-1 MICE; MULTILOCUS GENOTYPE DATA; USE DISORDERS; ALCOHOL-DEPENDENCE; SEMISTRUCTURED ASSESSMENT; MISSING HERITABILITY; NICOTINE DEPENDENCE; COCAINE DEPENDENCE; DRUG-DEPENDENCE AB Background: A genetic contribution to cannabis dependence (CaD) has been established but susceptibility genes for CaD remain largely unknown. Methods: We employed a multistage design to identify genetic variants underlying CaD. We first performed a genome-wide linkage scan for CaD in 384 African American (AA) and 354 European American families ascertained for genetic studies of cocaine and opioid dependence. We then conducted association analysis under the linkage peak, first using data from a genome-wide association study from the Study of Addiction: Genetics and Environment, followed by replication studies of prioritized single nucleotide polymorphisms (SNPs) in independent samples. Results: We identified the strongest linkage evidence with CaD (logarithm of odds = 2.9) on chromosome 8p21.1 in AAs. In the association analysis of the Study of Addiction: Genetics and Environment sample under the linkage peak, we identified one SNP (rs17664708) associated with CaD in both AAs (odds ratio [OR] = 2.93, p = .0022) and European Americans (OR = 1.38, p = .02). This SNP, located at NRG1, a susceptibility gene for schizophrenia, was prioritized for further study. We replicated the association of rs17664708 with CaD in an independent AAs sample (OR = 2.81, p = .0068). The joint analysis of the two AA samples demonstrated highly significant association between rs17664708 and CaD with adjustment for either global (p = .00044) or local ancestry (p = .00075). Conclusions: Our study shows that NRG1 is probably a susceptibility gene for CaD, based on convergent evidence of linkage and replicated associations in two independent AA samples. C1 [Gelernter, Joel] Yale Univ, Vet Affairs Connecticut Healthcare Ctr, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. [Kranzler, Henry R.; Oslin, David] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Kranzler, Henry R.; Oslin, David] Philadelphia Vet Affairs Med Ctr, Vet Integrated Serv Network Mental Illness Res Ed, Philadelphia, PA USA. [Anton, Raymond] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Med Biomed Genet, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Genet & Genom, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Biostat, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02118 USA. [Farrer, Lindsay A.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Gelernter, Joel] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Gelernter, Joel] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. RP Gelernter, J (reprint author), Yale Univ, Vet Affairs Connecticut Healthcare Ctr, Sch Med, Dept Psychiat, 950 Campbell Ave,116A2, West Haven, CT 06516 USA. EM joel.gelernter@yale.edu OI Farrer, Lindsay/0000-0001-5533-4225 FU National Institutes of Health (NIH) [R01 DA12690, R01 DA12849, RC2 DA028909, R01 DA18432, R01 AA11330, R01 AA017535, RO1 DA030976, K01 DA24758]; Veterans Affairs (VA) Connecticut Reserve Educational Assistance Program center; VA Merit Grant; VA National Center for Posttraumatic Stress Disorder Research; VA Connecticut and Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center Centers; Alcoholic Beverage Medical Research Foundation; National Institutes of Health [N01-HG-65403]; NIH Genes, Environment and Health Initiative [U01 HG004422, U01HG004438]; Gene Environment Association Studies under the Genes, Environment and Health Initiative; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; NIH [HHSN268200782096C]; Eli Lilly; Alkermes; GlaxoSmithKline; Merck; Lundbeck; Roche; American College of Neuropsychopharmacology Alcohol Clinical Trials Initiative; Alcohol Clinical Trials Initiative FX This study was supported by National Institutes of Health (NIH) Grants R01 DA12690, R01 DA12849, RC2 DA028909, R01 DA18432, R01 AA11330, R01 AA017535, RO1 DA030976, K01 DA24758, and the Veterans Affairs (VA) Connecticut Reserve Educational Assistance Program center, a VA Merit Grant, VA National Center for Posttraumatic Stress Disorder Research, and the VA Connecticut and Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center Centers. It was also partially supported by the Alcoholic Beverage Medical Research Foundation Grant (SH).; We are grateful to the volunteer families and individuals who participated in this research study. We gratefully acknowledge the assistance in recruitment and assessment provided at McLean Hospital by Roger Weiss, M. D., and at the Medical University of South Carolina by Kathleen Brady, M. D., Ph.D. Genotyping services of linkage analysis and our GWAS study were provided by the Center for Inherited Disease Research and Yale University (Keck Center). The Center for Inherited Disease Research is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). We are grateful to Ann Marie Lacobelle, Michelle Cucinelli, Christa Robinson, and Greg Kay for their excellent technical assistance, to the Semi-Structured Assessment for Drug Dependence and Alcoholism interviewers who devoted substantial time and effort to phenotype the study sample, and to John Farrell for database management assistance.; The datasets used for the analyses described in this manuscript were obtained from the database of Genotypes and Phenotypes at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs0 00092.v1.p1 through database of Genotypes and Phenotypes accession number phs000092.v1.p. Funding support for the Study of Addiction: Genetics and Environment was provided through the NIH Genes, Environment and Health Initiative (U01 HG004422). The Study of Addiction: Genetics and Environment is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under the Genes, Environment and Health Initiative. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies Coordinating Center (U01 HG004446).; Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (P01 CA089392), and the Family Study of Cocaine Dependence (R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH Genes, Environment and Health Initiative (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C).; Dr. Kranzler has been a paid consultant for Alkermes, GlaxoSmithKline, Gilead, Eli Lilly, Lundbeck, and Roche. Dr. Anton has received honoraria or grant support from Eli Lilly, Alkermes, GlaxoSmithKline, Merck, Lundbeck, and Roche and is a shareholder in Alcomed. Drs. Kranzler and Anton also report associations with Eli Lilly, Janssen, Schering Plough, Lundbeck, Alkermes, GlaxoSmithKline, Abbott, and Johnson & Johnson, as these companies provide support to the American College of Neuropsychopharmacology Alcohol Clinical Trials Initiative, and both receive support from the Alcohol Clinical Trials Initiative. The other authors reported no biomedical financial interests or potential conflicts of interest. NR 66 TC 12 Z9 12 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2012 VL 72 IS 8 BP 637 EP 644 DI 10.1016/j.biopsych.2012.02.038 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 016UQ UT WOS:000309545400005 PM 22520967 ER PT J AU Zhang, XY Zhang, WF Zhou, DF Chen, DC Xiu, MH Wu, HR Haile, CN Kosten, TA Kosten, TR AF Zhang, Xiang Yang Zhang, Wu-Fang Zhou, Dong-Feng Chen, Da Chun Xiu, Mei Hong Wu, Hao-Ran Haile, Colin N. Kosten, Therese A. Kosten, Thomas R. TI Brain-Derived Neurotrophic Factor Levels and Its Val66Met Gene Polymorphism Predict Tardive Dyskinesia Treatment Response to Ginkgo Biloba SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Brain-derived neurotrophic factor; extract of ginkgo biloba; genotype; pharmacogenetics; schizophrenia; tardive dyskinesia ID ACTIVITY-DEPENDENT SECRETION; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; SCHIZOPHRENIC-PATIENTS; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; EXTRACT; NEURONS; BDNF; ASSOCIATION AB Background: Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). Methods: Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). Results: TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. Conclusions: The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment. C1 [Zhang, Xiang Yang; Haile, Colin N.; Kosten, Therese A.; Kosten, Thomas R.] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Zhang, Xiang Yang; Chen, Da Chun; Xiu, Mei Hong; Kosten, Thomas R.] Beijing HuiLongGuan Hosp, Psychiat Res Ctr, Beijing, Peoples R China. [Zhang, Wu-Fang; Zhou, Dong-Feng] Peking Univ, Inst Mental Hlth, Key Lab Mental Hlth, Minist Hlth, Beijing 100871, Peoples R China. [Wu, Hao-Ran] Hebei Prov Rong Jun Hosp, Baoding, Peoples R China. RP Zhang, XY (reprint author), VA Med Ctr, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu OI Haile, Colin/0000-0001-8293-7291 FU Stanley Medical Research Institute [03T-459, 05T-726]; Department of Veterans Affairs, South Central VA Health Care Network (VISN 16); Mental Illness Research, Education and Clinical Center (MIRECC); U.S. National Institutes of Health [P50-DA18827, U01-MH79639] FX This study was funded by the Stanley Medical Research Institute (Grant Nos. 03T-459 and 05T-726), the Department of Veterans Affairs, South Central VA Health Care Network (VISN 16); Mental Illness Research, Education and Clinical Center (MIRECC); and U.S. National Institutes of Health Grant Nos. P50-DA18827 and U01-MH79639. NR 43 TC 22 Z9 25 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2012 VL 72 IS 8 BP 700 EP 706 DI 10.1016/j.biopsych.2012.04.032 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 016UQ UT WOS:000309545400014 PM 22695185 ER PT J AU Peppercorn, J Shapira, I Deshields, T Kroetz, D Friedman, P Spears, P Collyar, DE Shulman, LN Dressler, L Bertagnolli, MM AF Peppercorn, Jeffrey Shapira, Iuliana Deshields, Teressa Kroetz, Deanna Friedman, Paula Spears, Patricia Collyar, Deborah E. Shulman, Lawrence N. Dressler, Lynn Bertagnolli, Monica M. TI Ethical Aspects of Participation in the Database of Genotypes and Phenotypes of the National Center For Biotechnology Information The Cancer and Leukemia Group B Experience SO CANCER LA English DT Article DE ethics; informed consent; genome-wide association study; Database of Genotypes and Phenotypes of the National Center for Biotechnology Information; future use of tissue ID GENOME-WIDE ASSOCIATION; STORED BIOLOGICAL SAMPLES; TIME GENERAL CONSENT; BREAST-CANCER; GENETIC RESEARCH; PROSTATE-CANCER; SUSCEPTIBILITY LOCI; FUTURE-RESEARCH; INCIDENTAL FINDINGS; ENDOCRINE THERAPY AB BACKGROUND: The rapid pace of genetics research, coupled with evolving standards for informed consent, can create ethical challenges regarding future use of tissue or information from completed clinical trials. The Cancer and Leukemia Group B (CALGB) Oncology Cooperative Group was faced with an ethical dilemma regarding sharing genetic data from a completed genome-wide association study (GWAS) that was conducted as part of a large, multicenter breast cancer clinical trial with a national database: the Database of Genotypes and Phenotypes National Center for Biotechnology Information (dbGaP). METHODS: The CALGB Ethics Committee conducted a series of multidisciplinary meetings and teleconferences involving patient advocates, bioethicists, clinical researchers, and clinical oncologists to evaluate the ethical issues raised by this case and to identify lessons for improving informed consent to future genetics research in oncology trials. RESULTS: The Ethics Committee recommended that GWAS data be provided to dbGaP consistent with documented consent for future use of tissue among trial participants. Ethical issues, including adequacy of informed consent to future research, limitations of privacy in modern genetics research, the potential impact of population-based genetics research on health disparities, and recontact of research participants for clinical care or further research, were identified as major ethical considerations in this area. CONCLUSIONS: Although modern standards for informed consent should not prohibit research or sharing of data consistent with participant's intent and the public interest, there is an urgent need for national consensus on the appropriate use of archived tissue and standardized informed consent for future research among cancer clinical trial participants. Cancer 2012;118:5060-8. (C) 2012 American Cancer Society. C1 [Peppercorn, Jeffrey] Duke Univ, Div Med Oncol, Med Ctr, Durham, NC 27710 USA. [Shapira, Iuliana] Hofstra Univ, Dept Med, N Shore LIJ Hlth Syst, Manhasset, NY USA. [Deshields, Teressa] Barnes Jewish Hosp, Dept Psychooncol, St Louis, MO 63110 USA. [Kroetz, Deanna] Univ Calif San Francisco, Dept Biopharmaceut Sci & Pharmaceut Chem, San Francisco, CA 94143 USA. [Friedman, Paula] Canc & Leukemia Grp B, Chicago, IL USA. [Collyar, Deborah E.] Correlat Sci Operat, Canc & Leukemia Grp B, Chicago, IL USA. [Shulman, Lawrence N.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. [Dressler, Lynn] Univ N Carolina, Inst Pharmacogen & Individualized Therapy, Chapel Hill, NC USA. [Bertagnolli, Monica M.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Peppercorn, J (reprint author), Duke Univ, Div Med Oncol, Med Ctr, Box 3446, Durham, NC 27710 USA. EM jeffrey.peppercorn@duke.edu FU Greenwall Foundation Faculty Scholars Program in Bioethics FX Dr. Peppercorn is supported by the Greenwall Foundation Faculty Scholars Program in Bioethics. NR 78 TC 10 Z9 10 U1 2 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2012 VL 118 IS 20 BP 5060 EP 5068 DI 10.1002/cncr.27515 PG 9 WC Oncology SC Oncology GA 024BL UT WOS:000310082500019 PM 22415847 ER PT J AU Bashir, T Cloninger, C Artinian, N Anderson, L Bernath, A Holmes, B Benavides-Serrato, A Sabha, N Nishimura, RN Guha, A Gera, J AF Bashir, Tariq Cloninger, Cheri Artinian, Nicholas Anderson, Lauren Bernath, Andrew Holmes, Brent Benavides-Serrato, Angelica Sabha, Nesrin Nishimura, Robert N. Guha, Abhijit Gera, Joseph TI Conditional Astroglial Rictor Overexpression Induces Malignant Glioma in Mice SO PLOS ONE LA English DT Article ID GROWTH-FACTOR RECEPTOR; NEURAL STEM-CELLS; MOUSE ASTROCYTOMA MODEL; ADULT MAMMALIAN BRAIN; SUBVENTRICULAR ZONE; MTOR COMPLEX; GLIOBLASTOMA-MULTIFORME; CELLULAR COMPOSITION; PTEN LOSS; PATHWAY AB Background: Hyperactivation of the mTORC2 signaling pathway has been shown to contribute to the oncogenic properties of gliomas. Moreover, overexpression of the mTORC2 regulatory subunit Rictor has been associated with increased proliferation and invasive character of these tumor cells. Methodology/Principal Findings: To determine whether Rictor overexpression was sufficient to induce glioma formation in mice, we inserted a Cre-lox-regulated human Rictor transgene into the murine ROSA26 locus. This floxed Rictor strain was crossed with mice expressing the Cre recombinase driven from the glial fibrillary acidic protein (GFAP) promoter whose expression is limited to the glial cell compartment. Double transgenic GFAP-Cre/Rictor(loxP/loxP) mice developed multifocal infiltrating glioma containing elevated mTORC2 activity and typically involved the subventricular zone (SVZ) and lateral ventricle. Analysis of Rictor-dependent signaling in these tumors demonstrated that in addition to elevated mTORC2 activity, an mTORC2-independent marker of cortical actin network function, was also elevated. Upon histological examination of the neoplasms, many displayed oligodendroglioma-like phenotypes and expressed markers associated with oligodendroglial lineage tumors. To determine whether upstream oncogenic EGFRvIII signaling would alter tumor phenotypes observed in the GFAP-Cre/Rictor(loxP/loxP) mice, transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP) mice were generated. These mice developed mixed astrocytic-oligodendroglial tumors, however glioma formation was accelerated and correlated with increased mTORC2 activity. Additionally, the subventricular zone within the GFAP-Cre/Rictor(loxP/loxP) mouse brain was markedly expanded, and a further proliferation within this compartment of the brain was observed in transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor(loxP/loxP) mice. Conclusion/Significance: These data collectively establish Rictor as a novel oncoprotein and support the role of dysregulated Rictor expression in gliomagenesis via mTOR-dependent and mTOR-independent mechanisms. Furthermore, oncogenic EGFRvIII signaling appears to potentiate the in vivo proliferative capacity of GFAP-Cre/Rictor(loxP/loxP) gliomas. C1 [Bashir, Tariq; Cloninger, Cheri; Artinian, Nicholas; Anderson, Lauren; Bernath, Andrew; Holmes, Brent; Benavides-Serrato, Angelica; Nishimura, Robert N.; Gera, Joseph] Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, Los Angeles, CA USA. [Gera, Joseph] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Nishimura, Robert N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Sabha, Nesrin; Guha, Abhijit] Univ Toronto, Hosp Sick Children, Res Inst, Labatt Brain Tumor Res Ctr, Toronto, ON M5G 1X8, Canada. [Gera, Joseph] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. [Gera, Joseph] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. RP Gera, J (reprint author), Greater Los Angeles Vet Affairs Healthcare Syst, Dept Res & Dev, Los Angeles, CA USA. EM jgera@mednet.ucla.edu FU National Institutes of Health [R01CA109312]; Veterans Administration FX This work was supported, in part, by National Institutes of Health grant R01CA109312 and funds from the Veterans Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 17 Z9 19 U1 0 U2 1 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 OCT 15 PY 2012 VL 7 IS 10 AR e47741 DI 10.1371/journal.pone.0047741 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100158 PM 23077666 ER PT J AU Schneider, JC Trinh, NHT Selleck, E Fregni, F Salles, SS Ryan, CM Stein, J AF Schneider, Jeffrey C. Trinh, Nhi-Ha T. Selleck, Elizabeth Fregni, Felipe Salles, Sara S. Ryan, Colleen M. Stein, Joel TI The Long-Term Impact of Physical and Emotional Trauma: The Station Nightclub Fire SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; BECK DEPRESSION INVENTORY; BURN INJURIES; PSYCHOMETRIC PROPERTIES; HEALTH-STATUS; EVENT SCALE; POPULATION; PREVALENCE; PREDICTORS; VERSION AB Background: Survivors of physical and emotional trauma experience enduring occupational, psychological and quality of life impairments. Examining survivors from a large fire provides a unique opportunity to distinguish the impact of physical and emotional trauma on long-term outcomes. The objective is to detail the multi-dimensional long-term effects of a large fire on its survivor population and assess differences in outcomes between survivors with and without physical injury. Methods and Findings: This is a survey-based cross-sectional study of survivors of The Station fire on February 20, 2003. The relationships between functional outcomes and physical injury were evaluated with multivariate regression models adjusted for pre-injury characteristics and post-injury outcomes. Outcome measures include quality of life (Burn Specific Health Scale-Brief), employment (time off work), post-traumatic stress symptoms (Impact of Event Scale-Revised) and depression symptoms (Beck Depression Inventory). 104 fire survivors completed the survey; 47% experienced a burn injury. There was a 42% to 72% response rate range. Although depression and quality of life were associated with burn injury in univariate analyses (p<0.05), adjusted analyses showed no significant relationship between burn injury and these outcomes (p = 0.91; p = .51). Post-traumatic stress symptoms were not associated with burn injury in the univariate (p = 0.13) or adjusted analyses (p = 0.79). Time off work was the only outcome in which physical injury remained significant in the multivariate analysis (p = 0.03). Conclusions: Survivors of this large fire experienced significant life disruption, including occupational, psychological and quality of life sequelae. The findings suggest that quality of life, depression and post-traumatic stress outcomes are related to emotional trauma, not physical injury. However, physical injury is correlated with employment outcomes. The long-term impact of this traumatic event underscores the importance of longitudinal and mental health care for trauma survivors, with attention to those with and without physical injuries. C1 [Schneider, Jeffrey C.; Fregni, Felipe] Harvard Univ, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Sch Med, Boston, MA 02115 USA. [Trinh, Nhi-Ha T.] Massachusetts Gen Hosp, Dept Psychiat, Depress & Clin Res Program, Boston, MA 02114 USA. [Fregni, Felipe] Harvard Univ, Lab Neuromodulat, Spaulding Rehabil Hosp, Sch Med, Boston, MA USA. [Salles, Sara S.] Univ Kentucky, Dept Phys Med & Rehabil, Lexington, KY USA. [Ryan, Colleen M.] Massachusetts Gen Hosp, Dept Surg, Sumner Redstone Burn Ctr, Boston, MA 02114 USA. [Ryan, Colleen M.] Shriners Hosp Children Boston, Boston, MA USA. [Stein, Joel] New York Presbyterian Hosp, New York, NY USA. [Stein, Joel] Weill Cornell Med Coll, Div Rehabil Med, New York, NY USA. [Stein, Joel] Columbia Univ, Dept Rehabil & Regenerat Med, Med Ctr, New York, NY USA. RP Schneider, JC (reprint author), Harvard Univ, Dept Phys Med & Rehabil, Spaulding Rehabil Hosp, Sch Med, Boston, MA 02115 USA. EM jcschneider@partners.org FU International Association of Fire Fighters FX This project was supported by a pilot grant from the International Association of Fire Fighters. