FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yue, XM Pourladian, IS Tootell, RBH Ungerleider, LG AF Yue, Xiaomin Pourladian, Irene S. Tootell, Roger B. H. Ungerleider, Leslie G. TI Curvature-processing network in macaque visual cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE curvature patches; face patches; curved Gabor filters ID INFERIOR TEMPORAL CORTEX; POSTERIOR INFEROTEMPORAL CORTEX; FUSIFORM FACE AREA; STRIATE CORTEX; RETINOTOPIC ORGANIZATION; OBJECT REPRESENTATIONS; SHAPE REPRESENTATION; CARTESIAN GRATINGS; FUNCTIONAL-ANATOMY; NONHUMAN-PRIMATES AB Our visual environment abounds with curved features. Thus, the goal of understanding visual processing should include the processing of curved features. Using functional magnetic resonance imaging in behaving monkeys, we demonstrated a network of cortical areas selective for the processing of curved features. This network includes three distinct hierarchically organized regions within the ventral visual pathway: a posterior curvature-biased patch (PCP) located in the near-foveal representation of dorsal V4, a middle curvature-biased patch (MCP) located on the ventral lip of the posterior superior temporal sulcus (STS) in area TEO, and an anterior curvature-biased patch (ACP) located just below the STS in anterior area TE. Our results further indicate that the processing of curvature becomes increasingly complex from PCP to ACP. The proximity of the curvature-processing network to the well-known face-processing network suggests a possible functional link between them. C1 [Yue, Xiaomin; Pourladian, Irene S.; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Yue, XM (reprint author), NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. EM yuex@mail.nih.gov; ungerlel@mail.nih.gov FU National Institute of Mental Health Intramural Research Program; National Institutes of Health [R01 EY017081] FX The study was supported by National Institute of Mental Health Intramural Research Program (X.Y., I.S.P., and L.G.U.) and National Institutes of Health Grant R01 EY017081 (to R.B.H.T.). NR 78 TC 10 Z9 10 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 19 PY 2014 VL 111 IS 33 BP E3467 EP E3475 DI 10.1073/pnas.1412616111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AN2TS UT WOS:000340438800016 PM 25092328 ER PT J AU Natale, A Reddy, VY Monir, G Wilber, DJ Lindsay, BD McElderry, HT Kantipudi, C Mansour, MC Melby, DP Packer, DL Nakagawa, H Zhang, BH Stagg, RB Boo, LM Marchlinski, FE AF Natale, Andrea Reddy, Vivek Y. Monir, George Wilber, David J. Lindsay, Bruce D. McElderry, H. Thomas Kantipudi, Charan Mansour, Moussa C. Melby, Daniel P. Packer, Douglas L. Nakagawa, Hiroshi Zhang, Baohui Stagg, Robert B. Boo, Lee Ming Marchlinski, Francis E. TI Paroxysmal AF Catheter Ablation With a Contact Force Sensing Catheter Results of the Prospective, Multicenter SMART-AF Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE atrial fibrillation; catheter ablation; contact force; radiofrequency ID HUMAN ATRIAL-FIBRILLATION; ELECTRODE-TISSUE CONTACT; RADIOFREQUENCY ABLATION; WORLDWIDE SURVEY; PULMONARY VEINS; FOLLOW-UP; PREDICTORS; SELECTION; EFFICACY; TOCCATA AB BACKGROUND Catheter ablation is important for treatment of paroxysmal atrial fibrillation (PAF). Limited animal and human studies suggest a correlation between electrode-tissue contact and radiofrequency lesion generation. OBJECTIVES The study sought to assess the safety and effectiveness of an irrigated, contact force (CF)-sensing catheter in the treatment of drug refractory symptomatic PAF. METHODS A prospective, multicenter, nonrandomized study was conducted. Enrollment criteria included: >= 3 symptomatic episodes of PAF within 6 months of enrollment and failure of >= 1 antiarrhythmic drug (Class I to IV). Ablation included pulmonary vein isolation with confirmed entrance block as procedural endpoint. RESULTS A total of 172 patients were enrolled at 21 sites, where 161 patients had a study catheter inserted and 160 patients underwent radiofrequency application. Procedural-related serious adverse events occurring within 7 days of the procedure included tamponade (n = 4), pericarditis (n = 3), heart block (n = 1, prior to radiofrequency application), and vascular access complications (n = 4). By Kaplan-Meier analyses, 12-month freedom from atrial fibrillation/atrial flutter/atrial tachycardia recurrence was 72.5%. The average CF per procedure was 17.9 +/- 9.4 g. When the CF employed was between investigator selected working ranges >= 80% of the time during therapy, outcomes were 4.25 times more likely to be successful (p = 0.0054; 95% confidence interval: 1.53 to 11.79). CONCLUSIONS The SMART-AF trial demonstrated that this irrigated CF-sensing catheter is safe and effective for the treatment of drug refractory symptomatic PAF, with no unanticipated device-related adverse events. The increased percent of time within investigator-targeted CF ranges correlates with increased freedom from arrhythmia recurrence. Stable CF during radiofrequency application increases the likelihood of 12-month success. (THERMOCOOL (R) SMARTTOUCH (R) Catheter for Treatment of Symptomatic Paroxysmal Atrial Fibrillation; NCT01385202) (C) 2014 by the American College of Cardiology Foundation. C1 [Natale, Andrea] St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX 78705 USA. [Natale, Andrea] Stanford Univ, Div Cardiol, Stanford, CA 94305 USA. [Natale, Andrea] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Natale, Andrea] Calif Pacific Med Ctr, EP Serv, San Francisco, CA USA. [Natale, Andrea] Scripps Clin, San Diego, CA USA. [Natale, Andrea] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Reddy, Vivek Y.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Monir, George] Florida Hosp, Cardiovasc Inst, Orlando, FL USA. [Wilber, David J.] Loyola Univ, Maywood, IL 60153 USA. [Lindsay, Bruce D.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [McElderry, H. Thomas] Univ Alabama Birmingham, Birmingham, AL USA. [Kantipudi, Charan] Piedmont Heart Inst, Atlanta, GA USA. [Mansour, Moussa C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Melby, Daniel P.] Minneapolis Heart Inst Fdn, Minneapolis, MN USA. [Packer, Douglas L.] Mayo Clin, Rochester, MN USA. [Nakagawa, Hiroshi] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Zhang, Baohui; Stagg, Robert B.; Boo, Lee Ming] Biosense Webster Inc, Diamond Bar, CA USA. [Marchlinski, Francis E.] Hosp Univ Penn, Philadelphia, PA 19104 USA. RP Natale, A (reprint author), St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, 3000 N IH-35,Suite 700,705Res Fdn, Austin, TX 78705 USA. EM dr.natale@gmail.com FU Biosense Webster, Inc.; St. Jude Medical; Medtronic; Boston Scientific; Biotronik; Janssen; MC10; Boston Scientific/EPT; Endosense; EpiEP; EP Advocate; Medtronic CryoCath LP; Minnesota Partnership for Biotechnology and Medical Genomics/University of Minnesota; National Institutes of Health; CardioFocus; Hansen Medical; Siemens P4D; Siemens AcuNav; Thermedical (EP Limited) FX The study is funded by Biosense Webster, Inc. The institutions of employment for Drs. Natale, Reddy, Monir, Wilber, Lindsay, McElderry, Kantipudi, Mansour, Melby, Packer, and Marchlinski have received compensation from Biosense Webster, Inc. to participate as investigators in the study; there were no personal fees provided to the investigators for participating in the study or the manuscript development. The Mayo Clinic and Dr. Packer have a financial interest in mapping technology that may have been used at some of the centers participating in this research. In accordance with the Bayh-Dole Act, this technology has been licensed to St. Jude Medical, and the Mayo Clinic and Dr. Packer have received annual royalties >$10,000, the federal threshold for significant financial interest. Dr. Natale has received honoraria/consulting fees from Biosense Webster, Inc., St. Jude Medical, Medtronic, Boston Scientific, Biotronik, and Janssen outside the submitted work. Dr. Reddy has received grants from Biosense Webster, Inc. during the conduct of the study; personal fees from Biosense Webster, Inc. outside the submitted work; and consulting fees from St. Jude Medical. Dr. Monir has received personal fees from Biosense Webster, Inc. outside the submitted work. Dr. Wilber has received grants and lecture/consultant fees from Biosense Webster, Inc.; grants and consultant fees from Medtronic; and lecture fees from St. Jude Medical, outside the submitted work. Dr. Lindsay has received honoraria fees for educational programs and serves on the scientific advisory board from Biosense Webster, Inc., outside the submitted work. Dr. McElderry has received personal fees from Biosense Webster, Inc.; grants and personal fees from Boston Scientific; and personal fees from St. Jude Medical, outside the submitted work. Dr. Mansour has received grant support from St. Jude Medical, Boston Scientific, Biosense Webster, Inc., and MC10 outside the submitted work; and personal fees (consultation fee) from Biosense Webster, Inc. Dr. Packer has provided consulting services for Abiomed, Biosense Webster, Inc., Boston Scientific, CardioDX, CardioFocus, CardioInsight Technologies, Excerpta Medica, FoxP2 Medica LLC, InfoBionic, Inc., Johnson & Johnson Healthcare Systems, Johnson & Johnson, MediaSphere Medical, LLC, Medtronic CryoCath, OrthoMcNeill, Sanofi-Aventis, Siemens, St. Jude Medical, and Siemens AG, and has received no personal compensation for these consulting activities; has received research funding from Biosense Webster, Inc., Boston Scientific/EPT, Endosense, EpiEP, EP Advocate, Medtronic CryoCath LP, Minnesota Partnership for Biotechnology and Medical Genomics/University of Minnesota, National Institutes of Health, CardioFocus, Hansen Medical, Siemens P4D, St. Jude Medical, Siemens AcuNav, and Thermedical (EP Limited); and has received royalties from Blackwell Publishing and St. Jude Medical. Dr. Nakagawa has received grant support from Biosense Webster, Inc. during the conduct of the study as well as grants and personal fees from Biosense Webster, Inc. outside the submitted work. Ms. Zhang and Dr. Boo are employees of Biosense Webster, Inc. Dr. Stagg is an employee of Biosense Webster, Inc. and Johnson & Johnson, and owns stock (<$10,000) in Johnson & Johnson. Dr. Marchlinski has received consultant fees and lecture honoraria from Biosense Webster, Inc. NR 20 TC 80 Z9 81 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 19 PY 2014 VL 64 IS 7 BP 647 EP 656 DI 10.1016/j.jacc.2014.04.072 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AL UT WOS:000340243300003 PM 25125294 ER PT J AU Tian, J Dauerman, H Toma, C Samady, H Itoh, T Kuramitsu, S Domei, T Jia, HB Vergallo, R Soeda, T Hu, SN Minami, Y Lee, H Yu, B Jang, IK AF Tian, Jinwei Dauerman, Harold Toma, Catalin Samady, Habib Itoh, Tomonori Kuramitsu, Shoichi Domei, Takenori Jia, Haibo Vergallo, Rocco Soeda, Tsunenari Hu, Sining Minami, Yoshiyasu Lee, Hang Yu, Bo Jang, Ik-Kyung TI Prevalence and Characteristics of TCFA and Degree of Coronary Artery Stenosis An OCT, IVUS, and Angiographic Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE intravascular ultrasound; optical coherence tomography; plaque vulnerability; stenosis; thin-cap fibroatheroma ID OPTICAL COHERENCE TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; INTRAVASCULAR ULTRASOUND; PLAQUE RUPTURE; NONCULPRIT LESIONS; DISEASE; SEVERITY; VULNERABILITY; NEOVASCULARIZATION; ATHEROSCLEROSIS AB BACKGROUND The relationship between features of vulnerable plaque and angiographic coronary stenosis is unknown. OBJECTIVES The purpose of this study was to systematically investigate the absolute number, relative prevalence, and characteristics of thin-cap fibroatheroma (TCFA) at different degrees of stenosis using optical coherence tomography (OCT), intravascular ultrasound, and coronary angiography. METHODS We identified 643 plaques from 255 subjects who underwent OCT imaging in all 3 coronary arteries. They were divided into 3 groups on the basis of angiographic diameter stenosis: Group A (30% to 49%, n = 325), Group B (50% to 69%, n = 227), and Group C (>70%, n = 91). RESULTS OCT showed that the absolute number of TCFA was greatest in Group A (n = 58), followed by Groups B (n = 40) and C (n = 33). However, the relative prevalence of TCFA was higher in Group C (36%) than in Groups A (18%) or B (18%) (p = 0.003 and p = 0.002, respectively). Fibrous cap of TCFA was thinner in Group C than in Groups A (p < 0.001) or B (p = 0.001). intravascular ultrasound showed that the plaque burden of TCFA was largest in Group C (80.1 +/- 7.4%), compared with Groups B (67.5 +/- 9.4%) and A (58.1 +/- 8.4%). TCFA in Group C had a higher remodeling index than those in Group A (p = 0.002). CONCLUSIONS The absolute number of TCFA is 3 times greater in nonsevere stenosis than in severe stenosis. It is, however, twice as likely for a lesion to be TCFA in cases of severe stenosis than in nonsevere stenosis. Moreover, TCFA in severely-stenotic areas had more features of plaque vulnerability. (C) 2014 by the American College of Cardiology Foundation. C1 [Tian, Jinwei; Jia, Haibo; Hu, Sining; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Key Lab Myocardial Ischemia,Chinese Minist Educ, Harbin 150086, Peoples R China. [Tian, Jinwei; Jia, Haibo; Vergallo, Rocco; Soeda, Tsunenari; Hu, Sining; Minami, Yoshiyasu; Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Dauerman, Harold] Univ Vermont, Fletcher Allen Healthcare, Burlington, VT USA. [Toma, Catalin] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Samady, Habib] Emory Univ Hosp, Atlanta, GA 30322 USA. [Itoh, Tomonori] Mem Heart Ctr, Iwate Med Sch, Div Cardiol, Morioka, Iwate, Japan. [Kuramitsu, Shoichi; Domei, Takenori] Kokura Mem Hosp, Dept Cardiol, Kitakyushu, Fukuoka, Japan. [Lee, Hang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Biostat Unit, Boston, MA USA. RP Yu, B (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, 246 Xuefu Rd, Harbin 150086, Peoples R China. EM yubodr@163.com; ijang@partners.org FU National Natural Science Foundation of China [81300201, 81200076, 30871064]; China Postdoctoral Science Foundation [2013M531074]; Heilongjiang Post-doctoral Science Foundation [LBH-Z12180]; 2nd Affiliated Hospital of Harbin Medical University [BS2013-01]; Abbott Vascular and Medtronic; St. Jude Medical; Volcano Corp.; Medtronic; Abbott Vascular; "Enrico ed Enrica Sovena" Foundation; John Nam OCT fellowship grant FX This study was supported by the Dr. John Nam OCT fellowship grant and "Mr. and Mrs. Michael A. Park." Dr. Tian has received grants from the National Natural Science Foundation of China (81300201), China Postdoctoral Science Foundation (2013M531074), Heilongjiang Post-doctoral Science Foundation (LBH-Z12180), and the 2nd Affiliated Hospital of Harbin Medical University (BS2013-01). Dr. Dauerman has received research grants from Abbott Vascular and Medtronic; and has served as a consultant to Medtronic Dr. Samady has served as a consultant to The Medicines Company; and has received research grants from St. Jude Medical, Volcano Corp., Medtronic, and Abbott Vascular. Dr. Jia has received a grant from the National Natural Science Foundation of China (81200076). Dr. R. Vergallo received a grant from the "Enrico ed Enrica Sovena" Foundation. Dr. Yu received a grant from the National Natural Science Foundation of China (30871064). Dr. Jang received a research grant and consulting fee from St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Yu and Jang contributed equally to this work. NR 26 TC 29 Z9 33 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 19 PY 2014 VL 64 IS 7 BP 672 EP 680 DI 10.1016/j.jacc.2014.05.052 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AL UT WOS:000340243300007 PM 25125298 ER PT J AU Puchner, SB Liu, T Mayrhofer, T Truong, QA Lee, H Fleg, JL Nagurney, JT Udelson, JE Hoffmann, U Ferencik, M AF Puchner, Stefan B. Liu, Ting Mayrhofer, Thomas Truong, Quynh A. Lee, Hang Fleg, Jerome L. Nagurney, John T. Udelson, James E. Hoffmann, Udo Ferencik, Maros TI High-Risk Plaque Detected on Coronary CT Angiography Predicts Acute Coronary Syndromes Independent of Significant Stenosis in Acute Chest Pain Results From the ROMICAT-II Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute chest pain; acute coronary syndrome; coronary atherosclerotic plaque; coronary computed tomography ID COMPUTED TOMOGRAPHIC ANGIOGRAPHY; RADIOFREQUENCY DATA-ANALYSIS; NAPKIN-RING SIGN; DUAL-SOURCE CT; INTRAVASCULAR ULTRASOUND; NONINVASIVE ASSESSMENT; ATHEROSCLEROTIC PLAQUE; MYOCARDIAL-INFARCTION; VIRTUAL HISTOLOGY; CULPRIT LESIONS AB BACKGROUND It is not known whether high-risk plaque, as detected by coronary computed tomography angiography (CTA), permits improved early diagnosis of acute coronary syndromes (ACS) independently to the presence of significant coronary artery disease (CAD) in patients with acute chest pain. OBJECTIVES The primary aim of this study was to determine whether high-risk plaque features, as detected by CTA in the emergency department (ED), may improve diagnostic certainty of ACS independently and incrementally to the presence of significant CAD and clinical risk assessment in patients with acute chest pain but without objective evidence of myocardial ischemia or myocardial infarction (MI). METHODS We included patients randomized to the coronary CTA arm of the ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography II) trial. Readers assessed coronary CTA qualitatively for the presence of nonobstructive CAD (1% to 49% stenosis), significant CAD (>= 50% or >= 70% stenosis), and the presence of at least 1 of the high-risk plaque features (positive remodeling, low <30 Hounsfield units plaque, napkin-ring sign, spotty calcium). In logistic regression analysis, we determined the association of high-risk plaque with ACS (MI or unstable angina pectoris) during the index hospitalization and whether this was independent of significant CAD and clinical risk assessment. RESULTS Overall, 37 of 472 patients who underwent coronary CTA with diagnostic image quality (mean age 53.9 +/- 8.0 years; 52.8% men) had ACS (7.8%; MI n = 5; unstable angina pectoris n = 32). CAD was present in 262 patients (55.5%; nonobstructive CAD in 217 patients [46.0%] and significant CAD with >= 50% stenosis in 45 patients [9.5%]). High-risk plaques were more frequent in patients with ACS and remained a significant predictor of ACS (odds ratio [OR]: 8.9; 95% CI: 1.8 to 43.3; p = 0.006) after adjustment for >= 50% stenosis (OR: 38.6; 95% CI: 14.2 to 104.7; p < 0.001) and clinical risk assessment (age, sex, number of cardiovascular risk factors). Similar results were observed after adjustment for >= 70% stenosis. CONCLUSIONS In patients presenting to the ED with acute chest pain but negative initial electrocardiogram and troponin, presence of high-risk plaques on coronary CTA increased the likelihood of ACS independent of significant CAD and clinical risk assessment (age, sex, and number of cardiovascular risk factors). (Multicenter Study to Rule Out Myocardial Infarction by Cardiac Computed Tomography [ROMICAT-II]) (C) 2014 by the American College of Cardiology Foundation. C1 [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Puchner, Stefan B.; Liu, Ting; Mayrhofer, Thomas; Truong, Quynh A.; Lee, Hang; Nagurney, John T.; Hoffmann, Udo; Ferencik, Maros] Harvard Univ, Sch Med, Boston, MA USA. [Puchner, Stefan B.] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Vienna, Austria. [Liu, Ting] China Med Univ, Affiliated Hosp 1, Dept Radiol, Shenyang, Peoples R China. [Truong, Quynh A.; Lee, Hang; Hoffmann, Udo; Ferencik, Maros] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Udelson, James E.] Tufts Med Ctr, Div Cardiol, Boston, MA USA. [Udelson, James E.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA USA. [Ferencik, Maros] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, Portland, OR 97201 USA. RP Ferencik, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM maros_ferencik@hms.harvard.edu FU National Heart, Lung, and Blood Institute (NHLBI) [U01HL092040, U01HL092022]; National Institutes of Health/NHLBI [K23HL098370, L30HL093896]; Biosite/Allere; Brahms Limited/Thermo-Fisher; Nanosphere; NHLBI [U01HL092040, U01HL092022]; American Heart Association [13FTF16450001] FX This work was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) (U01HL092040 and U01HL092022). Dr. Truong has received support from the National Institutes of Health/NHLBI (K23HL098370 and L30HL093896), St. Jude Medical, American College of Radiology Imaging Network, and Duke Clinical Research Institute. Dr. Nagurney has received research grants from Biosite/Allere, Brahms Limited/Thermo-Fisher, and Nanosphere for work on cardiac biomarkers. Dr. Udelson has received research grants from the NHLBI (U01HL092040 and U01HL092022). Dr. Ferencik has received support from the American Heart Association (13FTF16450001). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 33 TC 57 Z9 58 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 19 PY 2014 VL 64 IS 7 BP 684 EP 692 DI 10.1016/j.jacc.2014.05.039 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AL UT WOS:000340243300009 PM 25125300 ER PT J AU Murphy, AK Fitzgerald, M Ro, T Kim, JH Rabinowitsch, AI Chowdhury, D Schildkraut, CL Borowiec, JA AF Murphy, Anar K. Fitzgerald, Michael Ro, Teresa Kim, Jee Hyun Rabinowitsch, Ariana I. Chowdhury, Dipanjan Schildkraut, Carl L. Borowiec, James A. TI Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SINGLE-STRANDED-DNA; CANCER SUSCEPTIBILITY GENE; PROTEIN-A; HOMOLOGOUS RECOMBINATION; BREAK REPAIR; HUMAN-CELLS; BRCA2; DAMAGE; POLYMERASE; CHECKPOINT AB Phosphorylation of replication protein A (RPA) by Cdk2 and the checkpoint kinase AIR (ATM and Rad3 related) during replication fork stalling stabilizes the replisome, but how these modifications safeguard the fork is not understood. To address this question, we used single-molecule fiber analysis in cells expressing a phosphorylation-defective RPA2 subunit or lacking phosphatase activity toward RPA2. Deregulation of RPA phosphorylation reduced synthesis at forks both during replication stress and recovery from stress. The ability of phosphorylated RPA to stimulate fork recovery is mediated through the PALB2 tumor suppressor protein. RPA phosphorylation increased localization of PALB2 and BRCA2 to RPA-bound nuclear foci in cells experiencing replication stress. Phosphorylated RPA also stimulated recruitment of PALB2 to single-strand deoxyribonucleic acid (DNA) in a cell-free system. Expression of mutant RPA2 or loss of PALB2 expression led to significant DNA damage after replication stress, a defect accentuated by poly-ADP (adenosine diphosphate) ribose polymerase inhibitors. These data demonstrate that phosphorylated RPA recruits repair factors to stalled forks, thereby enhancing fork integrity during replication stress. C1 [Murphy, Anar K.; Fitzgerald, Michael; Ro, Teresa; Kim, Jee Hyun; Rabinowitsch, Ariana I.; Borowiec, James A.] NYU, Sch Med, Inst Canc, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Schildkraut, Carl L.] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. RP Borowiec, JA (reprint author), NYU, Sch Med, Inst Canc, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA. EM James.Borowiec@nyumc.org OI Borowiec, James/0000-0003-4117-0826 FU National Institutes of Health [R01 GM083185]; Breast Cancer Alliance, National Cancer Institute, National Institutes of Health [P30CA16087, R01CA142698]; American Cancer Society, National Institutes of Health [5R01 GM045751]; Empire State Stem Cell Fund through New York State [C024348] FX This work was supported by National Institutes of Health grant R01 GM083185 (J.A. Borowiec), an Exceptional Project Award Grant from the Breast Cancer Alliance (J.A. Borowiec), National Cancer Institute grant P30CA16087 (J.A. Borowiec), National Institutes of Health grant R01CA142698 (D. Chowdhury), a Basic Scholar Grant from the American Cancer Society (D. Chowdhury), National Institutes of Health grant 5R01 GM045751 (C.L. Schildkraut), and the Empire State Stem Cell Fund through New York State contract C024348 (C.L. Schildkraut). NR 52 TC 20 Z9 21 U1 2 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD AUG 18 PY 2014 VL 206 IS 4 BP 493 EP 507 DI 10.1083/jcb.201404111 PG 15 WC Cell Biology SC Cell Biology GA AN6WQ UT WOS:000340739500005 PM 25113031 ER PT J AU Merali, HS Lipsitz, S Hevelone, N Gawande, AA Lashoher, A Agrawal, P Spector, J AF Merali, Hasan S. Lipsitz, Stuart Hevelone, Nathanael Gawande, Atul A. Lashoher, Angela Agrawal, Priya Spector, Jonathan TI Audit-identified avoidable factors in maternal and perinatal deaths in low resource settings: a systematic review SO BMC PREGNANCY AND CHILDBIRTH LA English DT Review DE Maternal; Fetal; Neonatal; Perinatal; Avoidable; Factors; Death; Mortality ID EMERGENCY OBSTETRIC CARE; MIDDLE-INCOME COUNTRIES; DAR-ES-SALAAM; MORTALITY AUDIT; UNDER-5 MORTALITY; NEONATAL SURVIVAL; RURAL TANZANIA; VERBAL AUTOPSY; CENTRAL REGION; HEALTH-CARE AB Background: Audits provide a rational framework for quality improvement by systematically assessing clinical practices against accepted standards with the aim to develop recommendations and interventions that target modifiable deficiencies in care. Most childbirth-associated mortality audits in developing countries are focused on a single facility and, up to now, the avoidable factors in maternal and perinatal deaths cataloged in these reports have not been pooled and analyzed. We sought to identity the most frequent avoidable factors in childbirth-related deaths globally through a systematic review of all published mortality audits in low and lower-middle income countries. Methods: We performed a systematic review of published literature from 1965 to November 2011 in Pubmed, Embase, CINAHL, POPLINE, LILACS and African Index Medicus. Inclusion criteria were audits from low and lower-middle income countries that identified at least one avoidable factor in maternal or perinatal mortality. Each study included in the analysis was assigned a quality score using a previously published instrument. A meta-analysis was performed for each avoidable factor taking into account the sample sizes and quality score from each individual audit. The study was conducted and reported according to PRISMA guidelines for systematic reviews. Results: Thirty-nine studies comprising 44 datasets and a total of 6,205 audited deaths met inclusion criteria. The analysis yielded 42 different avoidable factors, which fell into four categories: health worker-oriented factors, patient-oriented factors, transport/referral factors, and administrative/supply factors. The top three factors by attributable deaths were substandard care by a health worker, patient delay, and deficiencies in blood transfusion capacity (accounting for 688, 665, and 634 deaths attributable, respectively). Health worker-oriented factors accounted for two-thirds of the avoidable factors identified. Conclusions: Audits provide insight into where systematic deficiencies in clinical care occur and can therefore provide crucial direction for the targeting of interventions to mitigate or eliminate health system failures. Given that the main causes of maternal and perinatal deaths are generally consistent across low resource settings, the specific avoidable factors identified in this review can help to inform the rational design of health systems with the aim of achieving continued progress towards Millennium Development Goals Four and Five. C1 [Merali, Hasan S.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Lipsitz, Stuart; Hevelone, Nathanael; Gawande, Atul A.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Ariadne Labs Joint Ctr, Boston, MA 02115 USA. [Gawande, Atul A.; Agrawal, Priya; Spector, Jonathan] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lashoher, Angela] WHO, CH-1211 Geneva, Switzerland. [Spector, Jonathan] MassGen Hosp Children, Boston, MA USA. RP Merali, HS (reprint author), Hosp Sick Children, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM Hasan_Merali@post.harvard.edu FU World Health Organization [001] NR 67 TC 4 Z9 4 U1 4 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD AUG 16 PY 2014 VL 14 AR 280 DI 10.1186/1471-2393-14-280 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO0AN UT WOS:000340971300001 PM 25129069 ER PT J AU Viaud, S Daillere, R Boneca, IG Lepage, P Pittet, MJ Ghiringhelli, F Trinchieri, G Goldszmid, R Zitvogel, L AF Viaud, S. Daillere, R. Boneca, I. G. Lepage, P. Pittet, M. J. Ghiringhelli, F. Trinchieri, G. Goldszmid, R. Zitvogel, L. TI Harnessing the Intestinal Microbiome for Optimal Therapeutic Immunomodulation SO CANCER RESEARCH LA English DT Review ID HUMAN GUT MICROBIOME; REGULATORY T-CELLS; CYCLOPHOSPHAMIDE; RICHNESS; IMPACT; GENE AB Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. (C) 2014 AACR. C1 [Viaud, S.; Daillere, R.; Zitvogel, L.] INSERM, U1015, Villejuif, France. [Viaud, S.; Daillere, R.; Zitvogel, L.] Univ Paris 11, Le Kremlin Bicetre, France. [Boneca, I. G.] Inst Pasteur, Unit Biol & Genet Bacterial Cell Wall, Paris, France. [Boneca, I. G.] INSERM, Grp Avenir, Paris, France. [Lepage, P.] INRA, Micalis UMR1319, Jouy En Josas, France. [Lepage, P.] AgroParisTech, Micalis UMR1319, Jouy En Josas, France. [Pittet, M. J.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Pittet, M. J.] Harvard Univ, Sch Med, Boston, MA USA. [Ghiringhelli, F.] INSERM, U866, Ctr Georges Francois Leclerc, Dijon, France. [Ghiringhelli, F.] INSERM, Grp Avenir, Dijon, France. [Ghiringhelli, F.] Univ Bourgogne, Fac Med, Dijon, France. [Trinchieri, G.; Goldszmid, R.] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Zitvogel, L.] Gustave Roussy, Ctr Invest Clin Biotherapie CICBT 507, Villejuif, France. RP Zitvogel, L (reprint author), 114 Rue Edouard Vaillant, F-94805 Villejuif, France. EM laurence.zitvogel@gustaveroussy.fr RI Boneca, Ivo/H-1677-2014 OI Boneca, Ivo/0000-0001-8122-509X FU Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee); SIRIC Socrate; LABEX and PACRI Onco-Immunology; European Research Council (PGNfromSHAPEtoVIR) [202283]; ISREC Foundation FX This work was supported by the Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee), SIRIC Socrate, LABEX and PACRI Onco-Immunology, European Research Council starting grant (PGNfromSHAPEtoVIR no202283, to I. G. Boneca), and the ISREC Foundation. NR 32 TC 12 Z9 12 U1 3 U2 28 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4217 EP 4221 DI 10.1158/0008-5472.CAN-14-0987 PG 5 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700002 PM 25074615 ER PT J AU Srivastava, J Robertson, CL Rajasekaran, D Gredler, R Siddiq, A Emdad, L Mukhopadhyay, ND Ghosh, S Hylemon, PB Gil, G Shah, K Bhere, D Subler, MA Windle, JJ Fisher, PB Sarkar, D AF Srivastava, Jyoti Robertson, Chadia L. Rajasekaran, Devaraja Gredler, Rachel Siddiq, Ayesha Emdad, Luni Mukhopadhyay, Nitai D. Ghosh, Shobha Hylemon, Phillip B. Gil, Gregorio Shah, Khalid Bhere, Deepak Subler, Mark A. Windle, Jolene J. Fisher, Paul B. Sarkar, Devanand TI AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling SO CANCER RESEARCH LA English DT Article ID HUMAN HEPATOCELLULAR-CARCINOMA; ASTROCYTE ELEVATED GENE-1; FACTOR-KAPPA-B; BREAST-CANCER; RXR-ALPHA; SERINE-260 IMPAIRS; NUCLEAR RECEPTOR; ACID RECEPTORS; EXPRESSION; LOCALIZATION AB Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics. (C)2014 AACR. C1 [Srivastava, Jyoti; Robertson, Chadia L.; Rajasekaran, Devaraja; Gredler, Rachel; Siddiq, Ayesha; Emdad, Luni; Subler, Mark A.; Windle, Jolene J.; Fisher, Paul B.; Sarkar, Devanand] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA 23298 USA. [Robertson, Chadia L.; Gil, Gregorio] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. [Mukhopadhyay, Nitai D.] Virginia Commonwealth Univ, Dept Biostat, Richmond, VA 23298 USA. [Ghosh, Shobha] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA 23298 USA. [Hylemon, Phillip B.] Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. [Shah, Khalid; Bhere, Deepak] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Shah, Khalid; Bhere, Deepak] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Windle, Jolene J.; Fisher, Paul B.; Sarkar, Devanand] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Fisher, Paul B.; Sarkar, Devanand] Virginia Commonwealth Univ, VCU Inst Mol Med, Richmond, VA 23298 USA. RP Sarkar, D (reprint author), Virginia Commonwealth Univ, Massey Canc Ctr, 1220 East Broad St,Room 7044,POB 980035, Richmond, VA 23298 USA. EM dsarkar@vcu.edu RI SRIVASTAVA, JYOTI/J-6065-2014; OI SRIVASTAVA, JYOTI/0000-0002-5727-741X; Windle, Jolene/0000-0001-6690-385X FU James S. McDonnell Foundation; National Cancer Institute [R01 CA138540]; NIH [R01 CA134721] FX This study was supported in part by grants from The James S. McDonnell Foundation and National Cancer Institute Grant R01 CA138540 (D. Sarkar) and NIH grants R01 CA134721 (P. B. Fisher). D. Sarkar is the Harrison Endowed Scholar in Cancer Research and Blick scholar. P. B. Fisher holds the Thelma Newmeyer Corman Chair in Cancer Research. NR 38 TC 12 Z9 12 U1 4 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4364 EP 4377 DI 10.1158/0008-5472.CAN-14-0421 PG 14 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700016 PM 25125681 ER PT J AU Mimura, N Hideshima, T Shimomura, T Suzuki, R Ohguchi, H Rizq, O Kikuchi, S Yoshida, Y Cottini, F Jakubikova, J Cirstea, D Gorgun, G Minami, J Tai, YT Richardson, PG Utsugi, T Iwama, A Anderson, KC AF Mimura, Naoya Hideshima, Teru Shimomura, Toshiyasu Suzuki, Rikio Ohguchi, Hiroto Rizq, Ola Kikuchi, Shohei Yoshida, Yasuhiro Cottini, Francesca Jakubikova, Jana Cirstea, Diana Gorgun, Gullu Minami, Jiro Tai, Yu-Tzu Richardson, Paul G. Utsugi, Teruhiro Iwama, Atsushi Anderson, Kenneth C. TI Selective and Potent Akt Inhibition Triggers Anti-Myeloma Activities and Enhances Fatal Endoplasmic Reticulum Stress Induced by Proteasome Inhibition SO CANCER RESEARCH LA English DT Article ID UNFOLDED PROTEIN RESPONSE; MULTIPLE-MYELOMA; IN-VITRO; ANTITUMOR-ACTIVITY; 3-KINASE PATHWAY; KAPPA-B; PERIFOSINE; CELLS; KINASE; TARGET AB The PI3K/Akt pathway plays a crucial role in the pathogenesis of multiple myeloma (MM) in the bone marrow (BM) milieu. However, efficacy of selective and potent Akt inhibition has not yet been fully elucidated. In this study, we, therefore, examined the biologic impact of selective and potent Akt inhibition by a novel allosteric inhibitor TAS-117. TAS-117 induced significant growth inhibition, associated with downregulation of phosphorylated Akt (p-Akt), selectively in MM cell lines with high baseline p-Akt. Cytotoxicity of TAS-117 was also observed in patient MM cells, but not in normal peripheral blood mononuclear cells. Importantly, TAS-117 induced significant cytotoxicity in MM cells even in the presence of BM stromal cells, associated with inhibition of IL6 secretion. Oral administration of TAS-117 significantly inhibited human MM cell growth in murine xenograft models. TAS-117 triggered apoptosis and autophagy, as well as induction of endoplasmic reticulum (ER) stress response with minimal expression of C/EBP homologous protein (CHOP), a fatal ER stress marker. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity, associated with increased CHOP and PARP cleavage and blockade of bortezomib-induced p-Akt, suggesting that TAS-117 augments bortezomib-induced ER stress and apoptotic signaling. Carfilzomib-induced cytotoxicity was similarly enhanced by TAS-117. Importantly, TAS-117 enhanced bortezomib-induced cytotoxicity in vivo, associated with prolonged host survival. Our results show that selective and potent Akt inhibition by TAS-117 triggers anti-MM activities in vitro and in vivo, as well as enhances cytotoxicity of proteasome inhibition, providing the preclinical framework for clinical evaluation of selective Akt inhibitors, alone and in combination with proteasome inhibitors in MM. (C)2014 AACR. C1 [Mimura, Naoya; Hideshima, Teru; Suzuki, Rikio; Ohguchi, Hiroto; Kikuchi, Shohei; Yoshida, Yasuhiro; Cottini, Francesca; Jakubikova, Jana; Cirstea, Diana; Gorgun, Gullu; Minami, Jiro; Tai, Yu-Tzu; Richardson, Paul G.; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Mimura, Naoya; Rizq, Ola; Iwama, Atsushi] Chiba Univ, Grad Sch Med, Dept Cellular & Mol Med, Chiba, Japan. [Shimomura, Toshiyasu; Utsugi, Teruhiro] TAIHO Pharmaceut Co Ltd, Tsukuba Res Ctr, Tsukuba, Ibaraki, Japan. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Mayer 557,450 Brookline Ave, Boston, MA 02215 USA. EM kenneth_anderson@dfci.harvard.edu FU NIH [SPORE-P50100707, PO1-CA078378, RO1CA050947]; Japanese Society of Myeloma FX This work was supported by the NIH grants (SPORE-P50100707, PO1-CA078378, and RO1CA050947). N. Mimura was a recipient of the Kano-grant from the Japanese Society of Myeloma. K. C. Anderson is an American Cancer Society Clinical Research Professor. NR 40 TC 15 Z9 16 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 16 PY 2014 VL 74 IS 16 BP 4458 EP 4469 DI 10.1158/0008-5472.CAN-13-3652 PG 12 WC Oncology SC Oncology GA AO2WH UT WOS:000341186700024 PM 24934808 ER PT J AU Cavender, MA Sabatine, MS AF Cavender, Matthew A. Sabatine, Marc S. TI Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials SO LANCET LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; GLYCOPROTEIN IIB/IIIA INHIBITORS; ASSOCIATION TASK-FORCE; UNFRACTIONATED HEPARIN; CLINICAL-TRIALS; PRACTICE GUIDELINES; ACUTE CATHETERIZATION; PRIMARY PCI; CLOPIDOGREL; ABCIXIMAB AB Background Bivalirudin is an alternative to heparin in patients undergoing percutaneous coronary intervention (PCI). We aimed to define the effects of a bivalirudin-based anticoagulation regimen compared with a heparin-based anticoagulation regimen on ischaemic and bleeding outcomes. Methods We searched Medline, the Cochrane Library, and relevant meeting abstracts (search done on April 9, 2014) for randomised trials that assessed bivalirudin versus heparin in patients planned for PCI. The primary efficacy endpoint was the incidence of major adverse cardiac events (MACE) up to 30 days. Secondary efficacy endpoints were death, myocardial infarction, ischaemia-driven revascularisation, and stent thrombosis. The primary safety endpoint was major bleeding up to 30 days. We calculated pooled risk ratios and 95% CIs using random-effects models. Findings We included data from 16 trials involving 33 958 patients, of whom 2422 experienced MACE and 1406 had a major bleed. There was an increase in the risk of MACE with bivalirudin-based regimens compared with heparin-based regimens (risk ratio 1.09, 95% CI 1.01-1 17; p=0.0204), which was largely driven by increases in myocardial infarction (1.12, 1.03-1.23) and seemingly also by ischaemia-driven revascularisation (1.16, 0.997-1.34) with bivalirudin compared with heparin, with no effect on mortality (0 99, 0 82-1.18). Bivalirudin increased the risk of stent thrombosis (risk ratio 1.38, 95% CI 1.09-1.74; p=0.0074), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4.27, 2.28-8 00; p<0 0001). Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio 0.62, 95% CI 0 49-0.78; p<0 0001), but the magnitude of this effect varied greatly (p<0 0001) depending on whether glycoprotein IIb/IIIa inhibitors were used predominantly in the heparin arm only (0.53, 0.47-0 61; p<0 0001), provisionally in both arms (0.78, 0.51-1.19; p=0 25), or planned in both arms (1.07, 0.87-1.31; p=0 53). Interpretation Compared with a heparin-based regimen, a bivalirudin-based regimen increases the risk of myocardial infarction and stent thrombosis, but decreases the risk of bleeding, with the magnitude of the reduction depending on concomitant glycoprotein IIb/IIIa inhibitor use. Physicians should weigh the trade-off between ischaemic and bleeding events when choosing between different anticoagulant regimens. C1 [Cavender, Matthew A.; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA. [Cavender, Matthew A.; Sabatine, Marc S.] Harvard Univ, Sch Med, Boston, MA USA. RP Sabatine, MS (reprint author), TIMI Study Grp, Office Level One,350 Longwood Ave, Boston, MA 02115 USA. EM msabatine@partners.org FU Brigham and Women's Hospital from Abbott Laboratories; Accumetrics; Amgen; AstraZeneca; Bristol-Myers Squibb; Critical Diagnostics; Daiichi-Sankyo; Eisai; Genzyme; GlaxoSmithKline; Intarcia; Merck; Nanosphere; Roche Diagnostics; Sanofi-Aventis; Takeda FX MSS has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, Bristol-Myers Squibb, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Roche Diagnostics, Sanofi-Aventis, and Takeda; and has done consulting for Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Cubist, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Pfizer, Quest Diagnostics, Sanofi-Aventis, Vertex, and Zeus Scientific. MAC declares no competing interests. NR 42 TC 77 Z9 77 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD AUG 16 PY 2014 VL 384 IS 9943 BP 599 EP 606 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AN4QR UT WOS:000340573300032 PM 25131979 ER PT J AU Radford, EJ Ito, M Shi, H Corish, JA Yamazawa, K Isganaitis, E Seisenberger, S Hore, TA Reik, W Erkek, S Peters, AHFM Patti, ME Ferguson-Smith, AC AF Radford, Elizabeth J. Ito, Mitsuteru Shi, Hui Corish, Jennifer A. Yamazawa, Kazuki Isganaitis, Elvira Seisenberger, Stefanie Hore, Timothy A. Reik, Wolf Erkek, Serap Peters, Antoine H. F. M. Patti, Mary-Elizabeth Ferguson-Smith, Anne C. TI In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism SO SCIENCE LA English DT Article ID LOW-BIRTH-WEIGHT; PROMOTER DNA METHYLATION; EMBRYONIC STEM-CELLS; TRANSGENERATIONAL INHERITANCE; ACTIVATING MUTATIONS; EPIGENETIC MEMORY; GENE-EXPRESSION; C. ELEGANS; MOUSE; GENOME AB Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F-2 mouse metabolism, we demonstrate that the in utero nutritional environment of F-1 embryos alters the germline DNA methylome of F-1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F-2 development. Differential methylation is not maintained in F-2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. C1 [Radford, Elizabeth J.; Ito, Mitsuteru; Shi, Hui; Corish, Jennifer A.; Yamazawa, Kazuki; Ferguson-Smith, Anne C.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England. [Isganaitis, Elvira; Patti, Mary-Elizabeth] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Isganaitis, Elvira; Patti, Mary-Elizabeth] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Seisenberger, Stefanie; Hore, Timothy A.; Reik, Wolf] Babraham Inst, Cambridge, England. [Seisenberger, Stefanie; Hore, Timothy A.; Reik, Wolf] Wellcome Trust Sanger Inst, Cambridge, England. [Erkek, Serap; Peters, Antoine H. F. M.] Friedrich Miescher Inst Biomed Res, Basel, Switzerland. [Erkek, Serap; Peters, Antoine H. F. M.] Univ Basel, Fac Sci, Basel, Switzerland. [Erkek, Serap] Swiss Inst Bioinformat, Basel, Switzerland. RP Patti, ME (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM mary.elizabeth.patti@joslin.harvard.edu; afsmith@mole.bio.cam.ac.uk OI Reik, Wolf/0000-0003-0216-9881 FU U.K. Medical Research Council; Wellcome Trust; European Commission FP7, EpiGeneSys; European Commission FP7, EpiHealth; Pediatric Endocrine Society; Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; American Diabetes Association; Graetz Foundation; NIH [P30DK036836]; Novartis Research Foundation FX We are grateful to members of the Ferguson-Smith and Patti labs for useful discussions of this work and to K. Tabbada and D. Oxley for expert technical assistance with Illumina sequencing and mass spectrometry. Work was supported by grants from the U.K. Medical Research Council; Wellcome Trust; and European Commission FP7, EpiGeneSys and EpiHealth (to A.C.F.-S.), from the Pediatric Endocrine Society and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (to E.I.), and from the American Diabetes Association, the Graetz Foundation, and NIH P30DK036836 (to M.-E.P.). W.R. is a consultant for Cambridge Epigenetix. The MeDIP-Seq data sets have been deposited in GEO with accession number GSE58747. A.H.F.M.P. and S.E. are funded by the Novartis Research Foundation. NR 42 TC 140 Z9 142 U1 9 U2 42 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD AUG 15 PY 2014 VL 345 IS 6198 BP 785 EP + AR 1255903 DI 10.1126/science.1255903 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB6ZT UT WOS:000349776300001 PM 25011554 ER PT J AU Hamouda, MA Belhacene, N Puissant, A Colosetti, P Robert, G Jacquel, A Mari, B Auberger, P Luciano, F AF Hamouda, Mohamed-Amine Belhacene, Nathalie Puissant, Alexandre Colosetti, Pascal Robert, Guillaume Jacquel, Arnaud Mari, Bernard Auberger, Patrick Luciano, Frederic TI The small heat shock protein B8 (HSPB8) confers resistance to bortezomib by promoting autophagic removal of misfolded proteins in multiple myeloma cells SO ONCOTARGET LA English DT Article DE multiple myeloma; velcade; resistance; HSPB8; aggregates; autophagy ID PROTEASOME INHIBITION; CHAPERONE ACTIVITY; PEPTIDE-TRANSPORT; LYMPHOMA-CELLS; ER STRESS; PSMB5; GENE; MACROAUTOPHAGY; COMPLEX; SYSTEM AB Velcade is one of the inescapable drug to treat patient suffering from multiple myeloma (MM) and resistance to this drug represents a major drawback for patients. However, the mechanisms underlying velcade resistance remain incompletely understood. We derived several U266 MM cell clones that resist to velcade. U266-resistant cells were resistant to velcade-induced cell death but exhibited a similar sensitivity to various proapoptotic stimuli. Careful analysis of proteosomal subunits and proteasome enzymatic activities showed that neither the composition nor the activity of the proteasome was affected in velcade-resistant cells. Elimination of velcade-induced poly-ubiquitinated proteins and protein aggregates was drastically stimulated in the resistant cells and correlated with increased cell survival. Inhibition of the lysosomal activity in velcade-resistant cells resulted in an increase of cell aggregates and decrease survival, indicating that aggregates are eliminated through lysosomal degradation. In addition, pangenomic profiling of velcade-sensitive and resistant cells showed that the small heat shock protein HSPB8 was overexpressed in resistant cells. Finally, gain and loss of function experiment demonstrated that HSPB8 is a key factor for velcade resistance. In conclusion, HSPB8 plays an important role for the elimination of aggregates in velcade-resistant cells that contributes to their enhanced survival. C1 [Hamouda, Mohamed-Amine; Belhacene, Nathalie; Colosetti, Pascal; Robert, Guillaume; Jacquel, Arnaud; Auberger, Patrick; Luciano, Frederic] C3M, INSERM, U1065, Team 2, Nice, France. [Hamouda, Mohamed-Amine; Belhacene, Nathalie; Colosetti, Pascal; Robert, Guillaume; Jacquel, Arnaud; Auberger, Patrick; Luciano, Frederic] Univ Nice Sophia Antipolis, Nice, France. [Puissant, Alexandre] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Puissant, Alexandre] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Mari, Bernard] UMR7275 CNRS UNS, Inst Pharmacol Mol & Cellulaire, Valbonne, France. RP Luciano, F (reprint author), C3M, INSERM, U1065, Team 2, Nice, France. EM fluciano@unice.fr RI Mari, Bernard/D-7445-2015; PUISSANT, ALEXANDRE/O-9575-2016; AUBERGER, Patrick/G-1491-2013 OI Mari, Bernard/0000-0002-0422-9182; PUISSANT, ALEXANDRE/0000-0002-3997-9282; AUBERGER, Patrick/0000-0002-2481-8275 FU Ligue Nationale Contre le Cancer (Equipe Labellisee); Fondation de France and the Association pour la Recherche Contre le Cancer; French government (National Research Agency, ANR) through the 'Investments for the future' LABEX SIGNALIFE [ANR-11-LABX-0028-01] FX This work was supported by the Ligue Nationale Contre le Cancer (Equipe Labellisee 2011-2013), the Fondation de France and the Association pour la Recherche Contre le Cancer. This Work was also funded by the French government (National Research Agency, ANR) through the 'Investments for the future' LABEX SIGNALIFE : program reference # ANR-11-LABX-0028-01. We acknowledge the technological expertise of the Nice Sophia-Antipolis Functional Genomics Platform. We greatly acknowledge Dr Jacques Landry (Centre of recherche cancerologie, University of Laval, Canada) for PcDNA3-Myc-HSPB8 vector. NR 49 TC 4 Z9 4 U1 1 U2 6 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD AUG 15 PY 2014 VL 5 IS 15 BP 6252 EP 6266 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AZ0EQ UT WOS:000347919500032 PM 25051369 ER PT J AU Matthews, CE Cohen, SS Fowke, JH Han, XJ Xiao, Q Buchowski, MS Hargreaves, MK Signorello, LB Blot, WJ AF Matthews, Charles E. Cohen, Sarah S. Fowke, Jay H. Han, Xijing Xiao, Qian Buchowski, Maciej S. Hargreaves, Margaret K. Signorello, Lisa B. Blot, William J. TI Physical Activity, Sedentary Behavior, and Cause-Specific Mortality in Black and White Adults in the Southern Community Cohort Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE blacks; cancer; exercise; prevention; sedentary behavior ID ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; US ADULTS; AFRICAN-AMERICANS; SITTING TIME; QUESTIONNAIRE; RISK; WOMEN; POPULATION; EXERCISE AB There is limited evidence demonstrating the benefits of physical activity with regard to mortality risk or the harms associated with sedentary behavior in black adults, so we examined the relationships between these health behaviors and cause-specific mortality in a prospective study that had a large proportion of black adults. Participants (40-79 years of age) enrolled in the Southern Community Cohort Study between 2002 and 2009 (n = 63,308) were prospectively followed over 6.4 years, and 3,613 and 1,394 deaths occurred in blacks and whites, respectively. Black adults who reported the highest overall physical activity level (= 32.3 metabolic equivalent-hours/day vs. <9.7 metabolic equivalent-hours/day) had lower risks of death from all causes (hazard ratio (HR) = 0.76. 95% confidence interval (CI): 0.69, 0.85), cardiovascular disease (HR = 0.81, 95% CI: 0.67, 0.98), and cancer (HR = 0.76, 95% CI: 0.62, 0.94). In whites, a higher physical activity level was associated with a lower risk of death from all causes (HR = 0.76, 95% CI: 0.64, 0.90) and cardiovascular disease (HR = 0.69, 95% CI: 0.49, 0.99) but not cancer (HR = 0.95, 95% CI: 0.67, 1.34). Spending more time being sedentary (>12 hours/day vs. <5.76 hours/day) was associated with a 20%-25% increased risk of all-cause mortality in blacks and whites. Blacks who reported the most time spent being sedentary (= 10.5 hours/day) and lowest level of physical activity (<12.6 metabolic equivalent-hours/day) had a greater risk of death (HR = 1.47, 95% CI: 1.25, 1.71). Our study provides evidence that suggests that health promotion efforts to increase physical activity level and decrease sedentary time could help reduce mortality risk in black adults. C1 [Matthews, Charles E.; Xiao, Qian] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Rockville, MD USA. [Cohen, Sarah S.] EpidStat Inst, Ann Arbor, MI USA. [Fowke, Jay H.; Buchowski, Maciej S.; Blot, William J.