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 6 Z9 6 U1 3 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 OCT 15 PY 2012 VL 7 IS 10 AR e47339 DI 10.1371/journal.pone.0047339 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100093 PM 23077593 ER PT J AU Wang, H Yang, YP Wang, GJ Wang, SM Yeap, BY Sykes, M Yang, YG AF Wang, Hui Yang, Yanping Wang, Guanjun Wang, Shumei Yeap, Beow Yong Sykes, Megan Yang, Yong-Guang TI Donor Bone Marrow-Derived T Cells Inhibit GVHD Induced by Donor Lymphocyte Infusion in Established Mixed Allogeneic Hematopoietic Chimeras SO PLOS ONE LA English DT Article ID VERSUS-HOST-DISEASE; REFRACTORY HEMATOLOGIC MALIGNANCIES; REGULATORY-CELLS; TRANSPLANTATION; INDUCTION; THERAPY; SUPPRESSION; ENVIRONMENT; TOLERANCE; REJECTION AB Delayed administration of donor lymphocyte infusion (DLI) to established mixed chimeras has been shown to achieve antitumor responses without graft-vs.-host disease (GVHD). Herein we show that de novo donor BM-derived T cells that are tolerant of the recipients are important in preventing GVHD in mixed chimeras receiving delayed DLI. Mixed chimeras lacking donor BM-derived T cells developed significantly more severe GVHD than those with donor BM-derived T cells after DLI, even though both groups had comparable levels of total T cells at the time of DLI. Post-DLI depletion of donor BM-derived T cells in mixed chimeras, as late as 20 days after DLI, also provoked severe GVHD. Although both CD4 and CD8 T cells contributed to the protection, the latter were significantly more effective, suggesting that inhibition of GVHD was not mainly mediated by CD4 regulatory T cells. The lack of donor BM-derived T cells was associated with markedly increased accumulation of DLI-derived alloreactive T cells in parenchymal GVHD target tissues. Thus, donor BM-derived T cells are an important factor in determining the risk of GVHD and therefore, offer a potential therapeutic target for preventing and ameliorating GVHD in the setting of delayed DLI in established mixed chimeras. C1 [Wang, Hui; Sykes, Megan; Yang, Yong-Guang] Columbia Univ Coll Phys & Surg, Columbia Ctr Translat Immunol, New York, NY 10032 USA. [Wang, Hui; Yang, Yanping; Wang, Shumei] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. [Yang, Yanping; Wang, Guanjun; Yang, Yong-Guang] Jilin Univ, Bethune Hosp 1, Changchun 130023, Jilin, Peoples R China. [Yeap, Beow Yong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Yang, YG (reprint author), Columbia Univ Coll Phys & Surg, Columbia Ctr Translat Immunol, 630 W 168th St, New York, NY 10032 USA. EM yy2324@columbia.edu FU NIH [PO1 CA111519, RC1 HL100117, R01 AI064569] FX This work was supported by grants from NIH (PO1 CA111519, RC1 HL100117 and R01 AI064569). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 15 PY 2012 VL 7 IS 10 AR e47120 DI 10.1371/journal.pone.0047120 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 022WO UT WOS:000309995100064 PM 23077554 ER PT J AU Rothman, RD Baggish, AL O'Callaghan, C Lowry, PA Bhatt, AB MacRae, CA Yannekis, G Sanborn, DM Mela, T Yeh, RW Palacios, I Vlahakes, GJ Fifer, MA AF Rothman, Richard D. Baggish, Aaron L. O'Callaghan, Caitlin Lowry, Patricia A. Bhatt, Ami B. MacRae, Calum A. Yannekis, Gia Sanborn, Danita M. Mela, Theofanie Yeh, Robert W. Palacios, Igor Vlahakes, Gus J. Fifer, Michael A. TI Management Strategy in 249 Consecutive Patients With Obstructive Hypertrophic Cardiomyopathy Referred to a Dedicated Program SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID OUTFLOW TRACT OBSTRUCTION; ALCOHOL SEPTAL ABLATION; ASSOCIATION TASK-FORCE; LONG-TERM SURVIVAL; SYMPTOMATIC PATIENTS; PRACTICE GUIDELINES; SUBAORTIC STENOSIS; DOUBLE-BLIND; DISOPYRAMIDE; CROSSOVER AB The likelihood of success of conservative management of obstructive hypertrophic cardiomyopathy (HC) and the predictors of failure of conservative therapy are not known. We therefore evaluated the efficacy of an algorithm for the management of symptoms and predictors of failed conservative therapy in 249 consecutive symptomatic patients with obstructive HC referred to a dedicated HC program for management in general or for septal reduction therapy (SRT) in particular. There was considerable practice variation in the extent to which conservative therapy was optimized before referral for SRT. Over 3.7 +/- 2.9-year follow-up, symptoms resolved with addition of or increase in dosage of a beta blocker, calcium channel blocker, or disopyramide in 16%, 10%, and 10% of patients, respectively. Pacing with short atrioventricular delay controlled symptoms in 4 of 9 patients. In 63% of patients, conservative measures failed to control symptoms. Multivariate predictors of failure of conservative therapy were presence of New York Heart Association class III or IV symptoms (hazard ratio 2.0, 95% confidence interval 1.4 to 2.9, p = 0.001) and greater septal wall thickness (hazard ratio 1.06, 95% confidence interval 1.02 to 1.10, p = 0.003) at presentation. At time of presentation, 93 patients (37%) were already on optimal therapy and were referred for SRT. Of the remaining 156 patients who did not require immediate SRT, 93 (60%) were free from a recommendation for SRT at the end of the follow-up period. In conclusion, in symptomatic patients with obstructive HC, conservative therapy is successful in >1/3 of referred patients at 3.7-year follow-up, obviating SRT in these patients. Clinicians in programs offering SRT should optimize conservative therapy before recommending SRT. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1169-1174) C1 [Rothman, Richard D.; Baggish, Aaron L.; O'Callaghan, Caitlin; Lowry, Patricia A.; Bhatt, Ami B.; MacRae, Calum A.; Yannekis, Gia; Sanborn, Danita M.; Mela, Theofanie; Yeh, Robert W.; Palacios, Igor; Fifer, Michael A.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Vlahakes, Gus J.] Massachusetts Gen Hosp, Dept Surg, Cardiac Surg Div, Boston, MA 02114 USA. [Vlahakes, Gus J.] Harvard Univ, Sch Med, Boston, MA USA. RP Rothman, RD (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. EM rrothman@partners.org NR 22 TC 3 Z9 3 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 OCT 15 PY 2012 VL 110 IS 8 BP 1169 EP 1174 DI 10.1016/j.amjcard.2012.05.056 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 026EI UT WOS:000310256700016 PM 22766229 ER PT J AU Ogino, S King, EE Beck, AH Sherman, ME Milner, DA Giovannucci, E AF Ogino, Shuji King, Emily E. Beck, Andrew H. Sherman, Mark E. Milner, Danny A. Giovannucci, Edward TI Interdisciplinary Education to Integrate Pathology and Epidemiology: Towards Molecular and Population-Level Health Science SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE education; public health professional; health care reform; individualized medicine; interdisciplinary communication; molecular epidemiology; pathology ID ISLAND METHYLATOR PHENOTYPE; BODY-MASS INDEX; ONE-CARBON METABOLISM; TUMOR MICROSATELLITE INSTABILITY; COLORECTAL-CANCER RISK; LIFE-STYLE FACTORS; MLH1-93G-GREATER-THAN-A PROMOTER POLYMORPHISM; ACID SYNTHASE EXPRESSION; GREATER-THAN T; COLON-CANCER AB In recent decades, epidemiology, public health, and medical sciences have been increasingly compartmentalized into narrower disciplines. The authors recognize the value of integration of divergent scientific fields in order to create new methods, concepts, paradigms, and knowledge. Herein they describe the recent emergence of molecular pathological epidemiology (MPE), which represents an integration of population and molecular biologic science to gain insights into the etiologies, pathogenesis, evolution, and outcomes of complex multifactorial diseases. Most human diseases, including common cancers (such as breast, lung, prostate, and colorectal cancers, leukemia, and lymphoma) and other chronic diseases (such as diabetes mellitus, cardiovascular diseases, hypertension, autoimmune diseases, psychiatric diseases, and some infectious diseases), are caused by alterations in the genome, epigenome, transcriptome, proteome, metabolome, microbiome, and interactome of all of the above components. In this era of personalized medicine and personalized prevention, we need integrated science (such as MPE) which can decipher diseases at the molecular, genetic, cellular, and population levels simultaneously. The authors believe that convergence and integration of multiple disciplines should be commonplace in research and education. We need to be open-minded and flexible in designing integrated education curricula and training programs for future students, clinicians, practitioners, and investigators. C1 [Ogino, Shuji; Beck, Andrew H.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA 02215 USA. [Ogino, Shuji; King, Emily E.; Milner, Danny A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; King, Emily E.; Beck, Andrew H.; Milner, Danny A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Milner, Danny A.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, 450 Brookline Ave,Room JF-215C, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health [R01 CA151993, K23 AI072033, P01 CA87969, P01 CA55075]; Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This work was supported in part by National Institutes of Health grants (grant R01 CA151993 to Shuji Ogino, grant K23 AI072033 to Danny A. Milner, grant P01 CA87969 to Susan E. Hankinson, and grant P01 CA55075 to Walter C. Willett) and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 86 TC 32 Z9 33 U1 0 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2012 VL 176 IS 8 BP 659 EP 667 DI 10.1093/aje/kws226 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 024ZW UT WOS:000310152800001 PM 22935517 ER PT J AU Ogino, S Beck, AH King, EE Sherman, ME Milner, DA Giovannucci, E AF Ogino, Shuji Beck, Andrew H. King, Emily E. Sherman, Mark E. Milner, Danny A. Giovannucci, Edward TI Ogino et al. Respond to "The 21st Century Epidemiologist" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID COLORECTAL-CANCER RISK; BODY-MASS INDEX; MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; LIFE-STYLE FACTORS; MICROSATELLITE INSTABILITY; PHYSICAL-ACTIVITY; SURVIVAL; DIAGNOSIS; THERAPY; FIELD C1 [Ogino, Shuji; Beck, Andrew H.; Giovannucci, Edward] Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, Boston, MA 02215 USA. [Ogino, Shuji; King, Emily E.; Milner, Danny A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Beck, Andrew H.; King, Emily E.; Milner, Danny A.; Giovannucci, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beck, Andrew H.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Sherman, Mark E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Milner, Danny A.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Harvard Canc Ctr, Canc Epidemiol Program, 450 Brookline Ave,Room JF-215C, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu FU Intramural NIH HHS; NCI NIH HHS [P01 CA055075, P01 CA087969, P01 CA55075, P01 CA87969, R01 CA151993]; NIAID NIH HHS [K23 AI072033] NR 29 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2012 VL 176 IS 8 BP 672 EP 674 DI 10.1093/aje/kws229 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 024ZW UT WOS:000310152800003 PM 22935516 ER PT J AU Gilman, SE Loucks, EB AF Gilman, Stephen E. Loucks, Eric B. TI Invited Commentary: Does the Childhood Environment Influence the Association Between Every X and Every Y in Adulthood? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE causal inference; education; health; mortality; siblings; social epidemiology ID PARENTAL DIFFERENTIAL TREATMENT; CORONARY-HEART-DISEASE; SOCIOECONOMIC-STATUS; MATERNAL SMOKING; BIRTH-ORDER; LIFE-COURSE; EDUCATIONAL-ATTAINMENT; SIBLING DIFFERENCES; EARLY ADVERSITY; HEALTH AB The conditions under which children are raised have a long-term impact on health throughout the life course. Because childhood conditions can have such a strong influence on adult risk factors for disease, failure to account for their influences could distort observed associations between adult risk factors and subsequent health outcomes. In other words, childhood conditions could confound the association between every X and Y when X is measured in adulthood. Comparisons of health outcomes between exposed and unexposed siblings have the potential to eliminate confounding effects due to vulnerability factors shared between siblings (i.e., 50 of their genes and aspects of the childhood environment that affect siblings equally). In a large, population-based study of siblings in Denmark, Sndergaard et al. (Am J Epidemiol. 2012;176(8):675683) found that individuals with higher educational qualifications lived longer than did their siblings with lower educational qualifications. Their results provide evidence for the returns to health resulting from investment in expanded educational opportunities. However, even sibling designs are not conclusive regarding causality; they remain subject to the unmeasured confounding influences of factors that vary within families. Nonetheless, sibling-based approaches should be used more often in studies of adult risk factors to address the long-term influences of the childhood environment on health. C1 [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Loucks, Eric B.] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. RP Gilman, SE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM sgilman@hsph.harvard.edu RI Gilman, Stephen/E-7632-2010; Loucks, Eric/I-1272-2014 OI Gilman, Stephen/0000-0002-8331-6419; Loucks, Eric/0000-0002-9962-0386 FU NIA NIH HHS [R01 AG023397, AG023397]; NIMH NIH HHS [MH087544, R01 MH087544] NR 60 TC 12 Z9 12 U1 3 U2 14 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 15 PY 2012 VL 176 IS 8 BP 684 EP 688 DI 10.1093/aje/kws228 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 024ZW UT WOS:000310152800005 PM 23024136 ER PT J AU Raab, MS Breitkreutz, I Anderhub, S Ronnest, MH Leber, B Larsen, TO Weiz, L Konotop, G Hayden, PJ Podar, K Fruehauf, J Nissen, F Mier, W Haberkorn, U Ho, AD Goldschmidt, H Anderson, KC Clausen, MH Kramer, A AF Raab, Marc S. Breitkreutz, Iris Anderhub, Simon Ronnest, Mads H. Leber, Blanka Larsen, Thomas O. Weiz, Ludmila Konotop, Gleb Hayden, Patrick J. Podar, Klaus Fruehauf, Johannes Nissen, Felix Mier, Walter Haberkorn, Uwe Ho, Anthony D. Goldschmidt, Hartmut Anderson, Kenneth C. Clausen, Mads H. Kraemer, Alwin TI GF-15, a Novel Inhibitor of Centrosomal Clustering, Suppresses Tumor Cell Growth In Vitro and In Vivo SO CANCER RESEARCH LA English DT Article ID CANCER-CELLS; MULTIPLE-MYELOMA; MICROTUBULE DYNAMICS; GRISEOFULVIN ANALOGS; KINETOCHORE PAIRS; INSTABILITY; ABERRATIONS; PROGRESSION; CENTRIOLES; STABILITY AB In contrast to normal cells, malignant cells are frequently aneuploid and contain multiple centrosomes. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles in many cancer cells. Recently, we have shown that griseofulvin forces tumor cells with supernumerary centrosomes to undergo multipolar mitoses resulting in apoptotic cell death. Here, we describe the characterization of the novel small molecule GF-15, a derivative of griseofulvin, as a potent inhibitor of centrosomal clustering in malignant cells. At concentrations where GF-15 had no significant impact on tubulin polymerization, spindle tension was markedly reduced in mitotic cells upon exposure to GF-15. Moreover, isogenic cells with conditional centrosome amplification were more sensitive to GF-15 than parental controls. In a wide array of tumor cell lines, mean inhibitory concentrations (IC50) for proliferation and survival were in the range of 1 to 5 mu mol/L and were associated with apoptotic cell death. Importantly, treatment of mouse xenograft models of human colon cancer and multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival. These results show the in vitro and in vivo antitumor efficacy of a prototype small molecule inhibitor of centrosomal clustering and strongly support the further evaluation of this new class of molecules. Cancer Res; 72(20); 5374-85. (C) 2012 AACR. C1 [Anderhub, Simon; Leber, Blanka; Weiz, Ludmila; Kraemer, Alwin] Univ Heidelberg, German Canc Res, Clin Cooperat Unit Mol Hematol Oncol, D-69120 Heidelberg, Germany. [Raab, Marc S.; Anderhub, Simon; Leber, Blanka; Weiz, Ludmila; Ho, Anthony D.; Kraemer, Alwin] Univ Heidelberg, Dept Internal Med 5, D-69120 Heidelberg, Germany. [Breitkreutz, Iris; Podar, Klaus; Goldschmidt, Hartmut] Univ Heidelberg, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany. [Raab, Marc S.; Weiz, Ludmila; Konotop, Gleb] Univ Heidelberg Hosp, German Canc Res Ctr DKFZ, Max Eder Grp Expt Therapies Hematol Malignancies, Heidelberg, Germany. [Nissen, Felix; Mier, Walter; Haberkorn, Uwe] Univ Heidelberg Hosp, Dept Nucl Med, Heidelberg, Germany. [Raab, Marc S.; Breitkreutz, Iris; Hayden, Patrick J.; Podar, Klaus; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fruehauf, Johannes] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Ronnest, Mads H.; Clausen, Mads H.] Tech Univ Denmark, Ctr Nanomed & Theranost, DK-2800 Lyngby, Denmark. [Ronnest, Mads H.; Clausen, Mads H.] Tech Univ Denmark, Dept Chem, DK-2800 Lyngby, Denmark. [Ronnest, Mads H.; Larsen, Thomas O.] Tech Univ Denmark, Dept Syst Biol, Ctr Microbial Biotechnol, DK-2800 Lyngby, Denmark. RP Kramer, A (reprint author), Univ Heidelberg, German Canc Res, Clin Cooperat Unit Mol Hematol Oncol, Neuenheimer Feld 581, D-69120 Heidelberg, Germany. EM a.kraemer@dkfz.de RI Clausen, Mads/A-9656-2015 OI Clausen, Mads/0000-0001-9649-1729 FU Max-Eder-Program, Deutsche Krebshilfe; Hopp-Foundation; DFG; Deutsche Krebshilfe; Tumorzentrum Heidelberg/Mannheim; Danish Research Council [274-07-0561]; Danish Cancer Society; Karen Krieger Fonden; NIH [RO CA50947, PO-1 CA78378, P50 CA100707] FX This work was supported by a grant of the Max-Eder-Program, Deutsche Krebshilfe (M.S. Raab); the Hopp-Foundation (H. Goldschmidt); the DFG (A. Kramer); a Deutsche Krebshilfe grant (M. S. Raab and A. Kramer); the Tumorzentrum Heidelberg/Mannheim (A. Kramer); the Danish Research Council (ref. 274-07-0561; M. H. Ronnest, T.O. Larsen, and M. H. Clausen); the Danish Cancer Society and Karen Krieger Fonden (M. H. Clausen); the NIH grants RO CA50947, PO-1 CA78378, and P50 CA100707 (K.C. Anderson). NR 40 TC 27 Z9 27 U1 0 U2 18 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 OCT 15 PY 2012 VL 72 IS 20 BP 5374 EP 5385 DI 10.1158/0008-5472.CAN-12-2026 PG 12 WC Oncology SC Oncology GA 022PR UT WOS:000309972700026 PM 22942257 ER PT J AU Gallant-Behm, CL Ramsey, MR Bensard, CL Nojek, I Tran, J Liu, MH Ellisen, LW Espinosa, JM AF Gallant-Behm, Corrie L. Ramsey, Matthew R. Bensard, Claire L. Nojek, Ignacio Tran, Jack Liu, Minghua Ellisen, Leif W. Espinosa, Joaquin M. TI Delta Np63 alpha represses anti-proliferative genes via H2A.Z deposition SO GENES & DEVELOPMENT LA English DT Article DE transcriptional repression; squamous cell carcinoma; oncogene; SAMD9L; SRCAP; corepressor ID SQUAMOUS-CELL CARCINOMA; HISTONE H2A.Z; EPITHELIAL DEVELOPMENT; P53 HOMOLOG; STEM-CELLS; P63; BINDING; PROLIFERATION; TRANSCRIPTION; MAINTENANCE AB Delta Np63 alpha is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because Delta Np63 alpha and p53 bind virtually identical DNA sequence motifs, it has been proposed that Delta Np63 alpha functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress Delta Np63 alpha and inactivate p53, suggesting the autonomous action of these oncogenic events. Here we report the discovery of a novel mechanism of transcriptional repression by Delta Np63 alpha that reconciles these observations. We found that although both proteins bind the same genomic sites, they regulate largely nonoverlapping gene sets. Upon activation, p53 binds all enhancers regardless of Delta Np63 alpha status but fails to transactivate genes repressed by Delta Np63 alpha. We found that Delta Np63 alpha associates with the SRCAP chromatin regulatory complex involved in H2A/H2A.Z exchange and mediates H2A.Z deposition at its target loci. Interestingly, knockdown of SRCAP subunits or H2A.Z leads to specific induction of Delta Np63 alpha-repressed genes. We identified SAMD9L as a key anti-proliferative gene repressed by Delta Np63 alpha and H2A.Z whose depletion suffices to reverse the arrest phenotype caused by Delta Np63 alpha knockdown. Collectively, these results illuminate a molecular pathway contributing to the autonomous oncogenic effects of Delta Np63 alpha. C1 [Gallant-Behm, Corrie L.; Bensard, Claire L.; Nojek, Ignacio; Tran, Jack; Liu, Minghua; Espinosa, Joaquin M.] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. [Gallant-Behm, Corrie L.; Bensard, Claire L.; Nojek, Ignacio; Tran, Jack; Liu, Minghua; Espinosa, Joaquin M.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Ramsey, Matthew R.; Ellisen, Leif W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Espinosa, JM (reprint author), Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80309 USA. EM joaquin.espinosa@colorado.edu FU NIH [2R01CA117907-06, R01 DE-015945, F32CA159521-01]; ACS/Mass Biotech Council Cancer Research Challenge-AstraZeneca Pharmaceuticals LP Fellowship [PF-09-100-01 MGO] FX We thank the Taplin Mass Spectrometry facility (Harvard Medical School) for performing the mass spectrometry analysis. This work was supported by NIH grants 2R01CA117907-06 (to J.M.E.), R01 DE-015945 (to L.W.E.), and F32CA159521-01 (to C.L.G-B.), and by the ACS/Mass Biotech Council Cancer Research Challenge-AstraZeneca Pharmaceuticals LP Fellowship PF-09-100-01 MGO (M.R.R.). J.M.E. is an HHMI Early Career Scientist. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other supporting agencies. NR 47 TC 22 Z9 22 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 OCT 15 PY 2012 VL 26 IS 20 BP 2325 EP 2336 DI 10.1101/gad.198069.112 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 022RE UT WOS:000309978500008 PM 23019126 ER PT J AU Manka, JT Vinson, PN Gregory, KJ Zhou, Y Williams, R Gogi, K Days, E Jadhav, S Herman, EJ Lavreysen, H Mackie, C Bartolome, JM Macdonald, GJ Steckler, T Daniels, JS Weaver, CD Niswender, CM Jones, CK Conn, PJ Lindsley, CW Stauffer, SR AF Manka, Jason T. Vinson, Paige N. Gregory, Karen J. Zhou, Ya Williams, Richard Gogi, Kiran Days, Emily Jadhav, Satya Herman, Elizabeth J. Lavreysen, Hilde Mackie, Claire Bartolome, Jose M. Macdonald, Gregor J. Steckler, Thomas Daniels, J. Scott Weaver, C. David Niswender, Colleen M. Jones, Carrie K. Conn, P. Jeffrey Lindsley, Craig W. Stauffer, Shaun R. TI Optimization of an ether series of mGlu(5) positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Metabotropic glutamate receptor 5; mGlu(5); Positive allosteric modulator (PAM); Non-MPEP ID RECEPTOR SUBTYPE 5; METABOTROPIC GLUTAMATE RECEPTORS; RAT BEHAVIORAL-MODELS; IN-VIVO ACTIVITY; CNS DISORDERS; DISCOVERY; MGLUR5; PHARMACOLOGY; PROGRESS; POTENT AB We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Manka, Jason T.; Vinson, Paige N.; Gregory, Karen J.; Zhou, Ya; Williams, Richard; Gogi, Kiran; Days, Emily; Jadhav, Satya; Herman, Elizabeth J.; Daniels, J. Scott; Weaver, C. David; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. [Manka, Jason T.; Vinson, Paige N.; Gregory, Karen J.; Zhou, Ya; Williams, Richard; Gogi, Kiran; Jadhav, Satya; Herman, Elizabeth J.; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Manka, Jason T.; Zhou, Ya; Williams, Richard; Daniels, J. Scott; Niswender, Colleen M.; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Stauffer, Shaun R.] Vanderbilt Specialized Chem Ctr Probe Dev MLPCN, Nashville, TN 37232 USA. [Lindsley, Craig W.; Stauffer, Shaun R.] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. [Days, Emily; Weaver, C. David] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA. [Lavreysen, Hilde; Macdonald, Gregor J.; Steckler, Thomas] Janssen Res & Dev, Neurosci, B-2340 Beerse, Belgium. [Mackie, Claire] Janssen Res & Dev, CREATe ADME Tox, B-2340 Beerse, Belgium. [Bartolome, Jose M.] Janssen Res & Dev, Neurosci Med Chem, Toledo 45007, Spain. [Gregory, Karen J.] Monash Univ, MIPS, Parkville, Vic, Australia. [Gregory, Karen J.] Monash Univ, Dept Pharmacol, Parkville, Vic, Australia. [Jones, Carrie K.] US Dept Vet Affairs, Tennessee Valley Healthcare Syst, Nashville, TN 37212 USA. RP Stauffer, SR (reprint author), Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA. EM shaun.stauffer@vanderbilt.edu RI Zhou, Ya/F-1220-2013; OI Gregory, Karen/0000-0002-3833-2137 FU NIH [NS031373-15, MH073676-04]; Johnson Johnson; NARSAD; NHMRC FX This work was supported in part by grants from the NIH (NS031373-15, MH073676-04) and from an industry sponsored contract from Johnson & Johnson. K.J.G. thanks NARSAD and NHMRC for fellowship support. The authors thank Daryl F. Venable for technical assistance with radioligand binding assays. NR 33 TC 11 Z9 11 U1 0 U2 2 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 OCT 15 PY 2012 VL 22 IS 20 BP 6481 EP 6485 DI 10.1016/j.bmcl.2012.08.043 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 017RW UT WOS:000309609500032 PM 22981332 ER PT J AU Sumpter, TL Dangi, A Matta, BM Huang, C Stolz, DB Vodovotz, Y Thomson, AW Gandhi, CR AF Sumpter, Tina L. Dangi, Anil Matta, Benjamin M. Huang, Chao Stolz, Donna B. Vodovotz, Yoram Thomson, Angus W. Gandhi, Chandrashekhar R. TI Hepatic Stellate Cells Undermine the Allostimulatory Function of Liver Myeloid Dendritic Cells via STAT3-Dependent Induction of IDO SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; RAT-LIVER; INDOLEAMINE 2,3-DIOXYGENASE; IN-VIVO; ISCHEMIA/REPERFUSION INJURY; TRANSPLANT RECIPIENTS; TRYPTOPHAN CATABOLISM; ENDOTHELIN RECEPTORS; STAT3 ACTIVATION; UP-REGULATION AB Hepatic stellate cells (HSCs) are critical for hepatic wound repair and tissue remodeling. They also produce cytokines and chemokines that may contribute to the maintenance of hepatic immune homeostasis and the inherent tolerogenicity of the liver. The functional relationship between HSCs and the professional migratory APCs in the liver, that is, dendritic cells (DCs), has not been evaluated. In this article, we report that murine liver DCs colocalize with HSCs in vivo under normal, steady-state conditions, and cluster with HSCs in vitro. In vitro, HSCs secrete high levels of DC chemoattractants, such as M.P-1 alpha and MCP-1, as well as cytokines that modulate DC activation, including TNF-alpha, IL-6, and IL-1 beta. Culture of HSCs with conventional liver myeloid (m) DCs resulted in increased IL-6 and IL-10 secretion compared with that of either cell population alone. Coculture also resulted in enhanced expression of costimulatory (CD80, CD86) and coinhibitory (B7-H1) molecules on mDCs. HSC-induced mDC maturation required cell-cell contact and could be blocked, in part, by neutralizing MIP-1 alpha or MCP-1. HSC-induced mDC maturation was dependent on activation of STAT3 in mDCs and, in part, on HSC-secreted IL-6. Despite upregulation of costimulatory molecules, mDCs conditioned by HSCs demonstrated impaired ability to induce allogeneic T cell proliferation, which was independent of B7-H1, but dependent upon HSC-induced STAT3 activation and subsequent upregulation of IDO. In conclusion, by promoting IDO expression, HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity. The Journal of Immunology, 2012, 189:3848-3858. C1 [Sumpter, Tina L.; Dangi, Anil; Matta, Benjamin M.; Huang, Chao; Vodovotz, Yoram; Thomson, Angus W.; Gandhi, Chandrashekhar R.] Univ Pittsburgh, Sch Med, Thomas E Starzl Transplantat Inst, Dept Surg, Pittsburgh, PA 15213 USA. [Sumpter, Tina L.] Univ Pittsburgh, Sch Med, Dept Dermatol, Pittsburgh, PA 15213 USA. [Dangi, Anil; Huang, Chao; Gandhi, Chandrashekhar R.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Matta, Benjamin M.; Thomson, Angus W.] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15213 USA. [Stolz, Donna B.] Univ Pittsburgh, Sch Med, Dept Cell Biol, Pittsburgh, PA 15213 USA. [Gandhi, Chandrashekhar R.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15213 USA. RP Gandhi, CR (reprint author), Univ Pittsburgh, Sch Med, Thomas E Starzl Transplantat Inst, Dept Surg, E-1540 BST,200 Lothrop St, Pittsburgh, PA 15213 USA. EM Gandhics@upmc.edu FU National Institutes of Health [PO1AI81678, T32 AI74490]; Veterans Administration Merit Review Award; American Society of Transplantation Basic Science Fellowship; American Liver Foundation Roger Jenkins Fellowship FX This work was supported by National Institutes of Health Grants PO1AI81678 (to A.W.T. and C.R.G.) and T32 AI74490 (to A.W.T.), a Veterans Administration Merit Review Award (to C.R.G.), and an American Society of Transplantation Basic Science Fellowship and an American Liver Foundation Roger Jenkins Fellowship (to T.L.S.). NR 85 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2012 VL 189 IS 8 BP 3848 EP 3858 DI 10.4049/jimmunol.1200819 PG 11 WC Immunology SC Immunology GA 017LH UT WOS:000309590900012 PM 22962681 ER PT J AU Chou, CK Schietinger, A Liggitt, HD Tan, XX Funk, S Freeman, GJ Ratliff, TL Greenberg, NM Greenberg, PD AF Chou, Cassie K. Schietinger, Andrea Liggitt, H. Denny Tan, Xiaoxia Funk, Sarah Freeman, Gordon J. Ratliff, Timothy L. Greenberg, Norman M. Greenberg, Philip D. TI Cell-Intrinsic Abrogation of TGF-beta Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; CHRONIC VIRAL-INFECTION; TRANSGENIC MOUSE MODEL; ADOPTIVE IMMUNOTHERAPY; POSITIVE SELECTION; ANTITUMOR IMMUNITY; CTLA-4 BLOCKADE; SOLID TUMORS; PHASE-I; ANTIGEN AB Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of antitumor activity of transferred T cells remain major problems. TGF-beta is a potent immunosuppressive cytokine that is often expressed at high levels within the tumor microenvironment, potentially limiting T cell-mediated antitumor activity. In this study, we used a model of autochthonous murine prostate cancer to evaluate the effect of cell-intrinsic abrogation of TGF-beta signaling in self/tumor-specific CD8 T cells used in ACT to target the tumor in situ. We found that persistence and antitumor activity of adoptively transferred effector T cells deficient in TGF-beta signaling were significantly improved in the cancerous prostate. However, over time, despite persistence in peripheral lymphoid organs, the numbers of transferred cells in the prostate decreased and the residual prostate-infiltrating T cells were no longer functional. These findings reveal that TGF-beta negatively regulates the accumulation and effector function of transferred self/tumor-specific CD8 T cells and highlight that, when targeting a tumor Ag that is also expressed as a self-protein, additional substantive obstacles are operative within the tumor microenvironment, potentially hampering the success of ACT for solid tumors. The Journal of Immunology, 2012, 189: 3936-3946. C1 [Chou, Cassie K.; Schietinger, Andrea; Greenberg, Philip D.] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98105 USA. [Liggitt, H. Denny] Univ Washington, Sch Med, Dept Comparat Med, Seattle, WA 98105 USA. [Tan, Xiaoxia; Funk, Sarah; Greenberg, Philip D.] Univ Washington, Sch Med, Dept Med Oncol, Seattle, WA 98105 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ratliff, Timothy L.] Purdue Univ, Ctr Canc Res, Dept Comparat Pathobiol, W Lafayette, IN 47907 USA. [Greenberg, Norman M.; Greenberg, Philip D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. RP Greenberg, PD (reprint author), Univ Washington, Dept Med, Off Hlth Sci Ctr H 461, Box 356425,1959 NE Pacific St, Seattle, WA 98195 USA. EM pgreen@uw.edu FU National Institutes of Health [R01 CA33084, P01 AI56299]; U.S. Army Medical Research and Materiel Command [W81XWH-09-1-0139] FX This work was supported by National Institutes of Health Grants R01 CA33084 (to P.D.G.) and P01 AI56299 (to G.J.F.). C.K.C. received support as provided by the Cancer Research Institute Institutional Pre-Doctoral Award and a Pre-Doctoral Prostate Cancer Training Award from the U.S. Army Medical Research and Materiel Command under Grant W81XWH-09-1-0139. NR 80 TC 11 Z9 12 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2012 VL 189 IS 8 BP 3936 EP 3946 DI 10.4049/jimmunol.1201415 PG 11 WC Immunology SC Immunology GA 017LH UT WOS:000309590900020 PM 22984076 ER PT J AU Tanwar, PS Kaneko-Tarui, T Zhang, LH Teixeira, JM AF Tanwar, Pradeep S. Kaneko-Tarui, Tomoko Zhang, LiHua Teixeira, Jose M. TI Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis SO HUMAN MOLECULAR GENETICS LA English DT Article ID PEUTZ-JEGHERS-SYNDROME; TUBEROUS SCLEROSIS COMPLEX; ACTIVATED PROTEIN-KINASE; SEMINIFEROUS EPITHELIUM; RAT TESTIS; TESTICULAR CANCER; TUMOR SUPPRESSION; MOUSE MODEL; IN-VIVO; LKB1 AB Male patients with PeutzJeghers syndrome (PJS) have defective spermatogenesis and are at increased risk of developing Sertoli cell tumors. Mutations in the Liver Kinase B1 (LKB1/STK11) gene are associated with the pathogenesis of PJS and have been identified in non-PJS patients with sporadic testicular cancers. The mechanisms controlled by LKB1 signaling in Sertoli cell functions and testicular biology have not been described. We have conditionally deleted the Lkb1 gene (Lkb1(cko)) in somatic testicular cells to define the molecular mechanisms involved in the development of the testicular phenotype observed in PJS patients. Focal vacuolization in some of the seminiferous tubules was observed in 4-week-old mutant testes but germ cell development appeared to be normal. However, similar to PJS patients, we observed progressive germ cell loss and Sertoli cell only tubules in Lkb1(cko) testes from mice older than 10 weeks, accompanied by defects in Sertoli cell polarity and testicular junctional complexes and decreased activation of the MAP/microtubule affinity regulating and focal adhesion kinases. Suppression of AMP kinase and activation of mammalian target of rapamycin (mTOR) signaling were also observed in Lkb1(cko) testes. Loss of Tsc1 or Tsc2 copies the progressive Lkb1(cko) phenotype, suggesting that dysregulated activation of mTOR contributes to the pathogenesis of the Lkb1(cko) testicular phenotype. Pten(cko) mice had a normal testicular phenotype, which could be explained by the comparative lack of mTOR activation detected. These studies describe the importance of LKB1 signaling in testicular biology and the possible molecular mechanisms driving the pathogenesis of the testicular defects observed in PJS patients. C1 [Tanwar, Pradeep S.; Kaneko-Tarui, Tomoko; Zhang, LiHua; Teixeira, Jose M.] Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol Thier 931, Boston, MA 02114 USA. [Tanwar, Pradeep S.; Kaneko-Tarui, Tomoko; Zhang, LiHua; Teixeira, Jose M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tanwar, Pradeep S.] Univ Newcastle, Sch Biomed Sci & Pharm, Callaghan, NSW 2308, Australia. RP Teixeira, JM (reprint author), Massachusetts Gen Hosp, Dept Obstet Gynecol & Reprod Biol, Vincent Ctr Reprod Biol Thier 931, 55 Fruit St, Boston, MA 02114 USA. EM teixeira@helix.mgh.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064 FU NICHD [HD052701]; Vincent Memorial Research Funds FX This work is supported by an NICHD grant HD052701 (to J.M.T.) and Vincent Memorial Research Funds. NR 73 TC 29 Z9 32 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2012 VL 21 IS 20 BP 4394 EP 4405 DI 10.1093/hmg/dds272 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 015QF UT WOS:000309460300003 PM 22791749 ER PT J AU Do, R Kathiresan, S Abecasis, GR AF Do, Ron Kathiresan, Sekar Abecasis, Goncalo R. TI Exome sequencing and complex disease: practical aspects of rare variant association studies SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISMS; DE-NOVO MUTATIONS; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; SUSCEPTIBILITY LOCI; GENETIC ASSOCIATION; FRAMESHIFT MUTATION; COMMON DISEASES; HIGH-THROUGHPUT AB Genetic association and linkage studies can provide insights into complex disease biology, guiding the development of new diagnostic and therapeutic strategies. Over the past decade, genetic association studies have largely focused on common, easy to measure genetic variants shared between many individuals. These common variants typically have subtle functional consequence and translating the resulting association signals into biological insights can be challenging. In the last few years, exome sequencing has emerged as a cost-effective strategy for extending these studies to include rare coding variants, which often have more marked functional consequences. Here, we provide practical guidance in the design and analysis of complex trait association studies focused on rare, coding variants. C1 [Do, Ron; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Do, Ron; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Do, Ron; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA USA. [Do, Ron; Kathiresan, Sekar] Broad Inst Harvard & MIT, Cambridge, MA USA. [Abecasis, Goncalo R.] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Abecasis, GR (reprint author), M4614 SPH 1 Tower,1415 Washington Hts, Ann Arbor, MI 48109 USA. EM goncalo@umich.edu RI Abecasis, Goncalo/B-7840-2010; OI Abecasis, Goncalo/0000-0003-1509-1825 FU US National Institutes of Health; CIHR; University of Michigan; National Human Genome Research Institute FX This work was supported in part by research grants from the US National Institutes of Health. R. D. is funded by a CIHR Banting Fellowship. Funding to pay the Open Access publication charges for this article was provided by the University of Michigan and the National Human Genome Research Institute. NR 104 TC 66 Z9 70 U1 80 U2 108 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2012 VL 21 SI 1 BP R1 EP R9 DI 10.1093/hmg/dds387 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 015QP UT WOS:000309461300001 PM 22983955 ER PT J AU Wylie, KP Rojas, DC Tanabe, J Martin, LF Tregellas, JR AF Wylie, Korey P. Rojas, Donald C. Tanabe, Jody Martin, Laura F. Tregellas, Jason R. TI Nicotine increases brain functional network efficiency SO NEUROIMAGE LA English DT Article DE Nicotine; Acetylcholine; Graph theory; Small-world; Network; fMRI ID SMALL-WORLD NETWORKS; ALZHEIMERS-DISEASE; ACETYLCHOLINE-RECEPTOR; TRANSDERMAL NICOTINE; BIPOLAR DISORDER; SCHIZOPHRENIA; CONNECTIVITY; MATTER; ATTENTION; COGNITION AB Despite the use of cholinergic therapies in Alzheimer's disease and the development of cholinergic strategies for schizophrenia, relatively little is known about how the system modulates the connectivity and structure of large-scale brain networks. To better understand how nicotinic cholinergic systems alter these networks, this study examined the effects of nicotine on measures of whole-brain network communication efficiency. Resting state fMRI was acquired from fifteen healthy subjects before and after the application of nicotine or placebo transdermal patches in a single blind, crossover design. Data, which were previously examined for default network activity, were analyzed with network topology techniques to measure changes in the communication efficiency of whole-brain networks. Nicotine significantly increased local efficiency, a parameter that estimates the network's tolerance to local errors in communication. Nicotine also significantly enhanced the regional efficiency of limbic and paralimbic areas of the brain, areas which are especially altered in diseases such as Alzheimer's disease and schizophrenia. These changes in network topology may be one mechanism by which cholinergic therapies improve brain function. Published by Elsevier Inc. C1 [Wylie, Korey P.; Rojas, Donald C.; Martin, Laura F.; Tregellas, Jason R.] Univ Colorado, Dept Psychiat, Aurora, CO 80045 USA. [Tanabe, Jody] Univ Colorado, Dept Radiol, Aurora, CO 80045 USA. [Tregellas, Jason R.] Eastern Colorado Hlth Syst, Res Serv 151, Denver VA Med Ctr, Res Serv, Denver, CO 80220 USA. RP Tregellas, JR (reprint author), Anschutz Med Campus Bldg 500,Mail Stop F546,13001, Aurora, CO 80045 USA. EM Jason.Tregellas@UCDenver.edu RI Tregellas, Jason/J-3637-2015; OI Rojas, Don/0000-0001-6560-9616 FU VA Biomedical Laboratory and Clinical Science Research and Development Service; National Association for Research in Schizophrenia and Affective Disorders (NARSAD); Blowitz-Ridgeway Foundation; NIH/NIDDK [R01 DK089095]; NIH/NIMH [P50 MH-086383] FX The research was supported by the VA Biomedical Laboratory and Clinical Science Research and Development Service, the National Association for Research in Schizophrenia and Affective Disorders (NARSAD), the Blowitz-Ridgeway Foundation, NIH/NIDDK R01 DK089095 and NIH/NIMH P50 MH-086383. NR 53 TC 18 Z9 18 U1 1 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 73 EP 80 DI 10.1016/j.neuroimage.2012.06.079 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300008 PM 22796985 ER PT J AU Yang, AI Wang, XY Doyle, WK Halgren, E Carlson, C Belcher, TL Cash, SS Devinsky, O Thesen, T AF Yang, Andrew I. Wang, Xiuyuan Doyle, Werner K. Halgren, Eric Carlson, Chad Belcher, Thomas L. Cash, Sydney S. Devinsky, Orrin Thesen, Thomas TI Localization of dense intracranial electrode arrays using magnetic resonance imaging SO NEUROIMAGE LA English DT Article DE Intracranial EEG; Electrocorticography; Electrode localization; Image co-registration; Epilepsy surgery; MRI ID HUMAN CEREBRAL-CORTEX; SUBDURAL ELECTRODES; EPILEPSY SURGERY; PRESURGICAL EVALUATION; GEOMETRICALLY ACCURATE; IMPLANTED ELECTRODES; DIGITAL PHOTOGRAPHY; MUTUAL INFORMATION; EEG ELECTRODES; BRAIN SHIFT AB Intracranial electrode arrays are routinely used in the pre-surgical evaluation of patients with medically refractory epilepsy, and recordings from these electrodes have been increasingly employed in human cognitive neurophysiology due to their high spatial and temporal resolution. For both researchers and clinicians, it is critical to localize electrode positions relative to the subject-specific neuroanatomy. In many centers, a post-implantation MRI is utilized for electrode detection because of its higher sensitivity for surgical complications and the absence of radiation. However, magnetic susceptibility artifacts surrounding each electrode prohibit unambiguous detection of individual electrodes, especially those that are embedded within dense grid arrays. Here, we present an efficient method to accurately localize intracranial electrode arrays based on pre- and post-implantation MR images that incorporates array geometry and the individual's cortical surface. Electrodes are directly visualized relative to the underlying gyral anatomy of the reconstructed cortical surface of individual patients. Validation of this approach shows high spatial accuracy of the localized electrode positions (mean of 0.96 mm +/- 0.81 mm for 271 electrodes across 8 patients). Minimal user input, short processing time, and utilization of radiation-free imaging are strong incentives to incorporate quantitatively accurate localization of intracranial electrode arrays with MRI for research and clinical purposes. Co-registration to a standard brain atlas further allows inter-subject comparisons and relation of intracranial EEG findings to the larger body of neuroimaging literature. (C) 2012 Elsevier Inc. All rights reserved. C1 [Thesen, Thomas] NYU, Sch Med, Comprehens Epilepsy Ctr, Dept Neurol, New York, NY 10016 USA. [Doyle, Werner K.; Devinsky, Orrin] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA. [Halgren, Eric; Thesen, Thomas] Univ Calif San Diego, Dept Radiol, San Diego, CA 92093 USA. [Halgren, Eric; Thesen, Thomas] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA. [Halgren, Eric; Thesen, Thomas] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA. [Cash, Sydney S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Epilepsy Div, Boston, MA 02114 USA. RP Thesen, T (reprint author), NYU, Sch Med, Comprehens Epilepsy Ctr, Dept Neurol, 223 E 34th St, New York, NY 10016 USA. EM thomas.thesen@med.nyu.edu RI Wang, Xiuyuan/A-7500-2013; OI