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. [Fowke, Jay H.; Buchowski, Maciej S.; Blot, William J.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Han, Xijing; Blot, William J.] Int Epidemiol Inst, Rockville, MD USA. [Hargreaves, Margaret K.] Meharry Med Coll, Dept Internal Med, Nashville, TN 37208 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. RP Matthews, CE (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 9609 Med Ctr Dr,Room 6E340,MSC 9704, Bethesda, MD 20892 USA. EM charles.matthews2@nih.gov RI matthews, Charles/E-8073-2015; OI matthews, Charles/0000-0001-8037-3103; Buchowski, Maciej/0000-0002-0566-1743 FU National Cancer Institute at the National Institutes of Health [R01 CA92447]; American Recovery and Reinvestment Act [3R01 CA092447-08S1]; National Institutes of Health [5P60 DK20593-24, 5U01 CA114641-05] FX The Southern Community Cohort Study is funded by grant R01 CA92447 from the National Cancer Institute at the National Institutes of Health, including special allocations from the American Recovery and Reinvestment Act (grant 3R01 CA092447-08S1). Partial support for M. K. H. was provided by National Institutes of Health grants 5P60 DK20593-24 and 5U01 CA114641-05. NR 36 TC 17 Z9 17 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2014 VL 180 IS 4 BP 394 EP 405 DI 10.1093/aje/kwu142 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AQ7XD UT WOS:000343032100008 PM 25086052 ER PT J AU Hwang, WY Peterson, RT Yeh, JRJ AF Hwang, Woong Y. Peterson, Randall T. Yeh, Jing-Ruey Joanna TI Methods for targeted mutagenesis in zebrafish using TALENs SO METHODS LA English DT Article DE Site-specific nuclease; Transcription activator-like effector nuclease; Knockout; Genome engineering; Gene targeting; Gene disruption; Zebrafish ID ZINC-FINGER NUCLEASES; CRISPR-CAS SYSTEMS; HOMOLOGOUS RECOMBINATION; GENE DISRUPTION; HUMAN-CELLS; GENOME; DNA; SPECIFICITY; GENERATION; MUTATIONS AB The transcription activator-like effector (TALE) nucleases, or TALENs, are customizable restriction enzymes that may be used to induce mutations at nearly any investigator-specified DNA sequence in zebrafish. The DNA-binding specificities of TALENs are determined by a protein array comprised of four types of TALE repeats, where each repeat recognizes a different DNA base. Here, we describe methods for constructing TALEN vectors that have been shown to achieve high success rates and mutation efficiencies in zebrafish. In addition, we discuss simple techniques and protocols that can be used to detect TALEN-induced mutations at almost any genomic locus. These methods should enable zebrafish researchers to quickly generate targeted mutations at their genes-of-interest. (C) 2014 Elsevier Inc. All rights reserved. C1 [Hwang, Woong Y.; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Hwang, Woong Y.; Peterson, Randall T.; Yeh, Jing-Ruey Joanna] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Peterson, Randall T.] Broad Inst, Cambridge, MA 02142 USA. RP Yeh, JRJ (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St,Room 4201, Charlestown, MA 02129 USA. EM JYEH1@mgh.harvard.edu FU National Institutes of Health [R01 GM088040, R01 CA140188]; Charles and Ann Sanders MGH Scholar Award FX We thank Drs. J. Keith Joung, Deepak Reyon, Jeffry D. Sander, Ms. Lindsay Cade and Mr. Samir Patel for their contribution to the development of the methods described in this article. This work is supported by the National Institutes of Health (R01 GM088040 and R01 CA140188) and by the Charles and Ann Sanders MGH Scholar Award. NR 56 TC 10 Z9 11 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD AUG 15 PY 2014 VL 69 IS 1 BP 76 EP 84 DI 10.1016/j.ymeth.2014.04.009 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AP1CH UT WOS:000341803500011 PM 24747922 ER PT J AU Leary, D Winkler, T Braune, A Maksym, GN AF Leary, D. Winkler, T. Braune, A. Maksym, G. N. TI Effects of airway tree asymmetry on the emergence and spatial persistence of ventilation defects SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE lung mechanics modeling; heterogeneity; ventilation defect persistence; airway closure; entropy ID HE-3 MAGNETIC-RESONANCE; OBSTRUCTIVE PULMONARY-DISEASE; SMOOTH-MUSCLE; FLOW OBSTRUCTION; 3.0 TESLA; IN-VIVO; ASTHMA; LUNG; MODEL; METHACHOLINE AB Asymmetry and documented, but their effects on bronchoconstriction and ventilation distribution in asthma are unclear. In a series of seminal studies, Venegas et al. have shown that bronchoconstriction may lead to self-organized patterns of patchy ventilation in a computational model that could explain areas of poor ventilation [ventilation defects (VDefs)] observed in positron emission tomography images during induced bronchoconstriction. To investigate effects of anatomic asymmetry on the emergence of VDefs we used the symmetric tree computational model that Venegas and Winkler developed using different trees, including an anatomic human airway tree provided by M. Tawhai (University of Auckland), a symmetric tree, and three trees with intermediate asymmetry (Venegas JG, Winkler T, Musch G, Vidal Melo MF, Layfield D, Tgavalekos N, Fischman AJ, Callahan RJ, Bellani G, Harris RS. Nature 434: 777-782, 2005 and Winkler T, Venegas JG. J Appl Physiol 103: 655-663, 2007). Ventilation patterns, lung resistance (R-L), lung elastance (E-L), and the entropy of the ventilation distribution were compared at different levels of airway smooth muscle activation. We found VDefs emerging in both symmetric and asymmetric trees, but VDef locations were largely persistent in asymmetric trees, and bronchoconstriction reached steady state sooner than in a symmetric tree. Interestingly, bronchoconstriction in the asymmetric tree resulted in lower R-L (similar to%50) and greater E-L (similar to%25). We found that VDefs were universally caused by airway instability, but asymmetry in airway branching led to local triggers for the self-organized patchiness in ventilation and resulted in persistent locations of VDefs. These findings help to explain the emergence and the persistence in location of VDefs found in imaging studies. C1 [Leary, D.; Maksym, G. N.] Dalhousie Univ, Halifax, NS, Canada. [Winkler, T.; Braune, A.] Massachusetts Gen Hosp, Boston, MA USA. [Winkler, T.; Braune, A.] Harvard Univ, Sch Med, Boston, MA USA. RP Maksym, GN (reprint author), Dalhousie Univ, Halifax, NS, Canada. EM gmaksym@dal.ca RI Winkler, Tilo/B-5337-2009 OI Winkler, Tilo/0000-0002-7276-5550 FU Natural Sciences and Engineering Research Council of Canada Strategic Operating Grant; Atlantic Canada Opportunities Agency; National Heart, Lung, and Blood Institute [R01HL087281]; Canadian Thoracic Society studentship FX This work was supported by a Natural Sciences and Engineering Research Council of Canada Strategic Operating Grant in partnership with an Atlantic Innovation Fund award from the Atlantic Canada Opportunities Agency, and by National Heart, Lung, and Blood Institute Grant R01HL087281. D. Leary is supported by a Canadian Thoracic Society studentship. NR 39 TC 9 Z9 10 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD AUG 15 PY 2014 VL 117 IS 4 BP 353 EP 362 DI 10.1152/japplphysiol.00881.2013 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA AO4LQ UT WOS:000341310200002 PM 24947031 ER PT J AU Liu, J Wang, PP Zou, LY Qu, J Litovsky, S Umeda, P Zhou, LF Chatham, J Marsh, SA Dell'Italia, LJ Lloyd, SG AF Liu, Jian Wang, Peipei Zou, Luyun Qu, Jing Litovsky, Silvio Umeda, Patrick Zhou, Lufang Chatham, John Marsh, Susan A. Dell'Italia, Louis J. Lloyd, Steven G. TI High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE diet; myocardial ischemia; reperfusion injury; mitochondria; arrhythmia ID ACID OXIDATION; CARDIAC-FUNCTION; GENE-EXPRESSION; VENTRICULAR-FIBRILLATION; MITOCHONDRIAL DYNAMICS; LIPID-ACCUMULATION; HEART-DISEASE; HIGH-PROTEIN; DYSFUNCTION; ARRHYTHMOGENESIS AB High-fat, low-carbohydrate diets (HFLCD) are often eaten by humans for a variety of reasons, but the effects of such diets on the heart are incompletely understood. We evaluated the impact of HFLCD on myocardial ischemia/reperfusion (I/R) using an in vivo model of left anterior descending coronary artery ligation. Sprague-Dawley rats (300 g) were fed HFLCD (60% calories fat, 30% protein, 10% carbohydrate) or control (CONT; 16% fat, 19% protein, 65% carbohydrate) diet for 2 wk and then underwent open chest I/R. At baseline (preischemia), diet did not affect left ventricular (LV) systolic and diastolic function. Oil red O staining revealed presence of lipid in the heart with HFLCD but not in CONT. Following I/R, recovery of LV function was decreased in HFLCD. HFLCD hearts exhibited decreased ATP synthase and increased uncoupling protein-3 gene and protein expression. HFLCD downregulated mitochondrial fusion proteins and upregulated fission proteins and store-operated Ca2+ channel proteins. HFLCD led to increased death during I/R; 6 of 22 CONT rats and 16 of 26 HFLCD rats died due to ventricular arrhythmias and hemodynamic shock. In surviving rats, HFLCD led to larger infarct size. We concluded that in vivo HFLCD does not affect nonischemic LV function but leads to greater myocardial injury during I/R, with increased risk of death by pump failure and ventricular arrhythmias, which might be associated with altered cardiac energetics, mitochondrial fission/fusion dynamics, and store-operated Ca2+ channel expression. C1 [Liu, Jian; Qu, Jing; Umeda, Patrick; Zhou, Lufang; Dell'Italia, Louis J.; Lloyd, Steven G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Zou, Luyun; Litovsky, Silvio; Chatham, John] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Wang, Peipei] Natl Univ Singapore, Natl Univ Hlth Syst, Cardiovasc Res Inst, Singapore 117548, Singapore. [Marsh, Susan A.] Washington State Univ, Dept Clin Pharmacol, Pullman, WA 99164 USA. [Dell'Italia, Louis J.; Lloyd, Steven G.] Birmingham VA Med Ctr, Birmingham, AL USA. RP Lloyd, SG (reprint author), Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, D-101 Cardiac MRI,1808 7th Ave South, Birmingham, AL 35294 USA. EM sglloyd@uab.edu RI Marsh, Sue/J-3711-2014 OI Marsh, Sue/0000-0002-7530-0417 FU American Heart Association (Scientist Development Grant) [0735212N]; National Institutes of Health [P30DK056336] FX This work was supported in part by the American Heart Association (Scientist Development Grant 0735212N) and by the National Institutes of Health (P30DK056336). NR 65 TC 3 Z9 3 U1 0 U2 12 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG 15 PY 2014 VL 307 IS 4 BP H598 EP H608 DI 10.1152/ajpheart.00058.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AN8FZ UT WOS:000340840200013 PM 24929857 ER PT J AU Smith, JA Stallons, LJ Schnellmann, RG AF Smith, Joshua A. Stallons, L. Jay Schnellmann, Rick G. TI Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE lipopolysaccharide; acute kidney injury; hexokinase; EGFR; pentose phosphate pathway ID GROWTH-FACTOR RECEPTOR; GLYCOGEN-SYNTHESIS PATHWAY; OXIDATIVE STRESS; IN-VIVO; MITOCHONDRIAL HEXOKINASE; OXYGEN-CONSUMPTION; AKT INHIBITOR; FAILURE; METABOLISM; CELLS AB While disruption of energy production is an important contributor to renal injury, metabolic alterations in sepsis-induced AKI remain understudied. We assessed changes in renal cortical glycolytic metabolism in a mouse model of sepsis-induced AKI. A specific and rapid increase in hexokinase (HK) activity (similar to 2-fold) was observed 3 h after LPS exposure and maintained up to 18 h, in association with a decline in renal function as measured by blood urea nitrogen (BUN). LPS-induced HK activation occurred independently of HK isoform expression or mitochondrial localization. No other changes in glycolytic enzymes were observed. LPS-mediated HK activation was not sufficient to increase glycolytic flux as indicated by reduced or unchanged pyruvate and lactate levels in the renal cortex. LPS-induced HK activation was associated with increased glucose-6-phosphate dehydrogenase activity but not glycogen production. Mechanistically, LPS-induced HK activation was attenuated by pharmacological inhibitors of the EGF receptor (EGFR) and Akt, indicating that EGFR/phosphatidylinositol 3-kinase/Akt signaling is responsible. Our findings reveal LPS rapidly increases renal cortical HK activity in an EGFR-and Akt-dependent manner and that HK activation is linked to increased pentose phosphate pathway activity. C1 [Smith, Joshua A.; Stallons, L. Jay; Schnellmann, Rick G.] Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, Charleston, SC 29425 USA. [Schnellmann, Rick G.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Schnellmann, RG (reprint author), Med Univ S Carolina, Dept Drug Discovery & Biomed Sci, 280 Calhoun St,MSC140, Charleston, SC 29425 USA. EM schnell@musc.edu FU National Institute of General Medical Sciences [GM084147, P20GM103542-02]; National Center for Research Resources [UL1-RR029882, C06-RR015455]; Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [5I01 BX-000851]; South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina FX This material is based on work supported in part by National Institute of General Medical Sciences Grants GM084147 (to R. G. Schnellmann) and P20GM103542-02 (to South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling); National Center for Research Resources Grant UL1-RR029882; the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [Grant 5I01 BX-000851 (to R. G. Schnellmann)], and the South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina. Animal facilities were funded by National Center for Research Resources Grant C06-RR015455. NR 75 TC 4 Z9 4 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X EI 1522-1466 J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG 15 PY 2014 VL 307 IS 4 BP F435 EP F444 DI 10.1152/ajprenal.00271.2014 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA AO1PN UT WOS:000341085600008 PM 24990892 ER PT J AU Birket, SE Chu, KK Liu, L Houser, GH Diephuis, BJ Wilsterman, EJ Dierksen, G Mazur, M Shastry, S Li, Y Watson, JD Smith, AT Schuster, BS Hanes, J Grizzle, WE Sorscher, EJ Tearney, GJ Rowe, SM AF Birket, Susan E. Chu, Kengyeh K. Liu, Linbo Houser, Grace H. Diephuis, Bradford J. Wilsterman, Eric J. Dierksen, Gregory Mazur, Marina Shastry, Suresh Li, Yao Watson, John D. Smith, Alexander T. Schuster, Benjamin S. Hanes, Justin Grizzle, William E. Sorscher, Eric J. Tearney, Guillermo J. Rowe, Steven M. TI A Functional Anatomic Defect of the Cystic Fibrosis Airway SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cystic fibrosis; airway epithelium; optical coherence tomography; mucus transport; viscosity ID TRANSMEMBRANE CONDUCTANCE REGULATOR; VASOACTIVE-INTESTINAL-PEPTIDE; CILIARY BEAT FREQUENCY; SURFACE LIQUID VOLUME; PHASIC SHEAR-STRESS; BICARBONATE SECRETION; SUBMUCOSAL GLANDS; MUCOCILIARY TRANSPORT; PERICILIARY LIQUID; HYPERTONIC SALINE AB Rationale: The mechanisms underlying cystic fibrosis (CF) lung disease pathogenesis are unknown. Objectives: To establish mechanisms linking anion transport with the functional microanatomy, we evaluated normal and CF piglet trachea as well as adult swine trachea in the presence of selective anion inhibitors. Methods: We investigated airway functional microanatomy using microoptical coherence tomography, a new imaging modality that concurrently quantifies multiple functional parameters of airway epithelium in a colocalized fashion. Measurements and Main Results: Tracheal explants from wild-type swine demonstrated a direct link between periciliary liquid (PCL) hydration and mucociliary transport (MCT) rates, a relationship frequently invoked but never experimentally confirmed. However, in CF airways this relationship was completely disrupted, with greater PCL depths associated with slowest transport rates. This disrupted relationship was recapitulated by selectively inhibiting bicarbonate transport in vitro and ex vivo. CF mucus exhibited increased viscosity in situ due to the absence of bicarbonate transport, explaining defective MCT that occurs even in the presence of adequate PCL hydration. Conclusions: An inherent defect in CF airway surface liquid contributes to delayed MCT beyond that caused by airway dehydration alone and identifies a fundamental mechanism underlying the pathogenesis of CF lung disease in the absence of antecedent infection or inflammation. C1 [Birket, Susan E.; Shastry, Suresh; Li, Yao; Smith, Alexander T.; Sorscher, Eric J.; Rowe, Steven M.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Houser, Grace H.; Rowe, Steven M.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35294 USA. [Mazur, Marina; Shastry, Suresh; Li, Yao; Sorscher, Eric J.; Rowe, Steven M.] Univ Alabama Birmingham, Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA. [Grizzle, William E.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Sorscher, Eric J.; Rowe, Steven M.] Univ Alabama Birmingham, Dept Cellular Dev & Integrat Biol, Birmingham, AL 35294 USA. [Chu, Kengyeh K.; Liu, Linbo; Diephuis, Bradford J.; Wilsterman, Eric J.; Dierksen, Gregory; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Chu, Kengyeh K.; Liu, Linbo; Wilsterman, Eric J.; Dierksen, Gregory] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chu, Kengyeh K.; Diephuis, Bradford J.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA USA. [Diephuis, Bradford J.; Tearney, Guillermo J.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Schuster, Benjamin S.; Hanes, Justin] Johns Hopkins Univ Hosp, Dept Biomed Engn, Baltimore, MD 21287 USA. [Schuster, Benjamin S.] Johns Hopkins Univ Hosp, Ctr Nanomed, Baltimore, MD 21287 USA. [Hanes, Justin; Sorscher, Eric J.; Rowe, Steven M.] Johns Hopkins Univ Hosp, Dept Ophthalmol, Baltimore, MD 21287 USA. [Hanes, Justin] Johns Hopkins Univ Hosp, Dept Neurosurg, Baltimore, MD 21287 USA. [Hanes, Justin] Inst NanoBioTechnol, Baltimore, MD USA. [Hanes, Justin] Ctr Canc Nanotechnol Excellence, Baltimore, MD USA. RP Rowe, SM (reprint author), 1720 2nd Ave South, Birmingham, AL 35294 USA. EM gtearney@partners.org; smrowe@uab.edu FU National Heart, Lung, and Blood Institute [P01HL51811, R01HL116213, 5T32HL105346]; National Institute of Diabetes and Digestive and Kidney Diseases [P30DK072482]; National Institute of Bioimaging and Bioengineering of the National Institutes of Health [R01EB003558]; Research Development Program [R464-CF]; Mucociliary Clearance Consortium of the Cystic Fibrosis Foundation; Flatley Foundation; Dixon Foundation FX Supported by the National Heart, Lung, and Blood Institute grants P01HL51811 (J.H.), R01HL116213 (G.J.T. and S.M.R.), and 5T32HL105346-04 (S.E.B.) and the National Institute of Diabetes and Digestive and Kidney Diseases grant P30DK072482 (E.J.S.) and the National Institute of Bioimaging and Bioengineering grant R01EB003558 (J.H.) of the National Institutes of Health, the Research Development Program (R464-CF), and the Mucociliary Clearance Consortium (J.H., G.J.T., and S.M.R.) of the Cystic Fibrosis Foundation, the Flatley Foundation (K.K.C., G.D., G.J.T., and S.M.R.), and the Dixon Foundation (G.H.H.). NR 55 TC 37 Z9 37 U1 1 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 15 PY 2014 VL 190 IS 4 BP 421 EP 432 DI 10.1164/rccm.201404-0670OC PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA AN6FR UT WOS:000340690900013 PM 25029666 ER PT J AU Haaland, B Chopra, A Acharyya, S Fay, AP Lopes, GD AF Haaland, Benjamin Chopra, Akhil Acharyya, Sanchalika Fay, Andre P. Lopes, Gilberto de Lima TI Comparative effectiveness of approved first-line anti-angiogenic and molecularly targeted therapeutic agents in the treatment of good and intermediate risk metastatic clear cell renal cell carcinoma SO BMC CANCER LA English DT Article DE Renal cell carcinoma; VEGF-targeted therapy; Bevacizumab; Sunitinib; Pazopanib; Interferon ID RANDOMIZED CONTROLLED-TRIALS; TREATMENT-RELATED MORTALITY; BLIND PHASE-III; INTERFERON-ALPHA; CANCER; METAANALYSIS; BEVACIZUMAB; SUNITINIB; SURVIVAL; PAZOPANIB AB Background: Based on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents. Methods: We performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined. Results: The meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR. Conclusions: Bevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment. C1 [Haaland, Benjamin; Acharyya, Sanchalika] Duke Natl Univ Singapore, Grad Sch Med, Off Clin Sci, Ctr Quantitat Med, Singapore 169857, Singapore. [Haaland, Benjamin] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117546, Singapore. [Chopra, Akhil] Johns Hopkins Singapore Int Med Ctr, Singapore 308433, Singapore. [Fay, Andre P.] Pontificia Univ Catolica Rio Grande do Sul, Sch Med, Postgrad Program, BR-90619900 Porto Alegre, RS, Brazil. [Fay, Andre P.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02215 USA. [Lopes, Gilberto de Lima] Oncoclin Brasil, Belo Horizonte, MG, Brazil. [Lopes, Gilberto de Lima] Hosp Coracao Canc Ctr HCor Onco, Sao Paulo, Brazil. [Lopes, Gilberto de Lima] Johns Hopkins Univ, Baltimore, MD USA. RP Haaland, B (reprint author), Duke Natl Univ Singapore, Grad Sch Med, Off Clin Sci, Ctr Quantitat Med, 8 Coll Rd, Singapore 169857, Singapore. EM ben.haaland@isye.gatech.edu FU BMRC (Singapore) [13/1/96/682]; CAPES - Brazil FX BH is supported by BMRC (Singapore) Translational Clinical Research Partnership for Duke-NUS/SingHealth Academic Clinical Programme grant number 13/1/96/682. AF receives a scholarship from CAPES - Brazil. NR 46 TC 4 Z9 4 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 15 PY 2014 VL 14 AR 592 DI 10.1186/1471-2407-14-592 PG 9 WC Oncology SC Oncology GA AN9ZB UT WOS:000340967100002 PM 25127891 ER PT J AU Philip, PA Chansky, K LeBlanc, M Rubinstein, L Seymour, L Ivy, SP Alberts, SR Catalano, PJ Crowley, J AF Philip, Philip A. Chansky, Kari LeBlanc, Michael Rubinstein, Lawrence Seymour, Lesley Ivy, S. Percy Alberts, Steven R. Catalano, Paul J. Crowley, John TI Historical Controls for Metastatic Pancreatic Cancer: Benchmarks for Planning and Analyzing Single-Arm Phase II Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; GEMCITABINE; COMBINATION; ADENOCARCINOMA; METAANALYSIS; CARCINOMA; SURVIVAL; BENEFIT AB We compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy. (C) 2014 AACR. C1 [Philip, Philip A.] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI USA. [Chansky, Kari; Crowley, John] Canc Res & Biostat, Seattle, WA 98101 USA. [LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA 98104 USA. [Rubinstein, Lawrence; Ivy, S. Percy] NCI, Bethesda, MD 20892 USA. [Alberts, Steven R.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Catalano, Paul J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Seymour, Lesley] NCIC Clin Trials Grp, Kingston, ON, Canada. RP Chansky, K (reprint author), Canc Res & Biostat, 1730 Minor Ave,Suite 1900, Seattle, WA 98101 USA. EM karic@crab.org FU NCI of the NIH [U10CA038926] FX This work was supported by the NCI of the NIH under award number U10CA038926 (to J. Crowley). NR 25 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4176 EP 4185 DI 10.1158/1078-0432.CCR-13-2024 PG 10 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100002 PM 24914040 ER PT J AU Okumura, S Janne, PA AF Okumura, Shunsuke Jaenne, Pasi A. TI Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; DOCETAXEL-INDUCED APOPTOSIS; COLORECTAL-CANCER; RAS MUTATIONS; AZD6244 ARRY-142886; KINASE INHIBITORS; SIGNALING PATHWAY; TUMOR-GROWTH; OPEN-LABEL; PHASE-II AB Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G(1) phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers. (C) 2014 AACR. C1 [Okumura, Shunsuke; Jaenne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM pasi_janne@dfci.harvard.edu NR 61 TC 4 Z9 4 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4193 EP 4199 DI 10.1158/1078-0432.CCR-13-2365 PG 7 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100004 PM 24907112 ER PT J AU Hussain, M Corn, PG Michaelson, MD Hammers, HJ Alumkal, JJ Ryan, CJ Bruce, JY Moran, S Lee, SY Lin, HM George, DJ AF Hussain, Maha Corn, Paul G. Michaelson, M. Dror Hammers, Hans J. Alumkal, Joshi J. Ryan, Charles J. Bruce, Justine Y. Moran, Susan Lee, Shih-Yuan Lin, H. Mark George, Daniel J. CA Prostate Canc Clinical Trials TI Phase II Study of Single-Agent Orteronel (TAK-700) in Patients with Nonmetastatic Castration-Resistant Prostate Cancer and Rising Prostate-Specific Antigen SO CLINICAL CANCER RESEARCH LA English DT Article ID ANDROGEN DEPRIVATION THERAPY; PLACEBO-CONTROLLED TRIAL; METASTASIS-FREE SURVIVAL; MEN; ABIRATERONE; PREDICTOR; DENOSUMAB; CRITERIA; PSA AB Purpose: Orteronel (TAK-700) is an investigational, nonsteroidal, oral, inhibitor of androgen synthesis with greater specificity for 17,20-lyase than for 17 alpha-hydroxylase. We investigated orteronel without steroids in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC; M-o). Experimental Design: Patients with nmCRPC and rising prostate-specific antigen (PSA) received orteronel 300 mg twice daily until PSA progression, metastases, or unacceptable toxicity. The primary endpoint was percentage of patients achieving PSA <= 0.2 ng/mL (undetectable levels) at 3 months. Secondary endpoints included safety, PSA response, time to metastases, and correlated endpoints. Results: Thirty-nine patients with a median baseline PSA doubling time of 2.4 months (range, 0.9-9.2) received a median of fourteen 28-day treatment cycles. PSA decreased >30% in 35 patients and 6 (16%) achieved PSA <= 0.2 ng/mL at 3 months. Median times to PSA progression and metastasis were 13.8 and 25.4 months, respectively. Kaplan-Meier estimates of freedom from PSA progression were 57% and 42% at 12 and 24 months, and of freedom from metastasis were 94% and 62% at 12 and 24 months, respectively. At 3 months, median testosterone declined by 89% from baseline. Adverse events led to therapy discontinuation in 12 patients and grade >= 3/4 adverse events occurred in 22 patients. Most frequent all-cause adverse events included fatigue (64%), hypertension (44%), diarrhea (38%), and nausea (33%), which were primarily grade 1/2. Conclusions: Single-agent orteronel produced marked and durable declines in PSA in patients with nmCRPC. Orteronel has moderate but manageable toxicities and its chronic administration without steroids appears feasible. (C) 2014 AACR. C1 [Hussain, Maha] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Corn, Paul G.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Michaelson, M. Dror] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Moran, Susan; Lee, Shih-Yuan] Takeda Pharmaceut Int Co, Osaka, Japan. [Lin, H. Mark] Millennium Takeda Oncol Co, Cambridge, MA USA. [Hammers, Hans J.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Alumkal, Joshi J.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Ryan, Charles J.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Bruce, Justine Y.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI USA. [George, Daniel J.] Duke Univ, Med Ctr, Durham, NC USA. RP Hussain, M (reprint author), Univ Michigan, Ctr Comprehens Canc, 7314,1500 East Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mahahuss@umich.edu OI Michaelson, Dror/0000-0001-9249-6338 FU Takeda Pharmaceuticals International Co. FX All study sites and institutions received funding from Takeda Pharmaceuticals International Co. to cover the expenses of the investigators, sub-investigators, and study staff for clinical trial execution. NR 32 TC 12 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4218 EP 4227 DI 10.1158/1078-0432.CCR-14-0356 PG 10 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100007 PM 24965748 ER PT J AU Moser, R Xu, C Kao, M Annis, J Lerma, LA Schaupp, CM Gurley, KE Jang, IS Biktasova, A Yarbrough, WG Margolin, AA Grandori, C Kemp, CJ Mendez, E AF Moser, Russell Xu, Chang Kao, Michael Annis, James Lerma, Luisa Angelica Schaupp, Christopher M. Gurley, Kay E. Jang, In Sock Biktasova, Asel Yarbrough, Wendell G. Margolin, Adam A. Grandori, Carla Kemp, Christopher J. Mendez, Eduardo TI Functional Kinomics Identifies Candidate Therapeutic Targets in Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; FOCAL-ADHESION KINASE; LOCALLY ADVANCED HEAD; DNA-DAMAGING AGENTS; SRC FAMILY KINASES; MALIGNANT PROGRESSION; TYROSINE KINASE; TUMOR-CELLS; WEE1 KINASE AB Purpose: To identify novel therapeutic drug targets for p53-mutant head and neck squamous cell carcinoma (HNSCC). Experimental Design: RNAi kinome viability screens were performed on HNSCC cells, including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19(Arf). Cross-species analysis of cell lines stratified by p53 mutational status and metastatic phenotype was used to select 38 kinase targets. Both primary and secondary RNAi validation assays were performed on additional HNSCC cell lines to credential these kinase targets using multiple phenotypic endpoints. Kinase targets were also examined via chemical inhibition using a panel of kinase inhibitors. A preclinical study was conducted on the WEE1 kinase inhibitor, MK-1775. Results: Our functional kinomics approach identified novel survival kinases in HNSCC involved in G(2)-M cell-cycle checkpoint, SFK, PI3K, and FAK pathways. RNAi-mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis. Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry. MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53-mutant HNSCC xenograft model. Conclusions: WEE1 kinase is a potential therapeutic drug target for HNSCC. This study supports the application of a functional kinomics strategy to identify novel therapeutic targets for cancer. (C) 2014 AACR. C1 [Moser, Russell; Gurley, Kay E.; Grandori, Carla; Kemp, Christopher J.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [Xu, Chang; Kao, Michael; Lerma, Luisa Angelica; Mendez, Eduardo] Univ Washington, Med Ctr, Dept Otolaryngol Head & Neck Surg, Seattle, WA 98195 USA. [Xu, Chang; Mendez, Eduardo] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Annis, James; Grandori, Carla] Univ Washington Med Res, Inst Stem Cell & Regenerat Med, Quellos High Throughput Facil, Seattle, WA USA. [Schaupp, Christopher M.] Univ Washington, Dept Environm & Occupat Hlth Sci, Toxicol Program, Seattle, WA 98195 USA. [Jang, In Sock; Margolin, Adam A.] Sage Bionetworks, Seattle, WA USA. [Biktasova, Asel; Yarbrough, Wendell G.] Yale Univ, Sch Med, Dept Surg Otolaryngol Head & Neck Surg, New Haven, CT USA. [Mendez, Eduardo] VA Puget Sound Hlth Care Syst, Surg & Perioperat Care Serv, Seattle, WA USA. RP Mendez, E (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave North, Seattle, WA 98109 USA. EM cjkemp@fhcrc.org; edmendez@u.washington.edu FU FHCRC/UW Cancer Consortium Pilot grants from the NIH [P30CA015704]; National Center for Research Resources [5KL2RR025015]; Howard Hughes Medical Institute Early Physician-Scientist Career Development Award; American Cancer Society [RSG TBG-123653]; Mouse Models of Human Cancer Consortium [U01 CA141550]; National Institute of Environmental Health Science [ES020116]; Integrated Cancer Biology Program [54CA149237]; National Cancer Institute [U01 CA176303]; Department of Otolaryngology/Head and Neck Surgery at the University of Washington; VA Puget Sound Health Care System FX This work was supported by two FHCRC/UW Cancer Consortium Pilot grants from the NIH (P30CA015704); the National Center for Research Resources (5KL2RR025015); the Howard Hughes Medical Institute Early Physician-Scientist Career Development Award; American Cancer Society grant (RSG TBG-123653); the Mouse Models of Human Cancer Consortium (U01 CA141550); the National Institute of Environmental Health Science (ES020116); the Integrated Cancer Biology Program (54CA149237); National Cancer Institute grant (U01 CA176303); and center funds from the Department of Otolaryngology/Head and Neck Surgery at the University of Washington and VA Puget Sound Health Care System NR 50 TC 13 Z9 13 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4274 EP 4288 DI 10.1158/1078-0432.CCR-13-2858 PG 15 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100012 PM 25125259 ER PT J AU Hu, CY Mohtat, D Yu, YT Ko, YA Shenoy, N Bhattacharya, S Izquierdo, MC Park, ASD Giricz, O Vallumsetla, N Gundabolu, K Ware, K Bhagat, TD Suzuki, M Pullman, J Liu, XS Greally, JM Susztak, K Verma, A AF Hu, Caroline Y. Mohtat, Davoud Yu, Yiting Ko, Yi-An Shenoy, Niraj Bhattacharya, Sanchari Izquierdo, Maria C. Park, Ae Seo Deok Giricz, Orsolya Vallumsetla, Nishanth Gundabolu, Krishna Ware, Kristin Bhagat, Tushar D. Suzuki, Masako Pullman, James Liu, X. Shirley Greally, John M. Susztak, Katalin Verma, Amit TI Kidney Cancer Is Characterized by Aberrant Methylation of Tissue-Specific Enhancers That Are Prognostic for Overall Survival SO CLINICAL CANCER RESEARCH LA English DT Article ID RENAL-CELL CARCINOMA; CYTOSINE METHYLATION; DNA-METHYLATION; HISTONE ACETYLATION; GENE; GENOME; DISEASE; DIFFERENTIATION; EPIGENETICS; PROFILES AB Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. Experimental Design: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. Results: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases of RCC in multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. Conclusions: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort. (C)2014 AACR. C1 [Hu, Caroline Y.; Mohtat, Davoud; Yu, Yiting; Shenoy, Niraj; Bhattacharya, Sanchari; Giricz, Orsolya; Vallumsetla, Nishanth; Gundabolu, Krishna; Bhagat, Tushar D.; Suzuki, Masako; Greally, John M.; Verma, Amit] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Ko, Yi-An; Izquierdo, Maria C.; Park, Ae Seo Deok; Susztak, Katalin] Univ Penn, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19104 USA. [Ware, Kristin; Pullman, James] Montefiore Med Ctr, Dept Pathol, New York, NY USA. [Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Verma, A (reprint author), Albert Einstein Coll Med, 1300 Morris Pk Ave,Chanin 302B, Bronx, NY 10461 USA. EM ksusztak@mail.med.upenn.edu; amit.verma@einstein.yu.edu FU NIH [R01DK087635]; Hershaft Family Foundation; Leukemia and Lymphoma Society; Department of Defense FX This work was supported by the NIH (R01DK087635), the Hershaft Family Foundation, the Leukemia and Lymphoma Society, and the Department of Defense. NR 42 TC 19 Z9 19 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4349 EP 4360 DI 10.1158/1078-0432.CCR-14-0494 PG 12 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100018 PM 24916699 ER PT J AU Sargent, DJ Shi, Q Gill, S Louvet, C Everson, RB Kellner, U Clancy, TE Pipas, JM Resnick, MB Meyers, MO Wu, TT Huntsman, D Validire, P Farooq, U Pavey, ES Beaudry, G Haince, JF Fradet, Y AF Sargent, Daniel J. Shi, Qian Gill, Sharlene Louvet, Christophe Everson, Richard B. Kellner, Udo Clancy, Thomas E. Pipas, J. Marc Resnick, Murray B. Meyers, Michael O. Wu, Tsung-Teh Huntsman, David Validire, Pierre Farooq, Umar Pavey, Emily S. Beaudry, Guillaume Haince, Jean-Francois Fradet, Yves TI Molecular Testing for Lymph Node Metastases as a Determinant of Colon Cancer Recurrence: Results from a Retrospective Multicenter Study SO CLINICAL CANCER RESEARCH LA English DT Article ID GUANYLYL CYCLASE-C; DEFECTIVE MISMATCH REPAIR; POLYMERASE CHAIN-REACTION; PN0 COLORECTAL-CANCER; TUMOR-CELLS; MICROSATELLITE-INSTABILITY; ADJUVANT CHEMOTHERAPY; MICROMETASTASES; SURVIVAL; ASSAY AB Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR 1.87, 95% CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status(HR = 0.77,95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR <= 0.20), and low (LNR <= 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. (C)2014 AACR. C1 [Sargent, Daniel J.; Shi, Qian; Pavey, Emily S.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN 55905 USA. [Wu, Tsung-Teh] Mayo Clin, Dept Anat Pathol, Rochester, MN 55905 USA. [Clancy, Thomas E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Clancy, Thomas E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pipas, J. Marc] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA. [Resnick, Murray B.] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Resnick, Murray B.] Rhode Isl Hosp, Providence, RI USA. [Meyers, Michael O.] Univ N Carolina, Div Surg Oncol, Chapel Hill, NC USA. [Everson, Richard B.; Farooq, Umar] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Gill, Sharlene; Huntsman, David] Univ British Columbia, BC Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Beaudry, Guillaume; Haince, Jean-Francois; Fradet, Yves] DiagnoCure Inc, Quebec City, PQ, Canada. [Louvet, Christophe] Inst Mutualiste Montsouris, Dept Oncol, Paris, France. [Validire, Pierre] Inst Mutualiste Montsouris, Dept Pathol, Paris, France. [Kellner, Udo] Johannes Wessling Klinikum Minden, Minden, Germany. RP Sargent, DJ (reprint author), Mayo Clin, 200 First St SW, Rochester, MN 55905 USA. EM sargent.daniel@mayo.edu NR 32 TC 2 Z9 3 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4361 EP 4369 DI 10.1158/1078-0432.CCR-13-2659 PG 9 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100019 PM 24919572 ER PT J AU Singhi, AD Nikiforova, MN Fasanella, KE McGrath, KM Pai, RK Ohori, NP Bartholow, TL Brand, RE Chennat, JS Lu, X Papachristou, GI Slivka, A Zeh, HJ Zureikat, AH Lee, KK Tsung, A Mantha, GS Khalid, A AF Singhi, Aatur D. Nikiforova, Marina N. Fasanella, Kenneth E. McGrath, Kevin M. Pai, Reetesh K. Ohori, N. Paul Bartholow, Tanner L. Brand, Randall E. Chennat, Jennifer S. Lu, Xuong Papachristou, Georgios I. Slivka, Adam Zeh, Herbert J. Zureikat, Amer H. Lee, Kenneth K. Tsung, Allan Mantha, Geeta S. Khalid, Asif TI Preoperative GNAS and KRAS Testing in the Diagnosis of Pancreatic Mucinous Cysts SO CLINICAL CANCER RESEARCH LA English DT Article ID INTERNATIONAL CONSENSUS GUIDELINES; FINE-NEEDLE-ASPIRATION; DNA ANALYSIS; MUTATIONS; MANAGEMENT; LESIONS; NEOPLASMS; CANCER; PRECURSORS; CYTOLOGY AB Purpose: Management guidelines for pancreatic intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are based on the assumption that mucinous cysts can be accurately distinguished from other pancreatic cystic lesions. Previous studies using surgical material have identified recurrent mutations in GNAS and KRAS in pancreatic mucinous neoplasms. Yet, the diagnostic utility of testing for both genes in pancreatic cyst fluid obtained by endoscopic ultrasound-fine-needle aspiration (EUS-FNA) remains unclear. Experimental Design: GNAS and KRAS testing was performed on EUS-FNA pancreatic cyst fluid from 91 pancreatic cysts: 41 IPMNs, 9 IPMNs with adenocarcinoma, 16 MCNs, 10 cystic pancreatic neuroendocrine tumors (PanNET), 9 serous cystadenomas (SCA), 3 retention cysts, 2 pseudocysts, and 1 lymphoepithelial cyst. Results: Mutations in GNAS were detected in 16 (39%) IPMNs and 2 (22%) IPMNs with adenocarcinoma. KRAS mutations were identified in 28 (68%) IPMNs, 7 (78%) IPMNs with adenocarcinoma, and 1 (6%) MCN. Mutations in either gene were present in 34 (83%) IPMNs, 8 (89%) IPMNs with adenocarcinoma, and 1 (6%) MCN. No mutations were found in cystic PanNETs, SCAs, retention cysts, pseudocysts, and a lymphoepithelial cyst. GNAS and KRAS mutations had 100% specificity [95% confidence interval (CI), 0.83-1.00] but 65% sensitivity (95% CI, 0.52-0.76) for mucinous differentiation. Among IPMNs, mutations in either gene had 98% specificity (95% CI, 0.86-1.00) and 84% sensitivity (95% CI, 0.70-0.92). Conclusions: The combination of GNAS and KRAS testing was highly specific and sensitive for IPMNs; however, the lack of sensitivity for MCNs highlights the need for additional markers to improve the detection of pancreatic mucinous neoplasms. (C)2014 AACR. C1 [Singhi, Aatur D.; Nikiforova, Marina N.; Pai, Reetesh K.; Ohori, N. Paul; Bartholow, Tanner L.; Mantha, Geeta S.] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15213 USA. [Fasanella, Kenneth E.; McGrath, Kevin M.; Brand, Randall E.; Chennat, Jennifer S.; Lu, Xuong; Papachristou, Georgios I.; Slivka, Adam; Khalid, Asif] Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA 15213 USA. [Zeh, Herbert J.; Zureikat, Amer H.; Lee, Kenneth K.; Tsung, Allan] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA 15213 USA. [Papachristou, Georgios I.; Khalid, Asif] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Singhi, AD (reprint author), Univ Pittsburgh, Med Ctr, Presbyterian Hosp, Scaife Hall,Room 616-2,200 Lothrop St, Pittsburgh, PA 15213 USA. EM singhiad@upmc.edu FU National Pancreas Foundation, Western Pennsylvania Chapter FX This study was supported in part by a grant from the National Pancreas Foundation, Western Pennsylvania Chapter (to A.D. Singhi). NR 26 TC 27 Z9 27 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2014 VL 20 IS 16 BP 4381 EP 4389 DI 10.1158/1078-0432.CCR-14-0513 PG 9 WC Oncology SC Oncology GA AO2WB UT WOS:000341186100021 PM 24938521 ER PT J AU Luyten, A Zang, CZ Liu, XS Shivdasani, RA AF Luyten, Annouck Zang, Chongzhi Liu, X. Shirley Shivdasani, Ramesh A. TI Active enhancers are delineated de novo during hematopoiesis, with limited lineage fidelity among specified primary blood cells SO GENES & DEVELOPMENT LA English DT Article DE tissue differentiation; hematopoiesis; chromatin dynamics; nucleosome dynamics; tissue-selective enhancers ID GLUCOCORTICOID-RECEPTOR BINDING; TRANSCRIPTION FACTOR NF-E2; EMBRYONIC STEM-CELLS; HUMAN GENOME; CHIP-SEQ; CHROMATIN ACCESSIBILITY; HISTONE MODIFICATIONS; PRECEDES COMMITMENT; PLATELET FORMATION; GENE-EXPRESSION AB Tissues may adopt diverse strategies to establish specific transcriptional programs in daughter lineages. In intestinal crypts, enhancers for genes expressed in both major cell types appear broadly permissive in stem and specified progenitor cells. In blood, another self-renewing tissue, it is unclear when chromatin becomes permissive for transcription of genes expressed in distinct terminal lineages. Using chromatin immunoprecipitation (ChIP) combined with deep sequencing (ChIP-seq) to profile activating histone marks, we studied enhancer dynamics in primary mouse blood stem, progenitor, and specified cells. Stem and multipotent progenitor cells show scant H3K4me2 marking at enhancers bound by specific transcription factors in their committed progeny. Rather, enhancers are modulated dynamically and serially, with substantial loss and gain of H3K4me2, at each cellular transition. Quantitative analysis of these dynamics accurately modeled hematopoiesis according to Waddington's notion of epigenotypes. Delineation of enhancers in terminal blood lineages coincides with cell specification, and enhancers active in single lineages show well-positioned H3K4me2- and H3K27ac-marked nucleosomes and DNaseI hypersensitivity in other cell types, revealing limited lineage fidelity. These findings demonstrate that enhancer chronology in blood cells differs markedly from that in intestinal crypts. Chromatin dynamics in hematopoiesis provide a useful foundation to consider classical observations such as cellular reprogramming and multilineage locus priming. C1 [Luyten, Annouck; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02215 USA. [Zang, Chongzhi; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Funct Canc Epigenet,Dept Biostat & Computat B, Boston, MA 02215 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Luyten, Annouck; Zang, Chongzhi; Shivdasani, Ramesh A.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu RI Zang, Chongzhi/D-1445-2011 FU National Institutes of Health [R01HL63143, R01GM099409]; Leukemia and Lymphoma Society FX We thank Myles Brown, Henry Long, and members of our groups for constructive discussions. This work was supported by National Institutes of Health grants R01HL63143 (R.A.S.) and R01GM099409 (X.S.L.) and a fellowship from the Leukemia and Lymphoma Society (C.Z.). NR 63 TC 11 Z9 12 U1 2 U2 6 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 EI 1549-5477 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2014 VL 28 IS 16 BP 1827 EP 1839 DI 10.1101/gad.240101.114 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA AO1KN UT WOS:000341071100009 PM 25128499 ER PT J AU Shanmugam, I Abbas, M Ayoub, F Mirabal, S Bsaili, M Caulder, EK Weinstock, DM Tomkinson, AE Hromas, R Shaheen, M AF Shanmugam, Ilanchezhian Abbas, Mohammad Ayoub, Farhan Mirabal, Susan Bsaili, Manal Caulder, Erin K. Weinstock, David M. Tomkinson, Alan E. Hromas, Robert Shaheen, Monte TI Ubiquitin-specific Peptidase 20 Regulates Rad17 Stability, Checkpoint Kinase 1 Phosphorylation and DNA Repair by Homologous Recombination SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRAND BREAK REPAIR; MAMMALIAN-CELLS; DAMAGE RESPONSE; ATR; ENDONUCLEASE; COMPLEXES; RECOVERY; REVEALS; FORK AB Rad17 is a subunit of the Rad9-Hus1-Rad1 clamp loader complex, which is required for Chk1 activation after DNA damage. Rad17 has been shown to be regulated by the ubiquitin-proteasome system. We have identified a deubiquitylase, USP20 that is required for Rad17 protein stability in the steady-state and post DNA damage. We demonstrate that USP20 and Rad17 interact, and that this interaction is enhanced by UV exposure. We show that USP20 regulation of Rad17 is at the protein level in a proteasome-dependent manner. USP20 depletion results in poor activation of Chk1 protein by phosphorylation, consistent with Rad17 role in ATR-mediated phosphorylation of Chk1. Similar to other DNA repair proteins, USP20 is phosphorylated post DNA damage, and its depletion sensitizes cancer cells to damaging agents that form blocks ahead of the replication forks. Similar to Chk1 and Rad17, which enhance recombinational repair of collapsed replication forks, we demonstrate that USP20 depletion impairs DNA double strand break repair by homologous recombination. Together, our data establish a new function of USP20 in genome maintenance and DNA repair. C1 [Shanmugam, Ilanchezhian; Abbas, Mohammad; Ayoub, Farhan; Mirabal, Susan; Bsaili, Manal; Caulder, Erin K.; Tomkinson, Alan E.; Shaheen, Monte] Univ New Mexico, Dept Internal Med, Div Hematol Oncol, Albuquerque, NM 87131 USA. [Shanmugam, Ilanchezhian; Abbas, Mohammad; Ayoub, Farhan; Mirabal, Susan; Bsaili, Manal; Caulder, Erin K.; Tomkinson, Alan E.; Shaheen, Monte] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Hromas, Robert] Univ Florida, Dept Med, Gainesville, FL 32610 USA. [Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. RP Shaheen, M (reprint author), Univ New Mexico, Ctr Canc, 1201 Camino de Salud NE, Albuquerque, NM 87131 USA. EM moshaheen@salud.unm.edu FU NIH [5K01HL103182-03]; UNM Cancer Center FX This work was supported, in whole or in part, by NIH Grant 5K01HL103182-03 (to M. S.) and start-up funds from the UNM Cancer Center. NR 21 TC 6 Z9 6 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 15 PY 2014 VL 289 IS 33 BP 22739 EP 22748 DI 10.1074/jbc.M114.550459 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO0QV UT WOS:000341017200019 PM 24923443 ER PT J AU Rui, XL Mehrbod, M Van Agthoven, JF Anand, S Xiong, JP Mofrad, MRK Arnaout, MA AF Rui, Xianliang Mehrbod, Mehrdad Van Agthoven, Johannes F. Anand, Saurabh Xiong, Jian-Ping Mofrad, Mohammad R. K. Arnaout, M. Amin TI The alpha-Subunit Regulates Stability of the Metal Ion at the Ligand-associated Metal Ion-binding Site in beta(3) Integrins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; MOLECULAR-DYNAMICS; EXTRACELLULAR SEGMENT; STRUCTURAL BASIS; ALPHA-V-BETA-3; ACTIVATION; ALPHA(V)BETA(3); ADHESION; TALIN; FIBRONECTIN AB The aspartate in the prototypical integrin-binding motif Arg-Gly-Asp binds the integrin beta A domain of the beta-subunit through a divalent cation at the metal ion-dependent adhesion site (MIDAS). An auxiliary metal ion at a ligand-associated metal ion-binding site (LIMBS) stabilizes the metal ion at MIDAS. LIMBS contacts distinct residues in the alpha-subunits of the two beta 3 integrins alpha(IIb)beta(3) and alpha(V)beta(3), but a potential role of this interaction on stability of the metal ion at LIMBS in beta(3) integrins has not been explored. Equilibrium molecular dynamics simulations of fully hydrated beta 3 integrin ectodomains revealed strikingly different conformations of LIMBS in unliganded alpha(IIb)beta(3) versus alpha(V)beta(3), the result of stronger interactions of LIMBS with alpha(V), which reduce stability of the LIMBS metal ion in alpha(V)beta(3). Replacing the alpha(IIb)-LIMBS interface residue Phe(191) in alpha(IIb) (equivalent to Trp179 in alpha(V)) with Trp strengthened this interface and destabilized the metal ion at LIMBS in alpha(IIb)beta(3); a Trp179 to Phe mutation in alpha(V) produced the opposite but weaker effect. Consistently, an F191/W substitution in cellular alpha(IIb)beta 3 and a W179/F substitution in alpha(V)beta(3) reduced and increased, respectively, the apparent affinity of Mn2+ to the integrin. These findings offer an explanation for the variable occupancy of the metal ion at LIMBS in alpha(V)beta(3) structures in the absence of ligand and provide new insights into the mechanisms of integrin regulation. C1 [Rui, Xianliang; Anand, Saurabh; Arnaout, M. Amin] Massachusetts Gen Hosp, Leukocyte Biol & Inflammat Program, Charlestown, MA 02129 USA. [Van Agthoven, Johannes F.; Xiong, Jian-Ping; Arnaout, M. Amin] Massachusetts Gen Hosp, Struct Biol Program, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Mehrbod, Mehrdad; Mofrad, Mohammad R. K.] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. [Mehrbod, Mehrdad; Mofrad, Mohammad R. K.] Univ Calif Berkeley, Dept Mech Engn, Berkeley, CA 94720 USA. RP Mofrad, MRK (reprint author), Univ Calif Berkeley, 208A Stanley Hall 1762, Berkeley, CA 94720 USA. EM mofrad@berkeley.edu; aarnaout1@mgh.harvard.edu FU National Institutes of Health [DK088327, DK096334, DK007540]; National Science Foundation CAREER Award [CBET-0955291] FX This work was supported, in whole or in part, by National Institutes of Health Grants DK088327, DK096334, and DK007540 (to M. A. A.) and by a National Science Foundation CAREER Award CBET-0955291 (to M. R. K. M.). NR 34 TC 3 Z9 3 U1 1 U2 12 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 15 PY 2014 VL 289 IS 33 BP 23256 EP 23263 DI 10.1074/jbc.M114.581470 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AO0QV UT WOS:000341017200061 PM 24975416 ER PT J AU Vardi, M Perez, J Griffin, PJ Burke, DA Yeh, RW Cutlip, DE AF Vardi, Moshe Perez, Jeremiah Griffin, Paula J. Burke, David A. Yeh, Robert W. Cutlip, Donald E. TI Usefulness of Postmarket Studies to Evaluate Long-Term Safety of Coronary Eluting Stents (from the ENDEAVOR and PROTECT Programs) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ANGIOGRAPHIC FOLLOW-UP; MEDICAL DEVICES; RANDOMIZED-TRIALS; IV TRIAL; SURVEILLANCE; LESIONS; IMPLANTATION; MULTICENTER; THROMBOSIS; OUTCOMES AB Differences in enrollment criteria and protocol requirements are believed to affect patient representation and outcomes from premarket and postmarket surveillance (PMS) trials. These differences have not been assessed in studies evaluating coronary stenting. We aimed to assess differences in clinical profile and long-term outcomes in patients enrolled into premarket versus PMS trials assessing the Endeavor zotarolimus-eluting stent (E-ZES). We pooled patient-level data for 2,132 and 4,357 E-ZES-treated subjects enrolled into the ENDEAVOR program (premarket) and Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PMS), respectively. Follow-up data were available through 3 years. Baseline characteristics and outcomes of patients enrolled in the 2 groups were compared. Propensity score adjusted Cox proportional hazards models were used to assess the effect of differences in baseline characteristics. We also adjusted for protocol-mandated repeat angiography to account for differences in follow-up requirements. Despite significant differences in baseline characteristics, the unadjusted 3-year rates of major adverse cardiac events, major adverse cardiac and cerebrovascular events, and target vessel failure were similar (premarket vs PMS: 11.9% vs 12.7%, p = 0.369; 12.7% vs 13.9%,. p = 0.191; and 13.8% vs 13.4%, p = 0.667, respectively). However, PMS trials had significantly higher rates of myocardial infarctions (p = 0.005) and definite or probable stent thrombosis (p = 0.016). After propensity score adjustment, myocardial infarction rates remained significantly different (hazard ratio 0.53, 95% confidence interval 0.30 to 0.91). To conclude, premarket and PMS trials assessing E-ZES implantation enrolled different patients. PMS trials were shown to be essential for the detection of safety signals. (C) 2014 Elsevier Inc. All rights reserved. C1 [Vardi, Moshe; Burke, David A.; Yeh, Robert W.; Cutlip, Donald E.] Harvard Clin Res Inst, Boston, MA 02215 USA. [Vardi, Moshe; Perez, Jeremiah; Griffin, Paula J.