Wang, Xiuyuan/0000-0001-6356-3386; Devinsky, Orrin/0000-0003-0044-4632 FU FACES (Finding a Cure for Epilepsy and Seizures); National Institute of Health [NS18741] FX The authors thank Henry Rusinek for helpful discussions, and Uzma Samadani, Andrew Dykstra, Mederic Descoins, Hyungwon Kim, and John Kim for comments on drafts of the manuscript. This study was supported in part by a grant from FACES (Finding a Cure for Epilepsy and Seizures) to T.T. and National Institute of Health (grant number NS18741) to E.H. NR 53 TC 15 Z9 15 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 157 EP 165 DI 10.1016/j.neuroimage.2012.06.039 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300017 PM 22759995 ER PT J AU Domoto-Reilly, K Sapolsky, D Brickhouse, M Dickerson, BC AF Domoto-Reilly, Kimiko Sapolsky, Daisy Brickhouse, Michael Dickerson, Bradford C. CA Alzheimer's Dis Neuroimaging Initi TI Naming impairment in Alzheimer's disease is associated with left anterior temporal lobe atrophy SO NEUROIMAGE LA English DT Article DE Magnetic resonance imaging; Cerebral cortex; Alzheimer's disease; Language; Anterior temporal lobe; Semantic memory ID PRIMARY-PROGRESSIVE-APHASIA; MILD COGNITIVE IMPAIRMENT; SEMANTIC MEMORY IMPAIRMENT; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; CORTICAL SURFACE; AD DEMENTIA; PROCESSING DEFICITS; COORDINATE SYSTEM; SYMPTOM SEVERITY AB There is considerable debate about the neuroanatomic localization of semantic memory, the knowledge of culturally shared elements such as objects, concepts, and people. Two recent meta-analyses of functional imaging studies (fMRI and PET) sought to identify cortical regions involved in semantic processing. Binder and colleagues (Binder et al., 2009) identified several regions of interest, widely distributed throughout the frontal, parietal, and temporal cortices. In contrast, Lambon Ralph and colleagues (2010) focused on the anterior temporal lobe, and found that when the potential for signal loss is accounted for (due, for example, to distortion artifact or field of view restriction), significant regional activation is detected. We set out to determine whether the anterior temporal lobe plays a significant role in picture naming, a task which relies on semantic memory. We examined a relatively large sample of patients with early Alzheimer's disease (N = 145), a multifocal disease process typically characterized in the early stages by problems with episodic memory and executive function. Hypothesis-driven analyses based on regions of interest derived from the meta-analyses as well as exploratory analyses across the entire cerebral cortex demonstrated a highly specific correlation between cortical thinning of the left anterior temporal lobe and impaired naming performance. These findings lend further support to theories that include a prominent role for the anterior temporal lobe in tasks that rely on semantic memory. (C) 2012 Elsevier Inc. All rights reserved. C1 [Domoto-Reilly, Kimiko; Sapolsky, Daisy; Brickhouse, Michael; Dickerson, Bradford C.] Harvard Univ, Sch Med, Boston, MA USA. [Domoto-Reilly, Kimiko; Sapolsky, Daisy; Brickhouse, Michael; Dickerson, Bradford C.] Massachusetts Gen Hosp, Frontotemporal Dementia Unit, Boston, MA 02114 USA. [Domoto-Reilly, Kimiko; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sapolsky, Daisy; Brickhouse, Michael; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sapolsky, Daisy] Massachusetts Gen Hosp, Dept Speech & Language Pathol, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Domoto-Reilly, K (reprint author), MGH Frontotemporal Disorders Unit, 149 13th St,Suite 2691, Boston, MA 02129 USA. EM kdomoto-reilly@partners.org RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007 OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514]; Dana Foundation; Alzheimer's Association; [MA R01-AG29411]; [R21-AG29840]; [P50-AG005134] FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; Bio-Clinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. In addition, this work was supported by grants from the MA R01-AG29411, R21-AG29840, P50-AG005134, and the Alzheimer's Association. The authors express special appreciation to Dr. Jeffrey Binder for sharing data with us. NR 64 TC 22 Z9 23 U1 1 U2 42 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 348 EP 355 DI 10.1016/j.neuroimage.2012.06.018 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300037 PM 22728617 ER PT J AU Setsompop, K Cohen-Adad, J Gagoski, BA Raij, T Yendiki, A Keil, B Wedeen, VJ Wald, LL AF Setsompop, K. Cohen-Adad, J. Gagoski, B. A. Raij, T. Yendiki, A. Keil, B. Wedeen, V. J. Wald, L. L. TI Improving diffusion MRI using simultaneous multi-slice echo planar imaging SO NEUROIMAGE LA English DT Article DE Diffusion MRI; Simultaneous multi-slice; CAIPIRINHA; Parallel imaging ID SPIN-ECHO; SELECTIVE EXCITATION; FIBER ORIENTATION; TENSOR MRI; IMAGES; GRADIENT; EPI; RECONSTRUCTIONS; ARRAYS; SIGNAL AB In diffusion MRI, simultaneous multi-slice single-shot EPI acquisitions have the potential to increase the number of diffusion directions obtained per unit time, allowing more diffusion encoding in high angular resolution diffusion imaging (HARDI) acquisitions. Nonetheless, unaliasing simultaneously acquired, closely spaced slices with parallel imaging methods can be difficult, leading to high g-factor penalties (i.e., lower SNR). The CAIPIRINHA technique was developed to reduce the g-factor in simultaneous multi-slice acquisitions by introducing interslice image shifts and thus increase the distance between aliased voxels. Because the CAIPIRINHA technique achieved this by controlling the phase of the RF excitations for each line of k-space, it is not directly applicable to single-shot EPI employed in conventional diffusion imaging. We adopt a recent gradient encoding method, which we termed "blipped-CAIPI", to create the image shifts needed to apply CAIPIRINHA to EPI. Here, we use pseudo-multiple replica SNR and bootstrapping metrics to assess the performance of the blipped-CAIPI method in 3 x simultaneous multi-slice diffusion studies. Further, we introduce a novel image reconstruction method to reduce detrimental ghosting artifacts in these acquisitions. We show that data acquisition times for Q-ball and diffusion spectrum imaging (DSI) can be reduced 3-fold with a minor loss in SNR and with similar diffusion results compared to conventional acquisitions. (C) 2012 Elsevier Inc. All rights reserved. C1 [Setsompop, K.; Cohen-Adad, J.; Raij, T.; Yendiki, A.; Keil, B.; Wedeen, V. J.; Wald, L. L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Setsompop, K.; Cohen-Adad, J.; Raij, T.; Yendiki, A.; Keil, B.; Wedeen, V. J.; Wald, L. L.] Harvard Univ, Sch Med, Boston, MA USA. [Gagoski, B. A.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. RP Setsompop, K (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM kawin@nmr.mgh.harvard.edu RI Keil, Boris/P-1411-2014; Setsompop, Kawin/P-1464-2014; Wald, Lawrence/D-4151-2009 OI Setsompop, Kawin/0000-0003-0455-7634; FU NIH, NIBIB [K99EB012107, R01EB006847]; NIH Blueprint for Neuroscience Research [U01MH093765]; NSF [PHY-0855161]; NIH, NIMH [R01MH652456]; NIH, NCRR [P41RR14075] FX Grant support: NIH: NIBIB K99EB012107, NIBIB R01EB006847, NIMH R01MH652456, NCRR P41RR14075, and the NIH Blueprint for Neuroscience Research U01MH093765 the Human Connectome project. NSF: PHY-0855161. NR 43 TC 62 Z9 62 U1 5 U2 32 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2012 VL 63 IS 1 BP 569 EP 580 DI 10.1016/j.neuroimage.2012.06.033 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 005SN UT WOS:000308770300058 PM 22732564 ER PT J AU Gardner, LI Marks, G Craw, JA Wilson, TE Drainoni, ML Moore, RD Mugavero, MJ Rodriguez, AE Bradley-Springer, LA Holman, S Keruly, JC Sullivan, M Skolnik, PR Malitz, F Metsch, LR Raper, JL Giordano, TP AF Gardner, Lytt I. Marks, Gary Craw, Jason A. Wilson, Tracey E. Drainoni, Mari-Lynn Moore, Richard D. Mugavero, Michael J. Rodriguez, Allan E. Bradley-Springer, Lucy A. Holman, Susan Keruly, Jeanne C. Sullivan, Meg Skolnik, Paul R. Malitz, Faye Metsch, Lisa R. Raper, James L. Giordano, Thomas P. CA Retention Care Study Grp TI A Low-Effort, Clinic-Wide Intervention Improves Attendance for HIV Primary Care SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID MEDICAL-CARE; RETENTION; ENGAGEMENT; PREVENTION; INFECTION AB Background. Retention in care for human immunodeficiency virus (HIV)-infected patients is a National HIV/AIDS Strategy priority. We hypothesized that retention could be improved with coordinated messages to encourage patients' clinic attendance. We report here the results of the first phase of the Centers for Disease Control and Prevention/Health Resources and Services Administration Retention in Care project. Methods. Six HIV-specialty clinics participated in a cross-sectionally sampled pretest-posttest evaluation of brochures, posters, and messages that conveyed the importance of regular clinic attendance. 10 018 patients in 20082009 (preintervention period) and 11 039 patients in 2009-2010 (intervention period) were followed up for clinic attendance. Outcome variables were the percentage of patients who kept 2 consecutive primary care visits and the mean proportion of all primary care visits kept. Stratification variables were: new, reengaging, and active patients, HIV RNA viral load, CD4 cell count, age, sex, race or ethnicity, risk group, number of scheduled visits, and clinic site. Data were analyzed by multivariable log-binomial and linear models using generalized estimation equation methods. Results. Clinic attendance for primary care was significantly higher in the intervention versus preintervention year. Overall relative improvement was 7.0% for keeping 2 consecutive visits and 3.0% for the mean proportion of all visits kept (P < .0001). Larger relative improvement for both outcomes was observed for new or reengaging patients, young patients and patients with elevated viral loads. Improved attendance among the new or reengaging patients was consistent across the 6 clinics, and less consistent across clinics for active patients. Conclusion. Targeted messages on staying in care, which were delivered at minimal effort and cost, improved clinic attendance, especially for new or reengaging patients, young patients, and those with elevated viral loads. C1 [Gardner, Lytt I.; Marks, Gary; Craw, Jason A.] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. [Craw, Jason A.] ICF Int, Atlanta, GA USA. [Wilson, Tracey E.] Suny Downstate Med Ctr, Dept Community Hlth Sci, Brooklyn, NY 11203 USA. [Holman, Susan] Suny Downstate Med Ctr, Coll Med, Brooklyn, NY 11203 USA. [Holman, Susan] Suny Downstate Med Ctr, Coll Nursing, Brooklyn, NY 11203 USA. [Drainoni, Mari-Lynn] Edith Nourse Rogers Mem VA Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Drainoni, Mari-Lynn] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02215 USA. [Drainoni, Mari-Lynn; Sullivan, Meg] Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Moore, Richard D.; Keruly, Jeanne C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Malitz, Faye] Hlth Resources & Serv Adm, Div Sci & Policy, Rockville, MD USA. [Moore, Richard D.; Raper, James L.] Univ Alabama Birmingham, HIV AIDS Clin 1917, Birmingham, AL USA. [Mugavero, Michael J.; Raper, James L.] Univ Alabama Birmingham, Dept Med, Birmingham, AL USA. [Rodriguez, Allan E.] Univ Miami, Miller Sch Med, Div Infect Dis, Coral Gables, FL 33124 USA. [Metsch, Lisa R.] Univ Miami, Dept Epidemiol & Publ Hlth, Coral Gables, FL 33124 USA. [Bradley-Springer, Lucy A.] Univ Colorado Denver, Sch Med, Denver, CO USA. [Skolnik, Paul R.] Univ Connecticut, Sch Med, Dept Med, Farmington, CT USA. [Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Giordano, Thomas P.] DeBakey VA Med Ctr, Houston, TX USA. RP Gardner, LI (reprint author), Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Mailstop E-45, Atlanta, GA 30333 USA. EM lig0@cdc.gov FU CDC; HRSA (CDC) [200-2007-23685, 200-2007-23690, 200-2007-23689, 200-2007-23687]; SUNY Downstate Medical Center [200-2007-23684]; [200-2007-23692] FX This work was supported by the CDC and the HRSA (CDC contracts 200-2007-23685 to Baylor College of Medicine, 200-2007-23690 to Boston Medical Center, 200-2007-23689 to Johns Hopkins University School of Medicine, 200-2007-23687 to Research Foundation of the State University of New York, SUNY Downstate Medical Center, 200-2007-23684 to University of Alabama at Birmingham, and 200-2007-23692 to University of Miami Miller School of Medicine). NR 26 TC 33 Z9 33 U1 2 U2 18 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 OCT 15 PY 2012 VL 55 IS 8 BP 1124 EP 1134 DI 10.1093/cid/cis623 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 010BX UT WOS:000309070500020 PM 22828593 ER PT J AU Martins, PN Sheiner, P Facciuto, M AF Martins, Paulo N. Sheiner, Patricia Facciuto, Marcelo TI Xanthogranulomatous cholecystitis mimicking gallbladder cancer and causing obstructive cholestasis SO HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL LA English DT Article DE xanthogranulomatous cholecystitis; gallbladder cancer; obstructive cholestasis ID SURGICAL RESECTION; CARCINOMA; JAUNDICE; LIVER AB BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is a destructive inflammatory disease of the gallbladder that can mimic gallbladder carcinoma. METHODS: We present the case of a 35-year-old Hispanic male complaining of right upper quadrant pain and jaundice for 2 months prior to admission. He denied a history of fever, nausea/vomiting, and weight loss. The past medical history was relevant only for diabetes. He had no previous history of jaundice or previous operations. RESULTS: CA19-9 was slightly elevated (52 U/mL). Abdominal ultrasonography showed an irregular thickening of the gallbladder wall and no gallstones were detected. CT scan also revealed an irregular thickening of the wall of the gallbladder body suggestive of malignancy. At laparotomy, the mass was adherent to the duodenum and colon, and although the frozen section biopsy was negative, the intraoperative findings were suggestive of malignancy, and the patient underwent left liver trisegmentectomy, resection of the common bile duct and Roux-en-Y hepaticojejunostomy. Pathological examination unexpectedly revealed XGC without malignancy. CONCLUSIONS: Preoperative and intraoperative differential diagnosis of XGC from gallbladder carcinoma remains a challenge when it is associated with inflammatory involvement of surrounding tissues. Since gallbladder carcinoma and XGC may coexist, radical resection is justified when malignancy cannot be completely ruled out. (Hepatobiliary Pancreat Dis Int 2012;11:549-552) C1 [Martins, Paulo N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplant Div, Boston, MA 02114 USA. [Sheiner, Patricia] New York Med Coll, Dept Surg, Div Hepatobiliary Surg & Transplantat, New York, NY USA. [Facciuto, Marcelo] Mt Sinai Hosp, Div Transplantat, New York, NY 10029 USA. RP Martins, PN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Transplant Div, 55 Fruit St, Boston, MA 02114 USA. EM martins.paulo@mgh.harvard.edu NR 20 TC 3 Z9 4 U1 1 U2 7 PU ZHEJIANG UNIV SCH MEDICINE PI HANGZHOU PA FIRST AFFILIATED HOSPITAL, 79 QINGCHUN ROAD, HANGZHOU, 310003, PEOPLES R CHINA SN 1499-3872 J9 HEPATOB PANCREAT DIS JI Hepatob. Pancreatic. Dis. Int. PD OCT 15 PY 2012 VL 11 IS 5 BP 549 EP 552 DI 10.1016/S1499-3872(12)60223-9 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 013VH UT WOS:000309333500015 PM 23060404 ER PT J AU Demetriou, SK Ona-Vu, K Sullivan, EM Dong, TK Hsu, SW Oh, DH AF Demetriou, Stephanie K. Ona-Vu, Katherine Sullivan, Erin M. Dong, Tiffany K. Hsu, Shu-Wei Oh, Dennis H. TI Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Merkel cell carcinoma; polyomavirus; DNA repair; cell cycle; ultraviolet radiation ID NUCLEOTIDE EXCISION-REPAIR; CYCLOBUTANE PYRIMIDINE DIMERS; GLOBAL GENOMIC REPAIR; HUMAN KERATINOCYTES; TUMOR-SUPPRESSOR; IN-VITRO; CARCINOMA; P53; DEFICIENT; INFECTION AB The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest after UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57 kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis. C1 [Demetriou, Stephanie K.; Ona-Vu, Katherine; Sullivan, Erin M.; Dong, Tiffany K.; Hsu, Shu-Wei; Oh, Dennis H.] San Francisco VA Med Ctr, Dermatol Res Unit, San Francisco, CA USA. [Demetriou, Stephanie K.; Ona-Vu, Katherine; Sullivan, Erin M.; Dong, Tiffany K.; Hsu, Shu-Wei; Oh, Dennis H.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. RP Oh, DH (reprint author), VA Med Ctr, Dermatol Res Serv 190, 4150 Clement St, San Francisco, CA 94121 USA. EM ohd@derm.ucsf.edu FU National Cancer Institute [P30 CA82103]; University of California Cancer Research Coordinating Committee; Department of Veterans Affairs; Dept. of Veterans Affairs, Office of Research and Development, Biomedical Laboratory FX Grant sponsor: National Cancer Institute; Grant number: P30 CA82103; Grant sponsors: University of California Cancer Research Coordinating Committee, Department of Veterans Affairs; The authors thank Drs. Yuan Chang and Patrick Moore for providing MKL-1 cells, the TAg206, TAg350, LT206 and sT vectors and the CM8E6 antibody; Dr. T. K. Das Gupta for UISO cells; and R. Griby of the Northern California Institute for Research and Education for assistance with flow cytometry. Work was supported by an HIV-associated malignancies pilot project award from NCI (P30 CA82103), a University of California Cancer Research Coordinating Committee grant, and a Dept. of Veterans Affairs, Office of Research and Development, Biomedical Laboratory Research and Development (Merit Award) (all to D.H.O.). NR 49 TC 15 Z9 15 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD OCT 15 PY 2012 VL 131 IS 8 BP 1818 EP 1827 DI 10.1002/ijc.27440 PG 10 WC Oncology SC Oncology GA 993XN UT WOS:000307893400009 PM 22261839 ER PT J AU Scirica, BM Bonaca, MP Braunwald, E De Ferrari, GM Isaza, D Lewis, BS Mehrhof, F Merlini, PA Murphy, SA Sabatine, MS Tendera, M Van de Werf, F Wilcox, R Morrow, DA AF Scirica, Benjamin M. Bonaca, Marc P. Braunwald, Eugene De Ferrari, Gaetano M. Isaza, Daniel Lewis, Basil S. Mehrhof, Felix Merlini, Piera A. Murphy, Sabina A. Sabatine, Marc S. Tendera, Michal Van de Werf, Frans Wilcox, Robert Morrow, David A. CA Tra 2 P-Timi 50 Steering Comm Inve TI Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2 degrees P-TIMI 50 trial SO LANCET LA English DT Article ID ACUTE CORONARY SYNDROMES; ATHEROTHROMBOTIC EVENTS; ANTIPLATELET THERAPY; RECEPTOR ANTAGONIST; DOUBLE-BLIND; TASK-FORCE; CLOPIDOGREL; ASPIRIN; INTERVENTION; PRASUGREL AB Background Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Methods In TRA 2 degrees P-TIMI 50-a randomised, placebo-controlled, parallel trial-we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2.5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2 degrees P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). Findings 17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2.5 years (IQR 2.0-2.9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8.1% vs 9.7%, HR 0.80, 95% CI 0.72-0.89; p<0.0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3.4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2.1%, 3-year Kaplan-Meier estimate], HR 1.61, 95% CI 1.31-1.97; p<0.0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0.6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0.4%, 3-year Kaplan-Meier estimate) with placebo (p=0.076). Other serious adverse events were equally distributed between groups. Interpretation For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. C1 [Scirica, Benjamin M.; Bonaca, Marc P.; Braunwald, Eugene; Murphy, Sabina A.; Sabatine, Marc S.; Morrow, David A.] Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Div,Dept Med,Med Sch, Boston, MA 02115 USA. [De Ferrari, Gaetano M.] Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Isaza, Daniel] Fdn CardioInfantil, Bogota, Colombia. [Lewis, Basil S.] Technion Israel Inst Technol, Lady Davis Carmel Med Ctr, Haifa, Israel. [Lewis, Basil S.] Technion Israel Inst Technol, Ruth & Bruce Rappaport Sch Med, Haifa, Israel. [Mehrhof, Felix] Charite, Dept Cardiol, D-13353 Berlin, Germany. [Merlini, Piera A.] Azienda Osped Niguarda Ca Granda, Div 4, Milan, Italy. [Tendera, Michal] Med Univ Silesia, Katowice, Poland. [Van de Werf, Frans] Katholieke Univ Leuven Hosp, Dept Cardiovasc Med, Louvain, Belgium. [Wilcox, Robert] Univ Nottingham Hosp, Queens Med Ctr, Nottingham NG7 2UH, England. RP Scirica, BM (reprint author), Harvard Univ, Brigham & Womens Hosp, TIMI Study Grp, Cardiovasc Div,Dept Med,Med Sch, Boston, MA 02115 USA. EM bscirica@partners.org RI De Ferrari, Gaetano/K-5188-2016; OI De Ferrari, Gaetano/0000-0003-4940-0876; Van de Werf, Frans/0000-0001-9479-7767 FU Merck; Abbott; AstraZeneca; Amgen; Bayer Healthcare; Bristol-Myers Squibb; Daichii Sankyo; Eli Lilly; Gilead; GlaxoSmithKline; Merck (SPRI); Novartis; Pfizer; Roche Diagnostics; Sanofi-Aventis; Johnson Johnson; Brigham and Women's Hospital from BRAHMS; Critical Diagnostics; Genzyme; Nanosphere; Takeda; Merck Sharp Dohme; Boehringer Ingelheim; Daiichi Sankyo FX Merck.; The TIMI Study Group has received research grants from Abbott, AstraZeneca, Amgen, Bayer Healthcare, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Merck (SPRI), Novartis, Pfizer, Roche Diagnostics, Sanofi-Aventis, and Johnson & Johnson and grant support through Brigham and Women's Hospital from BRAHMS, Critical Diagnostics, Genzyme, Nanosphere, Takeda. BMS has served as a consultant for Lexicon, Arena, Gilead, and Eisai. EB has served as a consultant for Merck (no compensation), Amorcyte, Daiichi Sankyo, Medicines Co, Ikaria, CardioRentis, Sanofi-Aventis, and CVRx (no compensation). GMDF has received honoraria from Merck for presentations and participation on advisory boards. BSL has received research support and served on advisory boards for Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Sanofi-Aventis, and Bayer Healthcare. FM has served on a national advisory board for vorapaxar for Merck Sharp & Dohme and has received honoraria from Essex Pharma for oral presentations. SAM has served as a consultant for Eli Lilly and Amarin Pharmaceuticals. MSS has served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, Diasorin, GlaxoSmithKline, Merck, Pfizer, and Sanofi-Aventis and given accredited Continuing Medical Education talks supported by medical education companies that received unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, Eli Lilly. FVdW has received honoraria from Merck for presentations and participation on advisory boards. DAM has served as consultant for Merck (SPRI), Boeringher Ingelheim, CV Therapeutics (now Gilead Sciences), Genentech, Ikaria, Johnson & Johnson, Menarini, Novartis, Servier, and Roche Diagnostics. NR 21 TC 102 Z9 107 U1 0 U2 8 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 OCT 13 PY 2012 VL 380 IS 9850 BP 1317 EP 1324 DI 10.1016/S0140-6736(12)61269-0 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 022BZ UT WOS:000309931400030 PM 22932716 ER PT J AU Liu, S Ren, JN Han, G Wang, GF Gu, GS Xia, QY Li, JS AF Liu, Song Ren, Jianan Han, Gang Wang, Gefei Gu, Guosheng Xia, Qiuyuan Li, Jieshou TI Mean platelet volume: a controversial marker of disease activity in Crohn's disease SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE Crohn's disease; Mean platelet volume; C-reactive protein; Erythrocyte sedimentation rate; Inflammatory bowel disease ID INFLAMMATORY-BOWEL-DISEASE; C-REACTIVE PROTEIN; ULCERATIVE-COLITIS; THERAPEUTIC IMPLICATIONS; BLOOD-PLATELETS; PATHOGENESIS; ACTIVATION; SIZE; THROMBOEMBOLISM; DIFFERENTIATION AB Background: We investigated and compared the capacity of mean platelet volume (MPV) and other inflammatory markers in detecting Crohn's disease (CD) activity and differentiating CD patients from healthy controls. Methods: MPV, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cells were measured in 61 CD patients and 50 healthy subjects. Disease activity was assessed by the Crohn's Disease Activity Index. Results: A significant decrease in MPV was noted in patients with CD compared with healthy controls (P <0.0001), but statistical difference was not found between active and inactive CD groups. In CD, no significant correlation was found between MPV and other inflammatory markers. The overall accuracy of MPV (cutoff: 10.35 fl), CRP (cutoff: 4.85 mg/dl) and ESR (cutoff: 8.5 mm/hour) in differentiating CD patients from healthy controls was 76.6%, 65.8% and 72.1% respectively. The overall accuracy of CRP (cutoff: 4.95 mg/dl) and ESR (cutoff: 16.5 mm/hour) in determination of active CD was 80.3% and 73.8%. Conclusions: MPV declined in CD patients compared with healthy subjects. MPV had the best accuracy in determination of CD patients and healthy controls. MPV did not show a discriminative value in disease activity. C1 [Liu, Song; Ren, Jianan; Wang, Gefei; Gu, Guosheng; Li, Jieshou] Nanjing Univ, Sch Med, Jinling Hosp, Dept Surg, Nanjing 210002, Peoples R China. [Liu, Song] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Liu, Song] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Han, Gang] Jilin Univ, Gen Surg Ctr, Dept Gen Surg, Affiliated Hosp 2, Changchun 130041, Peoples R China. [Xia, Qiuyuan] Nanjing Univ, Sch Med, Jinling Hosp, Dept Pathol, Nanjing 210002, Peoples R China. RP Ren, JN (reprint author), Nanjing Univ, Sch Med, Jinling Hosp, Dept Surg, 305 E Zhongshan Rd, Nanjing 210002, Peoples R China. EM jiananr@gmail.com OI LIU, SONG/0000-0002-4780-9697; Ren, Jianan/0000-0002-7978-8093 FU Climb Program in Natural Science Foundation of Jiangsu Province for Distinguished Scholars [BK2010017] FX This work was supported by grants from the Climb Program in Natural Science Foundation of Jiangsu Province for Distinguished Scholars (No. BK2010017). NR 49 TC 15 Z9 16 U1 2 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD OCT 12 PY 2012 VL 17 AR 27 DI 10.1186/2047-783X-17-27 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055YX UT WOS:000312455100001 PM 23058104 ER PT J AU Mekkaoui, C Huang, SN Chen, HH Dai, GP Reese, TG Kostis, WJ Thiagalingam, A Maurovich-Horvat, P Ruskin, JN Hoffmann, U Jackowski, MP Sosnovik, DE AF Mekkaoui, Choukri Huang, Shuning Chen, Howard H. Dai, Guangping Reese, Timothy G. Kostis, William J. Thiagalingam, Aravinda Maurovich-Horvat, Pal Ruskin, Jeremy N. Hoffmann, Udo Jackowski, Marcel P. Sosnovik, David E. TI Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Diffusion tensor imaging; Tractography; Myocardium; Remodeling; Heart ID OVINE LEFT-VENTRICLE; CARDIAC FIBER; TENSOR MRI; LAMINAR STRUCTURE; INFARCTION; HEART; RECONSTRUCTION; ORIENTATION; WALL; MICROSTRUCTURE AB Background: The study of myofiber reorganization in the remote zone after myocardial infarction has been performed in 2D. Microstructural reorganization in remodeled hearts, however, can only be fully appreciated by considering myofibers as continuous 3D entities. The aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts. Methods: Diffusion Tensor CMR of normal human, sheep, and rat hearts, as well as infarcted sheep hearts was performed ex vivo. Fiber tracts were generated with a fourth-order Runge-Kutta integration technique and classified statistically by the median, mean, maximum, or minimum helix angle (HA) along the tract. An index of tract coherence was derived from the relationship between these HA statistics. Histological validation was performed using phase-contrast microscopy. Results: In normal hearts, the subendocardial and subepicardial myofibers had a positive and negative HA, respectively, forming a symmetric distribution around the midmyocardium. However, in the remote zone of the infarcted hearts, a significant positive shift in HA was observed. The ratio between negative and positive HA variance was reduced from 0.96 +/- 0.16 in normal hearts to 0.22 +/- 0.08 in the remote zone of the remodeled hearts (p<0.05). This was confirmed histologically by the reduction of HA in the subepicardium from -52.03 degrees +/- 2.94 degrees in normal hearts to -37.48 degrees +/- 4.05 degrees in the remote zone of the remodeled hearts (p < 0.05). Conclusions: A significant reorganization of the 3D fiber continuum is observed in the remote zone of remodeled hearts. The positive (rightward) shift in HA in the remote zone is greatest in the subepicardium, but involves all layers of the myocardium. Tractography-based quantification, performed here for the first time in remodeled hearts, may provide a framework for assessing regional changes in the left ventricle following infarction. C1 [Mekkaoui, Choukri; Huang, Shuning; Chen, Howard H.; Dai, Guangping; Reese, Timothy G.; Kostis, William J.; Sosnovik, David E.] Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Kostis, William J.; Thiagalingam, Aravinda; Ruskin, Jeremy N.; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Mekkaoui, Choukri; Huang, Shuning; Chen, Howard H.; Dai, Guangping; Reese, Timothy G.; Maurovich-Horvat, Pal; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [Jackowski, Marcel P.] Univ Sao Paulo, Inst Math & Stat, Dept Comp Sci, Sao Paulo, Brazil. [Sosnovik, David E.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sosnovik, David E.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Sosnovik, DE (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. EM sosnovik@nmr.mgh.harvard.edu RI Jackowski, Marcel/G-7602-2012; OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU National Institutes of Health [R01 HL093038, P41RR14075]; Medical Discovery Fund Award from the Massachusetts General Hospital FX We thank Dr. Bruce R. Rosen for his support of this study. This research was supported in part by the following National Institutes of Health grants R01 HL093038 (D.E.S.), P41RR14075 (Athinoula A. Martinos Center for Biomedical Imaging) and by a Medical Discovery Fund Award from the Massachusetts General Hospital (C.M.). NR 27 TC 25 Z9 29 U1 1 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 12 PY 2012 VL 14 AR 70 DI 10.1186/1532-429X-14-70 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 044NS UT WOS:000311627500001 PM 23061749 ER PT J AU Lee, KY Kahn, CR AF Lee, Kevin Y. Kahn, C. Ronald TI Turning on Brown Fat and Muscle Metabolism: Hedging Your Bets SO CELL LA English DT Editorial Material ID ADIPOGENESIS; THERMOGENESIS C1 [Lee, Kevin Y.; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu FU NIDDK NIH HHS [R01 DK082659, P30 DK036836, RC1 DK087317, R21 DK090762] NR 10 TC 1 Z9 1 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 12 PY 2012 VL 151 IS 2 BP 248 EP 250 DI 10.1016/j.cell.2012.09.025 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022RX UT WOS:000309981000004 PM 23063118 ER PT J AU Handley, SA Thackray, LB Zhao, G Presti, R Miller, AD Droit, L Abbink, P Maxfield, LF Kambal, A Duan, E Stanley, K Kramer, J Macri, SC Permar, SR Schmitz, JE Mansfield, K Brenchley, JM Veazey, RS Stappenbeck, TS Wang, D Barouch, DH Virgin, HW AF Handley, Scott A. Thackray, Larissa B. Zhao, Guoyan Presti, Rachel Miller, Andrew D. Droit, Lindsay Abbink, Peter Maxfield, Lori F. Kambal, Amal Duan, Erning Stanley, Kelly Kramer, Joshua Macri, Sheila C. Permar, Sallie R. Schmitz, Joern E. Mansfield, Keith Brenchley, Jason M. Veazey, Ronald S. Stappenbeck, Thaddeus S. Wang, David Barouch, Dan H. Virgin, Herbert W. TI Pathogenic Simian Immunodeficiency Virus Infection Is Associated with Expansion of the Enteric Virome SO CELL LA English DT Article ID GUT MICROBIOME; IMMUNE ACTIVATION; HIV-INFECTION; GENE ATG16L1; METAGENOMICS; DISEASE; MOUSE; TRANSLOCATION; SEQUENCES; COLITIS AB Pathogenic simian immunodeficiency virus (SIV) infection is associated with enteropathy, which likely contributes to AIDS progression. To identify candidate etiologies for AIDS enteropathy, we used next-generation sequencing to define the enteric virome during SIV infection in nonhuman primates. Pathogenic, but not nonpathogenic, SIV infection was associated with significant expansion of the enteric virome. We identified at least 32 previously undescribed enteric viruses during pathogenic SIV infection and confirmed their presence by using viral culture and PCR testing. We detected unsuspected mucosal adenovirus infection associated with enteritis as well as parvovirus viremia in animals with advanced AIDS, indicating the pathogenic potential of SIV-associated expansion of the enteric virome. No association between pathogenic SIV infection and the family-level taxonomy of enteric bacteria was detected. Thus, enteric viral infections may contribute to AIDS enteropathy and disease progression. These findings underline the importance of metagenomic analysis of the virome for understanding AIDS pathogenesis. C1 [Abbink, Peter; Maxfield, Lori F.; Stanley, Kelly; Schmitz, Joern E.; Barouch, Dan H.] Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. [Handley, Scott A.; Thackray, Larissa B.; Zhao, Guoyan; Droit, Lindsay; Kambal, Amal; Duan, Erning; Stappenbeck, Thaddeus S.; Wang, David; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Zhao, Guoyan; Droit, Lindsay; Wang, David; Virgin, Herbert W.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Presti, Rachel] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Miller, Andrew D.; Kramer, Joshua; Macri, Sheila C.; Mansfield, Keith] Harvard Univ, Sch Med, Dept Comparat Pathol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Miller, Andrew D.; Kramer, Joshua; Macri, Sheila C.; Mansfield, Keith] Harvard Univ, Sch Med, Dept Vet Resources, New England Primate Res Ctr, Southborough, MA 01772 USA. [Permar, Sallie R.] Duke Univ, Med Ctr, Human Vaccine Inst, Durham, NC 27710 USA. [Brenchley, Jason M.] NIAID, Program Barrier Immun, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Repair & Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Veazey, Ronald S.] Tulane Univ, Tulane Natl Primate Res Ctr, Sch Med, Covington, LA 70433 USA. [Barouch, Dan H.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Barouch, Dan H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Ctr Virol & Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu; virgin@wustl.edu RI zhou, zhenqing/H-4580-2014; Duan, Erning /H-4608-2014 FU Project 10 [U54 AI057160-08]; National Center for Research Resources [1R01 RR032309]; Office of Research Infrastructure Programs [OD11170-02]; Crohn's and Colitis Foundation [3132]; [AI066305]; [AI066924]; [AI078526]; [AI095985]; [AI65335]; [8P51OD011103-5] FX This work was supported by Project 10 of U54 AI057160-08 to D. W. for development of VirusHunter software, was initially funded by the National Center for Research Resources 1R01 RR032309, and is currently supported by the Office of Research Infrastructure Programs OD11170-02 to H. W. V. and D. H. B.; Crohn's and Colitis Foundation Grant 3132 to H. W. V. and T. S. S.; grants AI066305, AI066924, AI078526, and AI095985 to D. H. B.; AI65335 to J.E.S.; and grant 8P51OD011103-5 to A. D. M. and J.K. We would like to thank Angela Carville, Elizabeth Curran, and Vanessa Hirsch for assistance with these experiments. NR 38 TC 111 Z9 112 U1 1 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 12 PY 2012 VL 151 IS 2 BP 253 EP 266 DI 10.1016/j.cell.2012.09.024 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022RX UT WOS:000309981000006 PM 23063120 ER PT J AU Vo, TT Ryan, J Carrasco, R Neuberg, D Rossi, DJ Stone, RM DeAngelo, DJ Frattini, MG Letai, A AF Thanh-Trang Vo Ryan, Jeremy Carrasco, Ruben Neuberg, Donna Rossi, Derrick J. Stone, Richard M. DeAngelo, Daniel J. Frattini, Mark G. Letai, Anthony TI Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML SO CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; BH3 MIMETIC ABT-737; BCL-2 FAMILY; BH3-ONLY PROTEINS; CYTOCHROME-C; APOPTOSIS; DEATH; MCL-1; BAX; INHIBITOR AB Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis ("priming") might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker. C1 [Thanh-Trang Vo; Letai, Anthony] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Thanh-Trang Vo; Ryan, Jeremy; Carrasco, Ruben; Neuberg, Donna; Stone, Richard M.; DeAngelo, Daniel J.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Stem Cell & Regenerat Biol, Boston, MA 02115 USA. [Frattini, Mark G.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. RP Letai, A (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM anthony_letai@dfci.harvard.edu FU NIH [F31 CA150562, P01 CA139980, R01CA129974]; Gabrielle's Angel Foundation for Cancer Research FX The authors gratefully acknowledge support from the following sources: NIH grants F31 CA150562, P01 CA139980, and R01CA129974, Gabrielle's Angel Foundation for Cancer Research. A. L. is a Leukemia and Lymphoma Society Scholar. We thank Abbott Laboratories for providing ABT-737. We thank Martha Wadleigh, MD, and Ilene Galinsky, RN, and the Pasquarello Tissue Bank for help with clinical data and samples. A. L. was a cofounder and formerly served on the scientific advisory board of Eutropics Pharmaceuticals, which has a license for BH3 profiling. NR 37 TC 101 Z9 102 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 12 PY 2012 VL 151 IS 2 BP 344 EP 355 DI 10.1016/j.cell.2012.08.038 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 022RX UT WOS:000309981000013 PM 23063124 ER PT J AU Sikorski, TW Joo, YJ Ficarro, SB Askenazi, M Buratowski, S Marto, JA AF Sikorski, Timothy W. Joo, Yoo Jin Ficarro, Scott B. Askenazi, Manor Buratowski, Stephen Marto, Jarrod A. TI Proteomic Analysis Demonstrates Activator- and Chromatin-specific Recruitment to Promoters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; QUANTITATIVE PROTEOMICS; PREINITIATION COMPLEX; TRANSCRIPTION REINITIATION; IN-VIVO; MEDIATOR; QUANTIFICATION; IDENTIFICATION; MECHANISM; ENHANCER AB In-depth characterization of RNA polymerase II preinitiation complexes remains an important and challenging goal. We used quantitative mass spectrometry to explore context-dependent Saccharomyces cerevisiae preinitiation complex formation at the HIS4 promoter reconstituted on naked and chromatinized DNA templates. The transcription activators Gal4-VP16 and Gal4-Gcn4 recruited a limited set of chromatin-related coactivator complexes, namely the chromatin remodeler Swi/Snf and histone acetyltransferases SAGA and NuA4, suggesting that transcription stimulation is mediated through these factors. Moreover, the two activators differentially recruited the coactivator complexes, consistent with specific activator-coactivator interactions. Chromatinized templates suppressed recruitment of basal transcription factors, thereby amplifying the effect of activators, compared with naked DNA templates. This system is sensitive, highly reproducible, and easily applicable to mapping the repertoire of proteins found at any promoter. C1 [Sikorski, Timothy W.; Joo, Yoo Jin; Ficarro, Scott B.; Askenazi, Manor; Buratowski, Stephen; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Sikorski, Timothy W.; Ficarro, Scott B.; Askenazi, Manor; Marto, Jarrod A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Ficarro, Scott B.; Askenazi, Manor; Marto, Jarrod A.] Harvard Univ, Sch Med, Blais Prote Ctr, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Buratowski, S (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 240 Longwood Ave, Boston, MA 02115 USA. EM steveb@hms.harvard.edu; jarrod_marto@dfci.harvard.edu FU National Institutes of Health [GM46498]; Dana-Farber Strategic Research Initiative; National Defense Science and Engineering Graduate predoctoral fellowship; National Research Foundation of Korea FX This work was supported, in whole or in part, by National Institutes of Health Grant GM46498 (to S. B.). This work was also supported by the Dana-Farber Strategic Research Initiative (to J.A.M.).; Supported by a National Defense Science and Engineering Graduate predoctoral fellowship.; Supported by a National Research Foundation of Korea postdoctoral fellowship. NR 40 TC 5 Z9 5 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 12 PY 2012 VL 287 IS 42 BP 35397 EP 35408 DI 10.1074/jbc.M112.391581 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 022OF UT WOS:000309968000047 PM 22902623 ER PT J AU Belden, S Flaherty, KT AF Belden, Sarah Flaherty, Keith T. TI MEK and RAF inhibitors for BRAF-mutated cancers SO EXPERT REVIEWS IN MOLECULAR MEDICINE LA English DT Review ID CELL LUNG-CANCER; MELANOMA-CELLS; TUMOR PROGRESSION; BRAF(V600E) INHIBITION; METASTATIC MELANOMA; ACQUIRED-RESISTANCE; MALIGNANT-MELANOMA; KINASE INHIBITION; B-RAF; MUTATIONS AB The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathophysiology of many cancers. Under normal physiologic conditions, the RAS-RAF-mitogen-activated protein kinase kinase (MEK)-mitogen-activated protein kinase (ERK) signalling cascade interaction is initiated by ligation of a receptor-linked tyrosine kinase by its cognate growth factor. It has been demonstrated in many systems that aberrant autocrine or paracrine stimulation of growth factor receptors is pathogenic in large part because of MAPK activation. As one of the key downstream effector pathways of mutated RAS (KRAS, NRAS and HRAS), pharmacologic inhibition of components of the MAPK pathway has been pursued as a means to indirectly inhibit RAS, which remains a technical challenge for direct pharmacologic inhibition. RAF and MEK are the two non-membrane-bound, serine-threonine and tyrosine-threonine kinases, within the pathway that have been most extensively explored as drug targets. The discovery of activating BRAF mutations in cancer clarified which cancer types and subsets of certain cancers are most dependent on activation of the MAPK pathway for growth and survival. Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation. C1 [Belden, Sarah; Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Belden, Sarah] Univ New England, Coll Osteopath Med, Biddeford, ME USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org OI Belden, Sarah/0000-0002-7132-5318 NR 62 TC 18 Z9 18 U1 0 U2 28 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1462-3994 J9 EXPERT REV MOL MED JI Expert Rev. Mol. Med. PD OCT 12 PY 2012 VL 14 AR e17 DI 10.1017/erm.2012.11 PG 11 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 021ZL UT WOS:000309924600001 PM 23058743 ER PT J AU Rosen, MI Black, AC Arnsten, JH Simoni, JM Wagner, GJ Goggin, K Remien, RH Golin, CE Wang, Y Bangsberg, D Liu, HHH AF Rosen, Marc I. Black, Anne C. Arnsten, Julia H. Simoni, Jane M. Wagner, Glann J. Goggin, Kathleen Remien, Robert H. Golin, Carol E. Wang, Yan Bangsberg, David Liu, Honghu H. CA MACH14 Study Grp TI ART adherence changes among patients in community substance use treatment: a preliminary analysis from MACH14 SO AIDS RESEARCH AND THERAPY LA English DT Article DE Medication adherence; AIDS; Substance abuse; Treatment ID METHADONE-MAINTENANCE THERAPY; HIV TREATMENT OUTCOMES; INJECTION-DRUG USERS; ANTIRETROVIRAL THERAPY; CONTROLLED-TRIAL; MEDICATION; HEALTH AB Background: Opiate substitution treatment has been associated with better adherence to lifesaving antiretroviral medications, but the impact of other substance abuse treatment on adherence is unknown. Findings: In this study, 215 patients who had been in adherence-focused research studies provided electronically-measured adherence data and a measure of whether the patient had recently been in substance abuse treatment. Recent engagement in substance abuse treatment was independently associated with significantly higher adherence, after covarying for recent substance use and other factors potentially affecting adherence. Conclusions: The findings suggest that substance abuse treatment is associated with better adherence. Potential mechanisms by which substance abuse treatment improves adherence, such as more stability or more future-orientation, require further study. C1 [Rosen, Marc I.; Black, Anne C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Rosen, Marc I.; Black, Anne C.] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Arnsten, Julia H.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Arnsten, Julia H.] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Arnsten, Julia H.] Einstein Montefiore Ctr AIDS Res, Montefiore Med Ctr, Bronx, NY 10467 USA. [Simoni, Jane M.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Wagner, Glann J.] RAND Corp, Hlth Unit, Santa Monica, CA 90407 USA. [Goggin, Kathleen] Univ Missouri, Dept Psychol, Kansas City, MO 64110 USA. [Remien, Robert H.] NY State Psychiat Inst, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Remien, Robert H.] Columbia Univ, New York, NY 10032 USA. [Golin, Carol E.] Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. [Golin, Carol E.] Univ N Carolina, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC 27599 USA. [Golin, Carol E.] Univ N Carolina, Ctr AIDS Res, Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC 27599 USA. [Wang, Yan] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90095 USA. [Bangsberg, David] Mbarara Univ Sci & Technol, Boston, MA 02114 USA. [Bangsberg, David] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bangsberg, David] Ragon Inst MGH Harvard & MIT, Boston, MA 02114 USA. [Bangsberg, David] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02114 USA. [Bangsberg, David] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Liu, Honghu H.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90095 USA. [Liu, Honghu H.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. [Liu, Honghu H.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. RP Rosen, MI (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. EM Marc.Rosen@Yale.edu OI Simoni, Jane/0000-0002-8711-1576 FU National Institute of Mental Health (NIMH), Office on AIDS [R01MH078773]; [R01DA11869]; [MH54907]; [R01 NR04749]; [MH68197]; [R01 DA13826]; [K23MH01862]; [MH01584]; [R01 AI41413]; [R01 MH61173]; [NIH/ NIAID AI38858]; [AI069419]; [K02 DA017277]; [R01 DA15215]; [NIMH P01 MH49548]; [MH58986]; [RO1MH61695]; [CC99-SD003]; [CC02-SD-003]; [R01 DA015679] FX This research was supported by the multi-site adherence collaboration in HIV (MACH14) grant R01MH078773 from the National Institute of Mental Health (NIMH), Office on AIDS. The original grants of individual participating studies are: R01DA11869, MH54907, R01 NR04749, R01 NR04749, MH68197, R01 DA13826, K23MH01862, MH01584, R01 AI41413, R01 MH61173, NIH/ NIAID AI38858, AI069419, K02 DA017277, R01 DA15215, NIMH P01 MH49548, MH58986, RO1MH61695, CC99-SD003, CC02-SD-003 and R01 DA015679. We would like to thank all the patients who participated in each of the individual studies. The content of the paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 19 TC 3 Z9 3 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD OCT 11 PY 2012 VL 9 AR 30 DI 10.1186/1742-6405-9-30 PG 5 WC Infectious Diseases SC Infectious Diseases GA 072XI UT WOS:000313706600001 PM 23057423 ER PT J AU Bauer, DE Kamran, SC Orkin, SH AF Bauer, Daniel E. Kamran, Sophia C. Orkin, Stuart H. TI Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders SO BLOOD LA English DT Review ID SICKLE-CELL-DISEASE; KRUPPEL-LIKE FACTOR; PLURIPOTENT STEM-CELLS; GENOME-WIDE ASSOCIATION; YAC TRANSGENIC MICE; HUMAN GAMMA-GLOBIN; FACTOR KLF1 CAUSES; RED-BLOOD-CELLS; TRANSCRIPTION FACTOR; GENE-EXPRESSION AB The level of fetal hemoglobin (HbF) modifies the severity of the common beta-globin disorders. Knowledge of the normal mechanisms that repress HbF in the adult stage has remained limited until recently despite nearly 3 decades of molecular investigation, in part because of imperfect model systems. Recent studies have provided new insights into the developmental regulation of globin genes and identified specific transcription factors and epigenetic regulators responsible for physiologic silencing of HbF. Most prominent among these regulators is BCL11A, a transcriptional repressor that inhibits adult-stage HbF expression. KLF1 and c-Myb are additional critical HbF-regulating erythroid transcription factors more broadly involved in erythroid gene expression programs. Chromatin modifiers, including histone deacetylases and DNA methyltransferases, also play key roles in orchestrating appropriate globin gene expression. Taken together, these discoveries present novel therapeutic targets for further consideration. Although substantial hurdles remain, opportunities are now rich for the rational design of HbF inducers. (Blood. 2012; 120(15): 2945-2953) C1 [Bauer, Daniel E.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bauer, Daniel E.; Orkin, Stuart H.] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA. [Bauer, Daniel E.; Kamran, Sophia C.; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA USA. [Kamran, Sophia C.; Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM orkin@bloodgroup.tch.harvard.edu NR 119 TC 60 Z9 60 U1 1 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 11 PY 2012 VL 120 IS 15 BP 2945 EP 2953 DI 10.1182/blood2012-06-292078 PG 9 WC Hematology SC Hematology GA 044KY UT WOS:000311619300011 PM 22904296 ER PT J AU Landis, SC Amara, SG Asadullah, K Austin, CP Blumenstein, R Bradley, EW Crystal, RG Darnell, RB Ferrante, RJ Fillit, H Finkelstein, R Fisher, M Gendelman, HE Golub, RM Goudreau, JL Gross, RA Gubitz, AK Hesterlee, SE Howells, DW Huguenard, J Kelner, K Koroshetz, W Krainc, D Lazic, SE Levine, MS Macleod, MR McCall, JM Moxley, RT Narasimhan, K Noble, LJ Perrin, S Porter, JD Steward, O Unger, E Utz, U Silberberg, SD AF Landis, Story C. Amara, Susan G. Asadullah, Khusru Austin, Chris P. Blumenstein, Robi Bradley, Eileen W. Crystal, Ronald G. Darnell, Robert B. Ferrante, Robert J. Fillit, Howard Finkelstein, Robert Fisher, Marc Gendelman, Howard E. Golub, Robert M. Goudreau, John L. Gross, Robert A. Gubitz, Amelie K. Hesterlee, Sharon E. Howells, David W. Huguenard, John Kelner, Katrina Koroshetz, Walter Krainc, Dimitri Lazic, Stanley E. Levine, Michael S. Macleod, Malcolm R. McCall, John M. Moxley, Richard T., III Narasimhan, Kalyani Noble, Linda J. Perrin, Steve Porter, John D. Steward, Oswald Unger, Ellis Utz, Ursula Silberberg, Shai D. TI A call for transparent reporting to optimize the predictive value of preclinical research SO NATURE LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; CONTROLLED CLINICAL-TRIALS; EXPERIMENTAL STROKE; EMPIRICAL-EVIDENCE; STATISTICAL-ANALYSIS; CONSORT STATEMENT; PUBLICATION BIAS; DRUG DEVELOPMENT; ANIMAL RESEARCH; CANCER-RESEARCH AB The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress. C1 [Landis, Story C.; Finkelstein, Robert; Gubitz, Amelie K.; Koroshetz, Walter; Porter, John D.; Utz, Ursula; Silberberg, Shai D.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Amara, Susan G.] Univ Pittsburgh, Sch Med, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Asadullah, Khusru] Bayer HealthCare, D-13342 Berlin, Germany. [Austin, Chris P.] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20854 USA. [Blumenstein, Robi] CHDI Management CHDI Fdn, New York, NY 10001 USA. [Bradley, Eileen W.] NIH, Ctr Review, Bethesda, MD 20892 USA. [Crystal, Ronald G.] Weill Cornell Med Coll, Dept Genet Med, New York, NY 10021 USA. [Darnell, Robert B.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Fillit, Howard] Alzheimers Drug Discovery Fdn, New York, NY 10019 USA. [Fisher, Marc] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01545 USA. [Gendelman, Howard E.] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA. [Golub, Robert M.] JAMA, Chicago, IL 60654 USA. [Goudreau, John L.] Michigan State Univ, Dept Neurol, E Lansing, MI 48824 USA. [Gross, Robert A.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Hesterlee, Sharon E.] Parent Project Muscular Dystrophy, Hackensack, NJ 07601 USA. [Howells, David W.] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Heidelberg, Vic 3081, Australia. [Huguenard, John] Stanford Univ, Stanford, CA 94305 USA. [Kelner, Katrina] AAAS, Washington, DC USA. [Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Lazic, Stanley E.] F Hoffmann La Roche & Co Ltd, CH-4070 Basel, Switzerland. [Levine, Michael S.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Macleod, Malcolm R.] Univ Edinburgh, Western Gen Hosp, Dept Clin Neurosci, Edinburgh EH4 2XU, Midlothian, Scotland. [Moxley, Richard T., III] Univ Rochester, Med Ctr, Sch Med & Dent, Rochester, NY 14642 USA. [McCall, John M.] PharMac LLC, Boca Grande, FL 33921 USA. [Narasimhan, Kalyani] Nat Neurosci, New York, NY 10013 USA. [Noble, Linda J.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Perrin, Steve] ALS Therapy Dev Inst, Cambridge, MA 02139 USA. [Steward, Oswald] Univ Calif Irvine, Reeve Irvine Res Ctr, Irvine, CA 92697 USA. [Unger, Ellis] US FDA, Off New Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Silberberg, SD (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. EM silberbs@ninds.nih.gov RI Lazic, Stanley/F-1160-2011; Huguenard, John/I-5016-2012; Darnell, Robert/B-9022-2008; OI Huguenard, John/0000-0002-6950-1191; Darnell, Robert/0000-0002-5134-8088; Steward, Oswald/0000-0001-7069-8756; Macleod, Malcolm Robert/0000-0001-9187-9839 FU NINDS FX Funded by NINDS. NR 64 TC 380 Z9 386 U1 8 U2 91 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2012 VL 490 IS 7419 BP 187 EP 191 DI 10.1038/nature11556 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019IY UT WOS:000309733300036 PM 23060188 ER PT J AU Yang, J Loos, RJF Powell, JE Medland, SE Speliotes, EK Chasman, DI Rose, LM Thorleifsson, G Steinthorsdottir, V Maegi, R Waite, L Smith, AV Yerges-Armstrong, LM Monda, KL Hadley, D Mahajan, A Li, G Kapur, K Vitart, V Huffman, JE Wang, SR Palmer, C Esko, T Fischer, K Zhao, JH Demirkan, A Isaacs, A Feitosa, MF Luan, J Heard-Costa, NL White, C Jackson, AU Preuss, M Ziegler, A Eriksson, J Kutalik, Z Frau, F Nolte, IM Van Vliet-Ostaptchouk, JV Hottenga, JJ Jacobs, KB Verweij, N Goel, A Medina-Gomez, C Estrada, K Bragg-Gresham, JL Sanna, S Sidore, C Tyrer, J Teumer, A Prokopenko, I Mangino, M Lindgren, CM Assimes, TL Shuldiner, AR Hui, J Beilby, JP McArdle, WL Hall, P Haritunians, T Zgaga, L Kolcic, I Polasek, O Zemunik, T Oostra, BA Junttila, MJ Groenberg, H Schreiber, S Peters, A Hicks, AA Stephens, J Foad, NS Laitinen, J Pouta, A Kaakinen, M Willemsen, G Vink, JM Wild, SH Navis, G Asselbergs, FW Homuth, G John, U Iribarren, C Harris, T Launer, L Gudnason, V O'Connell, JR Boerwinkle, E Cadby, G Palmer, LJ James, AL Musk, AW Ingelsson, E Psaty, BM Beckmann, JS Waeber, G Vollenweider, P Hayward, C Wright, AF Rudan, I Groop, LC Metspalu, A Khaw, KT van Duijn, CM Borecki, IB Province, MA Wareham, NJ Tardif, JC Huikuri, HV Cupples, LA Atwood, LD Fox, CS Boehnke, M Collins, FS Mohlke, KL Erdmann, J Schunkert, H Hengstenberg, C Stark, K Lorentzon, M Ohlsson, C Cusi, D Staessen, JA Van der Klauw, MM Pramstaller, PP Kathiresan, S Jolley, JD Ripatti, S Jarvelin, MR de Geus, EJC Boomsma, DI Penninx, B Wilson, JF Campbell, H Chanock, SJ van der Harst, P Hamsten, A Watkins, H Hofman, A Witteman, JC Zillikens, MC Uitterlinden, AG Rivadeneira, F Zillikens, MC Kiemeney, LA Vermeulen, SH Abecasis, GR Schlessinger, D Schipf, S Stumvoll, M Toenjes, A Spector, TD North, KE Lettre, G McCarthy, MI Berndt, SI Heath, AC Madden, PAF Nyholt, DR Montgomery, GW Martin, NG McKnight, B Strachan, DP Hill, WG Snieder, H Ridker, PM Thorsteinsdottir, U Stefansson, K Frayling, TM Hirschhorn, JN Goddard, ME Visscher, PM AF Yang, Jian Loos, Ruth J. F. Powell, Joseph E. Medland, Sarah E. Speliotes, Elizabeth K. Chasman, Daniel I. Rose, Lynda M. Thorleifsson, Gudmar Steinthorsdottir, Valgerdur Maegi, Reedik Waite, Lindsay Smith, Albert Vernon Yerges-Armstrong, Laura M. Monda, Keri L. Hadley, David Mahajan, Anubha Li, Guo Kapur, Karen Vitart, Veronique Huffman, Jennifer E. Wang, Sophie R. Palmer, Cameron Esko, Toenu Fischer, Krista Zhao, Jing Hua Demirkan, Ayse Isaacs, Aaron Feitosa, Mary F. Luan, Jian'an Heard-Costa, Nancy L. White, Charles Jackson, Anne U. Preuss, Michael Ziegler, Andreas Eriksson, Joel Kutalik, Zoltan Frau, Francesca Nolte, Ilja M. Van Vliet-Ostaptchouk, Jana V. Hottenga, Jouke-Jan Jacobs, Kevin B. Verweij, Niek Goel, Anuj Medina-Gomez, Carolina Estrada, Karol Bragg-Gresham, Jennifer Lynn Sanna, Serena Sidore, Carlo Tyrer, Jonathan Teumer, Alexander Prokopenko, Inga Mangino, Massimo Lindgren, Cecilia M. Assimes, Themistocles L. Shuldiner, Alan R. Hui, Jennie Beilby, John P. McArdle, Wendy L. Hall, Per Haritunians, Talin Zgaga, Lina Kolcic, Ivana Polasek, Ozren Zemunik, Tatijana Oostra, Ben A. Junttila, M. Juhani Groenberg, Henrik Schreiber, Stefan Peters, Annette Hicks, Andrew A. Stephens, Jonathan Foad, Nicola S. Laitinen, Jaana Pouta, Anneli Kaakinen, Marika Willemsen, Gonneke Vink, Jacqueline M. Wild, Sarah H. Navis, Gerjan Asselbergs, Folkert W. Homuth, Georg John, Ulrich Iribarren, Carlos Harris, Tamara Launer, Lenore Gudnason, Vilmundur O'Connell, Jeffrey R. Boerwinkle, Eric Cadby, Gemma Palmer, Lyle J. James, Alan L. Musk, Arthur W. Ingelsson, Erik Psaty, Bruce M. Beckmann, Jacques S. Waeber, Gerard Vollenweider, Peter Hayward, Caroline Wright, Alan F. Rudan, Igor Groop, Leif C. Metspalu, Andres Khaw, Kay Tee van Duijn, Cornelia M. Borecki, Ingrid B. Province, Michael A. Wareham, Nicholas J. Tardif, Jean-Claude Huikuri, Heikki V. Cupples, L. Adrienne Atwood, Larry D. Fox, Caroline S. Boehnke, Michael Collins, Francis S. Mohlke, Karen L. Erdmann, Jeanette Schunkert, Heribert Hengstenberg, Christian Stark, Klaus Lorentzon, Mattias Ohlsson, Claes Cusi, Daniele Staessen, Jan A. Van der Klauw, Melanie M. Pramstaller, Peter P. Kathiresan, Sekar Jolley, Jennifer D. Ripatti, Samuli Jarvelin, Marjo-Riitta de Geus, Eco J. C. Boomsma, Dorret I. Penninx, Brenda Wilson, James F. Campbell, Harry Chanock, Stephen J. van der Harst, Pim Hamsten, Anders Watkins, Hugh Hofman, Albert Witteman, Jacqueline C. Zillikens, M. Carola Uitterlinden, Andre G. Rivadeneira, Fernando Zillikens, M. Carola Kiemeney, Lambertus A. Vermeulen, Sita H. Abecasis, Goncalo R. Schlessinger, David Schipf, Sabine Stumvoll, Michael Toenjes, Anke Spector, Tim D. North, Kari E. Lettre, Guillaume McCarthy, Mark I. Berndt, Sonja I. Heath, Andrew C. Madden, Pamela A. F. Nyholt, Dale R. Montgomery, Grant W. Martin, Nicholas G. McKnight, Barbara Strachan, David P. Hill, William G. Snieder, Harold Ridker, Paul M. Thorsteinsdottir, Unnur Stefansson, Kari Frayling, Timothy M. Hirschhorn, Joel N. Goddard, Michael E. Visscher, Peter M. TI FTO genotype is associated with phenotypic variability of body mass index SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; ENVIRONMENTAL SENSITIVITY; PHYSICAL-ACTIVITY; GENETIC-VARIATION; ADULT OBESITY; LOCI; VARIANTS; CHILDHOOD; SELECTION; TRAITS AB There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000. C1 [Yang, Jian; Powell, Joseph E.] Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. [Yang, Jian; Powell, Joseph E.; Medland, Sarah E.; Nyholt, Dale R.; Montgomery, Grant W.; Martin, Nicholas G.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Loos, Ruth J. F.; Zhao, Jing Hua; Luan, Jian'an; Wareham, Nicholas J.] Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Loos, Ruth J. F.] Mt Sinai Sch Med, New York, NY 10029 USA. [Speliotes, Elizabeth K.] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Speliotes, Elizabeth K.] Univ Michigan, Ctr Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. [Chasman, Daniel I.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur] deCODE Genet, IS-101 Reykjavik, Iceland. [Maegi, Reedik; Esko, Toenu; Fischer, Krista; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50410 Tartu, Estonia. [Maegi, Reedik; Mahajan, Anubha; Lindgren, Cecilia M.; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. 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[Zgaga, Lina; Wild, Sarah H.; Rudan, Igor; Wilson, James F.; Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Sch Med, Edinburgh EH16 4TJ, Midlothian, Scotland. [Zgaga, Lina] Univ Zagreb, Sch Med, Andrija Stampar Sch Publ Hlth, Zagreb 41001, Croatia. [Kolcic, Ivana; Polasek, Ozren; Zemunik, Tatijana] Univ Split, Fac Med, Split 21000, Croatia. [Junttila, M. Juhani; Huikuri, Heikki V.] Univ Oulu, Dept Internal Med, Inst Clin Med, Oulu 90014, Finland. [Peters, Annette] Univ Kiel, Inst Klin Mol Biol, D-24098 Kiel, Germany. [Peters, Annette] Munich Heart Alliance, D-80802 Munich, Germany. [Hicks, Andrew A.] European Acad Bozen Bolzano EURAC, Ctr Biomed, I-39100 Bolzano, Italy. [Stephens, Jonathan] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England. [Stephens, Jonathan; Jolley, Jennifer D.] NHS Blood & Transplant, Cambridge CB2 0PT, England. [Foad, Nicola S.] Finnish Inst Occupat Hlth, Oulu 90220, Finland. [Laitinen, Jaana] Natl Inst Hlth & Welf, Oulu 90101, Finland. 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[McKnight, Barbara] Washington Univ, Dept Biostat, St Louis, MO 63110 USA. [Hill, William G.] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh EH9 3JT, Midlothian, Scotland. [Thorsteinsdottir, Unnur; Stefansson, Kari] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland. [Frayling, Timothy M.] Univ Exeter, Inst Biomed & Clin Sci, Peninsula Med Sch, Exeter EX1 2LU, Devon, England. [Goddard, Michael E.] Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic 3010, Australia. [Goddard, Michael E.] Dept Primary Ind, Biosci Res Div, Bundoora, Vic 3083, Australia. [Visscher, Peter M.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia. RP Yang, J (reprint author), Univ Queensland, Diamantina Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia. RI Nyholt, Dale/C-8384-2013; Powell, Joseph/G-3027-2014; Pramstaller, Peter/C-2357-2008; Beckmann, Jacques S /A-9772-2008; Palmer, Lyle/K-3196-2014; Medland, Sarah/C-7630-2013; Gudnason, Vilmundur/K-6885-2015; Abecasis, Goncalo/B-7840-2010; Colaus, PsyColaus/K-6607-2013; van der Klauw, Melanie/A-2138-2014; Kiemeney, Lambertus/D-3357-2009; Schreiber, Stefan/B-6748-2008; Staessen, Jan/A-1065-2011; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Prokopenko, Inga/H-3241-2014; Peters, Annette/A-6117-2011; Vermeulen, H.H.M./L-4716-2015; Rudan, Igor/I-1467-2012; Smith, Albert/K-5150-2015; Yang, Jian/A-5852-2010; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Erdmann, Jeanette/P-7513-2014; Verweij, Niek/A-4499-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; OI Powell, Joseph/0000-0001-9031-6356; Beckmann, Jacques S /0000-0002-9741-1900; Palmer, Lyle/0000-0002-1628-3055; Medland, Sarah/0000-0003-1382-380X; Gudnason, Vilmundur/0000-0001-5696-0084; van der Klauw, Melanie/0000-0001-7178-009X; Kiemeney, Lambertus/0000-0002-2368-1326; Schreiber, Stefan/0000-0003-2254-7771; Staessen, Jan/0000-0002-3026-1637; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Prokopenko, Inga/0000-0003-1624-7457; Rudan, Igor/0000-0001-6993-6884; Smith, Albert/0000-0003-1942-5845; Yang, Jian/0000-0003-2001-2474; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Esko, Tonu/0000-0003-1982-6569; Sidore, Carlo/0000-0001-7504-7477; Goddard, Michael/0000-0001-9917-7946; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Erdmann, Jeanette/0000-0002-4486-6231; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Wang, Sophie Ran/0000-0002-7897-8389; Heard-Costa, Nancy/0000-0001-9730-0306; Kaakinen, Marika/0000-0002-9228-0462; Cupples, L. Adrienne/0000-0003-0273-7965; Magi, Reedik/0000-0002-2964-6011; Zgaga, Lina/0000-0003-4089-9703; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Ziegler, Andreas/0000-0002-8386-5397; Rivadeneira, Fernando/0000-0001-9435-9441; Verweij, Niek/0000-0002-4303-7685; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; John, Ulrich/0000-0003-0587-5298; Watkins, Hugh/0000-0002-5287-9016; Medina-Gomez, Carolina/0000-0001-7999-5538; Visscher, Peter/0000-0002-2143-8760; Martin, Nicholas/0000-0003-4069-8020 FU Australian National Health and Medical Research Council (NHMRC) [241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601, 1011506]; US National Institutes of Health [AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854, GM057091]; Australian Research Council (ARC) [DP1093502] FX We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506), the US National Institutes of Health (grants AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854 and GM057091) and the Australian Research Council (ARC grant DP1093502). A detailed list of acknowledgements by study is provided in the Supplementary Information. We apologize to authors whose work we could not cite owing to space restrictions. NR 36 TC 121 Z9 130 U1 6 U2 106 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2012 VL 490 IS 7419 BP 267 EP + DI 10.1038/nature11401 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019IY UT WOS:000309733300051 PM 22982992 ER PT J AU Murooka, TT Deruaz, M Marangoni, F Vrbanac, VD Seung, E von Andrian, UH Tager, AM Luster, AD Mempel, TR AF Murooka, Thomas T. Deruaz, Maud Marangoni, Francesco Vrbanac, Vladimir D. Seung, Edward von Andrian, Ulrich H. Tager, Andrew M. Luster, Andrew D. Mempel, Thorsten R. TI HIV-infected T cells are migratory vehicles for viral dissemination SO NATURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMANIZED BLT MICE; LYMPH-NODES; VIROLOGICAL SYNAPSES; SEXUAL TRANSMISSION; IMMUNE-RESPONSES; DOWN-MODULATION; ENVELOPE; NEF; RECEPTOR AB After host