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Burke, David A.; Cutlip, Donald E.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Vardi, M (reprint author), Harvard Clin Res Inst, Boston, MA 02215 USA. EM moshe.vardi@hcri.harvard.edu FU National Institutes of Health, Bethesda, MD [5T32GM074905-07] FX Ms. Griffin and Mr. Perez are supported by grant 5T32GM074905-07 from the National Institutes of Health, Bethesda, MD. The other authors have no conflicts of interest to disclose. NR 23 TC 4 Z9 4 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2014 VL 114 IS 4 BP 528 EP 533 DI 10.1016/j.amjcard.2014.05.028 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN2UX UT WOS:000340442600005 PM 24994546 ER PT J AU Quinn, GR Singer, DE Chang, YC Go, AS Borowsky, LH Udaltsova, N Fang, MC AF Quinn, Gene R. Singer, Daniel E. Chang, Yuchiao Go, Alan S. Borowsky, Leila H. Udaltsova, Natalia Fang, Margaret C. TI Effect of Selective Serotonin Reuptake Inhibitors on Bleeding Risk in Patients With Atrial Fibrillation Taking Warfarin SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PLATELET-FUNCTION; CLINICAL-PRACTICE; ELDERLY-PATIENTS; ANTIDEPRESSANTS; STROKE; ANTICOAGULATION; THERAPY; ASSOCIATION; MECHANISMS; HEMORRHAGE AB Selective serotonin reuptake inhibitor (SSRI) medications have been linked to increased bleeding risk; however, the actual association among warfarin, SSRI exposure, and bleeding risk has not been well-established. We studied the AnTicoagulation and Risk factors In Atrial fibrillation cohort of 13,559 adults with atrial fibrillation, restricted to the 9,186 patients contributing follow-up time while taking warfarin. Exposure to SSRIs and tricyclic antidepressants (TCAs) was assessed from pharmacy database dispensing data. The main outcome was hospitalization for major hemorrhage. Results were adjusted for bleeding risk and time in international normalized ratio range >3. We identified 461 major hemorrhages during 32,888 person-years of follow-up, 45 events during SSRI use, 12 during TCA-only use, and 404 without either medication. Hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years, p <0.001) and did not differ between TCA exposure and no antidepressants (1.30 per 100 person-years on TCAs, p = 0.94). After adjustment for underlying bleeding risk and time in international normalized ratio range >3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk 1.41, 95% confidence interval 1.04 to 1.92, p = 0.03), whereas TCA exposure was not (adjusted relative risk 0.82,95% confidence interval 0.46 to 1.46, p = 0.50). In conclusion, SSRI exposure was associated with higher major hemorrhage risk in patients taking warfarin, and this risk should be considered when selecting antidepressant treatments in those patients. (C) 2014 Elsevier Inc. All rights reserved. C1 [Quinn, Gene R.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Singer, Daniel E.; Chang, Yuchiao; Borowsky, Leila H.] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA USA. [Go, Alan S.; Udaltsova, Natalia] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Go, Alan S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Fang, Margaret C.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. RP Quinn, GR (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. EM gene.quinn@mail.harvard.edu FU National Institute on Aging (Bethesda, Maryland) [R01 AG15478]; National Heart, Lung, and Blood Institute (Bethesda, Maryland) [U19 HL91179, RC2HL101589]; Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston, Massachusetts) FX This study was supported by grant R01 AG15478 from the National Institute on Aging (Bethesda, Maryland), grants U19 HL91179 and RC2HL101589 from the National Heart, Lung, and Blood Institute (Bethesda, Maryland), the and the Eliot B. and Edith C. Shoolman fund of the Massachusetts General Hospital (Boston, Massachusetts). NR 26 TC 3 Z9 3 U1 1 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2014 VL 114 IS 4 BP 583 EP 586 DI 10.1016/j.amjcard.2014.05.037 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN2UX UT WOS:000340442600013 PM 25001151 ER PT J AU Eijsvogels, TMH Januzzi, JL Taylor, BA Isaacs, SK D'Hemecourt, P Zaleski, A Dyer, S Troyanos, C Weiner, RB Thompson, PD Baggish, AL AF Eijsvogels, Thijs M. H. Januzzi, James L. Taylor, Beth A. Isaacs, Stephanie K. D'Hemecourt, Pierre Zaleski, Amanda Dyer, Sophia Troyanos, Chris Weiner, Rory B. Thompson, Paul D. Baggish, Aaron L. TI Impact of Statin Use on Exercise-Induced Cardiac Troponin Elevations SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HUMAN SKELETAL-MUSCLE; ENDURANCE EXERCISE; BOSTON-MARATHON; HEALTHY HUMANS; I RELEASE; T RELEASE; ASSAYS; METAANALYSIS; INTENSITY; RUNNERS AB Marathon running commonly causes a transient elevation of creatine kinase and cardiac troponin I (cTnI). The use of statins before marathon running exacerbates the release of creatine kinase from skeletal muscle, but the effect of statin use on exercise-induced cTnI release is unknown. We therefore measured cTnI concentrations in statin-using (n = 30) and nonstatin-using (n = 41) runners who participated in the 2011 Boston Marathon. All runners provided venous blood samples the day before, within an hour of finishing, and 24 hours after the marathon. cTnI was assessed at each time point via both a contemporary cTnI and high-sensitivity cTnI (hsTnI) assay. Before the marathon, cTnI was detectable in 99% of runners with the use of the hsTnI assay. All participants completed the marathon (finish time: 4:04:09 +/- 0:41:10), and none had symptoms of an acute coronary syndrome. cTnI increased in all runners (p <0.001) immediately after the marathon, and half (hsTnI = 54% vs contemporary cTnI = 47%) exceeded the diagnostic cut-point for an acute myocardial infarction. Statin use did not affect the magnitude of cTnI release (group*time p = 0.47) or the incidence of runners with cTnI elevation greater than the diagnostic cut-point for myocardial infarction (57% vs 51%, p = 0.65). In addition, there was no significant association between statin potency and cTnI release (r = 0.09, p = 0.65). In conclusion, marathon-induced cTnI increases are not altered by statin use. (C) 2014 Elsevier Inc. All rights reserved. C1 [Eijsvogels, Thijs M. H.; Taylor, Beth A.; Zaleski, Amanda; Thompson, Paul D.] Hartford Hosp, Dept Cardiol, Henry Low Heart Ctr, Hartford, CT 06115 USA. [Eijsvogels, Thijs M. H.] Radboud Univ Nijmegen, Med Ctr, Dept Physiol, NL-6525 ED Nijmegen, Netherlands. [Januzzi, James L.; Isaacs, Stephanie K.; Weiner, Rory B.; Baggish, Aaron L.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Boston, MA 02114 USA. [Taylor, Beth A.] Univ Hartford, Dept Hlth Sci, Hartford, CT 06117 USA. [D'Hemecourt, Pierre; Dyer, Sophia; Troyanos, Chris; Baggish, Aaron L.] Boston Athlet Assoc, Boston, MA USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Performance Program, Boston, MA 02114 USA. EM abaggish@partners.org RI Eijsvogels, Thijs/P-7201-2015 OI Eijsvogels, Thijs/0000-0003-0747-4471 FU Massachusetts General Hospital (Boston, Massachusetts); Hartford Hospital (Hartford, Connecticut); Netherlands Organization [825.12.016] FX This study was funded by research grants from the Massachusetts General Hospital (Boston, Massachusetts) and Hartford Hospital (Hartford, Connecticut). T.M.H.E is financially supported by the Netherlands Organization for Scientific Research (Rubicon Grant 825.12.016). NR 26 TC 6 Z9 6 U1 1 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2014 VL 114 IS 4 BP 624 EP 628 DI 10.1016/j.amjcard.2014.05.047 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN2UX UT WOS:000340442600020 PM 25015693 ER PT J AU Tieu, MT Cigsar, C Ahmed, S Ng, A Diller, L Millar, BA Crystal, P Hodgson, DC AF Minh Thi Tieu Cigsar, Candemir Ahmed, Sameera Ng, Andrea Diller, Lisa Millar, B. -A. Crystal, Pavel Hodgson, David C. TI Breast Cancer Detection Among Young Survivors of Pediatric Hodgkin Lymphoma With Screening Magnetic Resonance Imaging SO CANCER LA English DT Article DE pediatric Hodgkin lymphoma; breast MRI; screening; second cancer ID CHEST RADIATION; WOMEN; MAMMOGRAPHY; RISK; SURVEILLANCE; EFFICACY; PROGRAM; HISTORY; DISEASE; COHORT AB BACKGROUND: Female survivors of pediatric Hodgkin lymphoma (HL) who have received chest radiotherapy are at increased risk of breast cancer. Guidelines for early breast cancer screening among these survivors are based on little data regarding clinical outcomes. This study reports outcomes of breast cancer screening with MRI and mammography (MMG) after childhood HL. METHODS: We evaluated the results of breast MRI and MMG screening among 96 female survivors of childhood HL treated with chest radiotherapy. Outcomes measured included imaging sensitivity and specificity, breast cancer characteristics, and incidence of additional imaging and breast biopsy. RESULTS: Median age at first screening was 30 years, and the median number of MRI screening rounds was 3. Ten breast cancers were detected in 9 women at a median age of 39 years (range, 24-43 years). Half were invasive and half were preinvasive. The median size of invasive tumors was 8 mm (range, 3-15 mm), and none had lymph node involvement. Sensitivity and specificity of the screening modalities were as follows: for MRI alone, 80% and 93.5%, respectively; MMG alone, 70% and 95%, respectively; both modalities combined, 100% and 88.6%, respectively. All invasive tumors were detected by MRI. Additional investigations were required in 52 patients, (54%), and 26 patients (27%) required breast biopsy, with 10 patients requiring more than 1 biopsy. CONCLUSIONS: Screening including breast MRI with MMG has high sensitivity and specificity in pediatric HL survivors, with breast cancers detected at an early stage, although it is associated with a substantial rate of additional investigations. (C) 2014 The Authors. C1 [Minh Thi Tieu; Cigsar, Candemir; Ahmed, Sameera; Millar, B. -A.; Hodgson, David C.] Univ Toronto, Princess Margaret Hosp, Radiat Med Program, Toronto, ON, Canada. [Minh Thi Tieu; Cigsar, Candemir; Ahmed, Sameera; Millar, B. -A.; Hodgson, David C.] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada. [Ng, Andrea; Diller, Lisa] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ng, Andrea; Diller, Lisa] Harvard Univ, Sch Med, Boston, MA USA. [Crystal, Pavel] Univ Toronto, Mt Sinai Hosp, Womens Coll Hosp, Joint Dept Med Imaging,Univ Hlth Network, Toronto, ON M5G 1X5, Canada. [Hodgson, David C.] Univ Toronto, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. RP Hodgson, DC (reprint author), Princess Margaret Canc Ctr, 610 Univ Ave, Toronto, ON M5T 2M9, Canada. EM david.hodgson@rmp.uhn.on.ca FU Canadian Cancer Society; Pediatric Oncology Group of Ontario; Research Chair from Cancer Care Ontario FX This work was supported by the Canadian Cancer Society and the Pediatric Oncology Group of Ontario. Dr. Hodgson is supported by a Research Chair from Cancer Care Ontario. NR 22 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2014 VL 120 IS 16 BP 2507 EP 2513 DI 10.1002/cncr.28747 PG 7 WC Oncology SC Oncology GA AN3DB UT WOS:000340464100018 PM 24888639 ER PT J AU Perkins, JL Chen, Y Harris, A Diller, L Stovall, M Armstrong, GT Yasui, Y Robison, LL Sklar, CA AF Perkins, Joanna L. Chen, Yan Harris, Anne Diller, Lisa Stovall, Marilyn Armstrong, Gregory T. Yasui, Yutaka Robison, Leslie L. Sklar, Charles A. CA Childhood Cancer Survivor Study TI Infections Among Long-Term Survivors of Childhood and Adolescent Cancer A Report From the Childhood Cancer Survivor Study SO CANCER LA English DT Article DE childhood cancer; adolescent cancer; late effects; infections; survivorship ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SOLID TUMORS; ANTIBIOTIC-PROPHYLAXIS; SERUM IMMUNOGLOBULINS; INTENSIVE TREATMENT; CHEMOTHERAPY; RECOVERY; BLOOD; LYMPHOCYTES; REMISSION AB BACKGROUND: Little is known about infections among adult survivors of childhood cancer. The authors report the occurrence of infections and risk factors for infections in a large cohort of survivors of childhood cancer. METHODS: The Childhood Cancer Survivor Study cohort was used to compare incidence rates of infections among 12,360 5-year survivors of childhood cancer with the rates of 4023 siblings. Infection-related mortality of survivors was compared with that of the US population. Demographic and treatment variables were analyzed using Poisson regression to determine the rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for associations with infectious complications. RESULTS: Compared with the US population, survivors were at an increased risk of death from infectious causes (standardized mortality ratio [SMR], 4.2; 95% CI, 3.2-5.4), with the greatest risk observed among females (SMR, 3.2; 95% CI, 1.5-6.9) and among those who had been exposed to total body irradiation (SMR, 7.8; 95% CI, 1.8-33.0). Survivors also reported higher rates than siblings of overall infectious complications (RR, 1.3; 95% CI, 1.2-1.4) and higher rates of all categories of infection. CONCLUSIONS: Survivors of childhood cancer remain at elevated risk for developing infectious-related complications, and they have a higher risk of infection-related mortality years after therapy. Further investigation is needed to provide insight into the mechanisms for the observed excess risks. 2014 American Cancer Society. C1 [Perkins, Joanna L.; Harris, Anne] Childrens Hosp & Clin Minnesota, Minneapolis, MN 55404 USA. [Chen, Yan; Yasui, Yutaka] Univ Alberta, Calgary, AB, Canada. [Diller, Lisa] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Armstrong, Gregory T.; Robison, Leslie L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Sklar, Charles A.] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. RP Perkins, JL (reprint author), Childrens Hosp & Clin Minnesota, 2530 Chicago Ave S,CSC-175, Minneapolis, MN 55404 USA. EM joanna.perkins@chindrensmn.org RI Yasui, Yutaka/E-2564-2015 OI Yasui, Yutaka/0000-0002-7717-8638 FU National Cancer Institute [U24 CA55727]; St. Jude Children's Research Hospital Cancer Center Support grant [CA21765]; American Lebanese Syrian Associated Charities (ALSAC) FX This work was supported by grant U24 CA55727 (to L. L. R.) from the National Cancer Institute, with additional support provided by the St. Jude Children's Research Hospital Cancer Center Support grant CA21765 and the American Lebanese Syrian Associated Charities (ALSAC). NR 35 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2014 VL 120 IS 16 BP 2514 EP 2521 DI 10.1002/cncr.28763 PG 8 WC Oncology SC Oncology GA AN3DB UT WOS:000340464100019 PM 24824782 ER PT J AU Xiong, GX Elkind, JA Kundu, S Smith, CJ Antunes, MB Tamashiro, E Kofonow, JM Mitala, CM Stein, SC Grady, MS Einhorn, E Cohen, NA Cohen, AS AF Xiong, Guoxiang Elkind, Jaclynn A. Kundu, Suhali Smith, Colin J. Antunes, Marcelo B. Tamashiro, Edwin Kofonow, Jennifer M. Mitala, Christina. M. Stein, Sherman C. Grady, M. Sean Einhorn, Eugene Cohen, Noam A. Cohen, Akiva S. TI Traumatic Brain Injury-Induced Ependymal Ciliary Loss Decreases Cerebral Spinal Fluid Flow SO JOURNAL OF NEUROTRAUMA LA English DT Article DE beta-tubulin; basal body; hydrocephalus; lateral fluid percussion; particle tracking ID POSTTRAUMATIC HYDROCEPHALUS; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; BEAT FREQUENCY; CHOROID-PLEXUS; MICE; DYSFUNCTION; DYSKINESIA; MOTILITY; SLEEP AB Traumatic brain injury (TBI) afflicts up to 2 million people annually in the United States and is the primary cause of death and disability in young adults and children. Previous TBI studies have focused predominantly on the morphological, biochemical, and functional alterations of gray matter structures, such as the hippocampus. However, little attention has been given to the brain ventricular system, despite the fact that altered ventricular function is known to occur in brain pathologies. In the present study, we investigated anatomical and functional alterations to mouse ventricular cilia that result from mild TBI. We demonstrate that TBI causes a dramatic decrease in cilia. Further, using a particle tracking technique, we demonstrate that cerebrospinal fluid flow is diminished, thus potentially negatively affecting waste and nutrient exchange. Interestingly, injury-induced ventricular system pathology resolves completely by 30 days after injury as ependymal cell ciliogenesis restores cilia density to uninjured levels in the affected lateral ventricle. C1 [Xiong, Guoxiang; Elkind, Jaclynn A.; Kundu, Suhali; Smith, Colin J.; Mitala, Christina. M.; Cohen, Akiva S.] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA. [Antunes, Marcelo B.; Tamashiro, Edwin; Kofonow, Jennifer M.; Cohen, Noam A.] Univ Penn, Perelman Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Stein, Sherman C.; Grady, M. Sean] Univ Penn, Perelman Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA. [Cohen, Akiva S.] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Einhorn, Eugene; Cohen, Noam A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Cohen, AS (reprint author), Univ Penn, Perelman Sch Med, Dept Pediat, 3615 Civ Ctr Blvd,816-H ARC, Philadelphia, PA 19104 USA. EM cohena@email.chop.edu RI Tamashiro, Edwin/C-5062-2012 OI Tamashiro, Edwin/0000-0002-3153-6292 FU National Institutes of Health [R01HD059288, R01NS069629] FX The authors thank Michael Schell for critiquing an earlier draft of the manuscript and Kathleen Joy Propert for statistical guidance. This study was supported in part by National Institutes of Health grants (R01HD059288 and R01NS069629; to A.S.C.). NR 59 TC 4 Z9 4 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 EI 1557-9042 J9 J NEUROTRAUM JI J. Neurotrauma PD AUG 15 PY 2014 VL 31 IS 16 BP 1396 EP 1404 DI 10.1089/neu.2013.3110 PG 9 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA AN4DB UT WOS:000340536700003 PM 24749541 ER PT J AU Kovacs, Z Schacht, T Herrmann, AK Albrecht, P Lefkimmiatis, K Methner, A AF Kovacs, Zsuzsa Schacht, Teresa Herrmann, Ann-Kathrin Albrecht, Philipp Lefkimmiatis, Konstantinos Methner, Axel TI Protein kinase inhibitor beta enhances the constitutive activity of G-protein-coupled zinc receptor GPR39 SO BIOCHEMICAL JOURNAL LA English DT Article DE G-protein-coupled receptor 39 (GPR39); oxidative stress; protein kinase A inhibitor beta (PKIB); zinc ID UP-REGULATION; IN-VITRO; EXPRESSION; CELLS; ACTIVATION; SECRETION; CLONING; FAMILY; TISSUE; MOUSE AB GPR39 is a G-protein-coupled zinc receptor that protects against diverse effectors of cell death. Its protective activity is mediated via constitutive activation of G(alpha 13) and the RhoA pathway, leading to increased SRE (serum-response element)-dependent transcription; the zinc-dependent immediate activation of GPR39 involves G(q)-mediated increases in cytosolic Ca2+ and G(s) coupling leading to increased cAMP levels. We used the cytosolic and soluble C-terminus of GPR39 in a Y2H (yeast-2-hybrid) screen for interacting proteins, thus identifying PKIB (protein kinase A inhibitor beta). Co-expression of GPR39 with PKIB increased the protective activity of GPR39 via the constitutive, but not the ligand-mediated, pathway. PKIB inhibits protein kinase A by direct interaction with its pseudosubstrate domain; mutation of this domain abolished the inhibitory activity of PKIB on protein kinase A activity, but had no effect on the interaction with GPR39, cell protection and induction of SRE-dependent transcription. Zinc caused dissociation of PKIB from GPR39, thereby liberating it to associate with protein kinase A and inhibit its activity, which would result in a negative-feedback loop with the ability to limit activation of the G(s) pathway by zinc. C1 [Kovacs, Zsuzsa; Albrecht, Philipp] Univ Dusseldorf, Dept Neurol, Fac Med, Dusseldorf, Germany. [Schacht, Teresa; Herrmann, Ann-Kathrin; Methner, Axel] Johannes Gutenberg Univ Mainz, Med Ctr Mainz, Dept Neurol, Focus Program Translat Neurosci FUN,Rhine Main Ne, D-55131 Mainz, Germany. [Lefkimmiatis, Konstantinos] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Lefkimmiatis, Konstantinos] VA Boston Healthcare Syst, Boston, MA USA. RP Methner, A (reprint author), Johannes Gutenberg Univ Mainz, Med Ctr Mainz, Dept Neurol, Focus Program Translat Neurosci FUN,Rhine Main Ne, Langenbeckstr 1, D-55131 Mainz, Germany. RI Lefkimmiatis, Konstantinos/I-1239-2016; OI Lefkimmiatis, Konstantinos/0000-0001-7137-7866; Herrmann, Ann-Kathrin/0000-0002-4339-8704; Schacht, Teresa/0000-0002-9398-3231 FU Dr Kurt und Irmgard Meister-Stiftung; Dr Robert Pfleger-Stiftung FX This work was supported by the Dr Kurt und Irmgard Meister-Stiftung and the Dr Robert Pfleger-Stiftung. NR 34 TC 2 Z9 2 U1 1 U2 12 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0264-6021 EI 1470-8728 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2014 VL 462 BP 125 EP 132 DI 10.1042/BJ20131198 PN 1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AM9RG UT WOS:000340218100011 PM 24869658 ER PT J AU Pillai, NE Okada, Y Saw, WY Ong, RTH Wang, X Tantoso, E Xu, WT Peterson, TA Bielawny, T Ali, M Tay, KY Poh, WT Tan, LWL Koo, SH Lim, WY Soong, R Wenk, M Raychaudhuri, S Little, P Plummer, FA Lee, EJD Chia, KS Luo, M De Bakker, PIW Teo, YY AF Pillai, Nisha Esakimuthu Okada, Yukinori Saw, Woei-Yuh Ong, Rick Twee-Hee Wang, Xu Tantoso, Erwin Xu, Wenting Peterson, Trevor A. Bielawny, Thomas Ali, Mohammad Tay, Koon-Yong Poh, Wan-Ting Tan, Linda Wei-Lin Koo, Seok-Hwee Lim, Wei-Yen Soong, Richie Wenk, Markus Raychaudhuri, Soumya Little, Peter Plummer, Francis A. Lee, Edmund J. D. Chia, Kee-Seng Luo, Ma De Bakker, Paul I. W. Teo, Yik-Ying TI Predicting HLA alleles from high-resolution SNP data in three Southeast Asian populations SO HUMAN MOLECULAR GENETICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; SINGLE-NUCLEOTIDE POLYMORPHISMS; GENOME-WIDE ASSOCIATION; TYPING IDENTIFIED 2; GENOTYPE-IMPUTATION; LINKAGE-DISEQUILIBRIUM; KENYAN POPULATION; HAPLOTYPE MAP; DISEASE; MHC AB The major histocompatibility complex (MHC) containing the classical human leukocyte antigen (HLA) Class I and Class II genes is among the most polymorphic and diverse regions in the human genome. Despite the clinical importance of identifying the HLA types, very few databases jointly characterize densely genotyped single nucleotide polymorphisms (SNPs) and HLA alleles in the same samples. To date, the HapMap presents the only public resource that provides a SNP reference panel for predicting HLA alleles, constructed with four collections of individuals of north-western European, northern Han Chinese, cosmopolitan Japanese and Yoruba Nigerian ancestry. Owing to complex patterns of linkage disequilibrium in this region, it is unclear whether the HapMap reference panels can be appropriately utilized for other populations. Here, we describe a public resource for the Singapore Genome Variation Project with: (i) dense genotyping across similar to 9000 SNPs in the MHC; (ii) four-digit HLA typing for eight Class I and Class II loci, in 96 southern Han Chinese, 89 Southeast Asian Malays and 83 Tamil Indians. This resource provides population estimates of the frequencies of HLA alleles at these eight loci in the three population groups, particularly for HLA-DPA1 and HLA-DPB1 that were not assayed in HapMap. Comparing between population-specific reference panels and a cosmopolitan panel created from all four HapMap populations, we demonstrate that more accurate imputation is obtained with population-specific panels than with the cosmopolitan panel, especially for the Malays and Indians but even when imputing between northern and southern Han Chinese. As with SNP imputation, common HLA alleles were imputed with greater accuracy than low-frequency variants. C1 [Pillai, Nisha Esakimuthu; Saw, Woei-Yuh; Ong, Rick Twee-Hee; Wang, Xu; Tantoso, Erwin; Xu, Wenting; Poh, Wan-Ting; Tan, Linda Wei-Lin; Lim, Wei-Yen; Chia, Kee-Seng; Teo, Yik-Ying] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore. [Koo, Seok-Hwee; Lee, Edmund J. D.] Natl Univ Singapore, Dept Pharmacol, Singapore 117597, Singapore. [Okada, Yukinori; Raychaudhuri, Soumya] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Okada, Yukinori; Raychaudhuri, Soumya] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. [Okada, Yukinori; Raychaudhuri, Soumya; De Bakker, Paul I. W.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Peterson, Trevor A.; Bielawny, Thomas; Plummer, Francis A.; Luo, Ma] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0Z2, Canada. [Peterson, Trevor A.; Bielawny, Thomas; Plummer, Francis A.; Luo, Ma] Natl Microbiol Lab, Winnipeg, MB, Canada. [Ali, Mohammad; Tay, Koon-Yong; Little, Peter; Teo, Yik-Ying] Natl Univ Singapore, Inst Life Sci, Singapore 117548, Singapore. [Teo, Yik-Ying] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Soong, Richie] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117599, Singapore. [Wenk, Markus] Natl Univ Singapore, Dept Biochem, Singapore 117596, Singapore. [Wenk, Markus] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore. [Raychaudhuri, Soumya; De Bakker, Paul I. W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Teo, Yik-Ying] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore. [Teo, Yik-Ying] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore 138672, Singapore. RP Teo, YY (reprint author), Natl Univ Singapore, Sch Publ Hlth, MD3 16 Med Dr, Singapore 117597, Singapore. EM statyy@nus.edu.sg RI de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU Saw Swee Hock School of Public Health; Yong Loo Lin School of Medicine; National University Health System; Life Science Institute; Office of Deputy President (Research and Technology) from the National University of Singapore; National Research Foundation Singapore [NRF-RF-2010-05] FX This project acknowledges the support of the Saw Swee Hock School of Public Health, the Yong Loo Lin School of Medicine, the National University Health System, the Life Science Institute and the Office of Deputy President (Research and Technology) from the National University of Singapore. N.E.P., R.T.H.O., W. T. P. and Y.Y.T. additionally acknowledge support from the National Research Foundation Singapore (NRF-RF-2010-05). NR 42 TC 25 Z9 25 U1 3 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2014 VL 23 IS 16 BP 4443 EP 4451 DI 10.1093/hmg/ddu149 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AM7SX UT WOS:000340070100020 PM 24698974 ER PT J AU Andrews, JR Morrow, C Walensky, RP Wood, R AF Andrews, Jason R. Morrow, Carl Walensky, Rochelle P. Wood, Robin TI Integrating Social Contact and Environmental Data in Evaluating Tuberculosis Transmission in a South African Township SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE social contacts; tuberculosis; epidemiology; environment; mathematical models ID HIGH-INCIDENCE AREA; MYCOBACTERIUM-TUBERCULOSIS; PULMONARY TUBERCULOSIS; AIRBORNE INFECTION; MIXING PATTERNS; ANNUAL RISK; IMPACT; VARIABILITY; PREVALENCE; EPIDEMICS AB Background. Population models of tuberculosis transmission have not accounted for social contact structure and the role of the environment in which tuberculosis is transmitted. Methods. We utilized extensions to the Wells-Riley model of tuberculosis transmission, using exhaled carbon dioxide as a tracer gas, to describe transmission patterns in an endemic community. Drawing upon social interaction data and carbon dioxide measurements from a South African township, we created an age-structured model of tuberculosis transmission in households, public transit, schools, and workplaces. We fit the model to local data on latent tuberculosis prevalence by age. Results. Most tuberculosis infections (84%) were estimated to occur outside of one's own household. Fifty percent of infections among young adults (ages 15-19) occurred in schools, due to high contact rates and poor ventilation. Despite lower numbers of contacts in workplaces, assortative mixing among adults with high rates of smear-positive tuberculosis contributed to transmission in this environment. Households and public transit were important sites of transmission between age groups. Conclusions. Consistent with molecular epidemiologic estimates, a minority of tuberculosis transmission was estimated to occur within households, which may limit the impact of contact investigations. Further work is needed to investigate the role of schools in tuberculosis transmission. C1 [Andrews, Jason R.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Morrow, Carl; Wood, Robin] Univ Cape Town, Desmond Tutu HIV Ctr, Inst Infect Dis & Mol Med, ZA-7700 Rondebosch, South Africa. RP Andrews, JR (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jandrews6@partners.org OI Andrews, Jason/0000-0002-5967-251X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [R01 AI093269, R01 AI058736, T32AI007433, U01 AI069924, U01 AI069519]; Harvard Global Health Institute FX This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant numbers R01 AI093269, R01 AI058736, T32AI007433, U01 AI069924, U01 AI069519) and the Harvard Global Health Institute. NR 37 TC 11 Z9 11 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2014 VL 210 IS 4 BP 597 EP 603 DI 10.1093/infdis/jiu138 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AN0AN UT WOS:000340243500013 PM 24610874 ER PT J AU Tsai, AC AF Tsai, Alexander C. TI Reliability and Validity of Depression Assessment Among Persons With HIV in Sub-Saharan Africa: Systematic Review and Meta-analysis SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Review DE depression; HIV; Africa; south of the Sahara; sensitivity and specificity; reproducibility of results ID COMMON MENTAL-DISORDERS; ANTIDEPRESSANT MEDICATION TREATMENT; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; MIDDLE-INCOME COUNTRIES; PRIMARY-HEALTH-CARE; CD4 CELL COUNT; RURAL UGANDA; PSYCHOLOGICAL DISTRESS; EXPLANATORY MODELS AB Objective: The aim of this study was to systematically review the reliability and validity of instruments used to screen for major depressive disorder or assess depression symptom severity among persons with HIV in sub-Saharan Africa. Design: Systematic review and meta-analysis. Methods: A systematic evidence search protocol was applied to 7 bibliographic databases. Studies examining the reliability and/or validity of depression assessment tools were selected for inclusion if they were based on the data collected from HIV-positive adults in any African member state of the United Nations. A random-effects meta-analysis was used to calculate pooled estimates of depression prevalence. In a subgroup of studies of criterion-related validity, the bivariate random-effects model was used to calculate pooled estimates of sensitivity and specificity. Results: Of 1117 records initially identified, I included 13 studies of 5373 persons with HIV in 7 sub-Saharan African countries. Reported estimates of Cronbach alpha ranged from 0.63 to 0.95, and analyses of internal structure generally confirmed the existence of a depression-like construct accounting for a substantial portion of variance. The pooled prevalence of probable depression was 29.5% [95% confidence interval (CI): 20.5 to 39.4], whereas the pooled prevalence of major depressive disorder was 13.9% (95% CI: 9.7 to 18.6). The Center for Epidemiologic Studies Depression scale was the most frequently studied instrument, with a pooled sensitivity of 0.82 (95% CI: 0.73 to 0.87) for detecting major depressive disorder. Conclusions: Depression-screening instruments yielded relatively high false positive rates. Overall, few studies described the reliability and/or validity of depression instruments in sub-Saharan Africa. C1 [Tsai, Alexander C.] Massachusetts Gen Hosp, Dept Psychiat, MD Div Global Psychiat, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Harvard Univ, Sch Med, Boston, MA USA. [Tsai, Alexander C.] Mbarara Univ Sci & Technol, Mbarara, Uganda. 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 US National Institutes of Health [K23MH096620]; Robert Wood Johnson Health and Society Scholars Program FX No specific funding was awarded for the conduct of this study. The author receives salary support from US National Institutes of Health K23MH096620 and the Robert Wood Johnson Health and Society Scholars Program. NR 111 TC 19 Z9 19 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2014 VL 66 IS 5 BP 503 EP 511 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3FT UT WOS:000339012600010 PM 24853307 ER PT J AU Psaros, C Haberer, JE Katabira, E Ronald, A Tumwesigye, E Campbell, JD Wangisi, J Mugwanya, K Kintu, A Enyakoit, M Thomas, KK Donnell, D Krows, M Kidoguchi, L Ware, N Baeten, JM Celum, C Bangsberg, DR Safren, SA AF Psaros, Christina Haberer, Jessica E. Katabira, Elly Ronald, Allan Tumwesigye, Elioda Campbell, James D. Wangisi, Jonathan Mugwanya, Kenneth Kintu, Alex Enyakoit, Michael Thomas, Katherine K. Donnell, Deborah Krows, Meighan Kidoguchi, Lara Ware, Norma Baeten, Jared M. Celum, Connie Bangsberg, David R. Safren, Steve A. TI An Intervention to Support HIV Preexposure Prophylaxis Adherence in HIV-Serodiscordant Couples in Uganda SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE preexposure prophylaxis; adherence; intervention; serodiscordant couples; HIV prevention ID RANDOMIZED CONTROLLED-TRIAL; ANTIRETROVIRAL THERAPY; PREVENTION; TRANSMISSION; TENOFOVIR; MEN AB Background: Daily preexposure prophylaxis (PrEP) is an effective HIV prevention strategy, but adherence is required for maximum benefit. To date, there are no empirically supported PrEP adherence interventions. This article describes the process of developing a PrEP adherence intervention and presents results on its impact on adherence. Methods: The Partners PrEP Study was a placebo-controlled efficacy trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among uninfected members of HIV-serodiscordant couples. An ancillary adherence study was conducted at 3 study sites in Uganda. Participants with <80% adherence as measured by unannounced pill count received an additional adherence counseling intervention based on Lifesteps, an evidence-based HIV treatment adherence intervention, based on principles of cognitive-behavioral theory. Findings: Of the 1147 HIV-seronegative participants enrolled in the ancillary adherence study, 168 (14.6%) triggered the adherence intervention. Of participants triggering the intervention, 62% were men; median age was 32.5 years. The median number of adherence counseling sessions was 10. Mean adherence during the month before the intervention was 75.7% and increased significantly to 84.1% in the month after the first intervention session (P < 0.001). The most frequently endorsed adherence barriers at session 1 were travel and forgetting. Interpretation: A PrEP adherence intervention was feasible in a clinical trial of PrEP in Uganda and PrEP adherence increased after the intervention. Future research should identify PrEP users with low adherence for enhanced adherence counseling and determine optimal implementation strategies for interventions to maximize PrEP effectiveness. C1 [Psaros, Christina; Bangsberg, David R.; Safren, Steve A.] Massachusetts Gen Hosp Ctr, Dept Psychiat, Boston, MA USA. [Psaros, Christina; Haberer, Jessica E.; Ware, Norma; Safren, Steve A.] Harvard Univ, Sch Med, Boston, MA USA. [Haberer, Jessica E.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Katabira, Elly] Makerere Univ, Infect Dis Inst, Kampala, Uganda. [Ronald, Allan] Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada. [Tumwesigye, Elioda; Kintu, Alex] Kabwohe Clin Res Ctr, Kabwohe, Uganda. [Campbell, James D.; Wangisi, Jonathan] US Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Div HIV AIDS Prevent, Entebbe, Uganda. [Mugwanya, Kenneth] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kintu, Alex] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Enyakoit, Michael] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Thomas, Katherine K.; Donnell, Deborah; Krows, Meighan; Kidoguchi, Lara; Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Donnell, Deborah] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Med, Seattle, WA USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Psaros, C (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, One Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM cpsaros@partners.org OI Ronald, Allan/0000-0002-5746-3490; Donnell, Deborah/0000-0002-0587-7480 FU Bill and Melinda Gates Foundation [OOP47674, OOP52516] FX This study and the Partners PrEP Study were both supported by the Bill and Melinda Gates Foundation (Grants OOP47674 and OOP52516). Additional author time was supported by K23MH096651 (C.P.) and K24MH87227 (D.R.B.). NR 30 TC 9 Z9 9 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2014 VL 66 IS 5 BP 522 EP 529 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA AL3FT UT WOS:000339012600012 PM 24853311 ER PT J AU Sabuncu, MR Bernal-Rusiel, JL Reuter, M Greve, DN Fischl, B AF Sabuncu, Mert R. Bernal-Rusiel, Jorge L. Reuter, Martin Greve, Douglas N. Fischl, Bruce CA Alzheimer's Dis Neuroimaging TI Event time analysis of longitudinal neuroimage data SO NEUROIMAGE LA English DT Article DE Longitudinal studies; Linear mixed effects models; Event time analysis; Cox regression; Survival analysis ID MILD COGNITIVE IMPAIRMENT; SURFACE-BASED ANALYSIS; ALZHEIMERS-DISEASE; CORTICAL THICKNESS; HIPPOCAMPAL ATROPHY; COORDINATE SYSTEM; MRI PREDICTORS; MCI; RISK; AD AB This paper presents a method for the statistical analysis of the associations between longitudinal neuroimaging measurements, e.g., of cortical thickness, and the timing of a clinical event of interest, e.g., disease onset. The proposed approach consists of two steps, the first of which employs a linear mixed effects (LME) model to capture temporal variation in serial imaging data. The second step utilizes the extended Cox regression model to examine the relationship between time-dependent imaging measurements and the timing of the event of interest. We demonstrate the proposed method both for the univariate analysis of image-derived biomarkers, e.g., the volume of a structure of interest, and the exploratory mass-univariate analysis of measurements contained in maps, such as cortical thickness and gray matter density. The mass-univariate method employs a recently developed spatial extension of the LME model. We applied our method to analyze structural measurements computed using FreeSurfer, a widely used brain Magnetic Resonance Image (MRI) analysis software package. We provide a quantitative and objective empirical evaluation of the statistical performance of the proposed method on longitudinal data from subjects suffering from Mild Cognitive Impairment (MCI) at baseline. (C) 2014 Elsevier Inc. All rights reserved. C1 [Sabuncu, Mert R.; Bernal-Rusiel, Jorge L.; Reuter, Martin; Greve, Douglas N.; Fischl, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sabuncu, Mert R.; Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Reuter, Martin] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Sabuncu, MR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Room 2301, Charlestown, MA 02129 USA. EM msabuncu@nmr.mgh.harvard.edu RI Reuter, Martin/B-3456-2010 OI Reuter, Martin/0000-0002-2665-9693 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) - NIH [U01 AG024904]; National Institute on Aging (NIA); National Institute of Biomedical Imaging and Bioengineering; Abbott Laboratories; AstraZeneca AB; Bayer Schering Pharma AG; Bristol-Myers Squibb; Eisai Global Clinical Development; Elan Corporation Plc; Genentech Inc.; GE Healthcare; GlaxoSmithKline; Innogenetics; Johnson and Johnson Services Inc.; Eli Lilly and Company; Medpace Inc.; Merck and Co. Inc.; Novartis International AG; Pfizer Inc.; F. Hoffmann-La Roche Ltd.; Schering-Plough Corporation; CCBR-SYNARC Inc; Wyeth Pharmaceuticals; Alzheimer's Association; Alzheimer's Drug Discovery Foundation from the US Food and Drug Administration; Center for Functional Neuroimaging Technologies [P41EB015896]; National Institute of Biomedical Imaging and Bioengineering (NIBIB); National Institutes of Health; National Center for Research Resources [P41-RR14075]; National Institute for Biomedical Imaging and Bioengineering [R01EB006758]; National Institute on Aging [AG022381]; National Center for Alternative Medicine [RC1 AT005728-01]; National Institute for Neurological Disorders and Stroke [R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, 2R01NS042861-06A1, 5P01NS058793-03]; National Institute of Child Health and Human Development [R01-HD071664]; Shared Instrumentation [1S10RR023401, 1S10RR019307, 1S10RR023043]; The Autism & Dyslexia Project - Ellison Medical Foundation [NIH 5R01AG008122-22]; NIH Blueprint for Neuroscience Research [5U01-MH093765]; AHAF (BrightFocus) Alzheimer's Disease pilot grant [AHAF A2012333]; NIH K25 [NIBIB 1K25EB013649-01] FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; Principal Investigator: Michael Weiner; NIH grant U01 AG024904). The ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott Laboratories, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation Plc, Genentech Inc., GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson Services Inc., Eli Lilly and Company, Medpace Inc., Merck and Co. Inc., Novartis International AG, Pfizer Inc., F. Hoffmann-La Roche Ltd., Schering-Plough Corporation, CCBR-SYNARC Inc, and Wyeth Pharmaceuticals, as well as nonprofit partners the Alzheimer's Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to the ADNI are facilitated by the Foundation for the NIH. The grantee organization is the Northern California Institute for Research and Education Inc., and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. The ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; This research was carried out in whole or in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. Further support for this research was provided in part by the National Center for Research Resources (P41-RR14075), the National Institute for Biomedical Imaging and Bioengineering (R01EB006758), the National Institute on Aging (AG022381), the National Center for Alternative Medicine (RC1 AT005728-01), the National Institute for Neurological Disorders and Stroke (R01 NS052585-01, 1R21NS072652-01, 1R01NS070963, 2R01NS042861-06A1, 5P01NS058793-03), the National Institute of Child Health and Human Development (R01-HD071664), and was made possible by the resources provided by Shared Instrumentation Grants 1S10RR023401, 1S10RR019307, and 1S10RR023043. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation, by the NIH 5R01AG008122-22 grant, and by the NIH Blueprint for Neuroscience Research (5U01-MH093765), part of the multi-institutional Human Connectome Project. Dr. Sabuncu received support from an AHAF (BrightFocus) Alzheimer's Disease pilot grant (AHAF A2012333), and an NIH K25 grant (NIBIB 1K25EB013649-01). NR 53 TC 9 Z9 9 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 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2014 VL 97 BP 9 EP 18 DI 10.1016/j.neuroimage.2014.04.015 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA AJ8WL UT WOS:000337988700002 PM 24736175 ER PT J AU Badalian-Very, G AF Badalian-Very, Gayane TI A common progenitor cell in LCH and ECD SO BLOOD LA English DT Editorial Material ID ERDHEIM-CHESTER DISEASE; DENDRITIC CELLS; HISTIOCYTOSIS; EXPRESSION; MUTATIONS AB In this issue of Blood, Hervier et al has identified that cooccurrence of Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) in the same patient is not a rare event.(1) Mixed histiocytosis (MH) highlights existence of a link between distinct groups of histiocytic disorders and suggests presence of a common progenitor cell. Today, histiocytic disorders are classified into 3 groups based on clinical presentation and gross anatomic findings. C1 [Badalian-Very, Gayane] Dana Farber Canc Inst, Boston, MA 02215 USA. [Badalian-Very, Gayane] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Badalian-Very, G (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. NR 8 TC 3 Z9 3 U1 0 U2 0 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 AUG 14 PY 2014 VL 124 IS 7 BP 991 EP 992 DI 10.1182/blood-2014-06-581736 PG 2 WC Hematology SC Hematology GA AQ2MQ UT WOS:000342621100005 PM 25124781 ER PT J AU Richardson, PG Baz, R Wang, M Jakubowiak, AJ Laubach, JP Harvey, RD Talpaz, M Berg, D Liu, GH Yu, J Gupta, N Di Bacco, A Hui, AM Lonial, S AF Richardson, Paul G. Baz, Rachid Wang, Michael Jakubowiak, Andrzej J. Laubach, Jacob P. Harvey, R. Donald Talpaz, Moshe Berg, Deborah Liu, Guohui Yu, Jiang Gupta, Neeraj Di Bacco, Alessandra Hui, Ai-Min Lonial, Sagar TI Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients SO BLOOD LA English DT Article ID SINGLE-AGENT CARFILZOMIB; PERIPHERAL NEUROPATHY; ANTITUMOR-ACTIVITY; BORTEZOMIB; MLN9708; RISK; MALIGNANCIES; MODELS; CELLS AB Ixazomib is the first investigational oral proteasome inhibitor to be studied clinically. In this phase 1 trial, 60 patients with relapsed/refractory multiple myeloma (median of 4 prior lines of therapy; bortezomib, lenalidomide, thalidomide, and carfilzomib/marizomib in 88%, 88%, 62%, and 5%, respectively) received single-agent ixazomib 0.24 to 2.23 mg/m(2) (days 1, 4, 8, 11; 21-day cycles). Two dose-limiting toxicities (grade 3 rash; grade 4 thrombocytopenia) occurred at 2.23 mg/m(2). The maximum tolerated dose was 2.0 mg/m(2), which 40 patients received in 4 expansion cohorts. Patients received a median of 4 cycles (range, 1-39); 18% received >= 12 cycles. Eighty-eight percent had drug-related adverse events, including nausea (42%), thrombocytopenia (42%), fatigue (40%), and rash (40%); drug-related grade >= 3 events included thrombocytopenia (37%) and neutropenia (17%). Grade 1/2 drug-related peripheral neuropathy occurred in 12% (no grade >= 3). Two patients diedonthestudy (both considered unrelated to treatment). The terminal half-life of ixazomib was 3.3 to 7.4 days; plasma exposure increased proportionally with dose (0.48-2.23 mg/m(2)). Among 55 response-evaluable patients, 15% achieved partial response or better (76% stable disease or better). These findings have informed the subsequent clinical development of ixazomib in multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00932698. C1 [Richardson, Paul G.; Laubach, Jacob P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baz, Rachid] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Wang, Michael] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Jakubowiak, Andrzej J.; Talpaz, Moshe] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Harvey, R. Donald; Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Berg, Deborah; Liu, Guohui; Yu, Jiang; Gupta, Neeraj; Di Bacco, Alessandra; Hui, Ai-Min] Takeda Pharmaceut Int Co, Cambridge, MA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU Millennium: The Takeda Oncology Company FX The authors thank all patients included in this study and their families, as well as all other physicians, research nurses, study coordinators, and research staff participating in the study. The authors acknowledge Steve Hill, a medical writer with FireKite, part of KnowledgePoint360, an Ashfield Company, for writing support during the development of this manuscript, which was funded by Millennium: The Takeda Oncology Company. NR 28 TC 63 Z9 64 U1 5 U2 15 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 AUG 14 PY 2014 VL 124 IS 7 BP 1038 EP 1046 DI 10.1182/blood-2014-01-548826 PG 9 WC Hematology SC Hematology GA AQ2MQ UT WOS:000342621100015 PM 24920586 ER PT J AU Wang, LL Shalek, AK Lawrence, M Ding, RH Gaublomme, JT Pochet, N Stojanov, P Sougnez, C Shukla, SA Stevenson, KE Zhang, WD Wong, J Sievers, QL MacDonald, BT Vartanov, AR Goldstein, NR Neuberg, D He, X Lander, E Hacohen, N Regev, A Getz, G Brown, JR Park, H Wu, CJ AF Wang, Lili Shalek, Alex K. Lawrence, Mike Ding, Ruihua Gaublomme, Jellert T. Pochet, Nathalie Stojanov, Petar Sougnez, Carrie Shukla, Sachet A. Stevenson, Kristen E. Zhang, Wandi Wong, Jessica Sievers, Quinlan L. MacDonald, Bryan T. Vartanov, Alexander R. Goldstein, Natalie R. Neuberg, Donna He, Xi Lander, Eric Hacohen, Nir Regev, Aviv Getz, Gad Brown, Jennifer R. Park, Hongkun Wu, Catherine J. TI Somatic mutation as a mechanism of Wnt/beta-catenin pathway activation in CLL SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; WNT SIGNALING PATHWAY; CANCER; GENOME; GENES; CELLS; DYSREGULATION; ASSOCIATION; INHIBITION; IMPACT AB One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis. C1 [Wang, Lili; Shukla, Sachet A.; Zhang, Wandi; Wong, Jessica; Sievers, Quinlan L.; Wu, Catherine J.] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [Wang, Lili; Shukla, Sachet A.; Zhang, Wandi; Wong, Jessica; Sievers, Quinlan L.; Vartanov, Alexander R.; Goldstein, Natalie R.; Brown, Jennifer R.; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Shalek, Alex K.; Ding, Ruihua; Gaublomme, Jellert T.; Park, Hongkun] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Lawrence, Mike; Pochet, Nathalie; Stojanov, Petar; Sougnez, Carrie; Lander, Eric; Hacohen, Nir; Regev, Aviv; Getz, Gad] Broad Inst, Cambridge, MA USA. [Stevenson, Kristen E.; Neuberg, Donna; Wu, Catherine J.] Dana Farber Canc Inst, Boston, MA 02215 USA. [MacDonald, Bryan T.; He, Xi] Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA USA. [MacDonald, Bryan T.; He, Xi] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Dept Med, Div Allergy Immunol & Rheumatol, Boston, MA 02114 USA. [Brown, Jennifer R.; Wu, Catherine J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Wu, CJ (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Dana 540B, Boston, MA 02215 USA. EM cwu@partners.org OI Shalek, Alex K./0000-0001-5670-8778 FU National Institutes of Health [5DP1OD003893-03]; National Institutes of Health Centers of Excellence in Genomic Science Award [1P50HG006193-01]; National Institutes of Health; Howard Hughes Medical Institute; Merkin Foundation for Stem Cell Research at the Broad Institute; Fund for Scientific Research Flanders (FWO Vlaanderen), Belgium; National Institutes of Health, National Cancer Institute [K23 CA115682]; Melton and Rosenbach Funds; American Society of Hematology; Leukemia and Lymphoma Society; Blavatnik Family Foundation [SU2C/AACR]; Damon-Runyon Cancer Research Foundation [CI-38-07] FX This work was supported by a National Institutes of Health Director's Pioneer Award (5DP1OD003893-03) and National Institutes of Health Centers of Excellence in Genomic Science Award (1P50HG006193-01) (H. P.); a National Institutes of Health Director's Pioneer Award, the Howard Hughes Medical Institute, and a fellowship with the Merkin Foundation for Stem Cell Research at the Broad Institute (A. R.); the Fund for Scientific Research Flanders (FWO Vlaanderen), Belgium (N.P.); the National Institutes of Health, National Cancer Institute (K23 CA115682), the Melton and Rosenbach Funds, a Scholar of the American Society of Hematology, and a Scholar in Clinical Research of the Leukemia and Lymphoma Society (J.R.B.); and by the Blavatnik Family Foundation, an Innovative Research grant (SU2C/AACR) and the Damon-Runyon Cancer Research Foundation (CI-38-07) (C.J.W.). NR 37 TC 16 Z9 16 U1 0 U2 5 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 AUG 14 PY 2014 VL 124 IS 7 BP 1089 EP 1098 DI 10.1182/blood-2014-01-552067 PG 10 WC Hematology SC Hematology GA AQ2MQ UT WOS:000342621100021 PM 24778153 ER PT J AU Lindholm, D Varenhorst, C Cannon, CP Harrington, RA Himmelmann, A Maya, J Husted, S Steg, PG Cornel, JH Storey, RF Stevens, SR Wallentin, L James, SK AF Lindholm, Daniel Varenhorst, Christoph Cannon, Christopher P. Harrington, Robert A. Himmelmann, Anders Maya, Juan Husted, Steen Steg, Philippe Gabriel Cornel, Jan H. Storey, Robert F. Stevens, Susanna R. Wallentin, Lars James, Stefan K. TI Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial SO EUROPEAN HEART JOURNAL LA English DT Article DE Platelet inhibition; Acute coronary syndrome ID P2Y(12) RECEPTOR ANTAGONIST; SEGMENT ELEVATION; PLATELET-AGGREGATION; INVASIVE STRATEGY; ASPIRIN; INHIBITION; PRASUGREL; MANAGEMENT; DISEASE AB Aims The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization. Methods and results We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding. Conclusion In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days. C1 [Lindholm, Daniel; Varenhorst, Christoph; Wallentin, Lars; James, Stefan K.] Uppsala Univ, Dept Med Sci, SE-75237 Uppsala, Sweden. [Lindholm, Daniel; Varenhorst, Christoph; Wallentin, Lars; James, Stefan K.] Uppsala Univ, Uppsala Clin Res Ctr, SE-75237 Uppsala, Sweden. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Harrington, Robert A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Himmelmann, Anders] AstraZeneca Res & Dev, Molndal, Sweden. [Maya, Juan] AstraZeneca Res & Dev, Wilmington, DE USA. [Husted, Steen] Hosp Unit West, Dept Med, Herning Holstbro, Denmark. [Steg, Philippe Gabriel] INSERM, U1148, Paris, France. [Steg, Philippe Gabriel] Hop Bichat Claude Bernard, AP HP, Dept Hosp Univ FIRE, F-75877 Paris, France. [Steg, Philippe Gabriel] Royal Brompton Hosp, ICMS, NHLI Imperial Coll, London SW3 6LY, England. [Steg, Philippe Gabriel] Univ Paris Diderot, Paris, France. [Cornel, Jan H.] Med Ctr Alkmaar, Dept Cardiol, Alkmaar, Netherlands. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Stevens, Susanna R.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. RP James, SK (reprint author), Uppsala Univ, Dept Med Sci, MTC Bldg,Uppsala Sci Pk,Dag Hammarskjolds Vag, SE-75237 Uppsala, Sweden. EM stefan.james@ucr.uu.se OI Varenhorst, Christoph/0000-0002-8378-3869; Lindholm, Daniel/0000-0003-3526-0614 FU AstraZeneca FX This work was supported by AstraZeneca, who funded the PLATO trial. Funding to pay the Open Access publication charges for this article was provided by Astra Zeneca. NR 19 TC 39 Z9 45 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG 14 PY 2014 VL 35 IS 31 BP 2083 EP 2093 DI 10.1093/eurheartj/ehu160 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AP7BM UT WOS:000342232600013 PM 24727884 ER PT J AU Halassa, MM Chen, Z Wimmer, RD Brunetti, PM Zhao, SL Zikopoulos, B Wang, F Brown, EN Wilson, MA AF Halassa, Michael M. Chen, Zhe Wimmer, Ralf D. Brunetti, Philip M. Zhao, Shengli Zikopoulos, Basilis Wang, Fan Brown, Emery N. Wilson, Matthew A. TI State-Dependent Architecture of Thalamic Reticular Subnetworks SO CELL LA English DT Article ID NEURONS IN-VIVO; NEURAL MECHANISMS; SLEEP SPINDLES; ATTENTION; NUCLEUS; CORTEX; INFORMATION; COGNITION; OSCILLATIONS; DYNAMICS AB Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function. C1 [Halassa, Michael M.; Wimmer, Ralf D.] NYU, Langone Med Ctr, Inst Neurosci, New York, NY 10016 USA. [Halassa, Michael M.; Wimmer, Ralf D.] NYU, Langone Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA. [Halassa, Michael M.; Chen, Zhe; Wimmer, Ralf D.] NYU, Langone Med Ctr, Dept Psychiat, New York, NY 10016 USA. [Halassa, Michael M.; Wimmer, Ralf D.; Brunetti, Philip M.; Wilson, Matthew A.] MIT, Picower Inst Learning & Memory, Cambridge, MA 02139 USA. [Zhao, Shengli; Wang, Fan] Duke Univ, Dept Cell Biol, Durham, NC 27710 USA. [Zikopoulos, Basilis] Boston Univ, Dept Hlth Sci, Boston, MA 02215 USA. [Zikopoulos, Basilis] Boston Univ, Program Neurosci, Boston, MA 02215 USA. [Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Brown, Emery N.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Inst Med Engn & Sci, Cambridge, MA 02139 USA. RP Halassa, MM (reprint author), NYU, Langone Med Ctr, Inst Neurosci, New York, NY 10016 USA. EM michael.halassa@nyumc.org OI Chen, Zhe/0000-0002-6483-6056 FU NIH from the NINDS [K99 NS 078115]; NARSAD Young Investigator Award; NSF-CRCNS [IIS-1307645]; Early Career Award (Mathematical Biosciences Institute); NIMH [R01MH101209, R01MH057414]; NSF [SBE-0354378]; NIH [R01NS077986, DP1MH103908, R01-MH061976]; transformative R01 award [TR01-GM10498] FX We thank L. Acsady and T. Fellin for helpful comments, as well as all members of the M.A.W. laboratory. M.M.H. is supported by an NIH pathway to independence career award (K99 NS 078115) from the NINDS and a NARSAD Young Investigator Award. Z.C. is supported by an NSF-CRCNS grant (award IIS-1307645) and an Early Career Award (Mathematical Biosciences Institute). B.Z. is supported by grants from NIMH (R01MH101209 and R01MH057414) and NSF (CELEST and SBE-0354378). F.W. is supported by NIH grants (R01NS077986 and DP1MH103908). E.N.B. and M.A.W. are supported by a transformative R01 award (TR01-GM10498). M.A.W. is additionally supported by NIH grant R01-MH061976. NR 62 TC 47 Z9 47 U1 4 U2 26 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 808 EP 821 DI 10.1016/j.cell.2014.06.025 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700012 PM 25126786 ER PT J AU Ganem, NJ Cornils, H Chiu, SY O'Rourke, KP Arnaud, J Yimlamai, D Thery, M Camargo, FD Pellman, D AF Ganem, Neil J. Cornils, Hauke Chiu, Shang-Yi O'Rourke, Kevin P. Arnaud, Jonathan Yimlamai, Dean Thery, Manuel Camargo, Fernando D. Pellman, David TI Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation SO CELL LA English DT Article ID CELL-CYCLE PROGRESSION; MAMMALIAN-CELLS; CENTROSOME AMPLIFICATION; CHROMOSOMAL INSTABILITY; CLEAVAGE FAILURE; CANCER; YAP; TETRAPLOIDY; PLOIDY; LIVER AB Genetically unstable tetraploid cells can promote tumorigenesis. Recent estimates suggest that similar to 37% of human tumors have undergone a genome-doubling event during their development. This potentially oncogenic effect of tetraploidy is countered by a p53-dependent barrier to proliferation. However, the cellular defects and corresponding signaling pathways that trigger growth suppression in tetraploid cells are not known. Here, we combine RNAi screening and in vitro evolution approaches to demonstrate that cytokinesis failure activates the Hippo tumor suppressor pathway in cultured cells, as well as in naturally occurring tetraploid cells in vivo. Induction of the Hippo pathway is triggered in part by extra centrosomes, which alter small G protein signaling and activate LATS2 kinase. LATS2 in turn stabilizes p53 and inhibits the transcriptional regulators YAP and TAZ. These findings define an important tumor suppression mechanism and uncover adaptive mechanisms potentially available to nascent tumor cells that bypass this inhibitory regulation. C1 [Ganem, Neil J.; Cornils, Hauke; Chiu, Shang-Yi; O'Rourke, Kevin P.; Pellman, David] Harvard Univ, Sch Med, Childrens Hosp, Dana Farber Canc Inst,Howard Hughes Med Inst,Dept, Boston, MA 02115 USA. [Ganem, Neil J.; Cornils, Hauke; Chiu, Shang-Yi; O'Rourke, Kevin P.; Pellman, David] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Arnaud, Jonathan; Thery, Manuel] CEA UJF INRA CNRS, Inst Rech Technol & Sci Vivant, UMR5168, F-38054 Grenoble, France. [Yimlamai, Dean; Camargo, Fernando D.] Childrens Hosp Boston, Stem Cell Program, Boston, MA 02115 USA. [Thery, Manuel] Univ Paris Diderot, Hop St Louis, AP HP, INSERM,Inst Univ Hematol, F-75010 Paris, France. RP Ganem, NJ (reprint author), Boston Univ, Sch Med, Ctr Canc, Dept Pharmacol & Expt Therapeut,Div Hematol & Onc, Boston, MA 02118 USA. EM nganem@bu.edu; david_pellman@dfci.harvard.edu OI Yimlamai, Dean/0000-0002-7936-7168 FU NIH [1S10RR026582-01, DK099559, GM083299-1]; NCI K99 award [K99CA154531-01]; ERC [31047]; BCH Career Development Award; Manton Center for Orphan Disease Research FX We would like to thank S. Jhaveri-Schneider and A. Salic for comments on the manuscript; members of the ICCB screening facility; K. Lunquist for technical assistance; H. Li, K. Ross, and K. Stegmaier for assistance with microarray analysis; R. Beroukhim for assistance with ploidy analysis of the CCLE collection; S. Godinho for reagents; P. Nagaruri Gonchi and D. Williams for discussions; and T. Vignaud, F. Senger, and J.-L. Martiel for advice on traction force microscopy. NIH grant 1S10RR026582-01 to C. Shamu supported the IsoCyte/Velos laser scanning cytometer. N.J.G. is supported by an NCI K99 award (K99CA154531-01) and is a member of the Shamim and Ashraf Dahod Breast Cancer Research Laboratories; H.C. is a fellow of the Leukemia and Lymphoma Society; M.T. is supported by ERC grant 31047; D.Y. is supported by a BCH Career Development Award and is a George Ferry Young Investigator of NASPGHAN; F.D.C. is supported by the Manton Center for Orphan Disease Research and NIH grant DK099559; and D.P. is a HHMI investigator and is supported by NIH grant GM083299-1. NR 38 TC 83 Z9 83 U1 3 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 833 EP 848 DI 10.1016/j.cell.2014.06.029 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700014 PM 25126788 ER PT J AU Morris, SA Cahan, P Li, H Zhao, AM Roman, AKS Shivdasani, RA Collins, JJ Daley, GQ AF Morris, Samantha A. Cahan, Patrick Li, Hu Zhao, Anna M. Roman, Adrianna K. San Shivdasani, Ramesh A. Collins, James J. Daley, George Q. TI Dissecting Engineered Cell Types and Enhancing Cell Fate Conversion via CellNet SO CELL LA English DT Article ID TRANSCRIPTION FACTOR CDX2; DEFINED FACTORS; MOUSE FIBROBLASTS; FUNCTIONAL-NEURONS; STEM-CELLS; IDENTITY; TRANSPLANTATION; REGENERATION; HEPATOCYTES; BINDING AB Engineering clinically relevant cells in vitro holds promise for regenerative medicine, but most protocols fail to faithfully recapitulate target cell properties. To address this, we developed CellNet, a network biology platform that determines whether engineered cells are equivalent to their target tissues, diagnoses aberrant gene regulatory networks, and prioritizes candidate transcriptional regulators to enhance engineered conversions. Using CellNet, we improved B cell to macrophage conversion, transcriptionally and functionally, by knocking down predicted B cell regulators. Analyzing conversion of fibroblasts to induced hepatocytes (iHeps), CellNet revealed an unexpected intestinal program regulated by the master regulator Cdx2. We observed long-term functional engraftment of mouse colon by iHeps, thereby establishing their broader potential as endoderm progenitors and demonstrating direct conversion of fibroblasts into intestinal epithelium. Our studies illustrate how CellNet can be employed to improve direct conversion and to uncover unappreciated properties of engineered cells. C1 [Morris, Samantha A.; Cahan, Patrick; Zhao, Anna M.; Daley, George Q.] Boston Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol & Oncol,Stem Cell Transplantat, Boston, MA 02115 USA. [Morris, Samantha A.; Cahan, Patrick; Zhao, Anna M.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Morris, Samantha A.; Cahan, Patrick; Zhao, Anna M.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Morris, Samantha A.; Cahan, Patrick; Zhao, Anna M.; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Li, Hu] Mayo Clin, Coll Med, Ctr Individualized Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [Roman, Adrianna K. San; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Roman, Adrianna K. San; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Roman, Adrianna K. San; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Collins, James J.] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA. [Collins, James J.] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA 02215 USA. [Collins, James J.] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02215 USA. RP Daley, GQ (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol & Oncol,Stem Cell Transplantat, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu OI Cahan, Patrick/0000-0003-3652-2540 FU NIH (Progenitor Cell Biology Consortium) [UO1-HL100001, R24DK092760]; Boston Children's Hospital Stem Cell Program; Alex's Lemonade Stand Foundation; Mayo Clinic Center for Individualized Medicine; Mayo Clinic Center for Regenerative Medicine; NIH [R24DK092760, R01DK082889]; HHMI; [P50HG005550]; [1K01DK096013]; [2T32HL066987]; [5T32HL007623] FX We would like to thank members of the Daley laboratory for critical discussion, the Dana Farber Cancer Institute Hematological Neoplasia flow facility for assistance with cell sorting, and Thomas Graf for the C10 and RAW264.7 cells. G.Q.D. is supported by grants from the NIH (Progenitor Cell Biology Consortium UO1-HL100001 and R24DK092760), and the Boston Children's Hospital Stem Cell Program. G.Q.D. is an affiliate member of the Broad Institute, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. S.A.M. is supported by a Young Investigator Award from Alex's Lemonade Stand Foundation and P50HG005550. P.C is supported by 1K01DK096013, 2T32HL066987, and 5T32HL007623. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. J.J.C. is supported by NIH grant R24DK092760 and the HHMI. R.A.S. is supported by NIH grant R01DK082889. NR 33 TC 71 Z9 73 U1 2 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 889 EP 902 DI 10.1016/j.cell.2014.07.021 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700018 PM 25126792 ER PT J AU Cahan, P Li, H Morris, SA da Rocha, EL Daley, GQ Collins, JJ AF Cahan, Patrick Li, Hu Morris, Samantha A. da Rocha, Edroaldo Lummertz Daley, George Q. Collins, James J. TI CellNet: Network Biology Applied to Stem Cell Engineering SO CELL LA English DT Article ID TRANSCRIPTION FACTORS; GENE-EXPRESSION; DEFINED FACTORS; DIRECT CONVERSION; HUMAN FIBROBLASTS; NEURONS; BLOOD; CARDIOMYOCYTES; HEMATOPOIESIS; PROGENITORS AB Somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions between differentiated cell lineages represent powerful approaches to engineer cells for research and regenerative medicine. We have developed CellNet, a network biology platform that more accurately assesses the fidelity of cellular engineering than existing methodologies and generates hypotheses for improving cell derivations. Analyzing expression data from 56 published reports, we found that cells derived via directed differentiation more closely resemble their in vivo counterparts than products of direct conversion, as reflected by the establishment of target cell-type gene regulatory networks (GRNs). Furthermore, we discovered that directly converted cells fail to adequately silence expression programs of the starting population and that the establishment of unintended GRNs is common to virtually every cellular engineering paradigm. CellNet provides a platform for quantifying how closely engineered cell populations resemble their target cell type and a rational strategy to guide enhanced cellular engineering. C1 [Cahan, Patrick; Morris, Samantha A.; Daley, George Q.] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Howard Hughes Med Inst, Div Pediat Hematol & Oncol,Stem Cell Transplantat, Boston, MA 02115 USA. [Cahan, Patrick; Morris, Samantha A.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cahan, Patrick; Morris, Samantha A.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Cahan, Patrick; Morris, Samantha A.; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Li, Hu] Mayo Clin, Coll Med, Ctr Individualized Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [da Rocha, Edroaldo Lummertz; Collins, James J.] Boston Univ, Howard Hughes Med Inst, Dept Biomed Engn, Boston, MA USA. [da Rocha, Edroaldo Lummertz; Collins, James J.] Boston Univ, Ctr Synthet Biol, Boston, MA 02215 USA. [da Rocha, Edroaldo Lummertz] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [da Rocha, Edroaldo Lummertz] Univ Fed Santa Catarina, Grad Program Mat Sci & Engn, BR-88040900 Florianopolis, SC, Brazil. RP Daley, GQ (reprint author), Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Howard Hughes Med Inst, Div Pediat Hematol & Oncol,Stem Cell Transplantat, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu; jcollins@bu.edu OI Cahan, Patrick/0000-0003-3652-2540 FU NIH [R24DK092760]; HHMI; NIH (Progenitor Cell Biology Consortium) [R24DK092760, UO1-HL100001, P50HG005550]; Ellison Medical Foundation; Doris Duke Medical Foundation; Boston Children's Hospital Stem Cell Program; NIDDK [K01DK096013]; NHLBI [T32HL066987, T32HL007623]; Alex's Lemonade Stand Foundation; Mayo Clinic Center for Individualized Medicine; Mayo Clinic Center for Regenerative Medicine; National Council for Scientific and Technological Development; program Science Without Borders (CNPq, Brazil) FX J.J.C. is supported by NIH grant R24DK092760 and the HHMI. G.Q.D. is supported by grants from the NIH (Progenitor Cell Biology Consortium UO1-HL100001, R24DK092760, and P50HG005550), the Ellison Medical Foundation, Doris Duke Medical Foundation, and Boston Children's Hospital Stem Cell Program, and is an affiliate member of the Broad Institute. P.C. is supported by NIDDK (K01DK096013) and received support from NHLBI (T32HL066987 and T32HL007623). S.A.M. is supported by a Young Investigator Award from Alex's Lemonade Stand Foundation. H.L. is supported by Mayo Clinic Center for Individualized Medicine and Mayo Clinic Center for Regenerative Medicine. E.L.d.R. is supported by National Council for Scientific and Technological Development and the program Science Without Borders (CNPq, Brazil). NR 45 TC 117 Z9 121 U1 6 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 14 PY 2014 VL 158 IS 4 BP 903 EP 915 DI 10.1016/j.cell.2014.07.020 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN9RF UT WOS:000340944700019 PM 25126793 ER PT J AU Xue, JY Murthy, B Tran, NT Ghaffar, A AF Xue, Jiayin Murthy, Bhavini Tran, Nhan T. Ghaffar, Abdul TI Goal setting and knowledge generation through health policy and systems research in low- and middle-income countries SO HEALTH RESEARCH POLICY AND SYSTEMS LA English DT Article DE Country cooperation strategies; Health policy and systems research; Low- and middle-income countries; World Health Organization AB The importance of health policy and systems research (HPSR) and its role in aiding health system reforms has been increasingly recognized in recent years within the World Health Organization (WHO). An assessment of the 71 WHO Country Cooperation Strategies (CCS) that are publicly available and were published in English in 2012 was completed to determine the extent to which HPSR goals are incorporated at the global level. A review was then conducted using a Medline database search to determine the number of articles published by countries with HPSR goals. Sixty-six out of the 71 (93%) available CCS describe HPSR as an objective or strategy for achieving health system priorities. However, only 52 out of the 66 countries (79%) have any publications involving HPSR during their most recent CCS cycle. This suggests that although health systems strengthening through HPSR is increasingly emphasized by the WHO and country health ministries, actual HPSR progress may still be lacking. There is a need and an opportunity for the WHO and other global health agencies to focus on providing the necessary tools and building HPSR capacity in low-and middle-income countries. C1 [Xue, Jiayin] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Murthy, Bhavini] UNC Sch Med, Dept Social Med, Chapel Hill, NC 27599 USA. [Tran, Nhan T.; Ghaffar, Abdul] WHO, Alliance Hlth Policy & Syst Res, Hlth Syst & Innovat Cluster, CH-1211 Geneva, Switzerland. RP Xue, JY (reprint author), Massachusetts Gen Hosp, Dept Pediat, 5th Floor,175 Cambridge St, Boston, MA 02114 USA. EM jxue@partners.org; bmurthy@mail.harvard.edu FU World Health Organization [001] NR 8 TC 2 Z9 2 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-4505 J9 HEALTH RES POLICY SY JI Health Res. Policy Syst. PD AUG 14 PY 2014 VL 12 AR 39 DI 10.1186/1478-4505-12-39 PG 5 WC Health Policy & Services SC Health Care Sciences & Services GA AN9JJ UT WOS:000340922200001 PM 25123553 ER PT J AU Walensky, LD Bird, GH AF Walensky, Loren D. Bird, Gregory H. TI Hydrocarbon-Stapled Peptides: Principles, Practice, and Progress SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ALPHA-HELICAL PEPTIDES; CLOSING OLEFIN METATHESIS; BH3 HELIX; ASYMMETRIC-SYNTHESIS; BCL-2 DOMAINS; P53 PEPTIDE; AMINO-ACIDS; INHIBITOR; APOPTOSIS; CANCER AB Protein structure underlies essential biological processes and provides a blueprint for molecular mimicry that drives drug discovery. Although small molecules represent the lion's share of agents that target proteins for therapeutic benefit, there remains no substitute for the natural properties of proteins and their peptide subunits in the majority of biological contexts. The peptide a-helix represents a common structural motif that mediates communication between signaling proteins. Because peptides can lose their shape when taken out of context, developing chemical interventions to stabilize their bioactive structure remains an active area of research. The all-hydrocarbon staple has emerged as one such solution, conferring a-helical structure, protease resistance, cellular penetrance, and biological activity upon successful incorporation of a series of design and application principles. Here, we describe our more than decade-long experience in developing stapled peptides as biomedical research tools and prototype therapeutics, highlighting lessons learned, pitfalls to avoid, and keys to success. C1 [Walensky, Loren D.; Bird, Gregory H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Walensky, Loren D.; Bird, Gregory H.] Dana Farber Canc Inst, Linde Program Canc Chem Biol, Boston, MA 02215 USA. [Walensky, Loren D.] Harvard Univ, Childrens Hosp Boston, Dept Pediat, Sch Med, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, 450 Brookline Ave,Mayer 664, Boston, MA 02215 USA. EM loren_walensky@dfci.harvard.edu; greg_bird@dfci.harvard.edu FU NIH [5R01CA050239, 5R01GM0902995, R01AI084102]; LLS/SCOR project grant FX We thank E. Smith for editorial assistance and figure preparation. This work was supported by NIH Grants 5R01CA050239, 5R01GM0902995, and R01AI084102 and an LLS/SCOR project grant to L.D.W. L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics. NR 69 TC 127 Z9 128 U1 15 U2 96 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD AUG 14 PY 2014 VL 57 IS 15 BP 6275 EP 6288 DI 10.1021/jm4011675 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA AN2WE UT WOS:000340445900001 PM 24601557 ER PT J AU He, L Guo, L Vathipadiekal, V Sergent, PA Growdon, WB Engler, DA Rueda, BR Birrer, MJ Orsulic, S Mohapatra, G AF He, L. Guo, L. Vathipadiekal, V. Sergent, P. A. Growdon, W. B. Engler, D. A. Rueda, B. R. Birrer, M. J. Orsulic, S. Mohapatra, G. TI Identification of LMX1B as a novel oncogene in human ovarian cancer SO ONCOGENE LA English DT Article DE ovarian cancer; aCGH; LMX1B; tumor progression; transcription factor ID NAIL-PATELLA-SYNDROME; COMPARATIVE GENOMIC HYBRIDIZATION; MOUSE MODEL; MOLECULAR CHARACTERIZATION; HOMEODOMAIN PROTEINS; TRANSCRIPTION FACTOR; GENETIC CHANGES; BREAST CANCERS; KAPPA-B; INFLAMMATION AB Ovarian cancers are thought to result from the accumulation of multiple genetic aberrations that transform ovarian and/or fallopian tube surface epithelial cells, allowing for their abnormal growth, proliferation and metastasis. In the report presented here, we carried out genome-wide copy-number analysis using comparative genomic hybridization on a panel of mouse ovarian cancer (OVCA) cell lines previously established in our laboratory. We identified a recurrent focal amplification on mouse chromosomal region 2qB, which contains the LIM-homeodomain-containing transcription factor 1B (Lmx1b) gene. LMX1B is not expressed in normal human ovary, but is expressed in many human OVCA cell lines and primary tumors. High expression of LMX1B correlates with poor outcome. To clarify the role of LMX1B in ovarian carcinogenesis, we transduced LMX1B into a panel of mouse and human OVCA cell lines and demonstrated that LMX1B strongly promotes migration of cancer cells in culture and promotes xenograft growth in nude mice. Conversely, knockdown of LMX1B in a human cell line with endogenous high expression of LMX1B inhibits cell migration in vitro and tumor growth in vivo. Microarray analysis of cells overexpressing LMX1B identified the nuclear factor (NF)-kappa B pathway as a potential mediator of tumor progression and subsequent treatment of NF kappa B inhibitor decreased the migratory capacity of these cells. Thus, our data demonstrate that LMX1B is a novel oncogene in OVCA pathogenesis. C1 [He, L.; Mohapatra, G.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [He, L.; Vathipadiekal, V.; Growdon, W. B.; Rueda, B. R.; Birrer, M. J.; Mohapatra, G.] Harvard Univ, Sch Med, Boston, MA USA. [Guo, L.; Sergent, P. A.; Growdon, W. B.; Rueda, B. R.] Massachusetts Gen Hosp, Dept Vincent Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Vathipadiekal, V.; Birrer, M. J.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Vathipadiekal, V.; Birrer, M. J.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Engler, D. A.] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Orsulic, S.] Cedars Sinai Med Ctr, Womens Canc Res Inst, Los Angeles, CA 90048 USA. RP Mohapatra, G (reprint author), Massachusetts Gen Hosp, Dept Pathol, 70 Blossom St, Boston, MA 02114 USA. EM gmohapatra@partners.org OI Vathipadiekal, Vinod/0000-0002-8181-6890 FU American Cancer Society [118900-RSG-10-252-01-TBG]; Advanced Medical Research Foundation; Vincent Memorial Research Funds; Michael Wall Gynecologic Oncology Research Fund FX We thank Jinsong Liu (MD Anderson Cancer Center) for the T29-immortalized human ovarian surface epithelial cell line. This work was supported by the American Cancer Society Grant 118900-RSG-10-252-01-TBG (SO), Advanced Medical Research Foundation (BRR) and Vincent Memorial Research Funds (BRR) and the Michael Wall Gynecologic Oncology Research Fund (GM). NR 49 TC 5 Z9 5 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD AUG 14 PY 2014 VL 33 IS 33 BP 4226 EP 4235 DI 10.1038/onc.2013.375 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA AO2MB UT WOS:000341155800004 PM 24056967 ER PT J AU Sillesen, M Jin, G Johansson, PI Alam, HB AF Sillesen, Martin Jin, Guang Johansson, Par I. Alam, Hasan B. TI Resuscitation speed affects brain injury in a large animal model of traumatic brain injury and shock SO SCANDINAVIAN JOURNAL OF TRAUMA RESUSCITATION & EMERGENCY MEDICINE LA English DT Article DE Traumatic brain injury; Hemorrhagic shock resuscitation; Fresh frozen plasma; Swine ID RAPID INFUSION SYSTEM; HEMORRHAGIC-SHOCK; FLUID RESUSCITATION; ENDOTHELIAL GLYCOCALYX; 0.9-PERCENT SALINE; RINGERS SOLUTION; VOLUME KINETICS; BLOOD-VOLUME; ANESTHESIA; PLASMA AB Background: Optimal fluid resuscitation strategy following combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remain controversial and the effect of resuscitation infusion speed on outcome is not well known. We have previously reported that bolus infusion of fresh frozen plasma (FFP) protects the brain compared with bolus infusion of 0.9% normal saline (NS). We now hypothesize reducing resuscitation infusion speed through a stepwise infusion speed increment protocol using either FFP or NS would provide neuroprotection compared with a high speed resuscitation protocol. Methods: 23 Yorkshire swine underwent a protocol of computer controlled TBI and 40% hemorrhage. Animals were left in shock (mean arterial pressure of 35 mmHg) for two hours prior to resuscitation with bolus FFP (n = 5, 50 ml/min) or stepwise infusion speed increment FFP (n = 6), bolus NS (n = 5, 165 ml/min) or stepwise infusion speed increment NS (n = 7). Hemodynamic variables over a 6-hour observation phase were recorded. Following euthanasia, brains were harvested and lesion size as well as brain swelling was measured. Results: Bolus FFP resuscitation resulted in greater brain swelling (22.36 +/- 1.03% vs. 15.58 +/- 2.52%, p = 0.04), but similar lesion size compared with stepwise resuscitation. This was associated with a lower cardiac output (CO: 4.81 +/- 1.50 l/min vs. 5.45 +/- 1.14 l/min, p = 0.03). In the NS groups, bolus infusion resulted in both increased brain swelling (37.24 +/- 1.63% vs. 26.74 +/- 1.33%, p = 0.05) as well as lesion size (3285.44 +/- 130.81 mm(3) vs. 2509.41 +/- 297.44 mm(3), p = 0.04). This was also associated with decreased cardiac output (NS: 4.37 +/- 0.12 l/min vs. 6.35 +/- 0.10 l/min, p < 0.01). Conclusions: In this clinically relevant model of combined TBI and HS, stepwise resuscitation protected the brain compared with bolus resuscitation. C1 [Sillesen, Martin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Trauma Emergency Surg & Surg Crit C, Boston, MA 02114 USA. [Sillesen, Martin] Copenhagen Univ Hosp, Dept Surg, DK-3400 Hillerod, Denmark. [Jin, Guang; Alam, Hasan B.] Univ Michigan Hosp, Dept Surg, Ann Arbor, MI 48109 USA. [Johansson, Par I.] Rigshosp, Copenhagen Univ Hosp, Capital Reg Blood Bank, DK-2100 Copenhagen, Denmark. [Johansson, Par I.] Univ Texas Houston, Sch Med, Dept Surg, Houston, TX 77030 USA. RP Alam, HB (reprint author), Univ Michigan Hosp, Dept Surg, 2920 Taubman Ctr 5331,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM alamh@med.umich.edu RI Johansson, Par/P-9283-2015 OI Johansson, Par/0000-0001-9778-5964 FU U.S Army [T00521959]; Lundbeck foundation; Laerdal foundation FX The study was funded by a grant (GRANTT00521959) from the U.S Army to Hasan B. Alam and grants from the Laerdal and Lundbeck foundations to MS. NR 32 TC 4 Z9 4 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1757-7241 J9 SCAND J TRAUMA RESUS JI Scand. J. Trauma Resusc. Emerg. Med. PD AUG 14 PY 2014 VL 22 AR 46 DI 10.1186/s13049-014-0046-2 PG 10 WC Emergency Medicine SC Emergency Medicine GA AO2MC UT WOS:000341155900001 PM 25116886 ER PT J AU Hohmann, EL Ananthakrishnan, AN Deshpande, V AF Hohmann, Elizabeth L. Ananthakrishnan, Ashwin N. Deshpande, Vikram TI Case 25-2014: A 37-Year-Old Man with Ulcerative Colitis and Bloody Diarrhea SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; FECAL MICROBIOTA TRANSPLANTATION; CLOSTRIDIUM-DIFFICILE INFECTION; CYTOMEGALOVIRUS-INFECTION; PREVALENCE; MANAGEMENT C1 [Hohmann, Elizabeth L.; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hohmann, Elizabeth L.; Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Deshpande, Vikram] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Hohmann, EL (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. FU Seres Health; Cubist; AbbVie; Prometheus; Janssen FX Dr. Hohmann reports receiving grant support through her institution from Seres Health. Dr. Ananthakrishnan reports receiving fees for serving on advisory boards from Cubist, AbbVie, Prometheus, and Janssen. No other potential conflict of interest relevant to this article was reported. NR 23 TC 12 Z9 14 U1 3 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 14 PY 2014 VL 371 IS 7 BP 668 EP 675 DI 10.1056/NEJMcpc1400842 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AN7ZL UT WOS:000340819600013 PM 25119613 ER PT J AU Lin, AE Prakash, S Milewicz, DM AF Lin, Angela E. Prakash, Siddharth Milewicz, Dianna M. TI Aortic Dilatation with Bicuspid Aortic Valve SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID TURNER-SYNDROME C1 [Lin, Angela E.] MassGen Hosp Children, Boston, MA 02114 USA. [Prakash, Siddharth; Milewicz, Dianna M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA. RP Lin, AE (reprint author), MassGen Hosp Children, Boston, MA 02114 USA. EM lin.angela@mgh.harvard.edu NR 5 TC 0 Z9 0 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 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 14 PY 2014 VL 371 IS 7 BP 683 EP 683 DI 10.1056/NEJMc1407391 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AN7ZL UT WOS:000340819600020 PM 25119620 ER PT J AU Wang, Y Waters, J Leung, ML Unruh, A Roh, W Shi, XQ Chen, K Scheet, P Vattathil, S Liang, H Multani, A Zhang, H Zhao, R Michor, F Meric-Bernstam, F Navin, NE AF Wang, Yong Waters, Jill Leung, Marco L. Unruh, Anna Roh, Whijae Shi, Xiuqing Chen, Ken Scheet, Paul Vattathil, Selina Liang, Han Multani, Asha Zhang, Hong Zhao, Rui Michor, Franziska Meric-Bernstam, Funda Navin, Nicholas E. TI Clonal evolution in breast cancer revealed by single nucleus genome sequencing SO NATURE LA English DT Article ID GROWTH-RATE; CELL; MUTATIONS; CARCINOMAS; GENES; HETEROGENEITY; REARRANGEMENT; HYBRIDIZATION; NUCLEOTIDE; PHENOTYPE AB Sequencing studies of breast tumour cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumours. Here we developed a whole-genome and exome single cell sequencing approach called nuc-seq that uses G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumour nuclei from an oestrogen-receptor-positive(ER+) breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumour evolution and remained highly stable as the tumour masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Using targeted single-molecule sequencing, many of the diverse mutations were shown to occur at low frequencies (<10%) in the tumour mass. Using mathematical modelling we found that the triple-negative tumour cells had an increased mutation rate (13.3x), whereas the ER+ tumour cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer. C1 [Wang, Yong; Waters, Jill; Leung, Marco L.; Unruh, Anna; Roh, Whijae; Shi, Xiuqing; Multani, Asha; Navin, Nicholas E.] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Leung, Marco L.; Scheet, Paul; Vattathil, Selina; Navin, Nicholas E.] Univ Texas Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA. [Chen, Ken; Liang, Han; Navin, Nicholas E.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Zhang, Hong] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Zhao, Rui; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Zhao, Rui; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Meric-Bernstam, Funda] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA. RP Navin, NE (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. EM nnavin@mdanderson.org OI Roh, Whijae/0000-0002-7395-9939; Casasent, Anna/0000-0002-7857-179X FU NIH [R21CA174397-01, TR000371, U24CA143883]; NCI [1RO1CA169244-01, RO1CA172652, CA016672]; T.C. Hsu and the Alice-Reynolds Kleberg Foundation; Center for Genetics Genomics; Susan Komen [SAC10006]; PS-OC [U54CA143798]; Dell Foundation; ALA FX We thank L. Ramagli, H. Tang, E. Thompson, K. Khanna, W. Schober and J. Tyler. We are grateful to S. Kennedy and L. Loeb for help with the duplex protocols. We thank M. Edgerton, J. Hicks, M. Wigler and J. Kendall for discussions. We thank R. Krahe and M. Rui for reviewing the manuscript. N.E.N. is a Nadia's Gift Foundation Damon Runyon-Rachleff Innovator (DRR-25-13). This research was supported by grants to N.E.N. from NIH (R21CA174397-01) and NCI (1RO1CA169244-01). N.E.N. was supported by T. C. Hsu and the Alice-Reynolds Kleberg Foundation. N.E.N. and P. S. were supported by the Center for Genetics & Genomics. F.M.-B was supported by an NIH UL1 (TR000371) and Susan Komen (SAC10006). K. C. was supported by the NCI (RO1CA172652). H. L. was supported by the NIH (U24CA143883). F. M. was supported by PS-OC (U54CA143798). K. C. and H. L. were supported by the Dell Foundation. M. L. L. is a CPRIT scholar and is supported by ALA. This work was also supported by an NCI center grant (CA016672). A.U. is a Rosalie B. Hite Fellow. NR 52 TC 206 Z9 215 U1 10 U2 91 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 14 PY 2014 VL 512 IS 7513 BP 155 EP + DI 10.1038/nature13600 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM9KO UT WOS:000340200700023 PM 25079324 ER PT J AU Fletcher, AL Elman, JS Astarita, J Murray, R Saeidi, N D'Rozario, J Knoblich, K Brown, FD Schildberg, FA Nieves, JM Heng, TSP Boyd, RL Turley, SJ Parekkadan, B AF Fletcher, Anne L. Elman, Jessica S. Astarita, Jillian Murray, Ryan Saeidi, Nima D'Rozario, Joshua Knoblich, Konstantin Brown, Flavian D. Schildberg, Frank A. Nieves, Janice M. Heng, Tracy S. P. Boyd, Richard L. Turley, Shannon J. Parekkadan, Biju TI Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MESENCHYMAL STEM-CELLS; ACUTE KIDNEY INJURY; NITRIC-OXIDE; SEPTIC SHOCK; CECAL LIGATION; ANIMAL-MODELS; STROMAL CELLS; T-CELLS; MICE; ENDOTOXEMIA AB Sepsis is an aggressive inflammatory syndrome and a global health burden estimated to kill 7.3 million people annually. Single-target molecular therapies have not addressed the multiple disease pathways triggered by septic injury. Cell therapies might offer a broader set of mechanisms of action that benefit complex, multifocal disease processes. We describe a population of immune-specialized myofibroblasts derived from lymph node tissue, termed fibroblastic reticular cells (FRCs). Because FRCs have an immunoregulatory function in lymph nodes, we hypothesized that ex vivo-expanded FRCs would control inflammation when administered therapeutically. Indeed, a single injection of ex vivo-expanded allogeneic FRCs reduced mortality in mouse models of sepsis when administered at early or late time points after septic onset. Mice treated with FRCs exhibited lower local and systemic concentrations of proinflammatory cytokines and reduced bacteremia. When administered 4 hours after induction of lipopolysaccharide endotoxemia, or cecal ligation and puncture (CLP) sepsis in mice, FRCs reduced deaths by at least 70%. When administered late in disease (16 hours after CLP), FRCs still conveyed a robust survival advantage (44% survival compared to 0% for controls). FRC therapy was dependent on the metabolic activity of nitric oxide synthase 2 (NOS2) as the primary molecular mechanism of drug action in the mice. Together, these data describe a new anti-inflammatory cell type and provide preclinical evidence for therapeutic efficacy in severe sepsis that warrants further translational study. C1 [Fletcher, Anne L.; Astarita, Jillian; Knoblich, Konstantin; Brown, Flavian D.; Schildberg, Frank A.; Nieves, Janice M.; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Fletcher, Anne L.; Astarita, Jillian; Brown, Flavian D.; Schildberg, Frank A.; Nieves, Janice M.; Turley, Shannon J.] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA. [Fletcher, Anne L.; D'Rozario, Joshua; Heng, Tracy S. P.; Boyd, Richard L.] Monash Univ, Dept Anat & Dev Biol, Clayton, Vic 3800, Australia. [Fletcher, Anne L.] Univ Birmingham, Sch Immun & Infect, Birmingham B15 2TT, W Midlands, England. [Elman, Jessica S.; Murray, Ryan; Saeidi, Nima; Parekkadan, Biju] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Elman, Jessica S.; Murray, Ryan; Saeidi, Nima; Parekkadan, Biju] Shriners Hosp Children, Boston, MA 02114 USA. [Parekkadan, Biju] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Fletcher, AL (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM a.fletcher@bham.ac.uk; turley.shannon@gene.com; biju_parekkadan@hms.harvard.edu RI Knoblich, Konstantin/B-5980-2009 OI Knoblich, Konstantin/0000-0002-5646-837X FU U.S. NIH [R01EB012521, K01DK087770, R01 DK074500, P01 AI045757]; Shriners Hospitals for Children; National Health and Medical Research Council of Australia [546259]; Monash University, Australia; Birmingham Fellowship; University of Birmingham, UK; Australian Postdoctoral (Industry) Fellowship from the Australian Research Council [LP110201169] FX Supported in part by grants R01EB012521 (B.P.), K01DK087770 (B.P.), R01 DK074500 (S.J.T.), and P01 AI045757 (S.J.T.) from the U.S. NIH and by the Shriners Hospitals for Children (B.P.). A.L.F. was the recipient of an Early Career Fellowship (546259) from the National Health and Medical Research Council of Australia; a training grant from Monash University, Australia; and a Birmingham Fellowship, University of Birmingham, UK. T.S.P.H. was supported by an Australian Postdoctoral (Industry) Fellowship from the Australian Research Council (LP110201169). NR 80 TC 6 Z9 6 U1 1 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 EI 1946-6242 J9 SCI TRANSL MED JI Sci. Transl. Med. PD AUG 13 PY 2014 VL 6 IS 249 AR 249ra109 DI 10.1126/scitranslmed.3009377 PG 14 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA AN9PC UT WOS:000340938300006 PM 25122637 ER PT J AU Oberg, AS Hernandez-Diaz, S Frisell, T Greene, MF Almqvist, C Bateman, BT AF Oberg, Anna Sara Hernandez-Diaz, Sonia Frisell, Thomas Greene, Michael F. Almqvist, Catarina Bateman, Brian T. TI Genetic contribution to postpartum haemorrhage in Swedish population: cohort study of 466 686 births SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID RISK-FACTORS; FAMILIAL AGGREGATION; VAGINAL BIRTH; FETAL; PREGNANCY; EPIDEMIOLOGY; PREECLAMPSIA; SAMPLE AB Objective To investigate the familial clustering of postpartum haemorrhage in the Swedish population, and to quantify the relative contributions of genetic and environmental effects. Design Register based cohort study. Setting Swedish population (multi-generation and medical birth registers). Main outcome measure Postpartum haemorrhage, defined as >1000 mL estimated blood loss. Participants The first two live births to individuals in Sweden in 1997-2009 contributed to clusters representing intact couples (n=366 350 births), mothers with separate partners (n=53 292), fathers with separate partners (n=47 054), sister pairs (n=97 228), brother pairs (n=91 168), and mixed sibling pairs (n=177 944). Methods Familial clustering was quantified through cluster specific tetrachoric correlation coefficients, and the influence of potential sharing of known risk factors was evaluated with alternating logistic regression. Relative contributions of genetic and environmental effects to the variation in liability for postpartum haemorrhage were quantified with generalised linear mixed models. Results The overall prevalence of postpartum haemorrhage after vaginal deliveries in our sample was 4.6%. Among vaginal deliveries, 18% (95% confidence interval 9% to 26%) of the variation in postpartum haemorrhage liability was attributed to maternal genetic factors, 10% (1% to 19%) to unique maternal environment, and 11% (0% to 26%) to fetal genetic effects. Adjustment for known risk factors only partially explained estimates of familial clustering, suggesting that the observed shared genetic and environmental effects operate in part through pathways independent of known risk factors. There were similar patterns of familial clustering for both of the main subtypes examined (atony and retained placenta), though strongest for haemorrhage after retained placenta. Conclusions There is a maternal genetic predisposition to postpartum haemorrhage, but more than half of the total variation in liability is attributable to factors that are not shared in families. C1 [Oberg, Anna Sara; Hernandez-Diaz, Sonia] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Oberg, Anna Sara; Almqvist, Catarina] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Frisell, Thomas] Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, S-17176 Stockholm, Sweden. [Greene, Michael F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Almqvist, Catarina] Karolinska Univ Hosp, Lung & Allergy Unit, Astrid Lindgren Childrens Hosp, S-17176 Stockholm, Sweden. [Bateman, Brian T.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Bateman, Brian T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bateman, Brian T.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Bateman, Brian T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Oberg, AS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. EM oberg@hsph.harvard.edu RI Frisell, Thomas/E-2772-2017; Oberg, Anna/M-7469-2014; OI Oberg, Anna/0000-0001-6638-1895; Frisell, Thomas/0000-0002-5735-9626 FU Swedish Research Council [2012-340, 2011-3060]; Swedish Initiative for Research on microdata in the Social and Medical Science (SIMSAM) framework [340-2013-5867]; strategic research program in epidemiology at Karolinska Institutet; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [K08HD075831] FX This study was funded by the Swedish Research Council's international postdoc grant 2012-340 (ASO), research grant 2011-3060 (CA), and through the Swedish Initiative for Research on microdata in the Social and Medical Science (SIMSAM) framework grant 340-2013-5867 (ASO, CA), the strategic research program in epidemiology at Karolinska Institutet (CA), as well as by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award No K08HD075831 (BTB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 32 TC 7 Z9 7 U1 2 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD AUG 13 PY 2014 VL 349 AR g4984 DI 10.1136/bmj.g4984 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA AN3RV UT WOS:000340507100001 PM 25121825 ER PT J AU Song, ZR Sequist, TD Barnett, ML AF Song, Zirui Sequist, Thomas D. Barnett, Michael L. TI Patient Referrals A Linchpin for Increasing the Value of Care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID UNITED-STATES; HEALTH-CARE; MEDICARE; QUALITY C1 [Song, Zirui] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Song, Zirui; Sequist, Thomas D.; Barnett, Michael L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Song, Zirui] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Sequist, Thomas D.; Barnett, Michael L.] Brigham & Womens Hosp, Dept Med, Div Gen Med & Primary Care, Boston, MA 02115 USA. [Sequist, Thomas D.] Partners Healthcare Syst, Boston, MA USA. RP Song, ZR (reprint author), Massachusetts Gen Hosp, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM zsong@partners.org FU NIA NIH HHS [F30 AG039175] NR 8 TC 11 Z9 11 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 13 PY 2014 VL 312 IS 6 BP 597 EP 598 DI 10.1001/jama.2014.7878 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM8OU UT WOS:000340136400015 PM 24992078 ER PT J AU Fridman, V Murphy, SM AF Fridman, Vera Murphy, Sinead M. TI The spectrum of axonopathies SO NEUROLOGY LA English DT Editorial Material C1 [Fridman, Vera] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Murphy, Sinead M.] Adelaide & Meath Hosp Natl Childrens Hosp, Dept Neurol, Tallaght, Ireland. [Murphy, Sinead M.] Trinity Coll Dublin, Dept Med, Dublin, Ireland. RP Fridman, V (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM vfridman@partners.org NR 5 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 12 PY 2014 VL 83 IS 7 BP 580 EP 581 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AN6RB UT WOS:000340722700003 PM 25008393 ER PT J AU Lingwood, D AF Lingwood, Daniel TI Lipocalin 2 as a Membrane-Reorganizing Agent SO SCIENCE SIGNALING LA English DT Article ID LIPID RAFTS; PHOSPHATIDYLETHANOLAMINE; CAPACITATION; DYNAMICS AB Lipocalins are a class of proteins that scavenge hydrophobic molecules in diverse contexts, including the immune system, the nervous system, and cancer. A recent study by Watanbe et al. identifies lipocalin 2 produced by the female mouse reproductive tract as a sperm-capacitating agent that alters the membrane properties of sperm in preparation for fertilization. The potential for lipocalins to act as general modulators of plasma membrane bioactivity is discussed. C1 [Lingwood, Daniel] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Lingwood, Daniel] Harvard Univ, Cambridge, MA 02139 USA. RP Lingwood, D (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, 400 Technol Sq, Cambridge, MA 02139 USA. EM dlingwood@mgh.harvard.edu FU Ragon Institute FX I thank C. A. Lingwood (Hospital for Sick Children, Toronto, Canada) and K. Simons (Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany) for helpful comments, and M. Grzybek and U. Coskun (Paul-Langerhans-Institut, Dresden) for assembly of the figure. This work was supported by a Ragon Institute grant to D.L. NR 12 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD AUG 12 PY 2014 VL 7 IS 338 AR pe19 DI 10.1126/scisignal.2005563 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AO2XY UT WOS:000341192400001 PM 25118326 ER PT J AU Mason, EA Mar, JC Laslett, AL Pera, MF Quackenbush, J Wolvetang, E Wells, CA AF Mason, Elizabeth A. Mar, Jessica C. Laslett, Andrew L. Pera, Martin F. Quackenbush, John Wolvetang, Ernst Wells, Christine A. TI Gene Expression Variability as a Unifying Element of the Pluripotency Network SO STEM CELL REPORTS LA English DT Article ID EMBRYONIC STEM-CELLS; LINEAGE-COMMITMENT; HETEROGENEITY; NANOG; DIFFERENTIATION; EVOLUTION; SURVIVAL; STATES AB Heterogeneity is a hallmark of stem cell populations, in part due to the molecular differences between cells undergoing self-renewal and those poised to differentiate. We examined phenotypic and molecular heterogeneity in pluripotent stem cell populations, using public gene expression data sets. A high degree of concordance was observed between global gene expression variability and the reported heterogeneity of different human pluripotent lines. Network analysis demonstrated that low-variability genes were the most highly connected, suggesting that these are the most stable elements of the gene regulatory network and are under the highest regulatory constraints. Known drivers of pluripotency were among these, with lowest expression variability of POU5F1 in cells with the highest capacity for self-renewal. Variability of gene expression provides a reliable measure of phenotypic and molecular heterogeneity and predicts those genes with the highest degree of regulatory constraint within the pluripotency network. C1 [Mason, Elizabeth A.; Wolvetang, Ernst; Wells, Christine A.] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qsld 4072, Australia. [Mar, Jessica C.] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Laslett, Andrew L.] CSIRO, Mat Sci & Engn, Clayton, Vic 3168, Australia. [Pera, Martin F.] Univ Melbourne, Florey Neurosci & Mental Hlth Inst, Parkville, Vic 3010, Australia. [Pera, Martin F.] Univ Melbourne, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3010, Australia. [Quackenbush, John] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02215 USA. [Wells, Christine A.] Univ Glasgow, Inst Infect Immun & Inflammat, Coll Med Vet & Life Sci, Glasgow G12 8TA, Lanark, Scotland. RP Wells, CA (reprint author), Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qsld 4072, Australia. EM c.wells@uq.edu.au RI Mason, Elizabeth/N-2345-2014; Laslett, Andrew/A-9760-2011; PERA, MARTIN/A-9812-2012; Wolvetang, Ernst/D-6644-2017; OI Laslett, Andrew/0000-0003-4729-8193; PERA, MARTIN/0000-0001-6239-0428; Wells, Christine/0000-0003-3133-3628 FU Australian Postgraduate Award scholarship; QLD government Smart Futures Fellowship; ARC special research initiative; National Heart, Lung, and Blood Institute of the Unites States NIH [1R01HL111759] FX E.A.M. is supported by an Australian Postgraduate Award scholarship and receives an AIBN student stipend. C. A. W. is supported by a QLD government Smart Futures Fellowship. This work was supported by an ARC special research initiative to Stem Cells Australia (C. A. W., E. W., A. L. L., and M. F. P.) and a grant from the National Heart, Lung, and Blood Institute of the Unites States NIH (1R01HL111759; J.Q.). The authors wish to thank Mr. Othmar Korn and Mr. Rowland Mosbergen for their programming advice and assistance with data processing within the Stemformatics environment. NR 43 TC 10 Z9 10 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2213-6711 J9 STEM CELL REP JI Stem Cell Rep. PD AUG 12 PY 2014 VL 3 IS 2 BP 365 EP 377 DI 10.1016/j.stemcr.2014.06.008 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA AN8VE UT WOS:000340882400014 PM 25254348 ER PT J AU Ruff, CT Giugliano, RP Braunwald, E Mercuri, M Curt, V Betcher, J Grip, L Cange, AL Crompton, AE Murphy, SA Deenadayalu, N Antman, EM AF Ruff, Christian T. Giugliano, Robert P. Braunwald, Eugene Mercuri, Michele Curt, Valentin Betcher, Joshua Grip, Laura Cange, Abby L. Crompton, Andrea E. Murphy, Sabina A. Deenadayalu, Naveen Antman, Elliott M. TI Transition of Patients From Blinded Study Drug to Open-Label Anticoagulation The ENGAGE AF-TIMI 48 Trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE anticoagulation; atrial fibrillation; edoxaban; factor Xa inhibitor; new oral anticoagulants; vitamin K antagonist ID NONVALVULAR ATRIAL-FIBRILLATION; WARFARIN; THERAPY; DABIGATRAN; EDOXABAN; STROKE; END AB BACKGROUND At the end of 2 previous trials, an excess of stroke and bleeding was observed in patients with AF randomized to a new oral anticoagulant (NOAC) who transitioned to a vitamin K antagonist (VKA). OBJECTIVES The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF. An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period. METHODS All patients on the blinded study drug at the trial's conclusion were included in this analysis. In pre-specified analyses, stroke, bleeding, and death that occurred through 30 days after the end-of-trial visit were stratified by randomized treatment allocation and open-label anticoagulant selected post-trial. RESULTS Of the 13,642 patients taking the blinded study drug at the end of the trial, 9,304 (68.2%) were transitioned to open-label VKA and 4,258 patients (31.2%) to an NOAC. There were 21 strokes evenly distributed across the 3 randomized treatment arms: warfarin 7 (1.90%/year), edoxaban high dose 7 (1.89%/year), edoxaban low dose 7 (1.85%/year). Major bleeding was also similar across the 3 treatment arms: warfarin 11 (2.98%/year), edoxaban high dose 10 (2.69%/year), edoxaban low dose 18 (4.76%/year). In patients transitioned to VKA, 85% of patients had at least 1 INR >= 2 by day 14 after the transition and 99% by day 30. CONCLUSIONS The ENGAGE AF-TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants. (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [EngageAFTIMI48]; NCT00781391) (C) 2014 by the American College of Cardiology Foundation. C1 [Ruff, Christian T.; Giugliano, Robert P.; Braunwald, Eugene; Grip, Laura; Cange, Abby L.; Crompton, Andrea E.; Murphy, Sabina A.; Deenadayalu, Naveen; Antman, Elliott M.] Brigham & Womens Hosp, Harvard Med Sch, Boston, MA 02115 USA. [Mercuri, Michele; Curt, Valentin] Daiichi Sankyo Pharma Dev, Edison, NJ USA. [Betcher, Joshua] Quintiles Inc, Res Triangle Pk, NC USA. RP Ruff, CT (reprint author), TIMI Study Grp, 350 Longwood Ave,1st Floor Offices, Boston, MA 02115 USA. EM cruff@partners.org FU Daiichi Sankyo; Merck Co.; Johnson Johnson; Sanofi-Aventis; AstraZeneca; Brigham and Women's Hospital; Duke University; GlaxoSmithKline; Genyzme; Medicines Co.; Menarini International and Medscape FX The ENGAGE AF-TIMI 48 trial was funded by Daiichi Sankyo. Dr. Ruff has served as a consultant and has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, and Bristol-Myers Squibb. Dr. Giugliano has served as a consultant and had received honoraria from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck & Co., and Sanofi-Aventis; and grant support through his institution from Daiichi Sankyo, Merck & Co., Johnson & Johnson, Sanofi-Aventis, and AstraZeneca. Dr. Braunwald has received grants (through the Brigham and Women's Hospital) and personal fees for lectures from Daiichi Sankyo; for outside the submitted work he received grants (through the Brigham and Women's Hospital) from Duke University, AstraZeneca, Merck & Co., and GlaxoSmithKline; uncompensated personal fees for consultancy from Merck & Co., personal fees for consultancies from Genyzme, Medicines Co., and Sanofi-Aventis, uncompensated personal fees for lectures from Merck & Co.; and personal fees for lectures from Menarini International and Medscape. Dr. Mercuri is an employee of and owns stock in Daiichi Sankyo; and also holds a patent related to the clinical properties of edoxaban. Dr. Curt is an employee of Daiichi Sankyo. Dr. Betcher has reported that he has no relationships relevant to the contents of this paper to disclose. Ms. Grip, Ms. Cange, Ms. Crompton, Ms. Murphy, Mr. Deenadayalu, and Dr. Antman have received grant support through their institution from Daiichi Sankyo. NR 18 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 12 PY 2014 VL 64 IS 6 BP 576 EP 584 DI 10.1016/j.jacc.2014.05.028 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN0AB UT WOS:000340242100009 PM 25104527 ER PT J AU Dizdaroglu, B Ataer-Cansizoglu, E Kalpathy-Cramer, J Keck, K Chiang, MF Erdogmus, D AF Dizdaroglu, Bekir Ataer-Cansizoglu, Esra Kalpathy-Cramer, Jayashree Keck, Katie Chiang, Michael F. Erdogmus, Deniz TI Structure-based level set method for automatic retinal vasculature segmentation SO EURASIP JOURNAL ON IMAGE AND VIDEO PROCESSING LA English DT Article DE Color retinal fundus images; Phase map; Segmentation of retinal vasculature; Structure and texture parts of retinal fundus image; Structure-based level set method ID BLOOD-VESSEL SEGMENTATION; IMAGE SEGMENTATION; PLUS DISEASE; GRAY-LEVEL; MODEL; PREMATURITY; RETINOPATHY; EVOLUTION; AGREEMENT; DIAGNOSIS AB Segmentation of vasculature in retinal fundus image by level set methods employing classical edge detection methodologies is a tedious task. In this study, a revised level set-based retinal vasculature segmentation approach is proposed. During preprocessing, intensity inhomogeneity on the green channel of input image is corrected by utilizing all image channels, generating more efficient results compared to methods utilizing only one (green) channel. A structure-based level set method employing a modified phase map is introduced to obtain accurate skeletonization and segmentation of the retinal vasculature. The seed points around vessels are selected and the level sets are initialized automatically. Furthermore, the proposed method introduces an improved zero-level contour regularization term which is more appropriate than the ones introduced by other methods for vasculature structures. We conducted the experiments on our own dataset, as well as two publicly available datasets. The results show that the proposed method segments retinal vessels accurately and its performance is comparable to state-of-the-art supervised/ unsupervised segmentation techniques. C1 [Dizdaroglu, Bekir] Karadeniz Tech Univ, Dept Comp Engn, TR-61080 Trabzon, Turkey. [Dizdaroglu, Bekir; Ataer-Cansizoglu, Esra; Erdogmus, Deniz] Northeastern Univ, Cognit Syst Lab, Boston, MA 02115 USA. [Kalpathy-Cramer, Jayashree] Massachusetts Gen Hosp, Martinos Imaging Ctr, Boston, MA 02129 USA. [Keck, Katie; Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97239 USA. [Chiang, Michael F.] Oregon Hlth & Sci Univ, Dept Med Informat, Portland, OR 97239 USA. RP Dizdaroglu, B (reprint author), Karadeniz Tech Univ, Dept Comp Engn, TR-61080 Trabzon, Turkey. EM bekir@ktu.edu.tr OI Kalpathy-Cramer, Jayashree/0000-0001-8906-9618 FU TUBITAK [1059B191000548]; NSF; NIH FX This work is partially supported by grants from TUBITAK (grant no. 1059B191000548), NSF, and NIH. NR 45 TC 5 Z9 5 U1 1 U2 9 PU SPRINGER INTERNATIONAL PUBLISHING AG PI CHAM PA GEWERBESTRASSE 11, CHAM, CH-6330, SWITZERLAND SN 1687-5281 J9 EURASIP J IMAGE VIDE JI EURASIP J. Image Video Process. PD AUG 11 PY 2014 AR 39 DI 10.1186/1687-5281-2014-39 PG 26 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA AY4MC UT WOS:000347551400001 ER PT J AU Jin, JO Zhang, W Wong, KW Kwak, M van Driel, IR Yu, Q AF Jin, Jun-O Zhang, Wei Wong, Ka-Wing Kwak, Minseok van Driel, Ian R. Yu, Qing TI Inhibition of Breast Cancer Resistance Protein (ABCG2) in Human Myeloid Dendritic Cells Induces Potent Tolerogenic Functions during LPS Stimulation SO PLOS ONE LA English DT Article ID REGULATORY T-CELLS; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; EFFLUX PUMPS; PHASE-I; DIFFERENTIATION; TRANSPORTERS; COMBINATION; EXPRESSION; MATURATION AB Breast cancer resistance protein (ABCG2), a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR) in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs). ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c(+) mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs) abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c(+) mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4(+) T cells and promoted expansion of CD25(+) FOXP3(+) regulatory T (Treg) cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer. C1 [Jin, Jun-O; Zhang, Wei; Wong, Ka-Wing] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. [Kwak, Minseok] Pukyong Natl Univ, Dept Chem, Pusan, South Korea. [van Driel, Ian R.] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic, Australia. [Yu, Qing] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA USA. RP Jin, JO (reprint author), Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China. EM Junojin1@gmail.com OI van Driel, Ian/0000-0001-5371-120X; Kwak, Minseok/0000-0002-0480-1804 FU Shanghai Public Health Clinical Center in Fudan University [RCJJP17]; National Institutes of Health [DE023838] FX This study was supported by grant RCJJP17 from the Shanghai Public Health Clinical Center in Fudan University. Qing Yu was supported by grant DE023838 from the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 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 AUG 11 PY 2014 VL 9 IS 8 AR e104753 DI 10.1371/journal.pone.0104753 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1WB UT WOS:000341105100097 PM 25111504 ER PT J AU Lu, G Zhang, Q Huang, Y Song, JX Tomaino, R Ehrenberger, T Lim, E Liu, WB Bronson, RT Bowden, M Brock, J Krop, IE Dillon, DA Gygi, SP Mills, GB Richardson, AL Signoretti, S Yaffe, MB Kaelin, WG AF Lu, Gang Zhang, Qing Huang, Ying Song, Jiaxi Tomaino, Ross Ehrenberger, Tobias Lim, Elgene Liu, Wenbin Bronson, Roderick T. Bowden, Michaela Brock, Jane Krop, Ian E. Dillon, Deborah A. Gygi, Steven P. Mills, Gordon B. Richardson, Andrea L. Signoretti, Sabina Yaffe, Michael B. Kaelin, William G., Jr. TI Phosphorylation of ETS1 by Src Family Kinases Prevents Its Recognition by the COP1 Tumor Suppressor SO CANCER CELL LA English DT Article ID NEGATIVE BREAST-CANCER; TRANSCRIPTION FACTOR ETS-1; UBIQUITIN LIGASES; PROSTATE-CANCER; GENE FUSIONS; DNA-BINDING; HIF-ALPHA; C-JUN; DEGRADATION; EXPRESSION AB Oncoproteins and tumor suppressors antagonistically converge on critical nodes governing neoplastic growth, invasion, and metastasis. We discovered that phosphorylation of the ETS1 and ETS2 transcriptional oncoproteins at specific serine or threonine residues creates binding sites for the COP1 tumor suppressor protein, which is an ubiquitin ligase component, leading to their destruction. In the case of ETS1, however, phosphorylation of a neighboring tyrosine residue by Src family kinases disrupts COP1 binding, thereby stabilizing ETS1. Src-dependent accumulation of ETS1 in breast cancer cells promotes anchorage-independent growth in vitro and tumor growth in vivo. These findings expand the list of potential COP1 substrates to include proteins whose COP1-binding sites are subject to regulatory phosphorylation and provide insights into transformation by Src family kinases. C1 [Lu, Gang; Zhang, Qing; Lim, Elgene; Krop, Ian E.; Signoretti, Sabina; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Huang, Ying; Bowden, Michaela] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [Song, Jiaxi; Brock, Jane; Dillon, Deborah A.; Richardson, Andrea L.; Signoretti, Sabina] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tomaino, Ross; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ehrenberger, Tobias; Yaffe, Michael B.] MIT, Dept Biol, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Lim, Elgene] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02215 USA. [Liu, Wenbin; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dana Farber Harvard Canc Ctr, Rodent Histopathol Core, Boston, MA 02115 USA. [Richardson, Andrea L.] Dana Farber Canc Inst, Dept Canc Cell Biol, Boston, MA 02215 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM william_kaelin@dfci.harvard.edu OI Lim, Elgene/0000-0001-8065-8838; Huang, Ying/0000-0003-1145-3606 FU Ruth L. Kirschstein National Research Service Award postdoctoral fellowhip award; NIH; HHMI; Breast Cancer Research Foundation FX The authors thank Drs. Todd Golub, William Hahn, Kimberly Briggs, and Sungwoo Lee for providing reagents, Drs. Brian D. Lehmann, Melinda E. Sanders, and Jennifer A. Pietenpol for advice and technical assistance on the immunohistochemical studies, and Dr. Wenyi Wei and members of Kaelin Laboratory for helpful discussions. G.L. is supported by the Ruth L. Kirschstein National Research Service Award postdoctoral fellowhip award. W.G.K. is a Howard Hughes Medical Institute (HHMI) investigator and is supported by grants from NIH, HHMI, and the Breast Cancer Research Foundation. NR 56 TC 11 Z9 11 U1 1 U2 11 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 AUG 11 PY 2014 VL 26 IS 2 BP 222 EP 234 DI 10.1016/j.ccr.2014.06.026 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AN1LB UT WOS:000340343800010 PM 25117710 ER PT J AU Tremblay, AM Missiaglia, E Galli, GG Hettmer, S Urcia, R Carrara, M Judson, RN Thway, K Nadal, G Selfe, JL Murray, G Calogero, RA De Bari, C Zammit, PS Delorenzi, M Wagers, AJ Shipley, J Wackerhage, H Camargo, FD AF Tremblay, Annie M. Missiaglia, Edoardo Galli, Giorgio G. Hettmer, Simone Urcia, Roby Carrara, Matteo Judson, Robert N. Thway, Khin Nadal, Gema Selfe, Joanna L. Murray, Graeme Calogero, Raffaele A. De Bari, Cosimo Zammit, Peter S. Delorenzi, Mauro Wagers, Amy J. Shipley, Janet Wackerhage, Henning Camargo, Fernando D. TI The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation SO CANCER CELL LA English DT Article ID SKELETAL-MUSCLE; STEM-CELLS; GENE-EXPRESSION; GROWTH-CONTROL; SELF-RENEWAL; MYOD; DIFFERENTIATION; TRANSCRIPTION; PATHWAY; QUIESCENT AB The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy. C1 [Tremblay, Annie M.; Galli, Giorgio G.; Camargo, Fernando D.] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Tremblay, Annie M.; Galli, Giorgio G.; Hettmer, Simone; Wagers, Amy J.; Camargo, Fernando D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Tremblay, Annie M.; Galli, Giorgio G.; Hettmer, Simone; Wagers, Amy J.; Camargo, Fernando D.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Missiaglia, Edoardo; Delorenzi, Mauro] SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Missiaglia, Edoardo; Thway, Khin; Selfe, Joanna L.; Shipley, Janet] Inst Canc Res, Sarcoma Mol Pathol Team, Div Mol Pathol, Sutton SM2 5NG, Surrey, England. [Missiaglia, Edoardo; Thway, Khin; Selfe, Joanna L.; Shipley, Janet] Inst Canc Res, Sarcoma Mol Pathol Team, Div Canc Therapeut, Sutton SM2 5NG, Surrey, England. [Thway, Khin] Royal Marsden NHS Fdn Trust, Dept Histopathol, London SW3 6JJ, England. [Urcia, Roby; Judson, Robert N.; Nadal, Gema; Wackerhage, Henning] Univ Aberdeen, Sch Med Sci, Aberdeen AB25 2ZD, Scotland. [Murray, Graeme; De Bari, Cosimo] Univ Aberdeen, Sch Med & Dent, Aberdeen AB25 2ZD, Scotland. [Hettmer, Simone; Wagers, Amy J.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Hettmer, Simone; Wagers, Amy J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Hettmer, Simone] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hettmer, Simone] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Zammit, Peter S.] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. [Delorenzi, Mauro] Univ Lausanne, Ludwig Ctr Canc Res, CH-1015 Lausanne, Switzerland. [Delorenzi, Mauro] Univ Lausanne, Dept Oncol, CH-1015 Lausanne, Switzerland. [Carrara, Matteo; Calogero, Raffaele A.] Univ Torino, Dept Biotechnol & Hlth Sci, Ctr Mol Biotechnol, I-10126 Turin, Italy. [Judson, Robert N.] Univ British Columbia, Dept Med Genet, Biomed Res Ctr, Vancouver, BC V6T 1Z3, Canada. RP Camargo, FD (reprint author), Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. EM fernando.camargo@childrens.harvard.edu RI Carrara, Matteo/J-8692-2016; OI Carrara, Matteo/0000-0002-8559-8296; Calogero, Raffaele/0000-0002-2848-628X; Selfe, Joanna/0000-0002-9556-3628 FU Stand Up to Cancer-AACR initiative; NIH [AR064036, DK099559, DP2 OD004345-01]; Canadian Institutes of Health Research (CIHR); Medical Research Council [99477]; American-Italian Cancer Foundation; Oliver Bird PhD studentship; Friends of Anchor pilot grant; Sarcoma UK; Cancer Research UK [C5066/A10399]; Chris Lucas Trust; Stand Up to Cancer-AACR Innovative Research Grant [SU2C-AACR-IRG1111]; P.A.L.S. Bermuda/St. Baldrick's and Alex's Lemonade Stand Foundation; NHS; [NIH-P50-NS40828]; [NIH-P30-HD18655] FX We thank Kriti Shrestha for technical assistance. This research was funded by a Stand Up to Cancer-AACR initiative grant (F.D.C.), NIH grants AR064036 (F.D.C.) and DK099559 (F.D.C.), a Canadian Institutes of Health Research (CIHR) fellowship (A.M.T.), a Medical Research Council project grant (99477, H.W., P.S.Z., C.D.B.), an American-Italian Cancer Foundation postdoctoral research fellowship (G.G.G.), an Oliver Bird PhD studentship (R.J.), a Friends of Anchor pilot grant and a Sarcoma UK grant (H.W., G.M., C.D.B.), a Cancer Research UK project grant (C5066/A10399) (J.S.), a Chris Lucas Trust grant (J.S.), a Stand Up to Cancer-AACR Innovative Research Grant (SU2C-AACR-IRG1111) and NIH New Innovator Award (DP2 OD004345-01) (A.J.W.), and grants from P.A.L.S. Bermuda/St. Baldrick's and Alex's Lemonade Stand Foundation (S.H.). Mouse microarray studies were performed by the Molecular Genetics Core Facility at Children's Hospital Boston supported by NIH-P50-NS40828 and NIH-P30-HD18655. The Children's Cancer and Leukemia Group, and UK and NHS funding to the NIHR Biomedical Research Centre, assisted with human tissue collection. Confocal imaging was performed at the Children's Hospital Boston Imaging Core facility. NR 47 TC 34 Z9 36 U1 1 U2 11 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 AUG 11 PY 2014 VL 26 IS 2 BP 273 EP 287 DI 10.1016/j.ccr.2014.05.029 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AN1LB UT WOS:000340343800014 PM 25087979 ER PT J AU Ozawa, T Riester, M Cheng, YK Huse, JT Squatrito, M Helmy, K Charles, N Michor, F Holland, EC AF Ozawa, Tatsuya Riester, Markus Cheng, Yu-Kang Huse, Jason T. Squatrito, Massimo Helmy, Karim Charles, Nikki Michor, Franziska Holland, Eric C. TI Most Human Non-GCIMP Glioblastoma Subtypes Evolve from a Common Proneural-like Precursor Glioma SO CANCER CELL LA English DT Article ID HIGH-GRADE GLIOMA; GROWTH-FACTOR; IN-VIVO; SECONDARY GLIOBLASTOMA; RADIATION-RESISTANCE; NEURAL PROGENITORS; GENETIC EVENTS; HUMAN BRAIN; STEM-CELLS; DIFFERENTIATION AB To understand the relationships between the non-GCIMP glioblastoma (GBM) subgroups, we performed mathematical modeling to predict the temporal sequence of driver events during tumorigenesis. The most common order of evolutionary events is 1) chromosome (chr) 7 gain and chr10 loss, followed by 2) CDKN2A loss and/or TP53 mutation, and 3) alterations canonical for specific subtypes. We then developed a computational methodology to identify drivers of broad copy number changes, identifying PDGFA (chr7) and PTEN (chr10) as driving initial nondisjunction events. These predictions were validated using mouse modeling, showing that PDGFA is sufficient to induce proneural-like glionrias and that additional NF1 loss converts proneural to the mesenchymal subtype. Our findings suggest that most non-GCIMP mesenchymal GBMs arise as, and evolve from, a proneural-like precursor. C1 [Ozawa, Tatsuya; Holland, Eric C.] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Human Biol & Solid Tumor Translat Res, Dept Neurosurg, Seattle, WA 98109 USA. [Ozawa, Tatsuya; Holland, Eric C.] Univ Washington, Alvord Brain Tumor Ctr, Seattle, WA 98109 USA. [Riester, Markus; Cheng, Yu-Kang; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Riester, Markus; Cheng, Yu-Kang; Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Huse, Jason T.] Mem Sloan Kettering Canc Ctr, Pathogenesis Program, Dept Pathol & Human Oncol, New York, NY 10065 USA. [Squatrito, Massimo] Spanish Natl Canc Res Ctr, Canc Cell Biol Programme, Madrid 28029, Spain. [Helmy, Karim; Charles, Nikki] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, New York, NY 10065 USA. RP Michor, F (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. EM michor@jimmy.harvard.edu; eholland@fhcrc.org RI Squatrito, Massimo/F-4149-2016; OI Squatrito, Massimo/0000-0002-4593-3790; Riester, Markus/0000-0002-4759-8332 FU Brain Tumor Center Grants, MSKCC; NIH [U54CA163167-01, U01CA141502-01, RO1CA100688, U54CA143798] FX We thank Robert "Jim" Finney and Qunchao Zhang for technical assistance; Amanda Conlon, Christine Ferreira, Jenny Zhang, Raquel Sanchez, and Desert Horse-Grant for secretarial assistance; Jeffrey Zhao, Maryam Hassimi, and Agnes Viale for microarray analysis; and members of the E.C.H. and F.M. laboratories, Dr. Armida Fabius, Dr. Shigehisa Kitano, Dr. Atsushi Kawaguchi, Dr. Tatsuyuki Kakuma, and Dr. Mitsutoshi Nakada for helpful discussions. The results in this article are analyzed using data generated by the TCGA project (http://cancergenome.nih.gov). We thank Dr. Hideyuki Saya and Dr. Shinji Kuninaka, Keio University, for the pSUPER-GL2, Nf1, and p53 shRNA constructs and Dr. Cameron Brennan for the human GBM cell lines. This work was supported by 2009 and 2010 Brain Tumor Center Grants, MSKCC (to T.O.); NIH grants U54CA163167-01,U01CA141502-01, and RO1CA100688 (to E.C.H.), and 2009 and 2010 U54CA143798 Grant (to F.M. and E.C.H.). NR 55 TC 57 Z9 57 U1 1 U2 18 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 AUG 11 PY 2014 VL 26 IS 2 BP 288 EP 300 DI 10.1016/j.ccr.2014.06.005 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA AN1LB UT WOS:000340343800015 PM 25117714 ER PT J AU Choi, YJ Saez, B Anders, L Hydbring, P Stefano, J Bacon, NA Cook, C Kalaszczynska, I Signoretti, S Young, RA Scadden, DT Sicinski, P AF Choi, Yoon Jong Saez, Borja Anders, Lars Hydbring, Per Stefano, Joanna Bacon, Nickolas A. Cook, Colleen Kalaszczynska, Ilona Signoretti, Sabina Young, Richard A. Scadden, David T. Sicinski, Piotr TI D-Cyclins Repress Apoptosis in Hematopoietic Cells by Controlling Death Receptor Fas and Its Ligand FasL SO DEVELOPMENTAL CELL LA English DT Article ID RETINOBLASTOMA-PROTEIN; SELF-RENEWAL; DNA-BINDING; E2F FAMILY; CANCER; GENE; INHIBITION; SENESCENCE; CDK4; PROLIFERATION AB D-type cyclins (D1, D2, and D3) are components of the mammalian core cell-cycle machinery and function to drive cell proliferation. Here, we report that D-cyclins perform a rate-limiting antiapoptotic function in vivo. We found that acute shutdown of all three D-cyclins in bone marrow of adult mice resulted in massive apoptosis of all hematopoietic cell types. We demonstrate that adult hematopoietic stem cells are particularly dependent on D-cyclins for survival and that they are especially sensitive to cyclin D loss. Surprisingly, we found that the antiapoptotic function of D-cyclins also operates in quiescent hematopoietic stem and progenitor cells. Our analyses revealed that D-cyclins repress the expression of the death receptor Fas and its ligand, FasL. Acute ablation of D-cyclins upregulated these proapoptotic genes and led to Fas- and caspase 8-dependent apoptosis. These results reveal an unexpected function of cell-cycle proteins in controlling apoptosis in normal cell homeostasis. C1 [Choi, Yoon Jong; Anders, Lars; Hydbring, Per; Stefano, Joanna; Bacon, Nickolas A.; Kalaszczynska, Ilona; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Choi, Yoon Jong; Hydbring, Per; Stefano, Joanna; Bacon, Nickolas A.; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Saez, Borja; Cook, Colleen; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med & Canc Ctr, Boston, MA 02114 USA. [Saez, Borja; Cook, Colleen; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Saez, Borja; Cook, Colleen; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Anders, Lars; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, 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 RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; Kalaszczynska, Ilona/0000-0001-6698-1372 FU NIH [R01 CA108420] FX We thank Drs. R. Bremner, T. Yu, G. Leone, T. Prashant, N. Dyson, K. Tschoep, P. Farnham, M. Gaddis, J. Nevins and L. Jakoi, X. Lu, L. Fajas, A. Jean-Sebastien, K. Helin, and W. Kaelin for various E2F reagents, W. Sellers for the FasL promoter construct, and R. Shivdasani, N. Kodandaramireddy, J. Quackenbush, and Rene Rubio for help and advice. This work was supported by the NIH (grant R01 CA108420 to P.S.). NR 34 TC 11 Z9 13 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 EI 1878-1551 J9 DEV CELL JI Dev. Cell PD AUG 11 PY 2014 VL 30 IS 3 BP 255 EP 267 DI 10.1016/j.devcel.2014.06.015 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA AN1LI UT WOS:000340344600004 PM 25087893 ER PT J AU Bodhankar, S Chen, YX Lapato, A Vandenbark, AA Murphy, SJ Offner, H AF Bodhankar, Sheetal Chen, Yingxin Lapato, Andrew Vandenbark, Arthur A. Murphy, Stephaine J. Offner, Halina TI Targeting immune co-stimulatory effects of PD-L1 and PD-L2 might represent an effective therapeutic strategy n stroke SO FRONTIERS IN CELLULAR NEUROSCIENCE LA English DT Article DE MCAO; co-stimulatory pathway; programmed death ligand-1 and 2; T-cells; regulatory B cells ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PROGRAMMED DEATH-1 PD-1; T-CELL PROLIFERATION; ISCHEMIC-STROKE; INFARCT SIZE; IMMUNOLOGICAL-TOLERANCE; CEREBRAL-ISCHEMIA; CNS INFLAMMATION; DEFICIENT MICE; REGULATORY T AB Stroke outcome is worsened by the infiltration of inflammatory immune cells into ischemic brains. Our recent study demonstrated that PD-L1- and to a lesser extent PD-L2-deficient mice had smaller brain infarcts and fewer brain-infiltrating cells vs. wild-type (WI) mice, suggesting a pathogenic role for PD-ligands in experimental stroke. We sought to ascertain PD-L1 and PD-L2-expressing cell types that affect T-cell activation, post-stroke in the context of other known co-stimulatory molecules. Thus, cells from male WT and PD-1, deficient mice undergoing 60 min of middle cerebral artery occlusion (MCAO) followed by 96 h of reperfusion were treated with neutralizing antibodies to study co-stimulatory and co-inhibitory interactions between CD80, cytotoxic T-lymphocyte antigen-4 (CTLA-4), PD-1, and PD-Ls that regulate CD8+ and CD4+ T-cell activation. We found that antibody neutralization of PD-1 and CTLA-4 signaling post-MCAO resulted in higher proliferation in WT CD8+ and CD4+ T-cells, confirming an inhibitory role of PD-1 and CTLA-4 on Tcell activation. Also, CD80/CD28 interactions played a prominent regulatory role for the CD8+ T-cells and the PD-1/PD-L2 interactions were dominant in controlling the CD4+ T-cell responses in WT mice after stroke. A suppressive phenotype in PD-L1-deficient mice was attributed to CD80/CTLA-4 and PD-1/PD-L2 interactions. PD-L2 was crucial in modulating CD4+T-cell responses, whereas PD-L1 regulated both CD8+ and CD4+ T-cells. To establish the contribution of PD-L1 and PD-L2 on regulatory B-cells (Bregs), infarct volumes were evaluated in male PD-L1- and PD-L2-deficient mice receiving IL-10+ B-cells 4h post-MCAO. PD-L2- but not PD-L1-deficient recipients of IL-10+ B-cells had markedly reduced infarct volumes, indicating a regulatory role of PD-L2 on Bregs. These results imply that PDL1 and PD-L2 differentially control induction of T- and Breg-cell responses after MCAO, thus suggesting that selective targeting of PD-L1 and PD-L2 might represent a valuable therapeutic strategy in stroke. C1 [Bodhankar, Sheetal; Lapato, Andrew; Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, Portland, OR 97239 USA. [Bodhankar, Sheetal; Lapato, Andrew; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR USA. [Chen, Yingxin; Murphy, Stephaine J.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR USA. RP Offner, H (reprint author), Portland VA Med Ctr, R&D-31,3710 SW,US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH/NINDS [1R01 NS075887]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development; Biomedical Laboratory Research and Development FX The authors wish to thank Gail Kent for assistance in manuscript submission. This work was supported by NIH/NINDS 1R01 NS075887. This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 69 TC 1 Z9 1 U1 1 U2 12 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5102 J9 FRONT CELL NEUROSCI JI Front. Cell. Neurosci. PD AUG 11 PY 2014 VL 8 AR 228 DI 10.3389/fncel.2014.00228 PG 14 WC Neurosciences SC Neurosciences & Neurology GA AM7EH UT WOS:000340027000001 PM 25157219 ER PT J AU Aldrich, LN Castoreno, AB Kuo, SY Dancik, V Lassen, KG Goel, G Kuballa, P Clemons, PA Daly, MJ Shamji, AF Xavier, RJ Schreiber, SL AF Aldrich, Leslie N. Castoreno, Adam B. Kuo, Szu-Yu Dancik, Vlado Lassen, Kara G. Goel, Gautam Kuballa, Petric Clemons, Paul A. Daly, Mark J. Shamji, Alykhan F. Xavier, Ramnik J. Schreiber, Stuart L. TI Illuminating the therapeutic potential of autophagy in Crohn's disease: Development of small-molecule autophagy modulators SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Aldrich, Leslie N.; Schreiber, Stuart L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Aldrich, Leslie N.; Castoreno, Adam B.; Kuo, Szu-Yu; Dancik, Vlado; Lassen, Kara G.; Clemons, Paul A.; Shamji, Alykhan F.; Xavier, Ramnik J.; Schreiber, Stuart L.] Broad Inst Harvard & MIT, Ctr Sci Therapeut, Cambridge, MA 02142 USA. [Kuo, Szu-Yu] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Goel, Gautam; Kuballa, Petric; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Kuballa, Petric; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02144 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Schreiber, Stuart L.] Howard Hughes Med Inst, Cambridge, MA 02138 USA. EM laldrich@broadinstitute.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 44-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165100041 ER PT J AU Carolan, JP Van Dyke, AR Qi, J Bradner, JE Mapp, AK AF Carolan, James P. Van Dyke, Aaron R. Qi, Jun Bradner, James E. Mapp, Anna K. TI Alternative modulation of glucocorticoid receptor activity using bifunctional small molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Carolan, James P.; Mapp, Anna K.] Univ Michigan, Program Chem Biol, Ann Arbor, MI 48103 USA. [Carolan, James P.; Mapp, Anna K.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48103 USA. [Van Dyke, Aaron R.] Fairfield Univ, Dept Chem & Biochem, Fairfield, CT 06824 USA. [Qi, Jun; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Qi, Jun; Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. EM jcarolan@umich.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 186-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102089 ER PT J AU Collier, TL Liang, SH Vasdev, N AF Collier, Thomas L. Liang, Steven H. Vasdev, Neil TI Flow microfluidics for PET: Bench to bedside realized SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Collier, Thomas L.] Advion Inc, Dept Res & Dev, Ithaca, NY 14850 USA. [Collier, Thomas L.; Liang, Steven H.; Vasdev, Neil] Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Collier, Thomas L.; Liang, Steven H.; Vasdev, Neil] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. EM collierl@advion.com NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 12-FLUO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167400218 ER PT J AU Daniel, KB Martin, DP Smith, WB Bradner, JE Cohen, SM AF Daniel, Kevin B. Martin, David P. Smith, William B. Bradner, James E. Cohen, Seth M. TI Dual-mode HDAC prodrug induces an active site covalent modification with subsequent inhibitor release SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Daniel, Kevin B.; Martin, David P.; Cohen, Seth M.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Smith, William B.; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM kbdaniel@ucsd.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 520-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402312 ER PT J AU Hooker, JM AF Hooker, Jacob M. TI PET radiotracer development using modern late-stage fluorination SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Hooker, Jacob M.] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hooker, Jacob M.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 7-FLUO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167400213 ER PT J AU Hopkins, CR Schaldecker, T Kim, S Tarabanis, C Tian, DQ Hakroush, S Castonguay, P Ahn, W Wallentin, H Heid, H Lindsley, CW Salovich, JM Riccio, A Buvall, L Weins, A Greka, A AF Hopkins, Corey R. Schaldecker, Thomas Kim, Sookyung Tarabanis, Constantine Tian, Dequan Hakroush, Samy Castonguay, Philip Ahn, Wooin Wallentin, Hanna Heid, Hans Lindsley, Craig W. Salovich, James M. Riccio, Antonio Buvall, Lisa Weins, Astrid Greka, Anna TI Discovery and characterization of ML204, a novel inhibitor of the TRPC4 and TRPC5 ion channels that has been shown to protect the kidney filter SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Hopkins, Corey R.; Lindsley, Craig W.; Salovich, James M.] Vanderbilt Univ, Dept Pharmacol, Med Ctr, Nashville, TN 37232 USA. [Hopkins, Corey R.; Lindsley, Craig W.] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA. [Hopkins, Corey R.; Lindsley, Craig W.; Salovich, James M.] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA. [Schaldecker, Thomas; Kim, Sookyung; Tarabanis, Constantine; Tian, Dequan; Hakroush, Samy; Castonguay, Philip; Ahn, Wooin; Wallentin, Hanna; Buvall, Lisa; Weins, Astrid; Greka, Anna] Massachusetts Gen Hosptial, Dept Med, Boston, MA 02114 USA. [Schaldecker, Thomas; Kim, Sookyung; Tarabanis, Constantine; Tian, Dequan; Hakroush, Samy; Castonguay, Philip; Ahn, Wooin; Wallentin, Hanna; Buvall, Lisa; Weins, Astrid; Greka, Anna] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Heid, Hans] German Canc Res Ctr, Helmhotz Grp Cell Biol, Heidelberg, Germany. [Riccio, Antonio] Harvard Univ, Sch Med, Boston Childrens Hosptial, Dept Cardiol, Boston, MA 02114 USA. [Riccio, Antonio] Harvard Univ, Sch Med, Boston Childrens Hosptial, Manton Ctr Orphan Dis, Boston, MA 02114 USA. [Weins, Astrid] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02114 USA. EM corey.r.hopkins@vanderbilt.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 20-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167401726 ER PT J AU Kamat, NP Szostak, JW AF Kamat, Neha P. Szostak, Jack W. TI Driving RNA to protocell membranes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM nkamat@molbio.mgh.harvard.edu RI Kamat, Neha/L-2799-2016 NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 191-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165102093 ER PT J AU Liong, M Weissleder, R Lee, H AF Liong, Monty Weissleder, Ralph Lee, Hakho TI Point-of-care magnetic platforms for molecular analyses of pathogens SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Liong, Monty] Cardno ChemRisk, San Francisco, CA 94105 USA. [Liong, Monty; Weissleder, Ralph; Lee, Hakho] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. EM monty.liong@cardno.com NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 627-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165104154 ER PT J AU Patteson, JB Rotstein, BH Stephenson, N Vasdev, N Liang, SH AF Patteson, Jonathan B. Rotstein, Benjamin H. Stephenson, Nickeisha Vasdev, Neil Liang, Steven H. TI Synthesis of ylide-based precursors for reactions with [F-18] fluoride towards positron emission tomography (PET) radiopharmaceuticals SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Rotstein, Benjamin H.; Stephenson, Nickeisha; Vasdev, Neil; Liang, Steven H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. [Patteson, Jonathan B.] Univ Richmond, Dept Chem, Richmond, VA 23173 USA. EM jon.patteson@richmond.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 270-CHED PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8JN UT WOS:000349165103049 ER PT J AU Rotstein, BH Stephenson, NA Liang, SH Vasdev, N AF Rotstein, Benjamin H. Stephenson, Nickeisha A. Liang, Steven H. Vasdev, Neil TI [F-18]Fluorinated amino acids prepared using spirocyclic iodonium ylides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Rotstein, Benjamin H.; Stephenson, Nickeisha A.; Liang, Steven H.; Vasdev, Neil] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. EM rotstein.benjamin@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 445-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167402239 ER PT J AU Rotstein, BH Liang, SH Vasdev, N AF Rotstein, Benjamin H. Liang, Steven H. Vasdev, Neil TI (CO2)-C-11-fixation for discovery and development of novel carbon-11 and fluorine-18 labeled radiotracers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Rotstein, Benjamin H.; Liang, Steven H.; Vasdev, Neil] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. EM rotstein.benjamin@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 5-FLUO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167400211 ER PT J AU Stephenson, NA Rotstein, BH Liang, SH Vasdev, N AF Stephenson, Nickeisha A. Rotstein, Benjamin H. Liang, Steven H. Vasdev, Neil TI Spirocyclic hypervalent iodine(III)-mediated radiofluorination as a practical method to synthesize fluorine-18 labeled non-activated aromatics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 Harvard Univ, Sch Med, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. EM nstephenson@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 8-FLUO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167400214 ER PT J AU Vasdev, N AF Vasdev, Neil TI Cutting-edge technologies and methods in fluorine-18 radiochemistry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 248th National Meeting of the American-Chemical-Society (ACS) CY AUG 10-14, 2014 CL San Francisco, CA SP Amer Chem Soc C1 [Vasdev, Neil] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vasdev, Neil] Harvard Univ, Sch Med, Boston, MA 02114 USA. EM vasdev.neil@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 10 PY 2014 VL 248 MA 68-FLUO PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA CA8KC UT WOS:000349167400274 ER PT J AU D'Souza, G Gross, ND Pai, SI Haddad, R Anderson, KS Rajan, S Gerber, J Gillison, ML Posner, MR AF D'Souza, Gypsyamber Gross, Neil D. Pai, Sara I. Haddad, Robert Anderson, Karen S. Rajan, Shirani Gerber, Jennifer Gillison, Maura L. Posner, Marshall R. TI Oral Human Papillomavirus (HPV) Infection in HPV-Positive Patients With Oropharyngeal Cancer and Their Partners SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID UNITED-STATES; NECK-CANCER; TONSILLAR CANCER; RISK-FACTORS; YOUNG MEN; HEAD; PREVALENCE; TRANSMISSION; ADULTS AB Purpose To better understand oral human papillomavirus (HPV) infection and cancer risk among long-term sexual partners of patients with HPV-positive oropharyngeal cancer (HPV-OPC). Patients and Methods An oral rinse sample, risk factor survey, cancer history, and oral examination (partners only) were collected from patients with HPV-OPC and their partners. Oral rinse samples were evaluated for 36 types of HPV DNA using PGMY 09/11 primers and line-blot hybridization and HPV16 copy number using quantitative polymerase chain reaction. Oral HPV prevalence was compared with infection among those age 45 to 65 years using National Health and Nutrition Examination Survey (NHANES) 2009-2010. Results A total of 164 patients with HPV-OPC and 93 of their partners were enrolled. Patients were primarily men (90%), were never-smokers (51%), and had performed oral sex (97%), with a median age of 56 years; they had a high prevalence of oncogenic oral HPV DNA (61%) and oral HPV16 DNA (54%) at enrollment. Female partners had comparable oncogenic oral HPV prevalence compared with members of the general population of the same age (1.2% v 1.3%). Among the six male partners, no oncogenic oral HPV infections were detected. No precancers or cancers were identified during partner oral cancer screening examinations. However, a history of cervical disease was reported by nine partners (10.3%) and two female patients (11.8%), and three patients (2.0%) reported a previous partner who developed invasive cervical cancer. Conclusion Oral HPV16 DNA is commonly detected among patients with HPV-OPC at diagnosis, but not among their partners. Partners of patients with HPV-OPC do not seem to have elevated oral HPV infection compared with the general population. (C) 2014 by American Society of Clinical Oncology C1 [D'Souza, Gypsyamber; Rajan, Shirani; Gerber, Jennifer] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Pai, Sara I.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Gross, Neil D.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Haddad, Robert] Dana Farber Canc Inst, Boston, MA 02115 USA. [Anderson, Karen S.] Arizona State Univ, Tempe, AZ USA. [Gillison, Maura L.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Posner, Marshall R.] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP D'Souza, G (reprint author), 615 N Wolfe St,E6132B, Baltimore, MD 21205 USA. EM gdsouza@jhsph.edu FU Johns Hopkins Richard Gelb Cancer Prevention Award; Early Detection Research Network [U01CA117374] FX Supported by the Johns Hopkins Richard Gelb Cancer Prevention Award (G.D.) and Research Grant No. U01CA117374 from the Early Detection Research Network (K.S.A.). NR 28 TC 33 Z9 34 U1 1 U2 5 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 AUG 10 PY 2014 VL 32 IS 23 BP 2408 EP U191 DI 10.1200/JCO.2014.55.1341 PG 9 WC Oncology SC Oncology GA AN4KK UT WOS:000340556400007 PM 24778397 ER PT J AU Steensma, DP Kantarjian, HM AF Steensma, David P. Kantarjian, Hagop M. TI Improving the Protocol Implementation Process: The National Cancer Institute's Response Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Steensma, David P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Steensma, DP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [P30 CA016672] NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2014 VL 32 IS 23 BP 2516 EP 2516 DI 10.1200/JCO.2014.56.3882 PG 1 WC Oncology SC Oncology GA AN4KK UT WOS:000340556400025 PM 25002713 ER PT J AU Ahn, BJ Le, H Shin, MW Bae, SJ Lee, EJ Lee, SY Yang, JH Wee, HJ Cha, JH Seo, JH Lee, HS Lee, HJ Arai, K Lo, EH Jeon, S Oh, GT Kim, WJ Ryu, JK Suh, JK Kim, KW AF Ahn, Bum Ju Le, Hoang Shin, Min Wook Bae, Sung-Jin Lee, Eun Ji Lee, Sung Yi Yang, Ju Hee Wee, Hee-Jun Cha, Jong-Ho Seo, Ji Hae Lee, Hye Shin Lee, Hyo-Jong Arai, Ken Lo, Eng H. Jeon, Sejin Oh, Goo Taeg Kim, Woo Jean Ryu, Ji-Kan Suh, Jun-Kyu Kim, Kyu-Won TI Ninjurin1 Enhances the Basal Motility and Transendothelial Migration of Immune Cells by Inducing Protrusive Membrane Dynamics SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LEUKOCYTE MIGRATION; ADHESION MOLECULE; ENDOTHELIAL-CELLS; MYELOID CELLS; RHO GTPASES; FILOPODIA; EXTRAVASATION; INFLAMMATION; DIAPEDESIS AB Ninjurin1 is involved in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, by mediating leukocyte extravasation, a process that depends on homotypic binding. However, the precise regulatory mechanisms of Ninjurin1 during inflammation are largely undefined. We therefore examined the pro-migratory function of Ninjurin1 and its regulatory mechanisms in macrophages. Interestingly, Ninjurin1-deficient bone marrow-derived macrophages exhibited reduced membrane protrusion formation and dynamics, resulting in the impairment of cell motility. Furthermore, exogenous Ninjurin1 was distributed at the membrane of filopodial structures in Raw264.7 macrophage cells. In Raw264.7 cells, RNA interference of Ninjurin1 reduced the number of filopodial projections, whereas overexpression of Ninjurin1 facilitated their formation and thus promoted cell motility. Ninjurin1-induced filopodial protrusion formation required the activation of Rac1. In Raw264.7 cells penetrating an MBEC4 endothelial cell monolayer, Ninjurin1 was localized to the membrane of protrusions and promoted their formation, suggesting that Ninjurin1-induced protrusive activity contributed to transendothelial migration. Taking these data together, we conclude that Ninjurin1 enhances macrophage motility and consequent extravasation of immune cells through the regulation of protrusive membrane dynamics. We expect these findings to provide insight into the understanding of immune responses mediated by Ninjurin1. C1 [Ahn, Bum Ju; Le, Hoang; Shin, Min Wook; Bae, Sung-Jin; Lee, Eun Ji; Lee, Sung Yi; Yang, Ju Hee; Wee, Hee-Jun; Cha, Jong-Ho; Seo, Ji Hae; Lee, Hye Shin; Kim, Kyu-Won] Seoul Natl Univ, Coll Pharm, SNU Harvard NeuroVasc Protect Res Ctr, Seoul 151742, South Korea. [Ahn, Bum Ju; Le, Hoang; Shin, Min Wook; Bae, Sung-Jin; Lee, Eun Ji; Lee, Sung Yi; Yang, Ju Hee; Wee, Hee-Jun; Cha, Jong-Ho; Seo, Ji Hae; Lee, Hye Shin; Kim, Kyu-Won] Seoul Natl Univ, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. [Kim, Kyu-Won] Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea. [Kim, Kyu-Won] Seoul Natl Univ, Coll Pharm, Coll Med, Seoul 151742, South Korea. [Lee, Hyo-Jong] Inje Univ, Coll Pharm, Gimhae 621749, South Korea. [Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Boston, MA 02114 USA. [Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Boston, MA 02114 USA. [Arai, Ken; Lo, Eng H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Jeon, Sejin; Oh, Goo Taeg] Ewha Womans Univ, Dept Life Sci, Seoul 120750, South Korea. [Jeon, Sejin; Oh, Goo Taeg] Ewha Womans Univ, Program GT5, Seoul 120750, South Korea. [Kim, Woo Jean; Ryu, Ji-Kan; Suh, Jun-Kyu] Inha Univ, Natl Res Ctr Sexual Med, Sch Med, Inchon 402751, South Korea. [Kim, Woo Jean; Ryu, Ji-Kan; Suh, Jun-Kyu] Inha Univ, Dept Urol, Sch Med, Inchon 402751, South Korea. RP Kim, KW (reprint author), Seoul Natl Univ, Coll Pharm, SNU Harvard NeuroVasc Protect Res Ctr, Seoul 151742, South Korea. EM qwonkim@snu.ac.kr FU National Research Foundation of Korea; Ministry of Education, Science and Technology through the Global Research Laboratory Program [2011-0021874]; Brain Korea 21 Program; Global Core Research Center Program [2012-0001187]; Basic Science Research Program through the National Research Foundation - Ministry of Education, Science and Technology [2013R1A1A2058956]; National Institutes of Health [R37-NS37074, R01-76694, P01-NS55104]; National Research Foundation - Korean Government (Ministry of Education, Science and Technology) [2013003407]; Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs [A110076] FX This work was supported by a grant from a National Research Foundation of Korea, a grant funded by the Ministry of Education, Science and Technology through the Global Research Laboratory Program (2011-0021874), Brain Korea 21 Program, and the Global Core Research Center Program Grant 2012-0001187.; Supported by Basic Science Research Program through the National Research Foundation funded by Ministry of Education, Science and Technology Grant 2013R1A1A2058956.; Supported by National Institutes of Health Grants R37-NS37074, R01-76694, and P01-NS55104 (to E. H. L.).; Supported by National Research Foundation Grant 2013003407 funded by the Korean Government (Ministry of Education, Science and Technology).; Supported by Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs Grant A110076. NR 35 TC 2 Z9 2 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 8 PY 2014 VL 289 IS 32 BP 21926 EP 21936 DI 10.1074/jbc.M113.532358 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4XQ UT WOS:000340593500010 PM 24917672 ER PT J AU de Wit, D van Erp, NP Khosravan, R Wiltshire, R Allred, R Demetri, GD Guchelaar, HJ Gelderblom, H AF de Wit, Djoeke van Erp, Nielka P. Khosravan, Reza Wiltshire, Robin Allred, Randy Demetri, George D. Guchelaar, Henk-Jan Gelderblom, Hans TI Effect of gastrointestinal resection on sunitinib exposure in patients with GIST SO BMC CANCER LA English DT Article DE Sunitinib; Exposure; Gastrointestinal resection; GIST ID STROMAL TUMORS; IMATINIB MESYLATE; PHASE-I; EFFICACY; SAFETY; TRIAL; FAILURE; SU11248 AB Background: GIST patients often undergo GI-surgery. Previous studies have shown that imatinib and nilotinib exposures were decreased in GIST patients with prior major gastrectomy. We investigated whether major gastrectomy influences the exposure to sunitinib and its active metabolite SU12662. Methods: Pharmacokinetic data from 305 GIST patients included in 4 phase I-III trials were analyzed. Patients were subdivided into 6 groups according to their prior GI-surgery. Apparent clearance (CL/F) and dose-corrected steady-state plasma exposures (AUC(24,ss)) of sunitinib and SU12662 were estimated using a population PK approach. ANCOVA was performed to test for differences in AUC(24,ss) and