entry through mucosal surfaces, human immunodeficiency virus-1 (HIV-1) disseminates to lymphoid tissues to establish a generalized infection of the immune system. The mechanisms by which this virus spreads among permissive target cells locally during the early stages of transmission and systemically during subsequent dissemination are not known(1). In vitro studies suggest that the formation of virological synapses during stable contacts between infected and uninfected T cells greatly increases the efficiency of viral transfer(2). It is unclear, however, whether T-cell contacts are sufficiently stable in vivo to allow for functional synapse formation under the conditions of perpetual cell motility in epithelial(3) and lymphoid tissues(4). Here, using multiphoton intravital microscopy, we examine the dynamic behaviour of HIV-infected T cells in the lymph nodes of humanized mice. We find that most productively infected T cells migrate robustly, resulting in their even distribution throughout the lymph node cortex. A subset of infected cells formed multinucleated syncytia through HIV envelope-dependent cell fusion. Both uncoordinated motility of syncytia and adhesion to CD4(+) lymph node cells led to the formation of long membrane tethers, increasing cell lengths to up to ten times that of migrating uninfected T cells. Blocking the egress of migratory T cells from the lymph nodes into efferent lymph vessels, and thus interrupting T-cell recirculation, limited HIV dissemination and strongly reduced plasma viraemia. Thus, we have found that HIV-infected T cells are motile, form syncytia and establish tethering interactions that may facilitate cell-to-cell transmission through virological synapses. Migration of T cells in lymph nodes therefore spreads infection locally, whereas their recirculation through tissues is important for efficient systemic viral spread, suggesting new molecular targets to antagonize HIV infection. C1 [Murooka, Thomas T.; Deruaz, Maud; Marangoni, Francesco; Vrbanac, Vladimir D.; Seung, Edward; Tager, Andrew M.; Luster, Andrew D.; Mempel, Thorsten R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. RP Mempel, TR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. EM tmempel@mgh.harvard.edu RI von Andrian, Ulrich/A-5775-2008; Marangoni, Francesco/I-9087-2012 OI Marangoni, Francesco/0000-0002-2490-849X FU National Institutes of Health (NIH) [P01 AI0178897, R56 AI097052, R01 CA150975, P30 AI060354]; Ragon Institute of Massachusetts General Hospital (MGH); Massachusetts Institute of Technology (MIT); Harvard; MGH ECOR Tosteson Postdoctoral Fellowship Award; NIH [T32 AI007387] FX We thank J. Sodroski for the pSVIIIexE7 plasmid and A. Brown for HIV SF162R3; H. S. Shin, T. Tivey, K. Bankert and S. Tanno for technical assistance with the generation of humanized mice; A. Peixoto and D. Alvarez for management of the BL2+ multiphoton microscopy facility; A. Brass, T. Allen and T. Dudek for assistance with virological techniques; and N. Elpek, M. Byrne and A. Finzi for technical assistance. Funding for this study was through National Institutes of Health (NIH) grants P01 AI0178897, R56 AI097052, R01 CA150975 and P30 AI060354, and a Platform Award from the Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and Harvard. T. T. M. was supported by the MGH ECOR Tosteson Postdoctoral Fellowship Award and NIH training grant T32 AI007387. NR 38 TC 127 Z9 128 U1 1 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2012 VL 490 IS 7419 BP 283 EP + DI 10.1038/nature11398 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 019IY UT WOS:000309733300054 PM 22854780 ER PT J AU Lapenta, OM Fregni, F Oberman, LM Boggio, PS AF Lapenta, Olivia Morgan Fregni, Felipe Oberman, Lindsay M. Boggio, Paulo Sergio TI Bilateral temporal cortex transcranial direct current stimulation worsens male performance in a multisensory integration task SO NEUROSCIENCE LETTERS LA English DT Article DE Multisensory integration; tDCS; Superior temporal sulcus; Gender; Extreme male brain theory ID DC STIMULATION; BRAIN; MODULATION; AUTISM AB Somatosensory integration is a critical cognitive function for human social interaction. Though somatosensory integration has been highly explored in cognitive studies: only a few studies have explored focal modulation of cortical excitability using a speech perception paradigm. In the current study, we aimed to investigate the effects of tDCS applied over the temporal cortex of healthy subjects during a go-no-go task in which stimuli were shapes and non-words. Twenty-eight subjects were randomized to receive cathodal, anodal or sham tDCS bilaterally over the superior temporal cortex (the reference electrode was on deltoid) in a counterbalanced order. The effects on judgment of congruency between shapes and non-words in healthy volunteers were measured by a go-no-go task. Our findings show a significant modification of performance according to the polarity of stimulation, task and subject gender. We found that men performed worse on the no-go condition for congruent stimuli during cathodal tDCS. For reaction time, on the other hand, there was a similar effect for anodal and cathodal stimulation. There were significantly faster responses on incongruent trials during both anodal and cathodal tDCS. Along with previous literature showing gender differences in tasks associated with speech perception, the findings of this study provide additional evidence suggesting that men may have a more focal and restricted neural processing in this multisensory integration task. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Lapenta, Olivia Morgan; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, BR-01241001 Sao Paulo, Brazil. [Lapenta, Olivia Morgan; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Dev Disorders Program, BR-01241001 Sao Paulo, Brazil. [Fregni, Felipe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Fregni, Felipe] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Lab Neuromodulat, Boston, MA USA. [Fregni, Felipe; Oberman, Lindsay M.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Berenson Allen Ctr Noninvas Brain Stimulat, Boston, MA 02215 USA. RP Boggio, PS (reprint author), Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, Rua Piaui 181,10 Andar, BR-01241001 Sao Paulo, Brazil. EM boggio@mackenzie.br RI Boggio, Paulo/K-6272-2012 OI Boggio, Paulo/0000-0002-6109-0447 FU CNPq [305718/2009-6]; Master grant (CAPES-PROSUP-IES modality I) FX PSB is supported by a CNPq researcher grant (305718/2009-6). OML was supported by a Master grant (CAPES-PROSUP-IES modality I). NR 15 TC 11 Z9 11 U1 0 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 11 PY 2012 VL 527 IS 2 BP 105 EP 109 DI 10.1016/j.neulet.2012.08.076 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 024EP UT WOS:000310091800008 PM 22985520 ER PT J AU Kauramaki, J Jaaskelainen, IP Hanninen, JL Auranen, T Nummenmaa, A Lampinen, J Sams, M AF Kauramaki, Jaakko Jaaskelainen, Iiro P. Hanninen, Jarno L. Auranen, Toni Nummenmaa, Aapo Lampinen, Jouko Sams, Mikko TI Two-Stage Processing of Sounds Explains Behavioral Performance Variations due to Changes in Stimulus Contrast and Selective Attention: An MEG Study SO PLOS ONE LA English DT Article ID HUMAN AUDITORY-CORTEX; SUSTAINED MAGNETIC-FIELDS; SURFACE-BASED ANALYSIS; SHORT-TERM PLASTICITY; HIGH-RESOLUTION FMRI; RECEPTIVE-FIELDS; CRITICAL-BAND; HUMAN-BRAIN; NEUROMAGNETIC RESPONSES; NORMALIZATION MODEL AB Selectively attending to task-relevant sounds whilst ignoring background noise is one of the most amazing feats performed by the human brain. Here, we studied the underlying neural mechanisms by recording magnetoencephalographic (MEG) responses of 14 healthy human subjects while they performed a near-threshold auditory discrimination task vs. a visual control task of similar difficulty. The auditory stimuli consisted of notch-filtered continuous noise masker sounds, and of 1020-Hz target tones occasionally (p = 0.1) replacing 1000-Hz standard tones of 300-ms duration that were embedded at the center of the notches, the widths of which were parametrically varied. As a control for masker effects, tone-evoked responses were additionally recorded without masker sound. Selective attention to tones significantly increased the amplitude of the onset M100 response at similar to 100 ms to the standard tones during presence of the masker sounds especially with notches narrower than the critical band. Further, attention modulated sustained response most clearly at 300-400 ms time range from sound onset, with narrower notches than in case of the M100, thus selectively reducing the masker-induced suppression of the tone-evoked response. Our results show evidence of a multiple-stage filtering mechanism of sensory input in the human auditory cortex: 1) one at early (similar to 100 ms) latencies bilaterally in posterior parts of the secondary auditory areas, and 2) adaptive filtering of attended sounds from task-irrelevant background masker at longer latency (similar to 300 ms) in more medial auditory cortical regions, predominantly in the left hemisphere, enhancing processing of near-threshold sounds. C1 [Kauramaki, Jaakko; Jaaskelainen, Iiro P.; Hanninen, Jarno L.; Lampinen, Jouko; Sams, Mikko] Aalto Univ, Sch Sci, Brain & Mind Lab, Dept Biomed Engn & Computat Sci BECS, Espoo, Finland. [Auranen, Toni] Aalto Univ, Sch Sci, OV Lounasmaa Lab, Adv Magnet Imaging Ctr, Espoo, Finland. [Auranen, Toni] Aalto Univ, Sch Sci, OV Lounasmaa Lab, Brain Res Unit, Espoo, Finland. [Nummenmaa, Aapo] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Nummenmaa, Aapo] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. RP Kauramaki, J (reprint author), Aalto Univ, Sch Sci, Brain & Mind Lab, Dept Biomed Engn & Computat Sci BECS, Espoo, Finland. EM jaakko.kauramaki@aalto.fi RI Jaaskelainen, Iiro/C-7392-2012; Sams, Mikko/G-7060-2012; Auranen, Toni/J-7137-2012 OI Jaaskelainen, Iiro/0000-0001-6001-6950; FU Finnish Graduate School of Neuroscience; Emil Aaltonen Foundation; Ella and Georg Ehrnrooth Foundation; Academy of Finland [127624, 129670, 130412] FX This study was financially supported by the Finnish Graduate School of Neuroscience (JK), Emil Aaltonen Foundation (JK), Ella and Georg Ehrnrooth Foundation (JK) and by the Academy of Finland, grant nos. 127624 (AN), 129670 (IPJ and MS), 130412 (IJ). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 73 TC 6 Z9 8 U1 1 U2 6 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 OCT 11 PY 2012 VL 7 IS 10 AR e46872 DI 10.1371/journal.pone.0046872 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020KP UT WOS:000309807700039 PM 23071654 ER PT J AU Qi, L Zhang, XD Wu, JC Lin, F Wang, J DiFiglia, M Qin, ZH AF Qi, Lin Zhang, Xing-Ding Wu, Jun-Chao Lin, Fang Wang, Jin DiFiglia, Marian Qin, Zheng-Hong TI The Role of Chaperone-Mediated Autophagy in Huntingtin Degradation SO PLOS ONE LA English DT Article ID RAT-LIVER LYSOSOMES; MUTANT HUNTINGTIN; CYTOSOLIC PROTEINS; PEPTIDE SEQUENCES; SELECTIVE UPTAKE; ALPHA-SYNUCLEIN; CELL; DISEASE; NEURODEGENERATION; MACROAUTOPHAGY AB Huntington Disease (HD) is caused by an abnormal expansion of polyQ tract in the protein named huntingtin (Htt). HD pathology is featured by accumulation and aggregation of mutant Htt in striatal and cortical neurons. Aberrant Htt degradation is implicated in HD pathogenesis. The aim of this study was to investigate the regulatory role of chaperone-mediated autophagy (CMA) components, heat shock protein cognate 70 (Hsc70) and lysosome-associated protein 2A (LAMP-2A) in degradation of Htt fragment 1-552aa (Htt-552). A cell model of HD was produced by overexpression of Htt-552 with adenovirus. The involvement of CMA components in degradation of Htt-552 was determined with over-expression or silencing of Hsc70 and LAMP-2A. The results confirmed previous reports that both macroautophagy and CMA were involved in degradation of Htt-552. Changing the levels of CMA-related proteins affected the accumulation of Htt-552. The lysosomal binding and luminal transport of Htt-552 was demonstrated by incubation of Htt-552 with isolated lysosomes. Expansion of the polyQ tract in Htt-552 impaired its uptake and degradation by lysosomes. Mutation of putative KFERQ motif in wild-type Htt-552 interfered with interactions between Htt-552 and Hsc70. Endogenous Hsc70 and LAMP-2A interacted with exogenously expressed Htt-552. Modulating the levels of CMA related proteins degraded endogenous full-length Htt. These studies suggest that Hsc70 and LAMP-2A through CMA play a role in the clearance of Htt and suggest a novel strategy to target the degradation of mutant Htt. C1 [Qi, Lin; Zhang, Xing-Ding; Wu, Jun-Chao; Lin, Fang; Wang, Jin; Qin, Zheng-Hong] Soochow Univ, Sch Pharmaceut Sci, Dept Pharmacol, Suzhou, Peoples R China. [Qi, Lin; Zhang, Xing-Ding; Wu, Jun-Chao; Lin, Fang; Wang, Jin; Qin, Zheng-Hong] Soochow Univ, Sch Pharmaceut Sci, Lab Aging & Nervous Dis, Suzhou, Peoples R China. [DiFiglia, Marian] Massachusetts Gen Hosp, Lab Cellular Neurobiol, Charlestown, MA USA. [DiFiglia, Marian] Harvard Univ, Sch Med, Charlestown, MA USA. RP Qin, ZH (reprint author), Soochow Univ, Sch Pharmaceut Sci, Dept Pharmacol, Suzhou, Peoples R China. EM qinzhenhong@suda.edu.cn RI Zhang, Xingding/C-8780-2014 OI Zhang, Xingding/0000-0002-2759-5185 FU National Natural Science Foundation of China [30930035]; Priority Academic Program Development of Jiangsu Higher Education Institutes; Jiangsu Province's Outstanding Medical Academic Leader Program [LJ201139] FX This work was partially supported by the National Natural Science Foundation of China (No 30930035), and by The Priority Academic Program Development of Jiangsu Higher Education Institutes and by Jiangsu Province's Outstanding Medical Academic Leader Program (LJ201139). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 30 Z9 31 U1 2 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 OCT 11 PY 2012 VL 7 IS 10 AR e46834 DI 10.1371/journal.pone.0046834 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 020KP UT WOS:000309807700036 PM 23071649 ER PT J AU Qi, QB Chu, AY Kang, JH Jensen, MK Curhan, GC Pasquale, LR Ridker, PM Hunter, DJ Willett, WC Rimm, EB Chasman, DI Hu, FB Qi, L AF Qi, Qibin Chu, Audrey Y. Kang, Jae H. Jensen, Majken K. Curhan, Gary C. Pasquale, Louis R. Ridker, Paul M. Hunter, David J. Willett, Walter C. Rimm, Eric B. Chasman, Daniel I. Hu, Frank B. Qi, Lu TI Sugar-Sweetened Beverages and Genetic Risk of Obesity SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BODY-MASS INDEX; FOOD FREQUENCY QUESTIONNAIRE; GENOME-WIDE ASSOCIATION; MIDDLE-AGED WOMEN; PHYSICAL-ACTIVITY; WEIGHT-GAIN; DISEASE RISK; HEALTH; REPRODUCIBILITY; VARIANTS AB BACKGROUND Temporal increases in the consumption of sugar-sweetened beverages have paralleled the rise in obesity prevalence, but whether the intake of such beverages interacts with the genetic predisposition to adiposity is unknown. METHODS We analyzed the interaction between genetic predisposition and the intake of sugar-sweetened beverages in relation to body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and obesity risk in 6934 women from the Nurses' Health Study (NHS) and in 4423 men from the Health Professionals Follow-up Study (HPFS) and also in a replication cohort of 21,740 women from the Women's Genome Health Study (WGHS). The genetic-predisposition score was calculated on the basis of 32 BMI-associated loci. The intake of sugar-sweetened beverages was examined prospectively in relation to BMI. RESULTS In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P < 0.001 for interaction). For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P = 0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P = 0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P = 0.007 for interaction). CONCLUSIONS The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages. (Funded by the National Institutes of Health and others.) C1 [Qi, Qibin; Jensen, Majken K.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Curhan, Gary C.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chu, Audrey Y.; Ridker, Paul M.; Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Dis, Boston, MA 02115 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Kang, Jae H.; Curhan, Gary C.; Pasquale, Louis R.; Hunter, David J.; Willett, Walter C.; Rimm, Eric B.; Hu, Frank B.; Qi, Lu] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Pasquale, Louis R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu RI Qi, Qibin/H-9055-2012 FU National Institutes of Health; National Institutes of Health [DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, 5P30DK46200, U54CA155626, DK58845, U01HG004728-02, EY015473, DK70756, DK46200, HL043851, HL69757, CA047988]; Merck Research Laboratories; American Heart Association Scientist Development Award [0730094N]; Research to Prevent Blindness award; Harvard Ophthalmology Scholar Award; Harvard Glaucoma Center of Excellence; Amgen; Genzyme; Isis Pharmaceuticals; Vascular Biogenics; Merck; Abbott; Novartis; AstraZeneca; Novo Nordisk; California Walnut Commission; Kellogg FX Funded by the National Institutes of Health and others.; Supported by grants (DK091718, HL071981, HL073168, CA87969, CA49449, CA055075, HL34594, HL088521, U01HG004399, DK080140, 5P30DK46200, U54CA155626, DK58845, U01HG004728-02, EY015473, DK70756, and DK46200) from the National Institutes of Health, with additional support for genotyping from Merck Research Laboratories; an American Heart Association Scientist Development Award (0730094N, to Dr. L. Qi); and a Research to Prevent Blindness award and a Harvard Ophthalmology Scholar Award (both to Dr. Pasquale) from the Harvard Glaucoma Center of Excellence. The WGHS is supported by grants (HL043851, HL69757, and CA047988) from the National Institutes of Health, with collaborative scientific support and funding for genotyping provided by Amgen.; Dr. Ridker reports receiving consulting fees from Genzyme, Isis Pharmaceuticals, Vascular Biogenics, Merck, and Abbott and grant support to his institution from Novartis and AstraZeneca and being listed as a co-inventor on patents held by his institution that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes (patent and royalty payments are received by Brigham and Women's Hospital); Dr. Hu, receiving consulting fees from Novo Nordisk and grant support to his institution from Merck and the California Walnut Commission; and Dr. L. Qi, receiving lecture fees from Kellogg. No other potential conflict of interest relevant to this article was reported. NR 44 TC 166 Z9 172 U1 6 U2 53 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 11 PY 2012 VL 367 IS 15 BP 1387 EP 1396 DI 10.1056/NEJMoa1203039 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 018ID UT WOS:000309652700005 PM 22998338 ER PT J AU Yager, PH Singhal, AB Nogueira, RG AF Yager, Phoebe H. Singhal, Aneesh B. Nogueira, Raul G. TI Case 31-2012: An 18-Year-Old Man with Blurred Vision, Dysarthria, and Ataxia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; YOUNG-ADULTS; RISK-FACTORS; INTRAVENOUS THROMBOLYSIS; MYCOPLASMA-PNEUMONIAE; POOLED ANALYSIS; EXPERIENCE; CLASSIFICATION; HEMORRHAGE C1 [Yager, Phoebe H.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Singhal, Aneesh B.; Nogueira, Raul G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Yager, Phoebe H.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Singhal, Aneesh B.; Nogueira, Raul G.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Yager, PH (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. FU Pfizer; Photothera; Stryker/Concentric Medical; Covidien/ev3 Neurovascular; CoAxia; Penumbra; Rapid Medical; Reverse Medical; Neurointervention; Concentric Medical; Covidien FX Dr. Singhal reports grant support to his institution from Pfizer and Photothera and receiving fees for serving as an expert witness in medicolegal cases involving stroke in young adults. Dr. Nogueira reports receiving consulting fees from Stryker/Concentric Medical, Covidien/ev3 Neurovascular, CoAxia, Penumbra, Rapid Medical, Reverse Medical, and Neurointervention; fees from Concentric Medical, Covidien, and Penumbra for participation on committees for clinical trials; and fees for serving on a data safety and monitoring board for Rapid Medical. No other potential conflict of interest relevant to this article was reported. NR 46 TC 2 Z9 2 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 11 PY 2012 VL 367 IS 15 BP 1450 EP 1460 DI 10.1056/NEJMcpc1208150 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 018ID UT WOS:000309652700013 PM 23050529 ER PT J AU Wilt, TJ Brawer, MK Aronson, WJ AF Wilt, Timothy J. Brawer, Michael K. Aronson, William J. TI Radical Prostatectomy versus Observation for Prostate Cancer REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Wilt, Timothy J.] Minneapolis VA Ctr Chron Dis Outcomes Res, Minneapolis, MN USA. [Brawer, Michael K.] Myriad Genet, Salt Lake City, UT USA. [Aronson, William J.