CL/F between each surgery subgroup and controls. Results: Major gastrectomy did not influence sunitinib or SU12662 exposure. The geometric mean of sunitinib and SU12662 AUC(24,ss) was decreased by 21% and 28% in patients with both gastrectomy and small bowel resection (n = 8) compared to controls (n = 63) for sunitinib (931 ng*hr/mL (95%-CI; 676-1283) versus 1177 ng*hr/mL (95%-CI; 1097-1263); p < 0.05) and SU12662 (354 ng*hr/mL (95%-CI; 174-720) versus 492 ng*hr/mL (95%-CI; 435-555); p < 0.05). No significant differences in exposure were observed in each of the other subgroups versus controls. Conclusion: In contrast to previous results for imatinib and nilotinib, gastrectomy alone does not influence sunitinib or SU12662 exposure. This should be taken into account for the treatment of gastrectomized GIST patients with TKIs. In patients who had undergone both gastrectomy and small bowel resection, sunitinib and SU12662 exposures are significantly, although clinically not relevantly, decreased. C1 [de Wit, Djoeke; Guchelaar, Henk-Jan] Leiden Univ, Ctr Med, Dept Clin Pharm & Loxicol, Leiden, Netherlands. [van Erp, Nielka P.] Radboud Univ Nijmegen, Ctr Med, Dept Clin Pharm, NL-6500 HB Nijmegen, Netherlands. [Khosravan, Reza; Allred, Randy] Pfizer Inc, San Diego, CA USA. [Wiltshire, Robin] Pfizer Inc, Tadworth, Surrey, England. [Demetri, George D.] Dana Farber Canc Inst, Ludwig Ctr, Dept Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA. [Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. [Gelderblom, Hans] Leiden Univ, Med Ctr, Dept Clin Oncol, Leiden, Netherlands. RP van Erp, NP (reprint author), Radboud Univ Nijmegen, Ctr Med, Dept Clin Pharm, Route 864,Postbus 9101, NL-6500 HB Nijmegen, Netherlands. EM Nielka.vanErp@radboudumc.nl RI van Erp, Nielka/A-1907-2016 FU Pfizer Inc. FX We would like to thank Gerard Stege, Pfizer the Netherlands, for his contribution to this study. All 4 studies included in the analyses were sponsored by Pfizer Inc. NR 27 TC 5 Z9 5 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 8 PY 2014 VL 14 AR 575 DI 10.1186/1471-2407-14-575 PG 8 WC Oncology SC Oncology GA AN5RZ UT WOS:000340650300001 PM 25102852 ER PT J AU Abad, CL Moseley, RH Crnich, CJ Saint, S Safdar, N AF Abad, Cybele L. Moseley, Richard H. Crnich, Christopher J. Saint, Sanjay Safdar, Nasia TI A Gut Instinct SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TUBERCULOSIS INFECTION; ABDOMINAL-PAIN C1 [Abad, Cybele L.; Crnich, Christopher J.; Safdar, Nasia] Univ Wisconsin, Sch Med, Dept Med, Madison, WI 53706 USA. [Crnich, Christopher J.; Safdar, Nasia] William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53705 USA. [Moseley, Richard H.; Saint, Sanjay] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA. [Moseley, Richard H.; Saint, Sanjay] Ann Arbor Healthcare Syst & Hlth Serv Res & Dev C, Dept Vet Affairs, Ann Arbor, MI USA. RP Safdar, N (reprint author), William S Middleton Mem Vet Adm Med Ctr, 2500 Overlook Terrace, Madison, WI 53705 USA. EM ns2@medicine.wisc.edu FU Covance; Doximity; Jvion FX Dr. Moseley reports providing expert testimony in a case related to chronic hepatitis B virus infection; Dr. Crnich, receiving fees for serving on a data and safety monitoring board from Covance; and Dr. Saint, receiving fees for board membership from Doximity and Jvion. No other potential conflict of interest relevant to this article was reported. NR 12 TC 1 Z9 1 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 7 PY 2014 VL 371 IS 6 BP 560 EP 564 DI 10.1056/NEJMcps1202137 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100012 PM 25099581 ER PT J AU Castillo, A Paul, A Sun, B Huang, TH Wang, YC Yazinski, SA Tyler, J Li, L You, J Zou, L Yao, J Wang, B AF Castillo, Andy Paul, Atanu Sun, Baohua Huang, Ting Hsiang Wang, Yucai Yazinski, Stephanie A. Tyler, Jessica Li, Lei You, James Zou, Lee Yao, Jun Wang, Bin TI The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression SO CELL REPORTS LA English DT Article ID DNA-DAMAGE RESPONSE; FANCONI-ANEMIA; BREAST-CANCER; BRCT DOMAIN; BINDING; PHOSPHOPEPTIDE; PATHWAY; COMPLEX; REPLICATION; REPEATS AB Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are required for BRCA1's tumor-suppressor function. In this study, we demonstrated that Abraxas, aBRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair and maintain genome stability. Both homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence. The gene encoding Abraxas suffers from gene copy loss and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers, suggesting that mutation and loss of function of Abraxas may contribute to tumor development in human patients. C1 [Castillo, Andy; Paul, Atanu; Sun, Baohua; Wang, Bin] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. [Huang, Ting Hsiang; Tyler, Jessica] Univ Texas MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Wang, Yucai; Li, Lei] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. [You, James] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Yao, Jun] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Paul, Atanu; Huang, Ting Hsiang; Wang, Bin] Univ Texas Houston, Grad Sch Biomed Sci, Genes & Dev Program, Houston, TX 77030 USA. [Yazinski, Stephanie A.; Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. RP Wang, B (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA. EM bwang3@mdanderson.org OI Paul, Atanu/0000-0002-9967-6005; Huang, Ting-Hsiang/0000-0001-8739-0571 FU Training Grant in Molecular Genetics of Cancer [CA009299]; Schissler Foundation Fellowship; NIH [CA127945, CA179441, CA164346, CA155025]; MD Anderson Cancer Center (Leukemia SPORE, Center for Inflammation and Cancer, Center for Genetics and Genomics, IRG, SINF, and Physician Scientist Award) [CA100632]; Mel Klein Family Fund; University of Texas MD Anderson Cancer Center (IRG, Center for Genetics and Genomics Pilot Award) FX We thank Michael Huang and Drs. Jianxin Liu and Ling Wu for providing technical support, Henry P. Adams for assistance with the use of the microscope, Dr. Xiaochun Yu for providing mouse BRCA1 antibody used in this work. We also thank Drs. Dong Zhang, Randy Legerski, and Guillermina Lozano for helpful discussions. A.C. was a recipient of the Training Grant in Molecular Genetics of Cancer (CA009299). A.P. is a recipient of the Schissler Foundation Fellowship for Translational Studies in Cancer Research. L.L. is supported by NIH CA127945 and CA179441 grant. M.J.Y. is supported by NIH CA164346 grant and funds from the MD Anderson Cancer Center (Leukemia SPORE CA100632, Center for Inflammation and Cancer, Center for Genetics and Genomics, IRG, SINF, and Physician Scientist Award). This work was supported by the NIH (CA155025 to B.W.), the Mel Klein Family Fund, and funds from the University of Texas MD Anderson Cancer Center (IRG, Center for Genetics and Genomics Pilot Award). NR 32 TC 11 Z9 11 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 7 PY 2014 VL 8 IS 3 BP 807 EP 817 DI 10.1016/j.celrep.2014.06.050 PG 11 WC Cell Biology SC Cell Biology GA AO7ZR UT WOS:000341572200017 PM 25066119 ER PT J AU Elvington, M Scheiber, M Yang, XF Lyons, K Jacqmin, D Wadsworth, C Marshall, D Vanek, K Tomlinson, S AF Elvington, Michelle Scheiber, Melissa Yang, Xiaofeng Lyons, Katherine Jacqmin, Dustin Wadsworth, Casey Marshall, David Vanek, Kenneth Tomlinson, Stephen TI Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy SO CELL REPORTS LA English DT Article ID CD8(+) T-CELLS; APOPTOTIC CELLS; NEUTROPHIL RECRUITMENT; DOSE RADIOTHERAPY; MURINE MODEL; TUMOR-GROWTH; CANCER; INHIBITION; INTERLEUKIN-10; MELANOMA AB Complement is traditionally thought of as a proinflammatory effector mechanism of antitumor immunity. However, complement is also important for effective clearance of apoptotic cells, which can be an anti-inflammatory and tolerogenic process. We show that localized fractionated radiation therapy (RT) of subcutaneous murine lymphoma results in tumor cell apoptosis and local complement activation. Cotreatment of mice with tumor-targeted complement inhibition markedly improved therapeutic outcome of RT, an effect linked to early increases in apoptotic cell numbers and increased inflammation. Improved outcome was dependent on an early neutrophil influx and was characterized by increased numbers of mature dendritic cells and the subsequent modulation of T cell immunity. Appropriate complement inhibition may be a promising strategy to enhance a mainstay of treatment for cancer. C1 [Elvington, Michelle; Scheiber, Melissa; Yang, Xiaofeng; Wadsworth, Casey; Tomlinson, Stephen] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Lyons, Katherine; Jacqmin, Dustin; Marshall, David; Vanek, Kenneth] Med Univ S Carolina, Dept Radiat Oncol, Charleston, SC 29425 USA. [Tomlinson, Stephen] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Tomlinson, S (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. EM tomlinss@musc.edu FU NIH [RO1CA158179] FX This work was supported by a grant from the NIH (RO1CA158179). We thank Ms. Emily Paulling for expert technical assistance. S.T. holds licensed patents for CR2-targeted complement inhibitors. NR 44 TC 7 Z9 7 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD AUG 7 PY 2014 VL 8 IS 3 BP 818 EP 830 DI 10.1016/j.celrep.2014.06.051 PG 13 WC Cell Biology SC Cell Biology GA AO7ZR UT WOS:000341572200018 PM 25066124 ER PT J AU Hong, CS Abrams, MK Ferris, TG AF Hong, Clemens S. Abrams, Melinda K. Ferris, Timothy G. TI Toward Increased Adoption of Complex Care Management SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Hong, Clemens S.; Ferris, Timothy G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ferris, Timothy G.] Partners Hlth Care, Boston, MA USA. [Abrams, Melinda K.] Commonwealth Fund, New York, NY USA. RP Hong, CS (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 10 Z9 10 U1 2 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 7 PY 2014 VL 371 IS 6 BP 491 EP 493 DI 10.1056/NEJMp1401755 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100002 PM 25099573 ER PT J AU Dreijerink, KMA Goudet, P Burgess, JR Valk, GD AF Dreijerink, Koen M. A. Goudet, Pierre Burgess, John R. Valk, Gerlof D. CA Int Breast Canc Men1 Study Grp TI Breast-Cancer Predisposition in Multiple Endocrine Neoplasia Type 1 SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Dreijerink, Koen M. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goudet, Pierre] Univ Burgundy, Dijon, France. [Burgess, John R.] Univ Tasmania, Hobart, Tas, Australia. [Valk, Gerlof D.] Univ Med Ctr Utrecht, Utrecht, Netherlands. RP Dreijerink, KMA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM koen_dreijerink@dfci.harvard.edu OI Dreijerink, Koen/0000-0002-3140-3502 FU NIDDK NIH HHS [R01 DK100584, R01DK100584] NR 5 TC 10 Z9 10 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 7 PY 2014 VL 371 IS 6 BP 583 EP 584 DI 10.1056/NEJMc1406028 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM5LE UT WOS:000339899100030 PM 25099597 ER PT J AU Schuemann, J Dowdell, S Grassberger, C Min, CH Paganetti, H AF Schuemann, J. Dowdell, S. Grassberger, C. Min, C. H. Paganetti, H. TI Site-specific range uncertainties caused by dose calculation algorithms for proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; range uncertainty; analytical pencil-beam algorithm; range margins ID MONTE-CARLO SIMULATIONS; PENCIL BEAM ALGORITHM; CHARGED-PARTICLE RADIOTHERAPY; ENERGY COMPUTED-TOMOGRAPHY; STOPPING POWER RATIOS; REDEFINITION ALGORITHM; RADIATION-THERAPY; TREATMENT PLANS; BRAGG PEAK; CT AB The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries. C1 [Schuemann, J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Schuemann, J (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jschuemann@mgh.harvard.edu FU NIH/NCI [P01 CA21239] FX This work was supported by NIH/NCI under P01 CA21239 ('Proton Therapy Research'). We would like to thank the MGH Monte Carlo group for many fruitful discussions. We thank Jonathan Jackson and Tao Song of the Enterprise Research Infrastructure and Services (ERIS) group at Partners Healthcare for their in-depth support and smooth computing cluster operations, upgrades and fixes. NR 47 TC 33 Z9 33 U1 1 U2 11 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 AUG 7 PY 2014 VL 59 IS 15 BP 4007 EP 4031 DI 10.1088/0031-9155/59/15/4007 PG 25 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AM7OI UT WOS:000340056800003 PM 24990623 ER PT J AU Testa, M Min, CH Verburg, JM Schumann, J Lu, HM Paganetti, H AF Testa, Mauro Min, Chul Hee Verburg, Joost M. Schuemann, Jan Lu, Hsiao-Ming Paganetti, Harald TI Range verification of passively scattered proton beams based on prompt gamma time patterns SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE proton therapy; range verification; prompt-gamma ID MONTE-CARLO SIMULATIONS; POSITRON-EMISSION-TOMOGRAPHY; RADIATION-THERAPY; COMPTON CAMERA; RADIOTHERAPY; FIELDS; PATIENT; DESIGN; RAYS AB We propose a proton range verification technique for passive scattering proton therapy systems where spread out Bragg peak (SOBP) fields are produced with rotating range modulator wheels. The technique is based on the correlation of time patterns of the prompt gamma ray emission with the range of protons delivering the SOBP. The main feature of the technique is the ability to verify the proton range with a single point of measurement and a simple detector configuration. We performed four-dimensional (time-dependent) Monte Carlo simulations using TOPAS to show the validity and accuracy of the technique. First, we validated the hadronic models used in TOPAS by comparing simulations and prompt gamma spectrometry measurements published in the literature. Second, prompt gamma simulations for proton range verification were performed for the case of a water phantom and a prostate cancer patient. In the water phantom, the proton range was determined with 2 mm accuracy with a full ring detector configuration for a dose of similar to 2.5 cGy. For the prostate cancer patient, 4 mm accuracy on range determination was achieved for a dose of similar to 15 cGy. The results presented in this paper are encouraging in view of a potential clinical application of the technique. C1 [Testa, Mauro; Verburg, Joost M.; Schuemann, Jan; Lu, Hsiao-Ming; Paganetti, Harald] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02163 USA. [Min, Chul Hee] Yonsei Univ, Dept Radiol Sci, Wonju 220710, Gangwon, South Korea. [Verburg, Joost M.] Eindhoven Univ Technol, Sch Med Phys & Engn, NL-5600 MB Eindhoven, Netherlands. RP Testa, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02163 USA. EM hpaganetti@mgh.harvard.edu FU NCI [R01-CA140735, P01-CA21239] FX We thank Julien Smeets, PhD, at IBA for providing the data of the prompt gamma spectroscopy measurements in electronic form. Maryam Moteabbed, PhD, performed the treatment plan for the AP prostate field at MGH. This work was supported by NCI grants R01-CA140735 and P01-CA21239. NR 36 TC 16 Z9 16 U1 0 U2 7 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 AUG 7 PY 2014 VL 59 IS 15 BP 4181 EP 4195 DI 10.1088/0031-9155/59/15/4181 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AM7OI UT WOS:000340056800013 PM 25004257 ER PT J AU Phillips, J Gueorguiev, G Shackleford, JA Grassberger, C Dowdell, S Paganetti, H Sharp, GC AF Phillips, Justin Gueorguiev, Gueorgui Shackleford, James A. Grassberger, Clemens Dowdell, Stephen Paganetti, Harald Sharp, Gregory C. TI Computing proton dose to irregularly moving targets SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article DE 4D treatment planning; irregular breathing; proton therapy; baseline drift ID LUNG-CANCER; MOTION; RADIOTHERAPY; THERAPY; TUMORS; BEAM AB Purpose: While four-dimensional computed tomography (4DCT) and deformable registration can be used to assess the dose delivered to regularly moving targets, there are few methods available for irregularly moving targets. 4DCT captures an idealized waveform, but human respiration during treatment is characterized by gradual baseline shifts and other deviations from a periodic signal. This paper describes a method for computing the dose delivered to irregularly moving targets based on 1D or 3D waveforms captured at the time of delivery. Methods: The procedure uses CT or 4DCT images for dose calculation, and 1D or 3D respiratory waveforms of the target position at time of delivery. Dose volumes are converted from their Cartesian geometry into a beam-specific radiological depth space, parameterized in 2D by the beam aperture, and longitudinally by the radiological depth. In this new frame of reference, the proton doses are translated according to the motion found in the 1D or 3D trajectory. These translated dose volumes are weighted and summed, then transformed back into Cartesian space, yielding an estimate of the dose that includes the effect of the measured breathing motion. The method was validated using a synthetic lung phantom and a single representative patient CT. Simulated 4DCT was generated for the phantom with 2 cm peak-to-peak motion. Results: A passively-scattered proton treatment plan was generated using 6 mm and 5 mm smearing for the phantom and patient plans, respectively. The method was tested without motion, and with two simulated breathing signals: a 2 cm amplitude sinusoid, and a 2 cm amplitude sinusoid with 3 cm linear drift in the phantom. The tumor positions were equally weighted for the patient calculation. Motion-corrected dose was computed based on the mid-ventilation CT image in the phantom and the peak exhale position in the patient. Gamma evaluation was 97.8% without motion, 95.7% for 2 cm sinusoidal motion, 95.7% with 3 cm drift in the phantom (2 mm, 2%), and 90.8% (3 mm, 3%) for the patient data. Conclusions: We have demonstrated a method for accurately reproducing proton dose to an irregularly moving target from a single CT image. We believe this algorithm could prove a useful tool to study the dosimetric impact of baseline shifts either before or during treatment. C1 [Phillips, Justin; Gueorguiev, Gueorgui; Grassberger, Clemens; Dowdell, Stephen; Paganetti, Harald; Sharp, Gregory C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Shackleford, James A.] Drexel Univ, Coll Engn, Philadelphia, PA 19104 USA. RP Phillips, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM jphillips0@mgh.harvard.edu OI Shackleford, James/0000-0002-7987-651X FU NCI [R01 CA111590] FX This work was supported by NCI under R01 CA111590. NR 21 TC 3 Z9 3 U1 0 U2 5 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 AUG 7 PY 2014 VL 59 IS 15 BP 4261 EP 4273 DI 10.1088/0031-9155/59/15/4261 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA AM7OI UT WOS:000340056800018 PM 25029239 ER PT J AU Lee, J Napadow, V Kim, J Lee, S Choi, W Kaptchuk, TJ Park, K AF Lee, Jeungchan Napadow, Vitaly Kim, Jieun Lee, Seunggi Choi, Woojin Kaptchuk, Ted J. Park, Kyungmo TI Phantom Acupuncture: Dissociating Somatosensory and Cognitive/Affective Components of Acupuncture Stimulation with a Novel Form of Placebo Acupuncture SO PLOS ONE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; AUTONOMIC NERVOUS-SYSTEM; PAIN; RESPONSES; HEART; ACTIVATION; EMOTION; HUMANS; MEMORY; BRAIN AB In a clinical setting, acupuncture treatment consists of multiple components including somatosensory stimulation, treatment context, and attention to needle-based procedures. In order to dissociate somatosensory versus contextual and attentional aspects of acupuncture, we devised a novel form of placebo acupuncture, a visual manipulation dubbed phantom acupuncture, which reproduces the acupuncture needling ritual without somatosensory tactile stimulation. Subjects (N = 20) received both real (REAL) and phantom (PHNT) acupuncture. Subjects were retrospectively classified into two groups based on PHNT credibility (PHNTc, who found phantom acupuncture credible; and PHNTnc, who did not). Autonomic and psychophysical responses were monitored. We found that PHNT can be delivered in a credible manner. Acupuncture needling, a complex, ritualistic somatosensory intervention, induces sympathetic activation (phasic skin conductance [SC] response), which may be specific to the somatosensory component of acupuncture. In contrast, contextual effects, such as needling credibility, are instead associated with a shift toward relative cardiovagal activation (decreased heart rate) during needling and sympathetic inhibition (decreased SC) and parasympathetic activation (decreased pupil size) following acupuncture needling. Visual stimulation characterizing the needling ritual is an important factor for phasic autonomic responses to acupuncture and may undelie the needling orienting response. Our study suggests that phantom acupuncture can be a viable sham control for acupuncture as it completely excludes the somatosensory component of real needling while maintaining the credibility of the acupuncture treatment context in many subjects. C1 [Lee, Jeungchan; Napadow, Vitaly; Park, Kyungmo] Kyung Hee Univ, Dept Biomed Engn, Yongin, Gyeonggi, South Korea. [Napadow, Vitaly; Kim, Jieun] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Lee, Seunggi; Choi, Woojin] Sangji Univ, Coll Korean Med, Dept Neuropsychiat, Wonju, Gangwon, South Korea. [Kaptchuk, Ted J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Program Placebo Studies, Boston, MA 02215 USA. RP Park, K (reprint author), Kyung Hee Univ, Dept Biomed Engn, Yongin, Gyeonggi, South Korea. EM saenim@khu.ac.kr FU Ministry of Science, ICT and Future Planning [NRF-2011-0028968, NRF-2009-0076345]; Ministry of Health & Welfare and Seoul Metropolitan Government (Traditional Korean Medicine RD Project) [HI13C0700]; National Center for Complementary and Alternative Medicine (NCCAM), at the United States of America National Institutes of Health (NIH) [P01-AT006663, R01-AT007550, R01-AT004714, K24-AT004095] FX The authors would like to thank the Korean National Research Foundation funded by the Ministry of Science, ICT and Future Planning (NRF-2011-0028968, NRF-2009-0076345), and the Ministry of Health & Welfare and Seoul Metropolitan Government (Traditional Korean Medicine R&D Project, HI13C0700). The study was also supported by the National Center for Complementary and Alternative Medicine (NCCAM), at the United States of America National Institutes of Health (NIH) (P01-AT006663, R01-AT007550, R01-AT004714 to VN, K24-AT004095 to TJK). The content is the sole responsibility of the authors and does not necessarily represent the official views of our funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 4 Z9 4 U1 6 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2014 VL 9 IS 8 AR e104582 DI 10.1371/journal.pone.0104582 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM6SB UT WOS:000339993900077 PM 25101637 ER PT J AU Chen, NC Jupiter, JB Steinmann, SP Ring, D AF Chen, Neal C. Jupiter, Jesse B. Steinmann, Scott P. Ring, David TI Nonacute Treatment of Elbow Fracture with Persistent Ulnohumeral Dislocation or Subluxation SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Review ID HINGED EXTERNAL FIXATION; POSTEROLATERAL ROTATORY INSTABILITY; RADIAL HEAD ARTHROPLASTY; ULNAR NERVE PALSY; CORONOID PROCESS; HETEROTOPIC OSSIFICATION; COLLATERAL LIGAMENT; INTERPOSITION ARTHROPLASTY; RESTORING STABILITY; SURGICAL-TREATMENT C1 Thomas Jefferson Univ, Philadelphia Hand Ctr, Philadelphia, PA 19107 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. RP Chen, NC (reprint author), Philadelphia Hand Ctr, PC, 834 Chestnut St,G114, Philadelphia, PA 19107 USA. EM ncchen@handcenters.com NR 70 TC 3 Z9 3 U1 1 U2 3 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 EI 1535-1386 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD AUG 6 PY 2014 VL 96A IS 15 BP 1308 EP 1316 DI 10.2106/JBJS.M.00817 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AR8AZ UT WOS:000343799200020 PM 25100779 ER PT J AU Vanduffel, W Zhu, Q Orban, GA AF Vanduffel, Wim Zhu, Qi Orban, Guy A. TI Monkey Cortex through fMRI Glasses SO NEURON LA English DT Review ID INFERIOR TEMPORAL CORTEX; FRONTAL EYE FIELD; ANTERIOR INTRAPARIETAL AREA; SELECTIVE CORTICAL REGIONS; POSTERIOR PARIETAL CORTEX; VISUALLY GUIDED SACCADES; EVENT-RELATED FMRI; MACAQUE MONKEY; FUNCTIONAL CONNECTIVITY; 3-DIMENSIONAL SHAPE AB In 1998 several groups reported the feasibility of fMRI experiments in monkeys, with the goal to bridge the gap between invasive nonhuman primate studies and human functional imaging. These studies yielded critical insights in the neuronal underpinnings of the BOLD signal. Furthermore, the technology has been successful in guiding electrophysiological recordings and identifying focal perturbation targets. Finally, invaluable information was obtained concerning human brain evolution. We here provide a comprehensive overview of awake monkey fMRI studies mainly confined to the visual system. We review the latest insights about the topographic organization of monkey visual cortex and discuss the spatial relationships between retinotopy and category- and feature-selective clusters. We briefly discuss the functional layout of parietal and frontal cortex and continue with a summary of some fascinating functional and effective connectivity studies. Finally, we review recent comparative fMRI experiments and speculate about the future of nonhuman primate imaging. C1 [Vanduffel, Wim; Zhu, Qi; Orban, Guy A.] KU Leuven Med Sch, Lab Neuro & Psychophysiol, B-3000 Leuven, Belgium. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Vanduffel, Wim] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Orban, Guy A.] Univ Parma, Dept Neurosci, I-43125 Parma, Italy. RP Vanduffel, W (reprint author), KU Leuven Med Sch, Lab Neuro & Psychophysiol, Campus Gasthuisberg, B-3000 Leuven, Belgium. EM wim@nmr.mgh.harvard.edu FU InterUniversity Attraction Pole [7/11]; Odysseus [G0007.12]; Programme Financing [PFV/10/008]; Impulsfinanciering Zware Apparatuur; KU Leuven; Fonds Wetenschappelijk Onderzoek-Vlaanderen [G0A5613N, G043912N, G062208N10, G059309N10, G083111N10, K714811N]; National Center for Research Resources [P41RR14075] FX We thank C. Galletti, Y. Miyashita, K. Miyamoto, T. Osada, Y. Adachi, R. Tootell, and S. Nasr for sharing their published data and S. Raiguel for his comments on the manuscript. This work received support from InterUniversity Attraction Pole 7/11, Odysseus G0007.12, Programme Financing PFV/10/008, Impulsfinanciering Zware Apparatuur, and Hercules funding of the KU Leuven, Fonds Wetenschappelijk Onderzoek-Vlaanderen G0A5613N, G043912N, G062208N10, G059309N10, G083111N10, and K714811N. Q.Z. is post-doctoral fellow of FWO-Vlaanderen. The Martinos Center for Biomedical Imaging is supported by National Center for Research Resources grant P41RR14075. NR 150 TC 31 Z9 31 U1 3 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD AUG 6 PY 2014 VL 83 IS 3 BP 533 EP 550 DI 10.1016/j.neuron.2014.07.015 PG 18 WC Neurosciences SC Neurosciences & Neurology GA AN3HY UT WOS:000340479100006 PM 25102559 ER PT J AU Bakaeen, FG Blaustein, A Kibbe, MR AF Bakaeen, Faisal G. Blaustein, Alvin Kibbe, Melina R. TI Health Care at the VA Recommendations for Change SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Bakaeen, Faisal G.] Texas Heart Inst, Div Cardiovasc Surg, Michael E DeBakey Vet Affairs Med Ctr, Dept Cardiovasc Surg, Houston, TX 77025 USA. [Bakaeen, Faisal G.] Baylor Coll Med, Div Cardiothorac Surg, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Blaustein, Alvin] Michael E DeBakey VA Med Ctr, Div Cardiol, Houston, TX 77030 USA. [Blaustein, Alvin] Baylor Coll Med, Dept Med, Div Cardiol, Houston, TX 77030 USA. [Kibbe, Melina R.] Jesse Brown Vet Affairs Med Ctr, Surg Serv, Chicago, IL USA. [Kibbe, Melina R.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. RP Bakaeen, FG (reprint author), Michael E DeBakey VA Med Ctr, OCL 112,2002 Holcombe Blvd, Houston, TX 77030 USA. EM fbakaeen@bcm.edu NR 6 TC 5 Z9 5 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 6 PY 2014 VL 312 IS 5 BP 481 EP 482 DI 10.1001/jama.2014.8054 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM4FL UT WOS:000339808600012 PM 24945974 ER PT J AU Anderson, TS Good, CB Gellad, WF AF Anderson, Timothy S. Good, Chester B. Gellad, Walid F. TI Potential Conflicts of Interest for Academic Medical Center Leaders Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Anderson, Timothy S.] Univ Pittsburgh, Med Ctr, Dept Internal Med, Pittsburgh, PA USA. [Good, Chester B.; Gellad, Walid F.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA 15240 USA. RP Gellad, WF (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, 151C Univ Dr, Pittsburgh, PA 15240 USA. EM wfg3@pitt.edu NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 6 PY 2014 VL 312 IS 5 BP 558 EP 559 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AM4FL UT WOS:000339808600031 PM 25096702 ER PT J AU Han, S Mallampalli, RK AF Han, SeungHye Mallampalli, Rama K. TI Sizing up Surfactant Synthesis SO CELL METABOLISM LA English DT Editorial Material ID LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE; II CELLS; PHOSPHOLIPIDS; LPCAT1 AB Phosphatidylcholine is generated through de novo synthesis and remodeling involving a lysophospholipid. In this issue of Cell Metabolism, research from the Shimizu lab (Harayama et al., 2014) demonstrates the highly selective enzymatic behavior of lysophospholipid acyltransferases. The authors present an enzymatic model for phosphatidylcholine molecular species diversification that impacts surfactant formation. C1 [Han, SeungHye; Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, Dept Med, Acute Lung Injury Ctr Excellence, 930 Scaife Hall, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU BLRD VA [I01 BX002200]; NHLBI NIH HHS [P01 HL114453, R01 HL081784, R01 HL096376, UH2 HL123502, R01 HL097376, R01 HL098174] NR 11 TC 0 Z9 0 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 5 PY 2014 VL 20 IS 2 BP 195 EP 196 DI 10.1016/j.cmet.2014.07.015 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5RJ UT WOS:000341402500002 PM 25100056 ER PT J AU Cawthorn, WP Scheller, EL Learman, BS Parlee, SD Simon, BR Mori, H Ning, XM Bree, AJ Schell, B Broome, DT Soliman, SS DelProposto, JL Lumeng, CN Mitra, A Pandit, SV Gallagher, KA Miller, JD Krishnan, V Hui, SK Bredella, MA Fazeli, PK Klibanski, A Horowitz, MC Rosen, CJ MacDougald, OA AF Cawthorn, William P. Scheller, Erica L. Learman, Brian S. Parlee, Sebastian D. Simon, Becky R. Mori, Hiroyuki Ning, Xiaomin Bree, Adam J. Schell, Benjamin Broome, David T. Soliman, Sandra S. DelProposto, Jenifer L. Lumeng, Carey N. Mitra, Aditi Pandit, Sandeep V. Gallagher, Katherine A. Miller, Joshua D. Krishnan, Venkatesh Hui, Susanta K. Bredella, Miriam A. Fazeli, Pouneh K. Klibanski, Anne Horowitz, Mark C. Rosen, Clifford J. MacDougald, Ormond A. TI Bone Marrow Adipose Tissue Is an Endocrine Organ that Contributes to Increased Circulating Adiponectin during Caloric Restriction SO CELL METABOLISM LA English DT Article ID ANOREXIA-NERVOSA; METABOLISM; EXPRESSION; MICE; PROTEIN; DIET; DIFFERENTIATION; MITOCHONDRIAL; PREGNANCY; GLUCOSE AB The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states. C1 [Cawthorn, William P.; Scheller, Erica L.; Learman, Brian S.; Parlee, Sebastian D.; Mori, Hiroyuki; Ning, Xiaomin; Bree, Adam J.; Schell, Benjamin; Broome, David T.; Soliman, Sandra S.; Lumeng, Carey N.; MacDougald, Ormond A.] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Simon, Becky R.; MacDougald, Ormond A.] Univ Michigan, Sch Med, Program Cell & Mol Biol, Ann Arbor, MI 48109 USA. [MacDougald, Ormond A.] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. [DelProposto, Jenifer L.; Lumeng, Carey N.] Univ Michigan, Sch Med, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA. [Mitra, Aditi; Pandit, Sandeep V.] Univ Michigan, Sch Med, Dept Internal Med Cardiol, Ctr Arrhythmia Res, Ann Arbor, MI 48109 USA. [Gallagher, Katherine A.] Univ Michigan Hosp, Dept Vasc Surg, Ann Arbor, MI 48109 USA. [Miller, Joshua D.] Univ Michigan Hosp, Dept Orthopaed Surg, Ann Arbor, MI 48109 USA. [Ning, Xiaomin] Northwest Agr & Forestry Univ, Coll Anim Sci & Technol, Yangling 712100, Shaanxi, Peoples R China. [Cawthorn, William P.; Krishnan, Venkatesh] Lilly Res Labs, Indianapolis, IN 46285 USA. [Hui, Susanta K.] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Hui, Susanta K.] Univ Minnesota, Minneapolis, MN 55455 USA. [Bredella, Miriam A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Fazeli, Pouneh K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Horowitz, Mark C.] Yale Univ, Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06519 USA. [Rosen, Clifford J.] Maine Med Ctr Res Inst, Scarborough, ME 04074 USA. RP Cawthorn, WP (reprint author), Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. EM cawthorn@umich.edu; macdouga@umich.edu OI MacDougald, Ormond/0000-0001-6907-7960; Scheller, Erica/0000-0002-1551-3816 FU National Institutes of Health [R24 DK092759, R01 DK62876, K99-DE-024178, R01 DK090262, 1R03AR055333, 1K12-HD055887, P30 DK089503]; Translational Science Institute of University of Minnesota [8UL1TR0001114]; Fulbright Scholar Award; Lilly Innovation Fellowship Award; Royal Commission [1851]; American Diabetes Association; University of Michigan Molecular & Integrative Physiology Department SURF program; Eli Lilly and Company; Biomet Biologics; Rhythm Pharmaceuticals FX This work was supported by the National Institutes of Health (R24 DK092759 to O.A.M., A.K., M.C.H., and C.J.R.; R01 DK62876 to O.A.M.; K99-DE-024178 to E.L.S.; R01 DK090262 to C.N.L.; 1R03AR055333 and 1K12-HD055887 to S.K.H.; P30 DK089503 to the Michigan Nutrition Obesity Research Center). S.K.H. is also supported by the Translational Science Institute of University of Minnesota (8UL1TR0001114). O.A.M. holds a Fulbright Scholar Award. W. P. C. holds a Lilly Innovation Fellowship Award and previously a Postdoctoral Research Fellowship from the Royal Commission for the Exhibition of 1851. H. M. was supported by a mentor-based postdoctoral fellowship from the American Diabetes Association. D. T. B. and S. S. S. were supported by the University of Michigan Molecular & Integrative Physiology Department SURF program. W. P. C. holds a postdoctoral fellowship funded by Eli Lilly and Company; V.K. is employed by Eli Lilly and Company; O.A.M. holds stock in MRK and ESRX and has received research funding from Eli Lilly and Company. E.L.S. and O.A.M. have received research funding from Biomet Biologics. A.K. has received research funding from Rhythm Pharmaceuticals. NR 28 TC 56 Z9 56 U1 4 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 EI 1932-7420 J9 CELL METAB JI Cell Metab. PD AUG 5 PY 2014 VL 20 IS 2 BP 368 EP 375 DI 10.1016/j.cmet.2014.06.003 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA AO5RJ UT WOS:000341402500021 PM 24998914 ER PT J AU Wong, CA Asch, DA Vinoya, CM Ford, CA Baker, T Town, R Merchant, RM AF Wong, Charlene A. Asch, David A. Vinoya, Cjloe M. Ford, Carol A. Baker, Tom Town, Robert Merchant, Raina M. TI The Experience of Young Adults on HealthCare.gov: Suggestions for Improvement SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Wong, Charlene A.; Vinoya, Cjloe M.; Ford, Carol A.; Merchant, Raina M.] Univ Penn, Philadelphia, PA 19104 USA. [Wong, Charlene A.; Ford, Carol A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Asch, David A.; Town, Robert] Univ Penn, Wharton Sch, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Baker, Tom] Univ Penn, Sch Law, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Wong, CA (reprint author), Univ Penn, Philadelphia, PA 19104 USA. FU NHLBI NIH HHS [K23 HL109083] NR 5 TC 9 Z9 9 U1 0 U2 1 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 5 PY 2014 VL 161 IS 3 BP 231 EP U107 DI 10.7326/L14-0287 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA AN3KH UT WOS:000340486000013 PM 25004086 ER PT J AU DeGutis, JM Chiu, C Grosso, ME Cohan, S AF DeGutis, Joseph M. Chiu, Christopher Grosso, Mallory E. Cohan, Sarah TI Face processing improvements in prosopagnosia: successes and failures over the last 50 years SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Review DE acquired prosopagnosia; developmental prosopagnosia; recovery; rehabilitation; treatment; cognitive training ID GALVANIC VESTIBULAR STIMULATION; VENTRAL TEMPORAL CORTEX; OXYTOCIN RECEPTOR GENE; VISUAL OBJECT AGNOSIA; DEVELOPMENTAL PROSOPAGNOSIA; CONGENITAL PROSOPAGNOSIA; ACQUIRED PROSOPAGNOSIA; HEREDITARY PROSOPAGNOSIA; OVERT RECOGNITION; FUSIFORM GYRUS AB Clinicians and researchers have widely believed that face processing cannot be improved in prosopagnosia. Though more than a dozen reported studies have attempted to enhance face processing in prosopagnosics over the last 50 years, evidence for effective treatment approaches has only begun to emerge. Here, we review the current literature on spontaneous recovery in acquired prosopagnosia (AP), as well as treatment attempts in acquired and developmental prosopagnosia (DP), differentiating between compensatory and remedial approaches. We find that for AP rather than remedial methods, strategic compensatory training such as verbalizing distinctive facial features has shown to be the most effective approach (despite limited evidence of generalization). In children with DP compensatory training has also shown some effectiveness. In adults with DP, two recent larger-scale studies, one using remedial training and another administering oxytocin, have demonstrated group-level improvements and evidence of generalization. These results suggest that DPs, perhaps because of their more intact face processing infrastructure, may benefit more from treatments targeting face processing than APs. C1 [DeGutis, Joseph M.; Chiu, Christopher; Grosso, Mallory E.] VA Boston Healthcare Syst, Boston Attent & Learning Lab, Jamaica Plain, MA USA. [DeGutis, Joseph M.; Cohan, Sarah] Harvard Univ, Dept Psychol, Vis Sci Lab, Cambridge, MA USA. RP DeGutis, JM (reprint author), VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, 150 S Huntington Ave, Boston, MA 02130 USA. EM degutis@wjh.harvard.edu NR 84 TC 5 Z9 5 U1 10 U2 58 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 5 PY 2014 VL 8 AR 561 DI 10.3389/fnhum.2014.00561 PG 14 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AN5HP UT WOS:000340621700001 PM 25140137 ER PT J AU Boekholdt, SM Hovingh, GK Mora, S Arsenault, BJ Amarenco, P Pedersen, TR LaRosa, JC Waters, DD DeMicco, DA Simes, RJ Keech, AC Colquhoun, D Hitman, GA Betteridge, J Clearfield, MB Downs, JR Colhoun, HM Gotto, AM Ridker, PM Grundy, SM Kastelein, JJP AF Boekholdt, S. Matthijs Hovingh, G. Kees Mora, Samia Arsenault, Benoit J. Amarenco, Pierre Pedersen, Terje R. LaRosa, John C. Waters, David D. DeMicco, David A. Simes, R. John Keech, Antony C. Colquhoun, David Hitman, Graham A. Betteridge, John Clearfield, Michael B. Downs, John R. Colhoun, Helen M. Gotto, Antonio M., Jr. Ridker, Paul M. Grundy, Scott M. Kastelein, John J. P. TI Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events A Meta-Analysis of Statin Trials SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE apolipoprotein B; LDL-cholesterol; meta-analysis; non-HDL-cholesterol ID LOW-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; SCANDINAVIAN SIMVASTATIN SURVIVAL; HIGH-DOSE ATORVASTATIN; CHOLESTEROL REDUCTION; PRIMARY PREVENTION; LDL CHOLESTEROL; LIPID TRIAL; TARGETS TNT; THERAPY AB BACKGROUND Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented. OBJECTIVES The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk. METHODS This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. RESULTS Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target < 70 mg/dl. Compared with patients who achieved an LDL-C > 175 mg/dl, those who reached an LDL-C 75 to < 100 mg/dl, 50 to < 75 mg/dl, and < 50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB. CONCLUSIONS The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, > 40% did not reach an LDL-C target < 70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels. (C) 2014 by the American College of Cardiology Foundation. C1 [Boekholdt, S. Matthijs] Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Hovingh, G. Kees; Arsenault, Benoit J.; Gotto, Antonio M., Jr.] Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Mora, Samia] Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA. [Amarenco, Pierre] Hop Xavier Bichat, Dept Neurol & Stroke Ctr, Paris, France. [Pedersen, Terje R.] Ulleval & Univ Oslo, Oslo Univ Hosp, Ctr Prevent Med, Oslo, Norway. [LaRosa, John C.] State Univ New York, Hlth Sci Ctr, Brooklyn, NY USA. [Waters, David D.] Univ Calif San Francisco, San Francisco Gen Hosp, Div Cardiol, San Francisco, CA 94143 USA. [DeMicco, David A.] Pfizer Inc, New York, NY USA. [Simes, R. John; Keech, Antony C.] Univ Sydney, NHMRC, Clin Trials Ctr, Sydney, NSW 2006, Australia. [Simes, R. John; Keech, Antony C.] Wesley Hosp, Brisbane, Qld, Australia. [Hitman, Graham A.] Univ London Queen Mary, Barts & London Sch Med & Dent, Ctr Diabet, London, England. [Betteridge, John] Univ Coll London Hosp, Dept Endocrinol & Diabet, London, England. [Clearfield, Michael B.] Touro Univ, Mare Island, CA USA. [Downs, John R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Downs, John R.] South Texas Vet Hlth Care Syst, VERDICT, San Antonio, TX USA. [Colhoun, Helen M.] Univ Dundee, Inst Med Res, Dundee, Scotland. [Gotto, Antonio M., Jr.] Weill Cornell Med Coll, New York, NY USA. [Grundy, Scott M.] Univ Texas Dallas, Ctr Human Nutr, SW Med Ctr, Dallas, TX 75230 USA. RP Kastelein, JJP (reprint author), Acad Med Ctr, Dept Vasc Med, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM j.j.kastelein@amc.uva.nl RI Simes, Robert/P-1497-2014; Colquhoun, David/F-9078-2013; Boekholdt, Matthijs/G-7562-2014; OI Colhoun, Helen/0000-0002-8345-3288 FU Netherlands Organisation for Scientific Research [91612122]; Pfizer Inc.; Atherotech Diagnostics; AstraZeneca Pharma U.S., Inc.; National Heart, Lung, and Blood Institute [HL117861]; Cerenis Therapeutics; Genzyme Corporation; Quest Diagnostics Inc.; AstraZeneca France; Bayer S.A.S.; Boehringer France S.A.S.; Boston Scientific-France; Bristol-Myers Squibb Agen; Daiichi Sankyo France S.A.S.; Edwards Lifesciences S.A.S.; Kowa Europe GmbH; H. Lundbeck A/S; Merck KGaA; Amgen Inc.; Merck Sharp & Dohme Corporation; Roche Therapeutics Inc.; Anthera Pharmaceuticals Inc.; Genentech U.S.A., Inc.; Laboratoires Servier; Aegerion Pharmaceuticals, Inc.; BioSante Pharmaceuticals, Inc.; Merck Co., Inc.; Sanofi-Aventis; Abbott Australasia Pty. Ltd.; AstraZeneca Australia; Bristol-Myers Squibb Australia; Eli Lilly Australia; Novartis A.G.; Roche Products Pty. Ltd.; Solvay Interox Pty.; AstraZeneca; Eli Lilly and Co. Ltd.; GlaxoSmithKline plc.; Merck Sharp Dohme Ltd.; Novo Nordisk Ltd.; OSI Pharmaceuticals Ltd.; Takeda U.K. Ltd.; Parke-Davis; Eli Lilly and Co., Ltd.; E.U. Innovative Medicines Initiative from AstraZeneca; Boehringer Ingelheim Ltd. U.K.; JRDF; Roche Products Ltd.; Novartis Pharmaceuticals U.K. Ltd.; Janssen Pharmaceuticals, Inc.; Kowa Pharmaceuticals America, Inc.; Abbott Laboratories; Boehringer-Ingelheim Pharmaceuticals; Isis Pharmaceuticals, Inc.; Vascular Biogenics Ltd. FX This meta-analysis was not supported by any funding. The contributing trials were funded by their respective sponsors and provided the requested data. They did not play any role in the statistical analysis, interpretation of the data, writing of the manuscript, or the decision to submit the manuscript. Dr. Hovingh is funded by a Veni grant (project number 91612122) from the Netherlands Organisation for Scientific Research. Drs. Boekholdt, Hovingh, and Arsenault have received consulting fees from Pfizer Inc. Dr. Hovingh has served on the speakers' bureaus of Amgen Europe B.V., Genzyme Netherlands, Merck Sharp & Dohme Corporation, Pfizer B.V., Roche Nederland B.V., and Sanofi-Aventis Netherlands B.V. Dr. Mora has received honoraria grants through her institution from Atherotech Diagnostics, AstraZeneca Pharma U.S., Inc., and the National Heart, Lung, and Blood Institute (HL117861); consulting fees from Cerenis Therapeutics, Genzyme Corporation, Pfizer Inc., and Quest Diagnostics Inc.; and travel accommodations/meeting expenses from Pfizer Inc.; and has served on the speakers' bureaus of Abbott Laboratories and AstraZeneca Pharma U.S., Inc. Dr. Amarenco has served on the speakers' bureaus of AstraZeneca France, Boehringer Ingelheim France S.A.S., Merck KGaA, Pfizer Inc., Sanofi-Aventis, and the government of France; and has received consulting fees from AstraZeneca France, Bayer S.A.S., Boehringer France S.A.S., Boston Scientific-France, Bristol-Myers Squibb Agen, Daiichi Sankyo France S.A.S., Edwards Lifesciences S.A.S., Kowa Europe GmbH, H. Lundbeck A/S, Merck KGaA, and Pfizer Inc. Dr. LaRosa has received consulting fees from Amgen Inc. and Pfizer Inc.; and travel expenses from Pfizer Inc. Dr. Pedersen has received honoraria grants and/or served on the speakers' bureaus of AstraZeneca Pharma U.S., Inc., Merck Sharp & Dohme Corporation, Pfizer Inc., and Roche Therapeutics Inc. Dr. Waters has received consulting fees from Anthera Pharmaceuticals Inc., Genentech U.S.A., Inc., Pfizer Inc., Roche Therapeutics Inc., and Laboratoires Servier; has served on the speakers' bureaus of Pfizer Inc. and Zydus Cadila Healthcare Ltd. (Medica); and has participated in committees of clinical trials sponsored by Aegerion Pharmaceuticals, Inc., BioSante Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., and Sanofi-Aventis. Dr. DeMicco is an employee of, and holds stock options in, Pfizer Inc. Prof. Keech has received honoraria grants from and/or served on the speakers' bureaus and/or advisory boards of Abbott Australasia Pty. Ltd., AstraZeneca Australia, Bristol-Myers Squibb Australia, Eli Lilly Australia, Merck KGaA, Novartis A.G., Pfizer Inc., Roche Products Pty. Ltd., and Solvay Interox Pty. Ltd. Dr. Hitman has received consulting fees from and/or served on the speakers' bureaus of AstraZeneca, Eli Lilly and Co. Ltd., GlaxoSmithKline plc., Merck Sharp & Dohme Ltd., Novo Nordisk Ltd., OSI Pharmaceuticals Ltd., Pfizer Inc., and Takeda U.K. Ltd.; and has received honoraria grants from Parke-Davis and Eli Lilly and Co., Ltd. Dr. Betteridge has served on the speakers' bureaus and/or advisory boards for Aegerion Pharmaceuticals, Inc., Amgen Europe B.V., AstraZeneca, Janssen Ltd., Kowa Europe GmbH, Merck Sharp & Dohme Ltd., Pfizer Inc., Roche Products Ltd., Sanofi-Synthelabo Ltd., and Takeda U.K. Ltd. Dr. Clearfield has received honoraria for consulting on the advisory boards for AstraZeneca Pharma U.S., Inc., and Merck Sharp & Dohme Corporation. Dr. Colhoun has received honoraria grants through the E.U.; Innovative Medicines Initiative from AstraZeneca, Boehringer Ingelheim Ltd. U.K., Eli Lilly and Co., Ltd., JRDF, Pfizer Inc., Roche Products Ltd., and Sanofi-Aventis; consulting fees from Eli Lilly and Co., Ltd., Novartis Pharmaceuticals U.K. Ltd., Pfizer Inc., and Sanofi-Aventis; has served on the speakers' bureaus of, and received travel expenses from, Pfizer Inc.; served on the advisory boards of Eli Lilly and Co., Ltd., Novartis Pharmaceuticals U.K. Ltd., Pfizer Inc., and Sanofi-Aventis; holds stock options in Roche Products Ltd.; and has participated in committees of clinical trials sponsored by Eli Lilly and Co., Ltd., JDRF, Novartis Pharmaceuticals U.K. Ltd., and Sanofi-Aventis. Dr. Gotto has received consulting fees from Roche Products Ltd., Janssen Pharmaceuticals, Inc., Kowa Pharmaceuticals America, Inc., Merck & Co., Inc., and Roche Therapeutics Inc.; has been a member of the boards of directors for Aegerion Pharmaceuticals, Inc. and Arisaph Pharmaceuticals, Inc.; and has been a member of the scientific advisory boards for DuPont, Haptocure Ltd., vascuVis Inc., and Vatera Healthcare Partners. Dr. Ridker has received honoraria grants from AstraZeneca Pharma U.S., Inc., Novartis A.G., and Pfizer Inc.; consulting fees from Abbott Laboratories, Boehringer-Ingelheim Pharmaceuticals, Isis Pharmaceuticals, Inc., Merck Sharp & Dohme Corporation, and Vascular Biogenics Ltd.; has been a member of the scientific advisory board for Boston Heart Diagnostics Corporation, Janssen Pharmaceuticals, Inc., Isis Pharmaceuticals, Inc., Merck Sharp & Dohme Corporation, and Pfizer Inc.; has received honoraria grants to his institution from Amgen Inc.; and is listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes and that have been licensed to AstraZeneca Pharma U.S., Inc. and Siemens Corporation. Dr. Kastelein has received honoraria for serving on the speakers' bureaus of AstraZeneca, Genzyme Australia, Labortoires Isispharma, Kowa Australia Pty. Ltd., Merck Sharp & Dohme Pty. Ltd., Novartis Pharmaceuticals Australia Pty. Ltd., Pfizer Inc., and Roche Products Pty. Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 34 TC 114 Z9 119 U1 1 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 5 PY 2014 VL 64 IS 5 BP 485 EP 494 DI 10.1016/j.jacc.2014.02.615 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9ZR UT WOS:000340241100011 PM 25082583 ER PT J AU Villafane, J Lantin-Hermoso, MR Bhatt, AB Tweddell, JS Geva, T Nathan, M Elliott, MJ Vetter, VL Paridon, SM Kochilas, L Jenkins, KJ Beekman, RH Wernovsky, G Towbin, JA AF Villafane, Juan Lantin-Hermoso, M. Regina Bhatt, Ami B. Tweddell, James S. Geva, Tal Nathan, Meena Elliott, Martin J. Vetter, Victoria L. Paridon, Stephen M. Kochilas, Lazaros Jenkins, Kathy J. Beekman, Robert H., III Wernovsky, Gil Towbin, Jeffrey A. CA American Coll Cardiol Adult TI D-Transposition of the Great Arteries The Current Era of the Arterial Switch Operation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE adult congenital heart disease; aortic dilation; congenital heart defect; congenital heart surgery and sequelae; coronary insufficiency; prostaglandin E ID CONGENITAL HEART-DISEASE; BALLOON ATRIAL SEPTOSTOMY; QUALITY-OF-LIFE; FLOW CARDIOPULMONARY BYPASS; HYPOTHERMIC CIRCULATORY ARREST; STANDARDIZED CLINICAL-ASSESSMENT; CEREBRAL OXYGEN-SATURATION; NEAR-INFRARED SPECTROSCOPY; PREOPERATIVE BRAIN-INJURY; INTACT VENTRICULAR SEPTUM AB This paper aims to update clinicians on "hot topics" in the management of patients with D-loop transposition of the great arteries (D-TGA) in the current surgical era. The arterial switch operation (ASO) has replaced atrial switch procedures for D-TGA, and 90% of patients now reach adulthood. The Adult Congenital and Pediatric Cardiology Council of the American College of Cardiology assembled a team of experts to summarize current knowledge on genetics, pre-natal diagnosis, surgical timing, balloon atrial septostomy, prostaglandin E-1 therapy, intraoperative techniques, imaging, coronary obstruction, arrhythmias, sudden death, neoaortic regurgitation and dilation, neurodevelopmental (ND) issues, and lifelong care of D-TGA patients. In simple D-TGA: 1) familial recurrence risk is low; 2) children diagnosed pre-natally have improved cognitive skills compared with those diagnosed post-natally; 3) echocardiography helps to identify risk factors; 4) routine use of BAS and prostaglandin E-1 may not be indicated in all cases; 5) early ASO improves outcomes and reduces costs with a low mortality; 6) single or intramural coronary arteries remain risk factors; 7) post-ASO arrhythmias and cardiac dysfunction should raise suspicion of coronary insufficiency; 8) coronary insufficiency and arrhythmias are rare but are associated with sudden death; 9) early-and late-onset ND abnormalities are common; 10) aortic regurgitation and aortic root dilation are well tolerated; and 11) the aging ASO patient may benefit from "exercise-prescription" rather than restriction. Significant strides have been made in understanding risk factors for cardiac, ND, and other important clinical outcomes after ASO. (C) 2014 by the American College of Cardiology Foundation. C1 [Villafane, Juan] Univ Kentucky, Dept Pediat Cardiol, Lexington, KY 40202 USA. [Lantin-Hermoso, M. Regina] Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. [Bhatt, Ami B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Adult Congenital Heart Dis Program, Boston, MA 02115 USA. [Tweddell, James S.] Childrens Hosp Wisconsin, Med Coll Wisconsin, Milwaukee, WI 53201 USA. [Geva, Tal] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Cardiol, Boston, MA 02115 USA. [Nathan, Meena] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Cardiac Surg, Boston, MA 02115 USA. [Elliott, Martin J.] NHS Fdn Trust, Great Ormond St Hosp Children, Dept Pediat Cardiothorac Surg, London, England. [Vetter, Victoria L.] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Philadelphia, PA 19104 USA. [Paridon, Stephen M.] Univ Penn, Sch Med, Perelman Sch Med, Dept Exercise Physiol, Philadelphia, PA 19104 USA. [Kochilas, Lazaros] Univ Minnesota, Childrens Hosp, Minneapolis, MN USA. [Jenkins, Kathy J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA USA. [Beekman, Robert H., III] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Coll Med, Div Cardiol, Cincinnati, OH USA. [Wernovsky, Gil] Florida Int Univ, Miami Childrens Hosp, Herbert Wertheim Coll Med, Heart Program, Miami, FL USA. [Towbin, Jeffrey A.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Coll Med, Inst Heart,Div Cardiol, Cincinnati, OH USA. RP Villafane, J (reprint author), Univ Kentucky, 743 East Broadway, 300, Louisville, KY 40202 USA. EM juanvillaf@yahoo.com RI Meijer, Anna/K-5118-2016 FU Thoracic Surgery Foundation for Research and Education; National Institutes of Health/National Heart, Lung, and Blood Institute [1R01 HL122392-01]; Johns Hopkins Medical Center; Medtronic; NuMed FX Dr. Villafane is a consultant with, and has received honoraria from BioMedical Systems. Dr. Tweddell is a member of the scientific advisory committee for CorMatrix. Dr. Geva is a consultant to Medtronic. Dr. Nathan has received grant support through the Thoracic Surgery Foundation for Research and Education. Dr. Kochilas has received support from the National Institutes of Health/National Heart, Lung, and Blood Institute (1R01 HL122392-01). Dr. Jenkins has received grant support from Johns Hopkins Medical Center, Medtronic, and NuMed. Dr. Beekman III is a proctor for St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 152 TC 38 Z9 41 U1 2 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 5 PY 2014 VL 64 IS 5 BP 498 EP 511 DI 10.1016/j.jacc.2014.06.1150 PG 14 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9ZR UT WOS:000340241100013 PM 25082585 ER PT J AU Connell, N Merabet, LB AF Connell, Nyssa Merabet, Lotfi B. TI Uncovering the connectivity of the brain in relation to novel vision rehabilitation strategies SO NEUROLOGY LA English DT Editorial Material ID CURRENT STIMULATION C1 [Connell, Nyssa] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Connell, Nyssa] New England Coll Optometry, Boston, MA USA. [Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Lab Visual Neuroplast,Dept Ophthalmol, Boston, MA USA. RP Connell, N (reprint author), VA Boston Healthcare Syst, Boston, MA 02130 USA. EM Nyssa.connell@va.gov NR 9 TC 1 Z9 1 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 5 PY 2014 VL 83 IS 6 BP 484 EP 485 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA AN1XV UT WOS:000340378200007 PM 24991035 ER PT J AU Morris, S Hunter, RM Ramsay, AIG Boaden, R McKevitt, C Perry, C Pursani, N Rudd, AG Schwamm, LH Turner, SJ Tyrrell, PJ Wolfe, CDA Fulop, NJ AF Morris, Stephen Hunter, Rachael M. Ramsay, Angus I. G. Boaden, Ruth McKevitt, Christopher Perry, Catherine Pursani, Nanik Rudd, Anthony G. Schwamm, Lee H. Turner, Simon J. Tyrrell, Pippa J. Wolfe, Charles D. A. Fulop, Naomi J. TI Impact of centralising acute stroke services in English metropolitan areas on mortality and length of hospital stay: difference-in-differences analysis SO BMJ-BRITISH MEDICAL JOURNAL LA English DT Article ID ACUTE ISCHEMIC-STROKE; UNIT CARE; ENGLAND; MODELS; IMPLEMENTATION; THROMBOLYSIS; TELEMEDICINE; METAANALYSIS; PERFORMANCE; SYSTEM AB Objective To investigate whether centralisation of acute stroke services in two metropolitan areas of England was associated with changes in mortality and length of hospital stay. Design Analysis of difference-in-differences between regions with patient level data from the hospital episode statistics database linked to mortality data supplied by the Office for National Statistics. Setting Acute stroke services in Greater Manchester and London, England. Participants 258 915 patients with stroke living in urban areas and admitted to hospital in January 2008 to March 2012. Interventions "Hub and spoke" model for acute stroke care. In London hyperacute care was provided to all patients with stroke. In Greater Manchester hyperacute care was provided to patients presenting within four hours of developing symptoms of stroke. Main outcome measures Mortality from any cause and at any place at 3, 30, and 90 days after hospital admission; length of hospital stay. Results In London there was a significant decline in risk adjusted mortality at 3, 30, and 90 days after admission. At 90 days the absolute reduction was -1.1% (95% confidence interval -2.1 to -0.1; relative reduction 5%), indicating 168 fewer deaths (95% confidence interval 19 to 316) during the 21 month period after reconfiguration in London. In both areas there was a significant decline in risk adjusted length of hospital stay: -2.0 days in Greater Manchester (95% confidence interval -2.8 to -1.2; 9%) and -1.4 days in London (-2.3 to -0.5; 7%). Reductions in mortality and length of hospital stay were largely seen among patients with ischaemic stroke. Conclusions A centralised model of acute stroke care, in which hyperacute care is provided to all patients with stroke across an entire metropolitan area, can reduce mortality and length of hospital stay. C1 [Morris, Stephen; Ramsay, Angus I. G.; Turner, Simon J.; Fulop, Naomi J.] UCL, Dept Appl Hlth Res, London WC1E 7HB, England. [Hunter, Rachael M.] UCL, Res Dept Primary Care & Populat Hlth, London NW3 2PF, England. [Boaden, Ruth; Perry, Catherine] Univ Manchester, Manchester Business Sch, Manchester M15 6PB, Lancs, England. [McKevitt, Christopher; Wolfe, Charles D. A.] Kings Coll London, Div Hlth & Social Care Res, Sch Med, London SE1 3QD, England. [Pursani, Nanik] Kings Coll London, Stroke Res Patients & Family Grp, Sch Med, Div Hlth & Social Care Res, London SE1 3QD, England. [Rudd, Anthony G.] Guys & St Thomas NHS Fdn Trust, St Thomas Hosp, London SE1 7EH, England. [Schwamm, Lee H.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tyrrell, Pippa J.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Salford Royal Hosp NHS Fdn Trust, Stroke & Vasc Ctr, Salford M6 8HD, Lancs, England. [Wolfe, Charles D. A.] Guys & St Thomas NHS Fdn Trust, Natl Inst Hlth, Res Comprehens Biomed Res Ctr, London SE1 7EH, England. [Wolfe, Charles D. A.] Kings Coll London, London SE1 3QD, England. RP Morris, S (reprint author), UCL, Dept Appl Hlth Res, London WC1E 7HB, England. EM steve.morris@ucl.ac.uk RI Boaden, Ruth/L-3443-2016; OI Boaden, Ruth/0000-0003-1927-6405; Schwamm, Lee/0000-0003-0592-9145; Tyrrell, Pippa/0000-0001-9609-1231 FU Department of Health [10/1009/09]; NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust; NIHR Biomedical Research Centre at King's College London; NIHR Collaboration for Leadership in Applied Health Research and Care Funding scheme FX This paper presents independent research commissioned by the health services and delivery research programme of the National Institute for Health Research (NIHR), funded by the Department of Health (study reference 10/1009/09). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. CDAW was supported by the NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, and also by the NIHR Collaboration for Leadership in Applied Health Research and Care Funding scheme. NR 42 TC 37 Z9 38 U1 3 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BMJ-BRIT MED J JI BMJ-British Medical Journal PD AUG 5 PY 2014 VL 349 AR g4757 DI 10.1136/bmj.g4757 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA AM9MP UT WOS:000340206000004 PM 25098169 ER PT J AU Aguirre, AD Vinegoni, C Sebas, M Weissleder, R AF Aguirre, Aaron D. Vinegoni, Claudio Sebas, Matt Weissleder, Ralph TI Intravital imaging of cardiac function at the single-cell level SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE intravital micoscopy; molecular imaging; cardiovascular imaging; fluorescence; pacing ID IN-SITU; SARCOMERE-LENGTH; 2-PHOTON MICROSCOPY; MURINE HEART; MOUSE HEARTS; RAT-HEART; LANGENDORFF; CARDIOMYOCYTES; PRESSURE; TENSION AB Knowledge of cardiomyocyte biology is limited by the lack of methods to interrogate single-cell physiology in vivo. Here we show that contracting myocytes can indeed be imaged with optical microscopy at high temporal and spatial resolution in the beating murine heart, allowing visualization of individual sarcomeres and measurement of the single cardiomyocyte contractile cycle. Collectively, this has been enabled by efficient tissue stabilization, a prospective real-time cardiac gating approach, an image processing algorithm for motion-artifact-free imaging throughout the cardiac cycle, and a fluorescent membrane staining protocol. Quantification of cardiomyocyte contractile function in vivo opens many possibilities for investigating myocardial disease and therapeutic intervention at the cellular level. C1 [Aguirre, Aaron D.; Vinegoni, Claudio; Sebas, Matt; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Aguirre, Aaron D.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Vinegoni, C (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM cvinegoni@mgh.harvard.edu; rweissleder@mgh.harvard.edu FU National Institutes of Health (NIH) [HHSN268201000044C, R01EB006432, T32HL094301] FX We thank Matthias Nahrendorf for insight on animal experiments. The project was funded by National Institutes of Health (NIH) Contracts HHSN268201000044C and R01EB006432. A.D.A. was funded by NIH Training Grant T32HL094301. NR 25 TC 14 Z9 14 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 AUG 5 PY 2014 VL 111 IS 31 BP 11257 EP 11262 DI 10.1073/pnas.1401316111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200017 PM 25053815 ER PT J AU Stangenberg, L Burzyn, D Binstadt, BA Weissleder, R Mahmood, U Benoist, C Mathis, D AF Stangenberg, Lars Burzyn, Dalia Binstadt, Bryce A. Weissleder, Ralph Mahmood, Umar Benoist, Christophe Mathis, Diane TI Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inflammation; nervous system; vascular system; autoantibody ID AUTOANTIBODY-MEDIATED ARTHRITIS; WALLERIAN DEGENERATION; MIGRATION; DISEASE; INTERLEUKIN-1-BETA; INVOLVEMENT; INHIBITION; CONTRIBUTE; PATHWAYS; ALPHA AB Two-way communication between the mammalian nervous and immune systems is increasingly recognized and appreciated. An intriguing example of such crosstalk comes from clinical observations dating from the 1930s: Patients who suffer a stroke and then develop rheumatoid arthritis atypically present with arthritis on only one side, the one not afflicted with paralysis. Here we successfully modeled hemiplegia-induced protection from arthritis using the K/BxN serum-transfer system, focused on the effector phase of inflammatory arthritis. Experiments entailing pharmacological inhibitors, genetically deficient mouse strains, and global transcriptome analyses failed to associate the protective effect with a single nerve quality (i.e., with the sympathetic, parasympathetic, or sensory nerves). Instead, there was clear evidence that denervation had a long-term effect on the limb microvasculature: The rapid and joint-localized vascular leak that typically accompanies and promotes serum-transferred arthritis was compromised in denervated limbs. This defect was reflected in the transcriptome of endothelial cells, the expression of several genes impacting vascular leakage or transendothelial cell transmigration being altered in denervated limbs. These findings highlight a previously unappreciated pathway to dissect and eventually target in inflammatory arthritis. C1 [Stangenberg, Lars; Weissleder, Ralph; Mahmood, Umar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Burzyn, Dalia; Binstadt, Bryce A.; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. RP Mathis, D (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA. EM dm@hms.harvard.edu OI Binstadt, Bryce/0000-0003-3127-3856 FU National Institutes of Health [AI054904]; Deutsche Forschungsgemeinschaft [STA 1025/1-1]; Pfizer Postdoctoral Fellowship in Rheumatology/Immunology FX This work was funded by National Institutes of Health Grant AI054904 (to D. M., C. B., and R. W.). L. S. was supported by a fellowship from the Deutsche Forschungsgemeinschaft, STA 1025/1-1, and B. A. B. was supported by a Pfizer Postdoctoral Fellowship in Rheumatology/Immunology. NR 36 TC 14 Z9 14 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2014 VL 111 IS 31 BP 11419 EP 11424 DI 10.1073/pnas.1410854111 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200044 PM 25049388 ER PT J AU Goni, GM Epifano, C Boskovic, J Camacho-Artacho, M Zhou, J Bronowska, A Martin, MT Eck, MJ Kremer, L Grater, F Gervasio, FL Perez-Moreno, M Lietha, D AF Goni, Guillermina M. Epifano, Carolina Boskovic, Jasminka Camacho-Artacho, Marta Zhou, Jing Bronowska, Agnieszka Teresa Martin, M. Eck, Michael J. Kremer, Leonor Graeter, Frauke Gervasio, Francesco Luigi Perez-Moreno, Mirna Lietha, Daniel TI Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell signaling; phosphoinositides ID CELL-MATRIX ADHESIONS; TYROSINE PHOSPHORYLATION; PHOSPHATE KINASE; STRUCTURAL BASIS; FERM DOMAIN; INTEGRIN ACTIVATION; SIGNALING PATHWAYS; TARGETING DOMAIN; GROWTH-FACTOR; FAK AB Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P-2]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P-2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P-2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P-2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P-2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type I. are important in linking integrin signaling to FAK activation. C1 [Goni, Guillermina M.; Boskovic, Jasminka; Camacho-Artacho, Marta; Lietha, Daniel] Spanish Natl Canc Res Ctr, Struct Biol & Biocomput Program, Madrid 28029, Spain. [Epifano, Carolina; Perez-Moreno, Mirna] Spanish Natl Canc Res Ctr, BBBVA Fdn Canc Cell Biol Program, Madrid 28029, Spain. [Zhou, Jing; Bronowska, Agnieszka; Graeter, Frauke] Heidelberg Inst Theoret Studies, D-69118 Heidelberg, Germany. [Teresa Martin, M.; Kremer, Leonor] CSIC, Ctr Nacl Biotecnol, Immunol & Oncol Dept, E-28049 Madrid, Spain. [Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Gervasio, Francesco Luigi] UCL, Inst Struct & Mol Biol, London WC1H 0AJ, England. [Gervasio, Francesco Luigi] UCL, Dept Chem, London WC1H 0AJ, England. RP Lietha, D (reprint author), Spanish Natl Canc Res Ctr, Struct Biol & Biocomput Program, Madrid 28029, Spain. EM dlietha@cnio.es RI Lietha, Daniel/L-8041-2014; ID, BioCAT/D-2459-2012; Kremer, Leonor/L-5445-2015; Grater, Frauke/D-3450-2009 OI Perez-Moreno, Mirna/0000-0002-0170-6406; Epifano, Carolina/0000-0002-8593-3373; Lietha, Daniel/0000-0002-6133-6486; Kremer, Leonor/0000-0002-2235-2010; Grater, Frauke/0000-0003-2891-3381 FU Ministerio de Economia y Competitividad [BFU2010-15923, BFU2009-11885]; Comunidad Autonoma de Madrid [S2010/BMD-2457]; Bundesministerium fur Bildung und Forschung; Klaus Tschira Foundation; Ramon y Cajal program [RYC-2010-06948]; Volkswagen Foundation FX We thank staff at European Synchrotron Radiation Facilities beamline ID14-4 and Swiss Light Source beamline X06SA and Liang Guo at Advanced Photon Source beamline 18ID for assistance. We also thank Diego Megias, head of the Confocal Microscopy Unit at the Centro Nacional de Investigaciones Oncologicas, for his help with FA quantifications. The research was supported by Spanish Ministerio de Ciencia e Innovacion (now Ministerio de Economia y Competitividad) Grants BFU2010-15923 (to D.L.) and BFU2009-11885 (to M.P.-M.), Comunidad Autonoma de Madrid Grant S2010/BMD-2457 (to D.L.), Bundesministerium fur Bildung und Forschung Grant, New Methods in Systems Biology (to F.G.), and a grant from the Klaus Tschira Foundation (to F.G.). D.L. is also the recipient of awards from the Ramon y Cajal program (Grant RYC-2010-06948) and the Volkswagen Foundation. NR 48 TC 21 Z9 23 U1 1 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 5 PY 2014 VL 111 IS 31 BP E3177 EP E3186 DI 10.1073/pnas.1317022111 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200002 PM 25049397 ER PT J AU Papadopoulos, E Jenni, S Kabha, E Takrouri, KJ Yi, TF Salvi, N Luna, RE Gavathiotis, E Mahalingam, P Arthanari, H Rodriguez-Mias, R Yefidoff-Freedman, R Aktas, BH Chorev, M Halperin, JA Wagner, G AF Papadopoulos, Evangelos Jenni, Simon Kabha, Eihab Takrouri, Khuloud J. Yi, Tingfang Salvi, Nicola Luna, Rafael E. Gavathiotis, Evripidis Mahalingam, Poornachandran Arthanari, Haribabu Rodriguez-Mias, Ricard Yefidoff-Freedman, Revital Aktas, Bertal H. Chorev, Michael Halperin, Jose A. Wagner, Gerhard TI Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allosteric inhibitor; NMR spectroscopy; inhibitor of protein-protein interaction ID CAP-DEPENDENT TRANSLATION; SMALL-MOLECULE INHIBITION; PROTEIN-SYNTHESIS; MESSENGER-RNAS; FACTOR EIF-4E; APOPTOSIS; CELLS; 4E; PHOSPHORYLATION; ACTIVATION AB The interaction of the eukaryotic translation initiation factor eIF4E with the initiation factor eIF4G recruits the 40S ribosomal particle to the 5' end of mRNAs, facilitates scanning to the AUG start codon, and is crucial for eukaryotic translation of nearly all genes. Efficient recruitment of the 40S particle is particularly important for translation of mRNAs encoding oncoproteins and growth-promoting factors, which often harbor complex 5' UTRs and require efficient initiation. Thus, inhibiting the eIF4E/eIF4G interaction has emerged as a previously unpursued route for developing anticancer agents. Indeed, we discovered small-molecule inhibitors of this eIF4E/eIF4G interaction (4EGIs) that inhibit translation initiation both in vitro and in vivo and were used successfully in numerous cancer-biology and neurobiology studies. However, their detailed molecular mechanism of action has remained elusive. Here, we show that the eIF4E/eIF4G inhibitor 4EGI-1 acts allosterically by binding to a site on eIF4E distant from the eIF4G binding epitope. Data from NMR mapping and high-resolution crystal structures are congruent with this mechanism, where 4EGI-1 attaches to a hydrophobic pocket of eIF4E between beta-sheet(2) (L-60-T-68) and alpha-helix(1) (E-69-N-77), causing localized conformational changes mainly in the H-78-L-85 region. It acts by unfolding a short 3(10)-helix (S-82-L-85) while extending a-helix1 by one turn (H-78-S-82). This unusual helix rearrangement has not been seen in any previous eIF4E structure and reveals elements of an allosteric inhibition mechanism leading to the dislocation of eIF4G from eIF4E. C1 [Papadopoulos, Evangelos; Jenni, Simon; Kabha, Eihab; Yi, Tingfang; Luna, Rafael E.; Arthanari, Haribabu; Rodriguez-Mias, Ricard; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kabha, Eihab; Takrouri, Khuloud J.; Mahalingam, Poornachandran; Yefidoff-Freedman, Revital; Chorev, Michael; Halperin, Jose A.] Harvard Univ, Sch Med, Lab Translat Res, Cambridge, MA 02139 USA. [Takrouri, Khuloud J.; Yefidoff-Freedman, Revital] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gavathiotis, Evripidis] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Gavathiotis, Evripidis] Albert Einstein Coll Med, Bronx, NY 10461 USA. [Mahalingam, Poornachandran] Harvard Univ, Rowland Inst, Cambridge, MA 02142 USA. RP Wagner, G (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM gerhard_wagner@hms.harvard.edu OI Salvi, Nicola/0000-0003-1515-6908 FU National Institutes of Health [CA121357, CA68262, GM47467]; Alexander S. Onassis Public Benefit Foundation; European Molecular Biology Organization [ALTF 612-2013]; Egenix, Inc. FX Data were collected at APS Synchrotron in Argonne Laboratory. This research was supported by National Institutes of Health Grants CA121357 (to M.C.), CA68262 (to G.W.), and GM47467 (to G.W.), a scholarship from the Alexander S. Onassis Public Benefit Foundation (to E.P.), European Molecular Biology Organization Long-Term Fellowship ALTF 612-2013 (to N.S.), and a grant from Egenix, Inc. NR 46 TC 17 Z9 18 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 AUG 5 PY 2014 VL 111 IS 31 BP E3187 EP E3195 DI 10.1073/pnas.1410250111 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AM4EZ UT WOS:000339807200003 PM 25049413 ER PT J AU Ignacio, RAB Chu, J Power, MC Douaiher, J Lane, JD Collins, JP Stone, VE AF Ignacio, Rachel A. Bender Chu, Jacqueline Power, Melinda C. Douaiher, Jeffrey Lane, Jordan D. Collins, Jeffrey P. Stone, Valerie E. TI Influence of providers and nurses on completion of non-targeted HIV screening in an urgent care setting SO AIDS RESEARCH AND THERAPY LA English DT Article DE HIV; Screening; Patient care; Urgent care ID EMERGENCY-DEPARTMENT; UNITED-STATES; RECOMMENDATIONS AB Introduction: Despite recommendations by the Centers for Disease Control (CDC) that all adults be offered non-targeted HIV screening in all care settings, screening in acute-care settings remains unacceptably low. We performed an observational study to evaluate an HIV screening pilot in an academic-community partnership health center urgent care clinic. Methods: We collected visit data via encounter forms and demographic and laboratory data from electronic medical records. A post-pilot survey of perceptions of HIV screening was administered to providers and nurses. Multivariable analysis was used to identify factors associated with completion of testing. Results: Visit provider and triage nurse were highly associated with both acceptance of screening and completion of testing, as were younger age, male gender, and race/ethnicity. 23.5% of patients completed tests, although 36.0% requested screening; time constraints as well as risk perceptions by both the provider and patient were cited as limiting completion of screening. Post-pilot surveys showed mixed support for ongoing HIV screening in this setting by providers and little support by nurses. Conclusions: Visit provider and triage nurse were strongly associated with acceptance of testing, which may reflect variable opinions of HIV screening in this setting by clinical staff. Among patients accepting screening, visit provider remained strongly associated with completion of testing. Despite longstanding recommendations for non-targeted HIV screening, further changes to improve the testing and results process, as well as provider education and buy-in, are needed to improve screening rates. C1 [Ignacio, Rachel A. Bender] Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA. [Chu, Jacqueline] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Power, Melinda C.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Douaiher, Jeffrey] Johns Hopkins Univ Hosp, Dept Surg, Baltimore, MD 21287 USA. [Lane, Jordan D.] Harvard Univ, Sch Med, Tosteson Med Educ Ctr, Boston, MA 02115 USA. [Collins, Jeffrey P.] Massachusetts Gen Hosp, Dept Med, CHC Urgent Care, Chelsea Healthcare Ctr, Chelsea, MA 02150 USA. [Collins, Jeffrey P.; Stone, Valerie E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Stone, Valerie E.] Mt Auburn Hosp, Dept Med, Cambridge, MA 02138 USA. [Ignacio, Rachel A. Bender] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Ignacio, RAB (reprint author), Univ Washington, Div Allergy & Infect Dis, 1959 NE Pacific St,BB545, Seattle, WA 98195 USA. EM rbi13@uw.edu OI Lane, Jordan/0000-0001-9523-3162 FU Winickoff Fellowship Program in Primary Care of the General Medicine Division, Massachusetts General Hospital; NIH [UL1 RR 025758]; Harvard University FX RBI and this study were funded in part by the Winickoff Fellowship Program in Primary Care of the General Medicine Division, Massachusetts General Hospital.; REDCaps is hosted by 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 centers). NR 16 TC 1 Z9 1 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-6405 J9 AIDS RES THER JI Aids Res. Ther. PD AUG 4 PY 2014 VL 11 AR 24 DI 10.1186/1742-6405-11-24 PG 11 WC Infectious Diseases SC Infectious Diseases GA AQ9KW UT WOS:000343173100001 ER PT J AU Marques, LM Lapenta, OM Merabet, LB Bolognini, N Boggio, PS AF Marques, Lucas Murrins Lapenta, Olivia Morgan Merabet, Lotfi B. Bolognini, Nadia Boggio, Paulo Sergio TI Tuning and disrupting the brain-modulating the McGurk illusion with electrical stimulation SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE McGurk illusion; superior temporal; parietal cortex; transcranial direct current stimulation; multisensory integration; speech ID AUDIOVISUAL SPEECH-PERCEPTION; SEEING VOICES; PARIETAL CORTEX; HEARING LIPS; INTEGRATION; RECALIBRATION; POLARIZATION; ASYNCHRONY; CHILDREN; EXCITABILITY AB In the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audiovisual integrated output occurs irrespective of the number of eye fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area. C1 [Marques, Lucas Murrins; Lapenta, Olivia Morgan; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Social & Cognit Neurosci Lab, BR-01241001 Sao Paulo, Brazil. [Marques, Lucas Murrins; Lapenta, Olivia Morgan; Boggio, Paulo Sergio] Univ Prebiteriana Mackenzie, Ctr Hlth & Biol Sci, Dev Disorders Program, BR-01241001 Sao Paulo, Brazil. [Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Lab Visual Neuroplast, Boston, MA USA. [Bolognini, Nadia] Univ Milano Bicocca, Dept Psychol, Milan, Italy. [Bolognini, Nadia] IRCCS Ist Auxol Italiano, Milan, Italy. 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; Marques, Lucas/F-5583-2016; BOLOGNINI, NADIA/J-5746-2016 OI Boggio, Paulo/0000-0002-6109-0447; BOLOGNINI, NADIA/0000-0002-2921-8658 FU scientific initiation grant (PIBIC); [FAPESP-2012/24696-1] FX We thank the Radio and Television Center of Mackenzie Presbyterian University for helping with the production of the stimuli. Lucas Muffins Marques is supported by a scientific initiation grant (PIBIC). Olivia Morgan Lapenta is supported by a PhD grant (FAPESP-2012/24696-1), Paulo Sergio Boggio is a CNPq research fellow, NR 55 TC 5 Z9 5 U1 2 U2 15 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 4 PY 2014 VL 8 AR 533 DI 10.3389/fnhum.2014.00533 PG 9 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA AN5DK UT WOS:000340609600001 PM 25140136 ER PT J AU Hingorani, DV Yoo, B Bernstein, AS Pagel, MD AF Hingorani, Dina V. Yoo, Byunghee Bernstein, Adam S. Pagel, Mark D. TI Detecting Enzyme Activities with Exogenous MRI Contrast Agents SO CHEMISTRY-A EUROPEAN JOURNAL LA English DT Review DE CEST MRI; enzymes; imaging agents; MR spectroscopy; relaxation-based MRI ID PHASE PEPTIDE-SYNTHESIS; HYPER-THYROID RATS; ACTIVITY IN-VIVO; MAGNETIC-RESONANCE; GENE-EXPRESSION; BETA-GALACTOSIDASE; PARACEST MRI; LABELED GLYCEROL; CYCLE METABOLISM; LIVING CELLS AB This review focuses on exogenous magnetic resonance imaging (MRI) contrast agents that are responsive to enzyme activity. Enzymes can catalyze a change in water access, rotational tumbling time, the proximity of a F-19-labeled ligand, the aggregation state, the proton chemical-ex-change rate between the agent and water, or the chemical shift of F-19, P-31, C-13 or a labile H-1 of an agent, all of which can be used to detect enzyme activity. The variety of agents attests to the creativity in developing enzyme-responsive MRI contrast agents. C1 [Hingorani, Dina V.; Pagel, Mark D.] Univ Arizona, Dept Chem & Biochemisty, Tucson, AZ 85721 USA. [Yoo, Byunghee] Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02114 USA. [Yoo, Byunghee] Harvard Univ, Sch Med, Boston, MA USA. [Bernstein, Adam S.] Univ Arizona, Dept Biomed Engn, Tucson, AZ USA. RP Pagel, MD (reprint author), Univ Arizona, Dept Chem & Biochemisty, 1515 N Campbell Ave, Tucson, AZ 85721 USA. EM mpagel@u.arizona.edu FU Phoenix Friends of the Arizona Cancer Center; NIH [R01 CA169774-01, P50 CA95060]; University of Arizona FX This work was supported by the Phoenix Friends of the Arizona Cancer Center, and NIH grants R01 CA169774-01 and P50 CA95060. D.V.H. was sponsored by the TRIF Fellowship Program of the University of Arizona. NR 117 TC 8 Z9 8 U1 4 U2 51 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0947-6539 EI 1521-3765 J9 CHEM-EUR J JI Chem.-Eur. J. PD AUG 4 PY 2014 VL 20 IS 32 BP 9840 EP 9850 DI 10.1002/chem.201402474 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA AN0ES UT WOS:000340257000001 PM 24990812 ER PT J AU Dreijerink, K Groner, A Rao, P Long, H Brown, M AF Dreijerink, K. Groner, A. Rao, P. Long, H. Brown, M. TI Genome-wide analysis of menin-H3K4me3 target genes SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Dreijerink, K.; Groner, A.; Brown, M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rao, P.; Long, H.] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA. EM koen_dreijerink@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 EI 1613-7671 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2014 VL 126 SU 3 MA P09 BP S151 EP S151 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA CJ1DH UT WOS:000355221700035 ER PT J AU Dreijerink, K Conemans, E Cornelissen, C Van Blokland, M Mannstadt, M Burgess, J Pieterman, C De Herder, W Havekes, B Fliers, E AF Dreijerink, K. Conemans, E. Cornelissen, C. Van Blokland, M. Mannstadt, M. Burgess, J. Pieterman, C. De Herder, W. Havekes, B. Fliers, E. TI Breast cancer predisposition in multiple endocrine neoplasia type 1 SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Meeting Abstract C1 [Dreijerink, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Dreijerink, K.; Conemans, E.; Cornelissen, C.; Van Blokland, M.; Pieterman, C.] Univ Med Ctr Utrecht, Utrecht, Netherlands. [Mannstadt, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Burgess, J.] Univ Tasmania, Hobart, Tas, Australia. [De Herder, W.] Erasmus MC, Rotterdam, Netherlands. [Havekes, B.] Univ Med Ctr, Maastricht, Netherlands. [Fliers, E.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. EM koen_dreijerink@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0043-5325 EI 1613-7671 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD AUG PY 2014 VL 126 SU 3 MA P10 BP S151 EP S152 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CJ1DH UT WOS:000355221700036 ER PT J AU Wong, ES Maciejewski, ML Hebert, PL Bryson, CL Liu, CF AF Wong, Edwin S. Maciejewski, Matthew L. Hebert, Paul L. Bryson, Christopher L. Liu, Chuan-Fen TI Massachusetts Health Reform and Veterans Affairs Health System Enrollment SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID AFFORDABLE CARE ACT; MEDICARE; COVERAGE; IMPACTS; ACCESS; RATES AB Objectives Veterans Health Administration (VA) operates the largest integrated health system in the nation. The Affordable Care Act (ACA) does not require any changes to VA, but the individual mandate and expanded health insurance options may change veterans' preferences for coverage. We examined the impact of healthcare reform in Massachusetts, which also included these policy changes, on veterans' enrollment in VA, private insurance, and Medicaid. Study Design Massachusetts' healthcare reform in June 2006 served as a natural experiment. Using data from the 2004-2013 Current Population Surveys, we examined enrollment in VA, private insurance, and Medicaid, comparing veterans residing in Massachusetts with veterans residing in neighboring New England states that did not undergo health reform. Methods We estimated the probability of being enrolled in VA, private insurance, and Medicaid before and after healthcare reform, using multivariate probit models while adjusting for individual characteristics. Using a difference-in-difference approach, we compared pre-post changes in enrollment probability among Massachusetts and non-Massachusetts veterans, respectively. Results Compared with other New England veterans, Massachusetts veterans decreased their enrollment in VA and private insurance by 0.2 (P =.857) and 0.9 (P = .666) percentage points, respectively, following health reform. In contrast, Medicaid enrollment increased by 2.5 percentage points (P = .038). Conclusions Healthcare reform in Massachusetts was associated with greater Medicaid enrollment, but was not significantly associated with VA and private insurance enrollment. Our results are significant for informing VA fiscal planning in the post ACA era. C1 [Wong, Edwin S.; Hebert, Paul L.; Bryson, Christopher L.; Liu, Chuan-Fen] VA Puget Sound Hlth Care Syst, Northwest Ctr Outcomes Res Older Adults, Seattle, WA USA. [Wong, Edwin S.; Hebert, Paul L.; Liu, Chuan-Fen] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Maciejewski, Matthew L.] Duke Univ, Dept Med, Div Gen Internal Med, Durham, NC USA. [Bryson, Christopher L.] Univ Washington, Dept Med, Seattle, WA USA. RP Wong, ES (reprint author), Ctr Innovat Vet Ctr & Value Driven Care, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM edwin.wong@va.gov FU VA Health Services Research and Development Career Development Award [CDA 13-024] FX Dr Wong is supported by a VA Health Services Research and Development Career Development Award (CDA 13-024). Dr Maciejewski is a VA Research Career Scientist (RCS 10-391). The views expressed are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs, the University of Washington, and Duke University. NR 25 TC 1 Z9 1 U1 0 U2 1 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD AUG PY 2014 VL 20 IS 8 BP 629 EP 636 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CD3PK UT WOS:000350990800011 PM 25295677 ER PT J AU Kimbro, LB Li, JN Turk, N Ettner, SL Moin, T Mangione, CM Duru, OK AF Kimbro, Lindsay B. Li, Jinnan Turk, Norman Ettner, Susan L. Moin, Tannaz Mangione, Carol M. Duru, O. Kenrik TI Optimizing Enrollment in Employer Health Programs: A Comparison of Enrollment Strategies in the Diabetes Health Plan SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID MEXICAN-AMERICANS; MEDICAL-CARE; INSURANCE; ACCULTURATION; ADHERENCE; SERVICES; ACCESS AB Background Many health programs struggle with low enrollment rates. Objectives To compare the characteristics of populations enrolled in a new health plan when employer groups implement voluntary versus automatic enrollment approaches. Study Design We analyzed enrollment rates resulting from 2 different strategies: voluntary and automatic enrollment. We used regression modeling to estimate the associations of patient characteristics with the probability of enrolling within each strategy. The subjects were 5014 eligible employees from 11 self-insured employers who had purchased the Diabetes Health Plan (DHP), which offers free or discounted copayments for diabetes related medications, testing supplies, and physician visits. Six employers used voluntary enrollment while five5 used automatic enrollment. The main outcome of interest was enrollment into the DHP. Predictors were gender, age, race/ethnicity, dependent status, household income, education level, number of comorbidities, and employer group. Results Overall, the proportion of eligible members who were enrolled within the automatic enrollment strategy was 91%, compared with 35% for voluntary enrollment. Income was a significant predictor for voluntary enrollment but not for automatic enrollment. Within automatic enrollment, covered dependents, Hispanics, and persons with 1 nondiabetes comorbidity were more likely to enroll than other subgroups. Employer group was also a significant correlate of enrollment. Notably, all demographic groups had higher DHP enrollment rates under automatic enrollment than under voluntary enrollment. Conclusions For employer-based programs that struggle with low enrollment rates, especially among certain employee subgroups, an automatic enrollment strategy may not only increase the total number of enrollees but may also decrease some enrollment disparities. C1 [Kimbro, Lindsay B.; Li, Jinnan; Turk, Norman; Ettner, Susan L.; Mangione, Carol M.; Duru, O. Kenrik] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Ettner, Susan L.; Mangione, Carol M.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [Moin, Tannaz] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Moin, Tannaz] Vet Affairs Greater Los Angeles Healthcare Syst, HSR&D Ctr Excellence Study Healthcare Provider Be, Los Angeles, CA USA. RP Kimbro, LB (reprint author), 10940 Wilshire Blvd,Ste 700, Los Angeles, CA 90095 USA. EM lkimbro@mednet.ucla.edu FU Centers for Disease Control and Prevention; National Institute of Diabetes and Digestive and Kidney Diseases as part of the Natural Experiments for the Translation of Diabetes (NEXT-D) Study [DP002722]; VA Office of Academic Affiliations, Health Services Research and Development through the Health Services Fellowship Training Program [TPM65-010]; VA Greater Los Angeles Healthcare System; University of California, Los Angeles; Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly (RCMAR/CHIME) under NIH/NIA [P30-AG021684]; [K08 AG033630] FX Funding received from the Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases as part of the Natural Experiments for the Translation of Diabetes (NEXT-D) Study (Grant number DP002722). Dr Moin is supported by VA Office of Academic Affiliations, Health Services Research and Development, through the Health Services Fellowship Training Program (TPM65-010), VA Greater Los Angeles Healthcare System. Dr Mangione and Dr Duru are supported in part by the University of California, Los Angeles, Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly (RCMAR/CHIME) under NIH/NIA Grant P30-AG021684. Dr Duru is supported in part by the Career Development award K08 AG033630. NR 19 TC 1 Z9 1 U1 0 U2 1 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD AUG PY 2014 VL 20 IS 8 BP E311 EP E319 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA CD3PK UT WOS:000350990800004 PM 25295794 ER PT J AU Campus, G Congiu, G Cocco, F Sale, S Cagetti, MG Sanna, G Lingstrom, P Garcia-Godoy, F AF Campus, Guglielmo Congiu, Giovanna Cocco, Fabio Sale, Silvana Cagetti, Maria Grazia Sanna, Gavino Lingstroem, Peter Garcia-Godoy, Franklin TI Fluoride content in breast milk after the use of fluoridated food supplement. A randomized clinical trial SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID ORAL-HEALTH; CARIES; AREA AB Purpose: To evaluate if the intake of a fluoridated food supplement in breastfeeding mothers increases the fluoride concentration in breast milk. Methods: A double-blind randomized placebo-controlled study was designed. Two groups of women were formed: a fluoride group (n=112), using a non-sucrose food supplement containing fluoride (1,500 mu g/l for each dose) and a control group (n=116), using a non-sucrose food supplement without fluoride content. The women were followed for 6 weeks. Samples of breast milk were collected and analyzed using an ion-specific electrode. Results: 85 women in the fluoride group and 83 in the control group concluded the trial. Fluoride concentrations in the two groups were statistically significantly different (515 mu g/l in the fluoride and 476 mu g/l in the control group P=0.04) at the end of the experimental period. In the fluoride group, a statistically significant increment in fluoride concentration during the experimental period was also observed (from 4681104 mu g/l to 5151105 mu g/l). The use of a non-sucrose food supplement containing fluoride resulted in a significant increment in fluoride concentration in breast milk. C1 [Campus, Guglielmo; Congiu, Giovanna; Sale, Silvana] Univ Sassari, Dept Surg Microsurg & Med Sci, Sch Dent, I-07100 Sassari, Italy. [Cocco, Fabio; Sanna, Gavino] Univ Sassari, Dept Chem & Pharm, I-07100 Sassari, Italy. [Cagetti, Maria Grazia] WHO Collaborating Ctr Milan Epidemiol & Commun, Milan, Italy. [Garcia-Godoy, Franklin] Univ Tennessee, Hlth Sci Ctr, Coll Dent, Dept Biosci Res, Memphis, TN USA. [Garcia-Godoy, Franklin] Forsyth Inst, Cambridge, MA USA. RP Campus, G (reprint author), Univ Sassari, Dept Surg Microsurg & Med Sci, Sch Dent, Viale San Pietro 43-C, I-07100 Sassari, Italy. EM gcampus@uniss.it RI Sanna, Gavino/C-8787-2011; COCCO, Fabio/L-9152-2014 OI Sanna, Gavino/0000-0001-9572-4041; COCCO, Fabio/0000-0003-1126-6157 NR 25 TC 0 Z9 0 U1 1 U2 2 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD AUG PY 2014 VL 27 IS 4 BP 199 EP 202 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA CC0EM UT WOS:000350008600005 PM 25831603 ER PT J AU Conner, JD Wolden-Hanson, T Quinn, LS AF Conner, Jennifer D. Wolden-Hanson, Tami Quinn, LeBris S. TI Assessment of Murine Exercise Endurance Without the Use of a Shock Grid: An Alternative to Forced Exercise SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Behavior; Issue 90; Exercise; Mouse; Treadmill; Endurance; Refinement ID PHYSICAL-ACTIVITY; MICE; PGC-1-ALPHA; RECEPTOR; OBESITY; INFLAMMATION; PERFORMANCE; METABOLISM; EXPRESSION; SPEED AB Using laboratory mouse models, the molecular pathways responsible for the metabolic benefits of endurance exercise are beginning to be defined. The most common method for assessing exercise endurance in mice utilizes forced running on a motorized treadmill equipped with a shock grid. Animals who quit running are pushed by the moving treadmill belt onto a grid that delivers an electric foot shock; to escape the negative stimulus, the mice return to running on the belt. However, avoidance behavior and psychological stress due to use of a shock apparatus can interfere with quantitation of running endurance, as well as confound measurements of postexercise serum hormone and cytokine levels. Here, we demonstrate and validate a refined method to measure running endurance in naive C57BL/6 laboratory mice on a motorized treadmill without utilizing a shock grid. When mice are preacclimated to the treadmill, they run voluntarily with gait speeds specific to each mouse. Use of the shock grid is replaced by gentle encouragement by a human operator using a tongue depressor, coupled with sensitivity to the voluntary willingness to run on the part of the mouse. Clear endpoints for quantifying running time-to-exhaustion for each mouse are defined and reflected in behavioral signs of exhaustion such as splayed posture and labored breathing. This method is a humane refinement which also decreases the confounding effects of stress on experimental parameters. C1 [Conner, Jennifer D.; Wolden-Hanson, Tami; Quinn, LeBris S.] VA Puget Sound Hlth Care Syst, Res Serv, Seattle, WA 98108 USA. [Conner, Jennifer D.] Seattle Inst Biomed & Clin Res, Seattle, WA USA. [Quinn, LeBris S.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Quinn, LeBris S.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. RP Quinn, LS (reprint author), VA Puget Sound Hlth Care Syst, Res Serv, Seattle, WA 98108 USA. EM quinnL@uw.edu FU Department of Veterans Affairs [BX001026]; NIA [5P30AG-013280]; University of Washington Diabetes Endocrinology Research Center (NIH) [P30 DK-17047] FX Supported by Merit Review #BX001026 from the Department of Veterans Affairs (LSQ), and use of resources and facilities at VA Puget Sound Health Care System, the Transgenic Resource Core at the University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging (NIA #5P30AG-013280), and the University of Washington Diabetes Endocrinology Research Center (NIH #P30 DK-17047). We thank Cynthia Pekow DVM and Kari L. Koszdin DVM, VA Puget Sound, provided helpful comments on the manuscript. NR 25 TC 0 Z9 0 U1 3 U2 6 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD AUG PY 2014 IS 90 AR e51846 DI 10.3791/51846 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA CB0EV UT WOS:000349299200068 PM 25145813 ER PT J AU Wood, KH Hoef, LWV Knight, DC AF Wood, Kimberly H. Hoef, Lawrence W. Ver Knight, David C. TI The Amygdala Mediates the Emotional Modulation of Threat-Elicited Skin Conductance Response SO EMOTION LA English DT Article DE fMRI; emotion; threat; amygdala; skin conductance ID FEAR-POTENTIATED STARTLE; FACIAL EXPRESSIONS; INDIVIDUAL-DIFFERENCES; TRAIT ANXIETY; CONDITIONED DIMINUTION; NEURAL RESPONSES; VIETNAM VETERANS; FUNCTIONAL MRI; LONG-TERM; ACTIVATION AB The ability to respond adaptively to threats in a changing environment is an important emotional function. The amygdala is a critical component of the neural circuit that mediates many emotion-related processes, and thus likely plays an important role in modulating the peripheral emotional response to threat. However, prior research has largely focused on the amygdala's response to stimuli that signal impending threat, giving less attention to the amygdala's response to the threat itself. From a functional perspective, however, it is the response to the threat itself that is most biologically relevant. Thus, understanding the factors that influence the amygdala's response to threat is critical for a complete understanding of adaptive emotional processes. Therefore, we used functional MRI to investigate factors (i.e., valence and arousal of co-occurring visual stimuli) that influence the amygdala's response to threat (loud white noise). We also assessed whether changes in amygdala activity varied with the peripheral expression of emotion (indexed via skin conductance response; SCR). The results showed that threat-elicited amygdala activation varied with the arousal, not valence, of emotional images. More specifically, threat-elicited amygdala activation was larger to the threat when presented during high-arousal (i.e., negative and positive) versus low-arousal (i.e., neutral) images. Further, the threat-elicited amygdala response was positively correlated with threat-elicited SCR. These findings indicate the amygdala's response to threat is modified by the nature (e.g., arousal) of other stimuli in the environment. In turn, the amygdala appears to mediate important aspects of the peripheral emotional response to threat. C1 [Wood, Kimberly H.; Knight, David C.] Univ Alabama Birmingham, Dept Psychol, Birmingham, AL 35233 USA. [Hoef, Lawrence W. Ver] Univ Alabama Birmingham, Sch Med, Dept Neurol, Birmingham, AL 35233 USA. [Hoef, Lawrence W. Ver] Birmingham VA Med Ctr, Dept Neurol, Birmingham, AL USA. RP Knight, DC (reprint author), Univ Alabama Birmingham, CIRC 235H,1720 2nd Ave South, Birmingham, AL 35233 USA. EM knightdc@uab.edu FU NIMH NIH HHS [MH098348, R01 MH098348] NR 68 TC 9 Z9 9 U1 5 U2 20 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 EI 1931-1516 J9 EMOTION JI Emotion PD AUG PY 2014 VL 14 IS 4 BP 693 EP 700 DI 10.1037/a0036636 PG 8 WC Psychology, Experimental SC Psychology GA CA9CS UT WOS:000349218600006 PM 24866521 ER PT J AU Huang, CM AF Huang, Chunmei TI Commentary on "Safety and Efficacy of Percutaneous Renal Biopsy by Physicians-in-Training in an Academic Teaching Setting'' SO SOUTHERN MEDICAL JOURNAL LA English DT Editorial Material ID COMPLICATIONS C1 Harvard Univ, Dept Internal Med, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Huang, CM (reprint author), Harvard Univ, Dept Internal Med, Sch Med, Massachusetts Gen Hosp, 55 Fruit St,Bulfinch 015, Boston, MA 02114 USA. EM chuang0@partners.org NR 6 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0038-4348 EI 1541-8243 J9 SOUTH MED J JI South.Med.J. PD AUG PY 2014 VL 107 IS 8 BP 526 EP 527 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA CA6VJ UT WOS:000349053600013 PM 25084193 ER PT J AU Guancial, EA Werner, L Bellmunt, J Bamias, A Choueiri, TK Ross, R Schutz, FA Park, RS O'Brien, RJ Hirsch, MS Barletta, JA Berman, DM Lis, R Loda, M Stack, EC Garraway, LA Riester, M Michor, F Kantoff, PW Rosenberg, JE AF Guancial, Elizabeth A. Werner, Lillian Bellmunt, Joaquim Bamias, Aristotle Choueiri, Toni K. Ross, Robert Schutz, Fabio A. Park, Rachel S. O'Brien, Robert J. Hirsch, Michelle S. Barletta, Justine A. Berman, David M. Lis, Rosina Loda, Massimo Stack, Edward C. Garraway, Levi A. Riester, Markus Michor, Franziska Kantoff, Philip W. Rosenberg, Jonathan E. TI FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder SO CANCER MEDICINE LA English DT Article DE Biomarker; bladder cancer; FGFR3; metastatic urothelial carcinoma; muscle-invasive urothelial carcinoma; targeted therapy ID GROWTH-FACTOR RECEPTOR-3; MUTATION STATUS; COPY-NUMBER; CANCER; SAMPLES; PROLIFERATION; MICROARRAYS; PROFILES AB While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon. C1 [Guancial, Elizabeth A.; Bellmunt, Joaquim; Choueiri, Toni K.; Ross, Robert; Schutz, Fabio A.; Park, Rachel S.; O'Brien, Robert J.; Garraway, Levi A.; Kantoff, Philip W.; Rosenberg, Jonathan E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Guancial, Elizabeth A.] Univ Rochester, Rochester, NY 14623 USA. [Werner, Lillian; Riester, Markus; Michor, Franziska] Harvard Univ, Sch Med, Boston, MA USA. [Bellmunt, Joaquim] Htal De Mar Res Inst IMIM, Barcelona, Spain. [Bamias, Aristotle] Univ Athens, Sch Med, Dept Clin Therapeut, GR-11527 Athens, Greece. [Hirsch, Michelle S.; Barletta, Justine A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Berman, David M.] Queens Univ, Dept Pathol & Mol Med, Kingston, ON, Canada. [Lis, Rosina; Loda, Massimo; Stack, Edward C.] Brigham & Womens Hosp, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Rosenberg, Jonathan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Guancial, EA (reprint author), Univ Rochester, 601 Elmwood Ave,Box 704, Rochester, NY 14623 USA. EM elizabeth_guancial@urmc.rochester.edu OI Rosenberg, Jonathan/0000-0003-2637-4249; Riester, Markus/0000-0002-4759-8332 FU Bladder Cancer Advocacy Network (BCAN) FX The authors gratefully acknowledge the support of the Bladder Cancer Advocacy Network (BCAN) for this work. NR 28 TC 18 Z9 21 U1 3 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2045-7634 J9 CANCER MED-US JI Cancer Med. PD AUG PY 2014 VL 3 IS 4 BP 835 EP 844 DI 10.1002/cam4.262 PG 10 WC Oncology SC Oncology GA AZ4WW UT WOS:000348222300009 PM 24846059 ER PT J AU Jahollari, A Sarac, A Tafaj, O Ozal, E AF Jahollari, Artan Sarac, Atilla Tafaj, Olta Ozal, Ertugrul TI Surgical Management of a Giant Right Coronary Artery Aneurysm SO HEART SURGERY FORUM LA English DT Article ID CLINICAL-SIGNIFICANCE; ECTASIA C1 [Jahollari, Artan; Sarac, Atilla; Ozal, Ertugrul] Med Pk Hosp, Dept Cardiovasc Surg, Samsun, Turkey. [Tafaj, Olta] Massachusetts Gen Hosp, Endocrine Res Unit, Boston, MA 02114 USA. RP Jahollari, A (reprint author), Med Pk Hosp, Mimar Sinan Mah Alparslan Bulv 17, TR-55200 Atakum Samsun, Turkey. EM artanjahollari@gmail.com NR 7 TC 1 Z9 1 U1 0 U2 0 PU FORUM MULTIMEDIA PUBLISHING, LLC PI CHARLOTTESVILLE PA 375 GREENBRIER DR, CHARLOTTESVILLE, VA 22901 USA SN 1098-3511 EI 1522-6662 J9 HEART SURG FORUM JI Heart Surg. Forum PD AUG PY 2014 VL 17 IS 4 BP E237 EP E238 DI 10.1532/HSF98.2014349 PG 2 WC Cardiac & Cardiovascular Systems; Surgery SC Cardiovascular System & Cardiology; Surgery GA AZ0CH UT WOS:000347913500015 ER PT J AU Tejera, P O'Mahony, DS Owen, CA Wei, YY Wang, ZX Gupta, K Su, L Villar, J Wurfel, M Christiani, DC AF Tejera, Paula O'Mahony, D. Shane Owen, Caroline A. Wei, Yongyue Wang, Zhaoxi Gupta, Kushagra Su, Li Villar, Jesus Wurfel, Mark Christiani, David C. TI Functional Characterization of Polymorphisms in the Peptidase Inhibitor 3 (Elafin) Gene and Validation of Their Contribution to Risk of Acute Respiratory Distress Syndrome SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE acute respiratory distress syndrome; elafin; single-nucleotide polymorphism; genetic association; replication ID ACUTE LUNG INJURY; ELASTASE-SPECIFIC INHIBITOR; LEUKOCYTE PROTEASE INHIBITOR; NEUTROPHIL ELASTASE; PRE-ELAFIN; PROTEINASE-INHIBITOR; HUMAN KERATINOCYTES; EPITHELIAL-CELLS; BACTERIAL LIPOPOLYSACCHARIDE; PSEUDOMONAS-AERUGINOSA AB Elafin (peptidase inhibitor 3 [PI3]) and its biologically active precursor, pre-elafin, are neutrophil serine proteinase inhibitors with an important role in preventing excessive tissue injury during inflammatory events. Recently, we reported an association between single-nucleotide polymorphism (SNP) rs2664581 in the PI3 gene, increased risk of acute respiratory distress syndrome (ARDS) and pre-elafin circulating levels. This study aims to validate the legitimacy of this association by using a cohort of patients who met the criteria for systemic inflammatory response syndrome and were at risk of developing ARDS (n = 840). A comprehensive functional study of SNPs in PI3 gene was also performed. Luciferase assays and electrophoretic mobility shift assays were conducted to determine the functional relevance of promoter region variants. The effect of the coding SNP rs2664581 on the neutrophil elastase inhibitory activity and transglutaminase binding properties of pre-elafin was also investigated. The variant allele of rs2664581 (C) was significantly associated with increased ARDS risk, mainly among subjects with sepsis (odds ratio = 1.44; 95% confidence interval = 1.04-1.99; P = 0.0276, adjusted by age, sex, and Acute Physiology and Chronic Health Evaluation III). Pre-elafin recombinant protein carrying the amino acid change associated with rs2664581 (Thr34Pro, mutant protein [MT]) had greater capacity to undergo transglutaminase-mediated cross-linking to immobilized fibronectin than wild-type protein in vitro (P < 0.003). No differences were observed in the neutrophil elastase inhibitory activities of wild-type versus MT proteins. In addition, the risk allele-promoter construct had significantly lower cytokine-induced transcriptional activity. Electrophoretic mobility shift assay results indicated a differential binding of nuclear proteins to the G and A alleles of SNP -338G. A. Our results confirm the association between SNP rs2664581 and enhanced risk of ARDS, further supporting the role of PI3 in ARDS development. SNPs in the PI3 locus may act synergistically by regulating PI3 gene expression and pre-elafin biological functions. C1 [Tejera, Paula; Wei, Yongyue; Wang, Zhaoxi; Su, Li; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [O'Mahony, D. Shane; Wurfel, Mark] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Owen, Caroline A.; Gupta, Kushagra] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Owen, Caroline A.