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Wilt, TJ (reprint author), Minneapolis VA Ctr Chron Dis Outcomes Res, Minneapolis, MN USA. EM tim.wilt@va.gov NR 5 TC 0 Z9 0 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 11 PY 2012 VL 367 IS 15 BP 1468 EP 1469 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 018ID UT WOS:000309652700022 ER PT J AU Larson, S Comina, G Gilman, RH Tracey, BH Bravard, M Lopez, JW AF Larson, Sandra Comina, German Gilman, Robert H. Tracey, Brian H. Bravard, Marjory Lopez, Jose W. TI Validation of an Automated Cough Detection Algorithm for Tracking Recovery of Pulmonary Tuberculosis Patients SO PLOS ONE LA English DT Article ID FREQUENCY; MODELS AB Background: A laboratory-free test for assessing recovery from pulmonary tuberculosis (TB) would be extremely beneficial in regions of the world where laboratory facilities are lacking. Our hypothesis is that analysis of cough sound recordings may provide such a test. In the current paper, we present validation of a cough analysis tool. Methodology/Principal Findings: Cough data was collected from a cohort of TB patients in Lima, Peru and 25.5 hours of recordings were manually annotated by clinical staff. Analysis software was developed and validated by comparison to manual scoring. Because many patients cough in bursts, coughing was characterized in terms of cough epochs. Our software correctly detects 75.5% of cough episodes with a specificity of 99.6% (comparable to past results using the same definition) and a median false positive rate of 4 false positives/hour, due to the noisy, real-world nature of our dataset. We then manually review detected coughs to eliminate false positives, in effect using the algorithm as a pre-screening tool that reduces reviewing time to roughly 5% of the recording length. This cough analysis approach provides a foundation to support larger-scale studies of coughing rates over time for TB patients undergoing treatment. C1 [Tracey, Brian H.] Tufts Univ, Dept Elect & Comp Engn, Medford, MA 02155 USA. [Larson, Sandra] Michigan State Univ, Coll Osteopath Med, E Lansing, MI 48824 USA. [Comina, German] Univ Nacl Ingn, Fac Ciencias, Lab Ingn Fis, Lima, Peru. [Gilman, Robert H.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Bravard, Marjory] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Lopez, Jose W.] Hosp Nacl Dos de Mayo, Unidad Epidemiol, Lima, Peru. RP Tracey, BH (reprint author), Tufts Univ, Dept Elect & Comp Engn, Medford, MA 02155 USA. EM btracey@eecs.tufts.edu RI Tracey, Brian/I-2181-2013; OI Lopez, Jose/0000-0003-0614-7284; Comina, German/0000-0003-2114-0486 FU National Institutes of Health [5D43TW006581, R21 AI094143]; NIH Fogarty Foundation; Consejo Nacional de Ciencia, Tecnologia e Innovacion Tecnologica of Peru (CONCYTEC) FX This work was funded in part by National Institutes of Health through awards 5D43TW006581 "Infectious Diseases Training Program in Peru'' and R21 AI094143 "Cough-A Rapid Indication of Response to Therapy in Pulmonary Tuberculosis''. JL and MB were supported by NIH Fogarty Foundation fellowships. G. Comina wants to thank the Consejo Nacional de Ciencia, Tecnologia e Innovacion Tecnologica of Peru (CONCYTEC) for their support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 16 TC 6 Z9 6 U1 0 U2 6 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 OCT 10 PY 2012 VL 7 IS 10 AR e46229 DI 10.1371/journal.pone.0046229 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZU UT WOS:000312385200017 PM 23071550 ER PT J AU Wu, G Zhu, J He, FH Wang, WW Hu, SN Yu, J AF Wu, Gang Zhu, Jiang He, Fuhong Wang, Weiwei Hu, Songnian Yu, Jun TI Gene and Genome Parameters of Mammalian Liver Circadian Genes (LCGs) SO PLOS ONE LA English DT Article ID EMBRYONIC STEM-CELLS; EXPRESSION; CLOCK; MOUSE; RHYTHMS; TIME; ORGANIZATION; DROSOPHILA; TRANSCRIPTION; ENTRAINMENT AB The mammalian circadian system controls various physiology processes and behavior responses by regulating thousands of circadian genes with rhythmic expressions. In this study, we redefined circadian-regulated genes based on published results in the mouse liver and compared them with other gene groups defined relative to circadian regulations, especially the non-circadian-regulated genes expressed in liver at multiple molecular levels from gene position to protein expression based on integrative analyses of different datasets from the literature. Based on the intra-tissue analysis, the liver circadian genes or LCGs show unique features when compared to other gene groups. First, LCGs in general have less neighboring genes and larger in both genomic and 3' UTR lengths but shorter in CDS (coding sequence) lengths. Second, LCGs have higher mRNA and protein abundance, higher temporal expression variations, and shorter mRNA half-life. Third, more than 60% of LCGs form major co-expression clusters centered in four temporal windows: dawn, day, dusk, and night. In addition, larger and smaller LCGs are found mainly expressed in the day and night temporal windows, respectively, and we believe that LCGs are well-partitioned into the gene expression regulatory network that takes advantage of gene size, expression constraint, and chromosomal architecture. Based on inter-tissue analysis, more than half of LCGs are ubiquitously expressed in multiple tissues but only show rhythmical expression in one or limited number of tissues. LCGs show at least three-fold lower expression variations across the temporal windows than those among different tissues, and this observation suggests that temporal expression variations regulated by the circadian system is relatively subtle as compared with the tissue expression variations formed during development. Taken together, we suggest that the circadian system selects gene parameters in a cost effective way to improve tissue-specific functions by adapting temporal variations from the environment over evolutionary time scales. C1 [Wu, Gang; Zhu, Jiang; He, Fuhong; Wang, Weiwei; Hu, Songnian; Yu, Jun] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing, Peoples R China. [Wu, Gang] Chinese Acad Sci, Grad Univ, Beijing, Peoples R China. [Zhu, Jiang] Harvard Univ, Sch Med, Boston, MA USA. [Zhu, Jiang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [He, Fuhong] Chinese Acad Sci, Beijing Inst Genom, Lab Dis Genom & Individualized Med, Beijing, Peoples R China. [Wang, Weiwei] Univ Alberta, Dept Med, Edmonton, AB, Canada. RP Yu, J (reprint author), Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing, Peoples R China. EM junyu@big.ac.cn RI Zhu, Jiang/E-3049-2013; OI Hu, Songnian/0000-0003-3966-3111 FU National Natural Science Foundation of China [2011CB944100, 2011CB944101, 90919024]; Ministry of Science and Technology [2009FY120100]; Ministry of Science and Technology of the People's Republic of China [2012AA020409] FX This work is supported by grants from the National Basic Research Program (973 Program; 2011CB944100 and 2011CB944101), National Natural Science Foundation of China (90919024), from the Special Foundation Work Program, the Ministry of Science and Technology (2009FY120100), from National Programs for High Technology Research and Development (863 Program), the Ministry of Science and Technology of the People's Republic of China (2012AA020409). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 4 Z9 5 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2012 VL 7 IS 10 AR e46961 DI 10.1371/journal.pone.0046961 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054ZU UT WOS:000312385200055 PM 23071677 ER PT J AU Lane, RF St George-Hyslop, P Hempstead, BL Small, SA Strittmatter, SM Gandy, S AF Lane, Rachel F. St George-Hyslop, Peter Hempstead, Barbara L. Small, Scott A. Strittmatter, Stephen M. Gandy, Sam TI Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; SPORADIC ALZHEIMERS-DISEASE; QUANTITATIVE TRAIT LOCUS; GENOME-WIDE ASSOCIATION; LR11/SORLA EXPRESSION; SUSCEPTIBILITY LOCI; NEUROTROPHIC FACTOR; PARKINSON DISEASE; BETA PRODUCTION; DOWN-SYNDROME AB Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to the trans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neurotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration. C1 [Lane, Rachel F.] Alzheimers Drug Discovery Fdn, New York, NY 10019 USA. [St George-Hyslop, Peter] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. [St George-Hyslop, Peter] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England. [St George-Hyslop, Peter] Univ Cambridge, Dept Clin Neurosci, Cambridge CB2 0XY, England. [Hempstead, Barbara L.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Small, Scott A.] Columbia Univ, Sch Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Small, Scott A.] Columbia Univ, Sch Phys & Surg, Taub Inst, New York, NY 10032 USA. [Strittmatter, Stephen M.] Yale Univ, Sch Med, Cellular Neurosci Neurodegenerat & Repair Program, Dept Neurol, New Haven, CT 06536 USA. [Strittmatter, Stephen M.] Yale Univ, Sch Med, Cellular Neurosci Neurodegenerat & Repair Program, Dept Neurobiol, New Haven, CT 06536 USA. [Gandy, Sam] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY 10029 USA. [Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY 10468 USA. RP Lane, RF (reprint author), Alzheimers Drug Discovery Fdn, 57 W 57th St,Suite 904, New York, NY 10019 USA. EM RLane@alzdiscovery.org; samuel.gandy@mssm.edu RI Strittmatter, Stephen/F-5739-2011 OI Strittmatter, Stephen/0000-0001-8188-3092 FU NIH [NS075685, NS030687, AG025161, NS074319, AG034924]; Wellcome Trust; Canadian Institutes of Health Research; Alzheimer Society of Ontario; Howard Hughes Medical Institute; Cure Alzheimer's Fund; US Department of Veteran Affairs FX We gratefully acknowledge the support of the NIH (NS075685 to S.G., NS030687 to B.L.H., AG025161 to S.A.S., NS074319 and AG034924 to S.M.S.), the Wellcome Trust, Canadian Institutes of Health Research, Alzheimer Society of Ontario, and Howard Hughes Medical Institute (P.StG.-H.), the Cure Alzheimer's Fund (S.G.), and the US Department of Veteran Affairs (S.G.). R.F.L. and S.G.thank Dr. Alan Attie for providing advice and helpful conversations during the preparation of this paper. NR 60 TC 25 Z9 26 U1 0 U2 18 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 OCT 10 PY 2012 VL 32 IS 41 BP 14080 EP 14086 DI 10.1523/JNEUROSCI.3359-12.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 022MO UT WOS:000309963700006 PM 23055476 ER PT J AU Inaba, H Coustan-Smith, E Cao, XY Pounds, SB Shurtleff, SA Wang, KY Raimondi, SC Onciu, M Jacobsen, J Ribeiro, RC Dahl, GV Bowman, WP Taub, JW Degar, B Leung, W Downing, JR Pui, CH Rubnitz, JE Campana, D AF Inaba, Hiroto Coustan-Smith, Elaine Cao, Xueyuan Pounds, Stanley B. Shurtleff, Sheila A. Wang, Kathleen Y. Raimondi, Susana C. Onciu, Mihaela Jacobsen, Jeffrey Ribeiro, Raul C. Dahl, Gary V. Bowman, W. Paul Taub, Jeffrey W. Degar, Barbara Leung, Wing Downing, James R. Pui, Ching-Hon Rubnitz, Jeffrey E. Campana, Dario TI Comparative Analysis of Different Approaches to Measure Treatment Response in Acute Myeloid Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MINIMAL RESIDUAL DISEASE; MULTIPARAMETER FLOW-CYTOMETRY; RT-PCR; CLINICAL-SIGNIFICANCE; PROGNOSTIC VALUE; COMPLETE REMISSION; DIRECTED THERAPY; CHILDHOOD AML; RQ-PCR; RELAPSE AB Purpose In acute myeloid leukemia (AML), initial treatment response by morphologic analysis of bone marrow predicts long-term outcome. Response can now be assessed by minimal residual disease (MRD) monitoring with flow cytometry or polymerase chain reaction (PCR). We determined the relation among the results of these approaches and their prognostic value. Patients and Methods In the multicenter AML02 study, follow-up bone marrow samples from 203 children and adolescents with newly diagnosed AML were examined by flow cytometry (n = 1,514), morphology (n = 1,382), and PCR amplification of fusion transcripts (n = 508). Results were correlated with treatment outcome. Results Among 1,215 samples with less than 5% leukemic myeloblasts by morphology, 100 (8.2%) were MRD positive (>= 0.1%) by flow cytometry, whereas 96 (57.5%) of the 167 samples with >= 5% blasts were MRD negative. Virtually all (308 of 311; 99.0%) MRD-negative samples by PCR were also MRD negative by flow cytometry. However, only 19 (9.6%) of the 197 PCR-positive samples were flow cytometry positive, with analyses of AML1-ETO and CBF beta-MYH11 accounting for most discrepancies, whereas eight of 13 MLL-positive samples had detectable MRD by flow cytometry. MRD by flow cytometry after induction 1 or 2 predicted lower event-free survival and higher relapse rate (P < .001) and was an independent prognostic factor in a multivariable analysis; prediction was not improved by morphologic information or molecular findings. Conclusion In childhood AML, morphologic assessment of treatment response has limited value if MRD is measured by flow cytometry. MLL fusion transcripts can provide prognostic information in some patients, whereas monitoring of AML1-ETO and CBF beta-MYH11 transcripts is largely uninformative. J Clin Oncol 30:3625-3632. (C) 2012 by American Society of Clinical Oncology C1 [Inaba, Hiroto] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 USA. [Inaba, Hiroto; Cao, Xueyuan; Pounds, Stanley B.; Shurtleff, Sheila A.; Wang, Kathleen Y.; Raimondi, Susana C.; Onciu, Mihaela; Jacobsen, Jeffrey; Ribeiro, Raul C.; Leung, Wing; Downing, James R.; Pui, Ching-Hon; Rubnitz, Jeffrey E.] Univ Tennessee, Coll Med, Memphis, TN USA. [Coustan-Smith, Elaine; Campana, Dario] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 117595, Singapore. [Dahl, Gary V.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Dahl, Gary V.] Stanford Canc Ctr, Palo Alto, CA USA. [Bowman, W. Paul] Cook Childrens Med Ctr, Ft Worth, TX USA. [Taub, Jeffrey W.] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Degar, Barbara] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Inaba, H (reprint author), St Jude Childrens Res Hosp, Dept Oncol, MS 260,262 Danny Thomas Pl, Memphis, TN 38105 USA. EM hiroto.inaba@stjude.org OI Pounds, Stanley/0000-0002-9167-2114 FU National Institutes of Health [R01 CA115422, R25 CA23944, P30 CA21765]; American Lebanese Syrian Associated Charities FX Supported by Grants No. R01 CA115422, R25 CA23944, and P30 CA21765 from the National Institutes of Health and by the American Lebanese Syrian Associated Charities. NR 48 TC 59 Z9 59 U1 0 U2 10 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 OCT 10 PY 2012 VL 30 IS 29 BP 3625 EP 3632 DI 10.1200/JCO.2011.41.5323 PG 8 WC Oncology SC Oncology GA 018IM UT WOS:000309653600013 PM 22965955 ER PT J AU Slatore, CG Wiener, RS Cooke, CR AF Slatore, Christopher G. Wiener, Renda Soylemez Cooke, Colin R. TI Is Intensive Care Unit Admission an Indicator of Patient-Centered Care for Patients With Advanced Lung Cancer in SEER-Medicare? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CODE STATUS C1 [Slatore, Christopher G.] Portland VA Med Ctr, Portland, OR USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Wiener, Renda Soylemez] Edith Nourse Rogers Mem Vet Affairs Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Wiener, Renda Soylemez] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Cooke, Colin R.] Univ Michigan, Ctr Healthcare Outcomes & Policy, Ann Arbor, MI 48109 USA. [Cooke, Colin R.] Univ Michigan Hlth Syst, Ann Arbor, MI USA. RP Slatore, CG (reprint author), Portland VA Med Ctr, Portland, OR USA. OI Slatore, Christopher/0000-0003-0958-8122 NR 5 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 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 10 PY 2012 VL 30 IS 29 BP 3652 EP 3653 DI 10.1200/JCO.2012.45.0296 PG 3 WC Oncology SC Oncology GA 018IM UT WOS:000309653600019 ER PT J AU Joynt, KE Blumenthal, DM Orav, EJ Resnic, FS Jha, AK AF Joynt, Karen E. Blumenthal, Daniel M. Orav, E. John Resnic, Frederic S. Jha, Ashish K. TI Association of Public Reporting for Percutaneous Coronary Intervention With Utilization and Outcomes Among Medicare Beneficiaries With Acute Myocardial Infarction SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CARDIOVASCULAR DATA REGISTRY; MORTALITY RISK PREDICTION; UNINTENDED CONSEQUENCES; HEART-ASSOCIATION; BYPASS-SURGERY; MANAGEMENT; UPDATE AB Context Public reporting of patient outcomes is an important tool to improve quality of care, but some observers worry that such efforts will lead clinicians to avoid high-risk patients. Objective To determine whether public reporting for percutaneous coronary intervention (PCI) is associated with lower rates of PCI for patients with acute myocardial infarction (MI) or with higher mortality rates in this population. Design, Setting, and Patients Retrospective observational study conducted using data from fee-for-service Medicare patients (49 660 from reporting states and 48 142 from nonreporting states) admitted with acute MI to US acute care hospitals between 2002 and 2010. Logistic regression was used to compare PCI and mortality rates between reporting states (New York, Massachusetts, and Pennsylvania) and regional nonreporting states (Maine, Vermont, New Hampshire, Connecticut, Rhode Island, Maryland, and Delaware). Changes in PCI rates over time in Massachusetts compared with nonreporting states were also examined. Main Outcome Measures Risk-adjusted PCI and mortality rates. Results In 2010, patients with acute MI were less likely to receive PCI in public reporting states than in nonreporting states (unadjusted rates, 37.7% vs 42.7%, respectively; risk-adjusted odds ratio [OR], 0.82 [95% CI, 0.71-0.93]; P=.003). Differences were greatest among the 6708 patients with ST-segment elevation MI (61.8% vs 68.0%; OR, 0.73 [95% CI, 0.59-0.89]; P=.002) and the 2194 patients with cardiogenic shock or cardiac arrest (41.5% vs 46.7%; OR, 0.79 [95% CI, 0.64-0.98]; P=.03). There were no differences in overall mortality among patients with acute MI in reporting vs nonreporting states. In Massachusetts, odds of PCI for acute MI were comparable with odds in nonreporting states prior to public reporting (40.6% vs 41.8%; OR, 1.00 [95% CI, 0.71-1.41]). However, after implementation of public reporting, odds of undergoing PCI in Massachusetts decreased compared with nonreporting states (41.1% vs 45.6%; OR, 0.81 [95% CI, 0.47-1.38]; P=.03 for difference in differences). Differences were most pronounced for the 6081 patients with cardiogenic shock or cardiac arrest (prereporting: 44.2% vs 36.6%; OR, 1.40 [95% CI, 0.85-2.32]; postreporting: 43.9% vs 44.8%; OR, 0.92 [95% CI, 0.38-2.22]; P=.03 for difference in differences). Conclusions Among Medicare beneficiaries with acute MI, the use of PCI was lower for patients treated in 3 states with public reporting of PCI outcomes compared with patients treated in 7 regional control states without public reporting. However, there was no difference in overall acute MI mortality between states with and without public reporting. JAMA. 2012;308(14):1460-1468 www.jama.com C1 [Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Orav, E. John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Joynt, Karen E.; Resnic, Frederic S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Orav, E. John; Jha, Ashish K.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Joynt, Karen E.; Jha, Ashish K.] VA Boston Healthcare Syst, Boston, MA USA. [Blumenthal, Daniel M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Joynt, KE (reprint author), 75 Francis St, Boston, MA 02115 USA. EM kjoynt@partners.org FU National Heart, Lung, and Blood Institute [1K23HL109177-01] FX Funding for this study was provided by grant 1K23HL109177-01 from the National Heart, Lung, and Blood Institute. NR 16 TC 80 Z9 82 U1 3 U2 8 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 OCT 10 PY 2012 VL 308 IS 14 BP 1460 EP 1468 DI 10.1001/jama.2012.12922 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 017GY UT WOS:000309579300025 PM 23047360 ER PT J AU Yu, EW Finkelstein, JS AF Yu, Elaine W. Finkelstein, Joel S. TI Bone Density Testing in Older Women Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID OSTEOPOROSIS; FRACTURE C1 [Yu, Elaine W.; Finkelstein, Joel S.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Yu, EW (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM ewyu@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 10 PY 2012 VL 308 IS 14 BP 1429 EP 1429 DI 10.1001/jama.2012.12820 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 017GY UT WOS:000309579300014 ER PT J AU Ho, JH de Moura, MB Lin, Y Vincent, G Thorne, S Duncan, LM Lin, HM Kirkwood, JM Becker, D Van Houten, B Moschos, SJ AF Ho, Jonhan de Moura, Michelle Barbi Lin, Yan Vincent, Garret Thorne, Stephen Duncan, Lyn M. Lin Hui-Min Kirkwood, John M. Becker, Dorothea Van Houten, Bennett Moschos, Stergios J. TI Importance of glycolysis and oxidative phosphorylation in advanced melanoma SO MOLECULAR CANCER LA English DT Article DE Melanoma; Lactate dehydrogenase; Glycolysis; Mitochondria; Oxidative phosphorylation; Monocarboxylate transporters ID LACTATE-DEHYDROGENASE; METASTATIC MELANOMA; TRANSPORTER MCT4; CELLS; EXPRESSION; HYPOXIA; CANCER; RESPIRATION; CARCINOMAS; METABOLISM AB Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy. C1 [Ho, Jonhan] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15213 USA. [de Moura, Michelle Barbi; Van Houten, Bennett] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15213 USA. [de Moura, Michelle Barbi; Van Houten, Bennett] Univ Pittsburgh, Dept Biol Chem, Pittsburgh, PA 15213 USA. [Lin, Yan; Lin Hui-Min] Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15213 USA. [Vincent, Garret; Kirkwood, John M.; Moschos, Stergios J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Thorne, Stephen] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15213 USA. [Duncan, Lyn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Becker, Dorothea] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA. RP Moschos, SJ (reprint author), Univ N Carolina, Dept Med, Phys Off Bldg,3rd Floor,Suite 3116,CB 7305,170 Ma, Chapel Hill, NC 27599 USA. EM moschos@med.unc.edu FU NIH [P50CA121973]; Pennsylvania Department of Health PA CURE award FX We would like to thank D. Bachorski for collecting sera for LDH and lactate studies, M. Acquafondata for antibody probing of the TMA. This work was supported by a Career Development Award to S. J. M. from the NIH P50CA121973 SPORE in Skin Cancer, and a Pennsylvania Department of Health PA CURE award to B. V. H. NR 41 TC 38 Z9 38 U1 0 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236