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Villar, Jesus] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Resp, Madrid, Spain. [Villar, Jesus] Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain. [Christiani, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave,Room 1-1407, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU National Institute of Health [HL 060710, ES00002]; CajaMadrid (Spain) FX This work was supported by National Institute of Health grants HL 060710 and ES00002, and by grant CajaMadrid (Spain) (P.T.). NR 49 TC 4 Z9 4 U1 1 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1044-1549 EI 1535-4989 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD AUG PY 2014 VL 51 IS 2 BP 262 EP 272 DI 10.1165/rcmb.2013-0238OC PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA AY2JW UT WOS:000347417100011 PM 24617927 ER PT J AU Ma, JT Sloan, M Fox, CS Hoffmann, U Smith, CE Saltzman, E Rogers, GT Jacques, PF McKeown, NM AF Ma, Jiantao Sloan, Matthew Fox, Caroline S. Hoffmann, Udo Smith, Caren E. Saltzman, Edward Rogers, Gail T. Jacques, Paul F. McKeown, Nicola M. TI Sugar-Sweetened Beverage Consumption Is Associated with Abdominal Fat Partitioning in Healthy Adults SO JOURNAL OF NUTRITION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; SUBCUTANEOUS ADIPOSE-TISSUE; CARDIOVASCULAR-DISEASE; INSULIN SENSITIVITY; COMPUTED-TOMOGRAPHY; LIPOPROTEIN-LIPASE; VISCERAL ADIPOSITY; METABOLIC SYNDROME; DIABETES-MELLITUS; HEART-DISEASE AB Abdominal adiposity, particularly visceral adipose tissue (VAT), is independently linked to the pathogenesis of diabetes and cardiovascular diseases. Emerging evidence suggests that greater intake of sugar-sweetened beverages (SSBs) may be associated with abnormal fat accumulation in VAT. We examined whether habitual SSB consumption and diet soda intakes are differentially associated with deposition of body fat. We conducted a cross-sectional analysis using previously collected data in 2596 middle-aged adults (1306 men and 1290 women) from the Framingham Heart Study Offspring and Third Generation cohorts. VAT and abdominal subcutaneous adipose tissue (SAT) were measured using multidetector computed tomography. Habitual intake of SSBs and diet soda was assessed by a validated food frequency questionnaire. We observed that SSB consumption was positively associated with VAT after adjustment for SAT and other potential confounders (P-trend < 0.001). We observed an inverse association between SSB consumption and SAT (P-trend = 0.04) that persisted after additional adjustment for VAT (P-trend < 0.001). Higher SSB consumption was positively associated with the VAT-to-SAT ratio (P-trend < 0.001). No significant association was found between diet soda consumption and either VAT or the VAT-to-SAT ratio, but diet soda was positively associated with SAT (P-trend < 0.001). Daily consumers of SSBs had a 10% higher absolute VAT volume and a 15% greater VAT-to-SAT ratio compared with nonconsumers, whereas consumption of diet soda was not associated with either volume or distribution of VAT. C1 [Ma, Jiantao; Rogers, Gail T.; Jacques, Paul F.; McKeown, Nicola M.] Tufts Univ, Nutr Epidemiol Program, Boston, MA 02111 USA. [Smith, Caren E.] Tufts Univ, Nutr & Genom Lab, Boston, MA 02111 USA. [Saltzman, Edward] Tufts Univ, Energy Metab Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Sloan, Matthew] Univ Massachusetts, Sch Med, Worcester, MA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol & Metab, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP McKeown, NM (reprint author), Tufts Univ, Nutr Epidemiol Program, Boston, MA 02111 USA. EM nicola.mckeown@tufts.edu FU NIH/National Heart, Lung, and Blood Institute Framingham Heart Study [N01-HC-25195]; Boston University School of Medicine; USDA [58-1950-0-014] FX Supported by NIH/National Heart, Lung, and Blood Institute Framingham Heart Study under contract N01-HC-25195, the Boston University School of Medicine, and USDA agreement 58-1950-0-014. NR 41 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 EI 1541-6100 J9 J NUTR JI J. Nutr. PD AUG PY 2014 VL 144 IS 8 BP 1283 EP 1290 DI 10.3945/jn.113.188599 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AX1GU UT WOS:000346696700022 PM 24944282 ER PT J AU Sconocchia, G Eppenberger, S Spagnoli, GC Tornillo, L Droeser, R Caratelli, S Ferrelli, F Coppola, A Arriga, R Lauro, D Iezzi, G Terracciano, L Ferrone, S AF Sconocchia, Giuseppe Eppenberger, Serenella Spagnoli, Giulio C. Tornillo, Luigi Droeser, Raoul Caratelli, Sara Ferrelli, Francesca Coppola, Andrea Arriga, Roberto Lauro, Davide Iezzi, Giandomenica Terracciano, Luigi Ferrone, Soldano TI NK cells and T cells cooperate during the clinical course of colorectal cancer SO ONCOIMMUNOLOGY LA English DT Article DE CD8 T cell; colorectal carcinoma; cooperation; lymphocyte; NK cell; survival; tumor ID NATURAL-KILLER-CELLS; IMPROVED SURVIVAL; ANTITUMOR IMMUNITY; INFILTRATION; EXPRESSION; CARCINOMA; LEUKEMIA; TRANSPLANTATION; RECEPTORS; PROGNOSIS AB Recent evidence suggests that natural killer (NK) cells are typically defective in infiltrating solid tumors, with the exception of gastrointestinal stromal tumors (GIST). Interestingly, however, infrequently infiltrating NK cells do not appear to have a direct effect on tumor progression. Here, prompted by the recent evidence that NK cell and T cell crosstalk may trigger, or enhance, tumor antigen-specific immune responses, we have tested the clinical significance of this reciprocal signaling. To this end, a tissue microarray constructed with 1410 colorectal carcinoma (CRC) patient specimens was stained with NK and T cell antigen-specific monoclonal antibodies, utilizing the immunoperoxidase staining technique. Cut-off scores for positive (>4 NK cells) and negative (<= 4 NK cells) NK cell CRC patient samples were determined using receiver operating characteristic curve analysis. Using this approach, NK cells were detected in 423 (30%) of the 1410 CRC specimens evaluated. The number of NK cells was >4 in only 132 (9%) of CRC samples. Correlation of the immunohistochemical staining results together with analysis of the clinical course of the disease revealed that the infiltration of colorectal tumors with both NK cells and CD8+ T cells is associated with prolonged patient survival. In contrast, infiltration of tumors with NK cells in combination with CD3(+) and CD4(+) T lymphocytes had no detectable effect on the clinical course of the disease. These results suggest that NK cell and CD8+ T cell crosstalk in the tumor microenvironment may benefit patient outcome and further, that the enumeration of infiltrating NK and CD8+ T cells in CRC tumors may provide useful prognostic information. C1 [Sconocchia, Giuseppe; Caratelli, Sara] CNR, Inst Translat Pharmacol, Lab Tumor Immunol & Immunotherapy, Rome, Italy. [Eppenberger, Serenella; Tornillo, Luigi; Terracciano, Luigi] Univ Basel, Inst Pathol, Basel, Switzerland. [Spagnoli, Giulio C.; Droeser, Raoul; Iezzi, Giandomenica] Univ Basel, Inst Surg Res & Hosp Management, Basel, Switzerland. [Ferrelli, Francesca; Coppola, Andrea; Arriga, Roberto; Lauro, Davide] Univ Roma Tor Vergata, Inst Syst Med, Rome, Italy. [Ferrone, Soldano] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Sconocchia, G (reprint author), CNR, Inst Translat Pharmacol, Lab Tumor Immunol & Immunotherapy, Rome, Italy. EM giuseppe.sconocchia@cnr.it OI Tornillo, Luigi/0000-0003-3610-3733; Coppola, Andrea/0000-0003-4391-8738 FU AIRC grant [IG10555]; Ministry of Education, University; Research (PRIN), grant [2010AX2JX7_005]; National Cancer Institute [RO1CA138188, RO1CA110249, P50CA121973] FX Giuseppe Sconocchia was supported by the AIRC grant: IG10555 and the Ministry of Education, University, and Research (PRIN), grant 2010AX2JX7_005. Soldano Ferrone was supported in part by PHS grants RO1CA138188, RO1CA110249 and P50CA121973 awarded by the National Cancer Institute. NR 32 TC 16 Z9 19 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD AUG PY 2014 VL 3 IS 8 AR e952197 DI 10.4161/21624011.2014.952197 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA AX4SR UT WOS:000346922100004 ER PT J AU Shen, JK Cote, GM Choy, E Hornicek, FJ Duan, ZF AF Shen, Jacson K. Cote, Gregory M. Choy, Edwin Hornicek, Francis J. Duan, Zhenfeng TI Targeting programmed cell death ligand 1 in osteosarcoma: an auto-commentary on therapeutic potential SO ONCOIMMUNOLOGY LA English DT Editorial Material DE immunotherapy; mRNA; osteosarcoma; PDL1; TILs ID CANCER; ANTIBODY; MELANOMA; SAFETY AB Programmed cell death ligand 1 (PDL1) expression was recently shown to correlate with tumor-infiltrating lymphocytes (TILs) in a subset of osteosarcoma patients. Among clinical factors evaluated across human osteosarcoma samples, a pulmonary origin of metastases correlated with high PDL1 expression and prominent TILs. Considering that multiple agents targeting PD-1/PDL1 are under development, targeting this immune checkpoint may be a novel immunotherapeutic route for osteosarcoma in future clinical trials. C1 [Shen, Jacson K.; Hornicek, Francis J.; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Cote, Gregory M.; Choy, Edwin] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. EM zduan@mgh.harvard.edu OI Cote, Gregory/0000-0003-0181-886X FU NCI NIH HHS [U54 CA168512] NR 10 TC 5 Z9 5 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 EI 2162-402X J9 ONCOIMMUNOLOGY JI OncoImmunology PD AUG PY 2014 VL 3 IS 8 AR e954467 DI 10.4161/21624011.2014.954467 PG 3 WC Oncology; Immunology SC Oncology; Immunology GA AX4SR UT WOS:000346922100013 PM 25610746 ER PT J AU Sarver, NW Gros, DF AF Sarver, Nina Wong Gros, Daniel F. TI A Modern Behavioral Treatment to Address Fetishism and Associated Functional Impairment SO CLINICAL CASE STUDIES LA English DT Article DE behavioral treatment; behavioral activation; sensate focused therapy; fetishism; paraphilias ID TERM PSYCHODYNAMIC PSYCHOTHERAPY; ACTIVATION TREATMENTS; SEXUAL DYSFUNCTION; DSM-IV; METAANALYSIS; THERAPY; AVERSION; INTERVENTIONS; SENSITIZATION; PARAPHILIAS AB The clinical research and treatment options for sexual paraphilias are scant and have generally been limited to psychodynamic and early behavioral approaches. This article highlights the application of two existing evidence-based modern behavioral interventions, specifically behavioral activation and sensate focused therapy, to treat foot fetishism/sexual impulses and co-occurring mood/anxiety symptoms in a 57-year-old male Vietnam War veteran. This brief 6-week treatment addressed the patient's complicating psychosocial factors and medical conditions, and focused on targeting behavioral avoidance symptoms associated with fetishism and depression (e.g., increasing socially and sexually appropriate and positive reinforcing behaviors in his environment). The patient no longer met diagnostic criteria for fetishism and endorsed significant reductions in depressed mood, anxiety, and stress at post-treatment and 1-month follow-up. This case illustrated how current behavioral treatments may be used to successfully treat patients with rare symptom presentations who may otherwise be neglected within a medical system. C1 [Sarver, Nina Wong] Boston Univ, Boston, MA 02215 USA. [Gros, Daniel F.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Gros, Daniel F.] Med Univ S Carolina, Charleston, SC USA. RP Gros, DF (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Mental Hlth Serv 116, 109 Bee St, Charleston, SC 29401 USA. EM grosd@musc.edu NR 64 TC 0 Z9 0 U1 3 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1534-6501 EI 1552-3802 J9 CLIN CASE STUD JI Clin. Case Stud. PD AUG PY 2014 VL 13 IS 4 BP 336 EP 351 DI 10.1177/1534650113512020 PG 16 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AW9PK UT WOS:000346589300004 ER PT J AU Walters, PR Zuckerbraun, BS AF Walters, Pamela R. Zuckerbraun, Brian S. TI Clostridium difficile Infection Clinical Challenges and Management Strategies SO CRITICAL CARE NURSE LA English DT Article ID POLYMERASE-CHAIN-REACTION; HEALTH-CARE SETTINGS; HOSPITALIZED-PATIENTS; SURGICAL-MANAGEMENT; DISEASE; DIARRHEA; COLITIS; EPIDEMIOLOGY; COLECTOMY; VANCOMYCIN AB Clostridium difficile has become the leading cause of nosocomial diarrhea in adults. A substantial increase has occurred in morbidity and mortality associated with disease caused by C difficile and in the identification of new hypervirulent strains, warranting a high clinical index of suspicion for infections due to this organism. Prevention of infection requires a multidisciplinary approach, including early recognition of disease, effective contact isolation precautions, adherence to disinfectant policies, and judicious use of antibiotics. Current treatment approaches are based on the severity of illness. As hypervirulent strains evolve, unsuccessful treatments are more common. Complicated colitis caused by C difficile may benefit from surgical intervention. Subtotal colectomy and end ileostomy have been the procedures of choice, but are associated with a high mortality rate because of late surgical consultation and use of surgery as a salvage therapy. A promising surgical alternative is creation of a diverting loop ileostomy with colonic lavage. C1 [Walters, Pamela R.] Univ Pittsburgh, Ctr Sports Med, Pittsburgh, PA 15213 USA. [Zuckerbraun, Brian S.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Zuckerbraun, Brian S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Walters, PR (reprint author), Univ Pittsburgh, Med Ctr, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM pamelarwalters@gmail.com NR 58 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 0279-5442 EI 1940-8250 J9 CRIT CARE NURSE JI Crit. Care Nurse PD AUG PY 2014 VL 34 IS 4 BP 24 EP 33 DI 10.4037/ccn2014822 PG 10 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA AW8WF UT WOS:000346538700003 PM 25086091 ER PT J AU Lane, SW Williams, DA Watt, FM AF Lane, Steven W. Williams, David A. Watt, Fiona M. TI Modulating the stem cell niche for tissue regeneration SO NATURE BIOTECHNOLOGY LA English DT Article ID SPINAL-CORD-INJURY; DYSTROPHIC EPIDERMOLYSIS-BULLOSA; BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC STEM; IN-VIVO; PROGENITOR CELLS; SELF-RENEWAL; VASCULAR NICHE; BETA-CATENIN; CIRCADIAN OSCILLATIONS AB The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell-extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell-niche interactions. C1 [Lane, Steven W.] Univ Queensland, Royal Brisbane Hosp, QIMR Berghofer Med Res Inst, Div Immunol, Herston, Qld, Australia. [Williams, David A.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Williams, David A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Williams, David A.] Harvard Stem Cell Inst, Boston, MA USA. [Watt, Fiona M.] Kings Coll London, Guys Hosp, Ctr Stem Cells & Regenerat Med, London, England. RP Watt, FM (reprint author), Kings Coll London, Guys Hosp, Ctr Stem Cells & Regenerat Med, London, England. EM fiona.watt@kcl.ac.uk RI Lane, Steven/C-3215-2012 OI Lane, Steven/0000-0002-8050-6209 FU National Health and Medical Research Council; Leukaemia Foundation of Australia; Rhys Pengelly Fellowship in Leukaemia Research; National Institutes of Health [DK062757]; Medical Research Council; Wellcome Trust FX We apologize for any omissions due to space constraints. S.W.L. is supported by research funding from the National Health and Medical Research Council, the Leukaemia Foundation of Australia and the Rhys Pengelly Fellowship in Leukaemia Research. D.A.W. is supported by National Institutes of Health DK062757. F.M.W. gratefully acknowledges the financial support of the Medical Research Council and the Wellcome Trust. NR 131 TC 74 Z9 76 U1 14 U2 54 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2014 VL 32 IS 8 BP 795 EP 803 DI 10.1038/nbt.2978 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AW7PF UT WOS:000346455900023 PM 25093887 ER PT J AU Naumova, AV Modo, M Moore, A Murry, CE Frank, JA AF Naumova, Anna V. Modo, Michel Moore, Anna Murry, Charles E. Frank, Joseph A. TI Clinical imaging in regenerative medicine SO NATURE BIOTECHNOLOGY LA English DT Article ID NEURAL STEM-CELLS; POSITRON-EMISSION-TOMOGRAPHY; PANCREATIC-ISLET CELLS; NONISCHEMIC DILATED CARDIOMYOPATHY; HEMATOPOIETIC PROGENITOR CELLS; REPORTER GENE-EXPRESSION; IRON-OXIDE NANOPARTICLES; MARROW MONONUCLEAR-CELLS; TYPE-1 DIABETES-MELLITUS; NORMAL ORGAN WEIGHTS AB In regenerative medicine, clinical imaging is indispensable for characterizing damaged tissue and for measuring the safety and efficacy of therapy. However, the ability to track the fate and function of transplanted cells with current technologies is limited. Exogenous contrast labels such as nanoparticles give a strong signal in the short term but are unreliable long term. Genetically encoded labels are good both short-and long-term in animals, but in the human setting they raise regulatory issues related to the safety of genomic integration and potential immunogenicity of reporter proteins. Imaging studies in brain, heart and islets share a common set of challenges, including developing novel labeling approaches to improve detection thresholds and early delineation of toxicity and function. Key areas for future research include addressing safety concerns associated with genetic labels and developing methods to follow cell survival, differentiation and integration with host tissue. Imaging may bridge the gap between cell therapies and health outcomes by elucidating mechanisms of action through longitudinal monitoring. C1 [Naumova, Anna V.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Naumova, Anna V.; Murry, Charles E.] Univ Washington, Ctr Cardiovasc Biol, Seattle, WA 98195 USA. [Naumova, Anna V.; Murry, Charles E.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Modo, Michel] Univ Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA USA. [Modo, Michel] Univ Pittsburgh, Ctr Neural Basis Cognit, Pittsburgh, PA USA. [Modo, Michel] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Modo, Michel] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Moore, Anna] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA USA. [Murry, Charles E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Murry, Charles E.] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Murry, Charles E.] Univ Washington, Dept Med Cardiol, Seattle, WA 98195 USA. [Frank, Joseph A.] NIH, Bethesda, MD 20892 USA. [Frank, Joseph A.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Murry, CE (reprint author), Univ Washington, Ctr Cardiovasc Biol, Seattle, WA 98195 USA. EM murry@uw.edu; jfrank@helix.nih.gov OI Modo, Michel/0000-0003-4436-735X FU Commonwealth of Pennsylvania, Department of Health [4100061184]; NINDS [R01NS082226]; NIBIB [1R01EB016629]; US National Institutes of Health (NIH) [P01HL094374, R01HL084642, U01HL100405, P01GM81619]; intramural research program in the Clinical Center and National Institutes of Biomedical Imaging and Bioengineering at the US National Institutes of Health; NIH [R24 DK096465] FX The authors would like to acknowledge Kristine Evers for proofreading of the manuscript and the following grant support: M.M. was supported by the Commonwealth of Pennsylvania, Department of Health (4100061184), NINDS (R01NS082226) and NIBIB (1R01EB016629). C.E.M. was supported by US National Institutes of Health (NIH) grants P01HL094374, R01HL084642, U01HL100405 and P01GM81619. J.A.F. was supported in part by the intramural research program in the Clinical Center and National Institutes of Biomedical Imaging and Bioengineering at the US National Institutes of Health. A.M. was supported in part by NIH grant R24 DK096465. NR 159 TC 52 Z9 55 U1 7 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 EI 1546-1696 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2014 VL 32 IS 8 BP 804 EP U121 DI 10.1038/nbt.2993 PG 15 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA AW7PF UT WOS:000346455900021 PM 25093889 ER PT J AU Lanuti, M Hong, HJ Ali, S Stock, C Temel, J Mathisen, D Michaelson, JS AF Lanuti, Michael Hong, Hyo-Jung Ali, Shihab Stock, Cameron Temel, Jennifer Mathisen, Douglas Michaelson, James S. TI Observations in lung cancer over multiple decades: an analysis of outcomes and cost at a single high-volume institution(aEuro) SO EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY LA English DT Article DE Lung cancer; Survival analysis; Time trends; Cost ID TRENDS; MORTALITY; SURVIVAL; SYSTEM AB This study reviews survival outcomes and cost of lung cancer care over multiple decades at a single high-volume institution. All patients with a diagnosis of lung cancer were analysed at a single institution from 1959 to 2010. Data were extracted from a tumour registry, which was linked to a longitudinal medical record, clinical data repository and social security master death index. In-depth survival analyses by stage were performed using Kaplan-Meier methods from 1981 to 2010. The analysis contains hospital billing data on 1025 lung cancer patients from 2004 to 2010. A total of 17 025 patients with lung cancer were identified over the study period. The 1-year, 5-year and 10-year all-cause mortality rates were 41, 78 and 87%, respectively. Non-small-cell lung cancer comprised 73% (n = 12 361) of cases where the median survival = 2.5 years and the population was 94% Caucasian. Lung cancer was most prevalent between ages 60-79 years of life. Female gender and adenocarcinoma were increasingly more prevalent over the decades. The 5-, 10- and 15-year survival for non-small-cell lung cancer (NSCLC) patients were 27, 15 and 5%, respectively. Death rates measured at 1 year after diagnosis were reduced; however, 5-year survival over each subsequent decade did not significantly change. In patients where the full scope of cost data were available, the median cost/patient with any stage NSCLC = $40 500, where 63% of the cost is expended in the first year after diagnosis. The average length of treatment for NSCLC was 20.2 months. The greatest single category of expense was chemotherapy (31%), followed by surgery (24%), inpatient medical (17%), radiation therapy (12%) and diagnostics (5%). For surgically treated patients, Stage II-IV costs were roughly twice those of Stage I. There has been no evident improvement over the past 3 decades in 5-year survival (similar to 27%) in patients diagnosed with NSCLC at a single high-volume institution. Improvement in 1-year survival is thought to be attributed to improvements in diagnosing lung cancer earlier. Most of the healthcare expenditure for lung cancer is incurred during the first year after diagnosis despite stage. C1 [Lanuti, Michael; Stock, Cameron; Mathisen, Douglas] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Lanuti, Michael; Hong, Hyo-Jung; Ali, Shihab; Stock, Cameron; Temel, Jennifer; Mathisen, Douglas; Michaelson, James S.] Harvard Univ, Sch Med, Boston, MA USA. [Hong, Hyo-Jung; Ali, Shihab; Michaelson, James S.] Massachusetts Gen Hosp, Lab Quantitat Med, Boston, MA 02114 USA. [Temel, Jennifer] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Lanuti, M (reprint author), 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM mlanuti@partners.org FU Division of Thoracic Surgery at the Massachusetts General Hospital FX Financial support for this study was provided by the Division of Thoracic Surgery at the Massachusetts General Hospital. NR 15 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1010-7940 EI 1873-734X J9 EUR J CARDIO-THORAC JI Eur. J. Cardio-Thorac. Surg. PD AUG PY 2014 VL 46 IS 2 BP 254 EP 261 DI 10.1093/ejcts/ezt611 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA AT5EZ UT WOS:000344968300020 PM 24453265 ER PT J AU Vivekanantham, S Dutta, A AF Vivekanantham, Sayinthen Dutta, Agneish TI Stanley Cobb (1887-1968): studying the link between the mind and the body SO JOURNAL OF MEDICAL BIOGRAPHY LA English DT Article DE Stanley Cobb; Massachusetts General Hospital; Harvard University; psychiatry; Harvey Cushing; neurology AB Stanley Cobb was an eminent neurologist that is regarded as 'the founder of biological psychiatry'. Having studied at Harvard university, Cobb had many varied interests, including ornithology and natural history. Following his undergraduate studies, he travelled widely and incorporated a period of study in Europe. Upon return to America, he was appointed Director of the Harvard Neurological Unit. Following a change of interest from neurology to psychiatry, Cobb was instrumental in establishing psychiatry as a specialty in America. The research laboratory, 'Stanley Cobb Laboratory for Psychiatric Research' at Massachusetts General Hospital was named in his honour and contribution to the service at the hospital. C1 [Vivekanantham, Sayinthen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Dutta, Agneish] Univ London Imperial Coll Sci Technol & Med, Sch Med, London, England. RP Vivekanantham, S (reprint author), 10 Woodside Way, Redhill RH1 5BD, Surrey, England. EM sayinthen.vivekanantham@gmail.com NR 8 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0967-7720 EI 1758-1087 J9 J MED BIOGR JI J. Med. Biogr. PD AUG PY 2014 VL 22 IS 3 BP 176 EP U84 DI 10.1177/0967772014526102 PG 5 WC History & Philosophy Of Science SC History & Philosophy of Science GA AU5DN UT WOS:000345627500009 PM 24737196 ER PT J AU Bichara, DA Bodugoz-Sentruk, H Ling, D Malchau, E Bragdon, CR Muratoglu, OK AF Bichara, David A. Bodugoz-Sentruk, Hatice Ling, Doris Malchau, Erik Bragdon, Charles R. Muratoglu, Orhun K. TI Osteochondral defect repair using a polyvinyl alcohol-polyacrylic acid (PVA-PAAc) hydrogel SO BIOMEDICAL MATERIALS LA English DT Article DE hydrogel; polyvinyl alcohol; polyacrylic acid; articular cartilage; osteochondral defect repair ID ARTICULAR-CARTILAGE; POLY(VINYL ALCOHOL); SURGICAL-TREATMENT; KNEE-JOINT; MICROFRACTURE; IMPLANTATION; SCAFFOLD; MODEL; WEAR AB Poly(vinyl alcohol) (PVA) hydrogels can be candidates for articular cartilage repair due to their high water content. We synthesized a PVA-poly(acrylic acid) (PAAc) hydrogel formulation and determined its ability to function as a treatment option for condylar osteochondral (OC) defects in a New Zealand white rabbit (NZWR) model for 12 weeks and 24 weeks. In addition to hydrogel OC implants, tensile bar-shaped hydrogels were also implanted subcutaneously to evaluate changes in mechanical properties as a function of in vivo duration. There were no statistically significant differences (p > 0.05) in the water content measured in the OC hydrogel implant that was harvested after 12 weeks and 24 weeks, and non-implanted controls. There were no statistically significant differences (p > 0.05) in the break stress, strain at break or modulus of the tensile bars either between groups. Histological analysis of the OC defect, synovial capsule and fibrous tissue around the tensile bars determined hydrogel biocompatibility. Twelve-week hydrogels were found to be in situ flush with the articular cartilage; meniscal tissue demonstrated an intact surface. Twenty-four week hydrogels protruded from the defect site due to lack of integration with subchondral tissue, causing fibrillation to the meniscal surface. Condylar micro-CT scans ruled out osteolysis and bone cysts of the subchondral bone, and no PVA-PAAc hydrogel contents were found in the synovial fluid. The PVA-PAAc hydrogel was determined to be fully biocompatible, maintained its properties over time, and performed well at the 12 week time point. Physical fixation of the PVA-PAAc hydrogel to the subchondral bone is required to ensure long-term performance of hydrogel plugs for OC defect repair. C1 [Bichara, David A.; Bodugoz-Sentruk, Hatice; Ling, Doris; Malchau, Erik; Bragdon, Charles R.; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Bichara, David A.; Bodugoz-Sentruk, Hatice; Bragdon, Charles R.; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Boston, MA USA. RP Bichara, DA (reprint author), Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. EM omuratoglu@partners.org FU DePuy Orthopaedics, Inc. FX This study was generously partially funded by DePuy Orthopaedics, Inc. NR 27 TC 3 Z9 3 U1 9 U2 29 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 1748-6041 EI 1748-605X J9 BIOMED MATER JI Biomed. Mater. PD AUG PY 2014 VL 9 IS 4 AR 045012 DI 10.1088/1748-6041/9/4/045012 PG 7 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA AU4YS UT WOS:000345614900012 PM 25050611 ER PT J AU Papakostas, GI Shelton, RC Zajecka, JM Bottiglieri, T Roffman, J Cassiello, C Stahl, SM Fava, M AF Papakostas, George I. Shelton, Richard C. Zajecka, John M. Bottiglieri, Teodoro Roffman, Joshua Cassiello, Clair Stahl, Stephen M. Fava, Maurizio TI Effect of Adjunctive L-Methylfolate 15 mg Among Inadequate Responders to SSRIs in Depressed Patients Who Were Stratified by Biomarker Levels and Genotype: Results From a Randomized Clinical Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID MAJOR DEPRESSION; PSYCHIATRIC-DISORDERS; RATING-SCALE; DOUBLE-BLIND; OBESITY; FOLATE; QUESTIONNAIRE; VITAMIN-B-12; HOMOCYSTEINE; METAANALYSIS AB Objective: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive l-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). Method: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design. Outpatients with SSRI-resistant MDD (DSM-IV criteria) received l-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by l-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to l-methylfolate versus placebo were evaluated; the primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28). The first patient was enrolled July 14, 2009, and the last patient completed April 28, 2011. Results: Seventy-five patients were enrolled. Patients with specific biological (body mass index >= 30 kg/m(2), elevated plasma levels of high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline had significantly (P <= .05) greater pooled mean change from baseline on the HDRS-28 with l-methylfolate versus placebo. Pooled mean change from baseline on the Clinical Global Impressions-Severity of Illness scale was significantly (P < .05) greater with l-methylfolate versus placebo for most genetic markers. Most combinations of baseline biological and genetic markers predicted significantly (P <= .05) greater reductions in pooled mean change from baseline in HDRS-28 scores with l-methylfolate versus placebo. Conclusions: Biomarkers associated with inflammation or metabolism and genomic markers associated with l-methylfolate synthesis and metabolism may identify patients with SSRI-resistant depression who are responsive to adjunctive therapy with l-methylfolate 15 mg. Confirmatory studies are needed. (C) Copyright 2014 Physicians Postgraduate Press, Inc. C1 [Papakostas, George I.; Roffman, Joshua; Cassiello, Clair; Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shelton, Richard C.] Univ Alabama Birmingham, Dept Psychiat, Birmingham, AL USA. [Zajecka, John M.] Rush Presbyterian St Lukes Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Bottiglieri, Teodoro] Baylor Res Inst, Inst Metab Dis, Dallas, TX USA. [Stahl, Stephen M.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Stahl, Stephen M.] Univ Cambridge, Cambridge CB2 1TN, England. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, One Bowdoin Sq,6th Fl, Boston, MA 02114 USA. EM gpapakostas@partners.org FU Pamlab, Inc, Covington, Louisiana FX This work was supported by grants from Pamlab, Inc, Covington, Louisiana. NR 40 TC 23 Z9 23 U1 1 U2 17 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2014 VL 75 IS 8 BP 855 EP 863 DI 10.4088/JCP.13m08947 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3RC UT WOS:000345530300013 PM 24813065 ER PT J AU Williams, NR Taylor, JJ Kerns, S Short, EB Kantor, EM George, MS AF Williams, Nolan R. Taylor, Joseph J. Kerns, Suzanne Short, E. Baron Kantor, Edward M. George, Mark S. TI Interventional Psychiatry: Why Now? SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter ID DEEP BRAIN-STIMULATION; OBSESSIVE-COMPULSIVE DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; TREATMENT-RESISTANT DEPRESSION; RANDOMIZED CONTROLLED-TRIAL; ELECTROCONVULSIVE-THERAPY; CLINICAL NEUROSCIENCE; MAJOR DEPRESSION; NEURAL CIRCUITS; EFFICACY C1 [Williams, Nolan R.; Taylor, Joseph J.; Kerns, Suzanne; Short, E. Baron; Kantor, Edward M.; George, Mark S.] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. [Williams, Nolan R.; Taylor, Joseph J.; George, Mark S.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Williams, NR (reprint author), Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. EM willianr@musc.edu OI Williams, Nolan/0000-0003-4368-3203 FU NIDA NIH HHS [R25 DA020537, F30 DA033748] NR 57 TC 2 Z9 2 U1 2 U2 3 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2014 VL 75 IS 8 BP 895 EP 897 DI 10.4088/JCP.13l08745 PG 3 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AU3RC UT WOS:000345530300019 PM 25191910 ER PT J AU Nigwekar, SU Solid, CA Ankers, E Malhotra, R Eggert, W Turchin, A Thadhani, RI Herzog, CA AF Nigwekar, Sagar U. Solid, Craig A. Ankers, Elizabeth Malhotra, Rajeev Eggert, William Turchin, Alexander Thadhani, Ravi I. Herzog, Charles A. TI Quantifying a Rare Disease in Administrative Data: The Example of Calciphylaxis SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE calciphylaxis; dialysis; renal disease; research design ID CALCIFIC UREMIC ARTERIOLOPATHY; CHRONIC KIDNEY-DISEASE; SODIUM-THIOSULFATE; VASCULAR CALCIFICATION; ATRIAL-FIBRILLATION; DIALYSIS; THERAPY; ANTICOAGULATION; CINACALCET AB BACKGROUND: Calciphylaxis, a rare disease seen in chronic dialysis patients, is associated with significant morbidity and mortality. As is the case with other rare diseases, the precise epidemiology of calciphylaxis remains unknown. Absence of a unique International Classification of Diseases (ICD) code impedes its identification in large administrative databases such as the United States Renal Data System (USRDS) and hinders patient-oriented research. This study was designed to develop an algorithm to accurately identify cases of calciphylaxis and to examine its incidence and mortality. DESIGN, PARTICIPANTS, AND MAIN MEASURES: Along with many other diagnoses, calciphylaxis is included in ICD-9 code 275.49, Other Disorders of Calcium Metabolism. Since calciphylaxis is the only disorder listed under this code that requires a skin biopsy for diagnosis, we theorized that simultaneous application of code 275.49 and skin biopsy procedure codes would accurately identify calciphylaxis cases. This novel algorithm was developed using the Partners Research Patient Data Registry (RPDR) (n = 11,451 chronic hemodialysis patients over study period January 2002 to December 2011) using natural language processing and review of medical and pathology records (the gold-standard strategy). We then applied this algorithm to the USRDS to investigate calciphylaxis incidence and mortality. KEY RESULTS: Comparison of our novel research strategy against the gold standard yielded: sensitivity 89.2 %, specificity 99.9 %, positive likelihood ratio 3,382.3, negative likelihood ratio 0.11, and area under the curve 0.96. Application of the algorithm to the USRDS identified 649 incident calciphylaxis cases over the study period. Although calciphylaxis is rare, its incidence has been increasing, with a major inflection point during 2006-2007, which corresponded with specific addition of calciphylaxis under code 275.49 in October 2006. Calciphylaxis incidence continued to rise even after limiting the study period to 2007 onwards (from 3.7 to 5.7 per 10,000 chronic hemodialysis patients; r = 0.91, p = 0.02). Mortality rates among calciphylaxis patients were noted to be 2.5-3 times higher than average mortality rates for chronic hemodialysis patients. CONCLUSIONS: By developing and successfully apply ing a novel algorithm, we observed a significant increase in calciphylaxis incidence. Because calciphylaxis is associated with extremely high mortality, our study provides valuable information for future patient-oriented calciphylaxis research, and also serves as a template for investigating other rare diseases. C1 [Nigwekar, Sagar U.; Malhotra, Rajeev; Turchin, Alexander; Thadhani, Ravi I.] Harvard Univ, Sch Med, Boston, MA USA. [Nigwekar, Sagar U.; Ankers, Elizabeth; Malhotra, Rajeev; Thadhani, Ravi I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Solid, Craig A.; Eggert, William; Herzog, Charles A.] Minneapolis Med Res Fdn Inc, Minneapolis, MN USA. [Turchin, Alexander] Brigham & Womens Hosp, Boston, MA 02115 USA. [Herzog, Charles A.] Univ Minnesota, Minneapolis, MN USA. [Herzog, Charles A.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. RP Nigwekar, SU (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sagarnigs@gmail.com OI Malhotra, Rajeev/0000-0003-0120-4630 FU NHLBI NIH HHS [K08 HL111210, K08HL111210, T32 HL007208]; NIDDK NIH HHS [DK094486, DK094872, HHSN267200715003C, K24 DK094872, R01 DK094486]; PHS HHS [HHSN267200715003C] NR 33 TC 15 Z9 15 U1 0 U2 0 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 AUG PY 2014 VL 29 SU 3 BP S924 EP S931 DI 10.1007/s11606-014-2910-1 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA AU1XU UT WOS:000345411700016 PM 25029979 ER PT J AU Prescott, J Bao, Y Viswanathan, AN Giovannucci, EL Hankinson, SE De Vivo, I AF Prescott, Jennifer Bao, Ying Viswanathan, Akila N. Giovannucci, Edward L. Hankinson, Susan E. De Vivo, Immaculata TI Dietary Insulin Index and Insulin Load in Relation to Endometrial Cancer Risk in the Nurses' Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GROWTH-FACTOR-I; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; C-PEPTIDE; GLYCEMIC INDEX; RESISTANCE; QUESTIONNAIRE; NUTRITION; GLUCOSE; WOMEN AB Background: Although unopposed estrogen exposure is considered the main driver of endometrial carcinogenesis, factors associated with states of insulin resistance and hyperinsulinemia are independently associated with endometrial cancer risk. We used dietary insulin load and insulin index scores to represent the estimated insulin demand of overall diets and assessed their association with endometrial cancer risk in the prospective Nurses' Health Study. Methods: We estimated incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of invasive endometrial cancer using Cox proportional hazards models. Between the baseline dietary questionnaire (1980) and 2010, we identified a total of 798 incident-invasive epithelial endometrial adenocarcinomas over 1,417,167 person-years of follow-up. Results: Dietary insulin scores were not associated with overall risk of endometrial cancer. Comparing women in the highest with the lowest quintile, the multivariable-adjusted RRs of endometrial cancer were 1.07 (95% CI, 0.84-1.35) for cumulative average dietary insulin load and 1.03 (95% CI, 0.82-1.31) for cumulative average dietary insulin index. Findings did not vary substantially by alcohol consumption, total dietary fiber intake, or body mass index and/or physical activity (P-heterogeneity >= 0.10). Conclusions: Intake of a diet predicted to stimulate a high postprandial insulin response was not associated with endometrial cancer risk in this large prospective study. Considering the complex interplay of diet, lifestyle, and genetic factors contributing to the hyperinsulinemic state, dietary measures alone may not sufficiently capture absolute long-term insulin exposure. Impact: This study is the first to investigate dietary insulin scores in relation to endometrial cancer risk. (C) 2014 AACR. C1 [Prescott, Jennifer; Bao, Ying; Giovannucci, Edward L.; Hankinson, Susan E.; De Vivo, Immaculata] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Prescott, Jennifer; Bao, Ying; Giovannucci, Edward L.; Hankinson, Susan E.; De Vivo, Immaculata] Harvard Univ, Sch Med, Boston, MA USA. [Viswanathan, Akila N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Prescott, Jennifer; De Vivo, Immaculata] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA. [Giovannucci, Edward L.] Harvard Univ, Sch Med, Dept Nutr & Epidemiol, Boston, MA USA. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP Prescott, J (reprint author), Brigham & Womens Hosp, 181 Longwood Ave,3rd Floor, Boston, MA 02115 USA. EM nhjxp@channing.harvard.edu FU NIH [P01 CA87969, R01 CA082838, U54 CA155626] FX The NHS project, E.L. Giovannucci, and S.E. Hankinson are supported by the NIH (P01 CA87969). I. De Vivo (R01 CA082838) and J. Prescott (U54 CA155626) were supported by funds from the NIH. NR 50 TC 5 Z9 5 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2014 VL 23 IS 8 BP 1512 EP 1520 DI 10.1158/1055-9965.EPI-14-0157 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200008 PM 24859872 ER PT J AU Jung, S Qian, ZR Yamauchi, M Bertrand, KA Fitzgerald, KC Inamura, K Kim, SA Mima, K Sukawa, Y Zhang, XH Wang, ML Smith-Warner, SA Wu, KN Fuchs, CS Chan, AT Giovannucci, EL Ng, K Cho, E Ogino, S Nishihara, R AF Jung, Seungyoun Qian, Zhi Rong Yamauchi, Mai Bertrand, Kimberly A. Fitzgerald, Kathryn C. Inamura, Kentaro Kim, Sun A. Mima, Kosuke Sukawa, Yasutaka Zhang, Xuehong Wang, Molin Smith-Warner, Stephanie A. Wu, Kana Fuchs, Charles S. Chan, Andrew T. Giovannucci, Edward L. Ng, Kimmie Cho, Eunyoung Ogino, Shuji Nishihara, Reiko TI Predicted 25(OH)D Score and Colorectal Cancer Risk According to Vitamin D Receptor Expression SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MOLECULAR PATHOLOGICAL EPIDEMIOLOGY; FOOD FREQUENCY QUESTIONNAIRE; MEDIATED ACTIVATION; SIGNALING PATHWAYS; PIK3CA MUTATION; KRAS MUTATIONS; COLON-CANCER; ASSOCIATIONS; DISEASE; MODELS AB Background: Despite accumulating evidence for the preventive effect of vitamin D on colorectal carcinogenesis, its precise mechanisms remain unclear. We hypothesized that vitamin D was associated with a lower risk of colorectal cancer with high-level vitamin D receptor (VDR) expression, but not with risk of tumor with low-level VDR expression. Methods: Among 140,418 participants followed from 1986 through 2008 in the Nurses' Health Study and the Health Professionals' Follow-up Study, we identified 1,059 incident colorectal cancer cases with tumor molecular data. The predicted 25-hydroxyvitamin D [25(OH)D] score was developed using the known determinants of plasma 25(OH)D. We estimated the HR for cancer subtypes using the duplication method Cox proportional hazards model. Results: Ahigher predicted 25(OH)D score was associated with a lower risk of colorectal cancer irrespective of VDR expression level (P-heterogeneity for subtypes = 0.75). Multivariate HRs (95% confidence intervals) comparing the highest with the lowest quintile of predicted 25(OH)D scores were 0.48 (0.30-0.78) for VDR-negative tumor and 0.56 (0.42-0.75) for VDR-positive tumor. Similarly, the significant inverse associations of the predicted 25(OH)D score with colorectal cancer risk did not significantly differ by KRAS, BRAF, or PIK3CA status (P-heterogeneity for subtypes >= 0.22). Conclusions: Ahigher predicted vitamin Dscore was significantly associated with a lower colorectal cancer risk, regardless of VDR status and other molecular features examined. Impact: The preventive effect of vitamin D on colorectal carcinogenesis may not totally depend on tumor factors. Host factors (such as local and systemic immunity) may need to be considered. (C) 2014 AACR. C1 [Jung, Seungyoun; Bertrand, Kimberly A.; Zhang, Xuehong; Fuchs, Charles S.; Chan, Andrew T.; Giovannucci, Edward L.; Cho, Eunyoung] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Div Network Med,Dept Med, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02115 USA. [Qian, Zhi Rong; Yamauchi, Mai; Inamura, Kentaro; Kim, Sun A.; Mima, Kosuke; Sukawa, Yasutaka; Fuchs, Charles S.; Ng, Kimmie; Ogino, Shuji; Nishihara, Reiko] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fitzgerald, Kathryn C.; Wang, Molin; Smith-Warner, Stephanie A.; Giovannucci, Edward L.; Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wang, Molin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Smith-Warner, Stephanie A.; Wu, Kana; Giovannucci, Edward L.; Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Inamura, Kentaro] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Cho, Eunyoung] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Providence, RI 02912 USA. RP Nishihara, R (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,Room 304, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu; rnishiha@hsph.harvard.edu FU NIH [P01 CA87969, P01 CA55075, UM1 CA167552, P50 CA127003, R01 CA137178, R01 CA151993, R01 CA136950, R25 CA098566, K07 CA148894]; American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation; Bennett Family Fund; Asan Medical Center; Japan Society for Promotion of Sciences; Takashi Tsuruo Memorial Fund; Uehara Memorial Foundation; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance FX This work was supported by NIH grants (P01 CA87969 to S.E. Hankinson; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S. Fuchs; R01 CA137178 to A.T. Chan; R01 CA151993 to S. Ogino; R01 CA136950 to E. Cho; R25 CA098566 to M.J. Stampfer, and K07 CA148894 to K. Ng), by grants from the American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation (Career Development Award to K. Ng), Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and by postdoctoral fellowships from Asan Medical Center (to S.A. Kim), Japan Society for Promotion of Sciences (to K. Inamura), Takashi Tsuruo Memorial Fund (to K. Inamura), and the Uehara Memorial Foundation (to K. Mima). NR 58 TC 7 Z9 7 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2014 VL 23 IS 8 BP 1628 EP 1637 DI 10.1158/1055-9965.EPI-14-0229 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200020 PM 24920642 ER PT J AU Mazzola, E Chipman, J Cheng, SC Parmigiani, G AF Mazzola, Emanuele Chipman, Jonathan Cheng, Su-Chun Parmigiani, Giovanni TI Recent BRCAPRO Upgrades Significantly Improve Calibration SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CONTRALATERAL BREAST-CANCER; MUTATION CARRIERS; INCREMENTAL VALUE; RISK; PREDICTION; MARKERS; PERFORMANCE; MODELS; WOMEN AB The recent release of version 2.0-8 of the BayesMendel package contains an updated BRCAPRO risk prediction model, which includes revised modeling of contralateral breast cancer (CBC) penetrance, provisions for pedigrees of mixed ethnicity and an adjustment for mastectomies among family members. We estimated penetrance functions for CBC by a combination of parametric survival modeling of literature data and deconvolution of SEER9 data. We then validated the resulting updated model of CBC in BRCAPRO by comparing it with the previous release (BayesMendel 2.0-7), using pedigrees from the Cancer Genetics Network (CGN) Model Validation Study. Version 2.0-8 of BRCAPRO discriminates BRCA1/BRCA2 carriers from noncarriers with similar accuracy compared with the previous version (increase in AUC, 0.0043), is slightly more precise in terms of the root-mean-square error (decrease in RMSE, 0.0108), and it significantly improves calibration (ratio of observed to expected events of 0.9765 in version 2.0-8, compared with 0.8910 in version 2.0-7). We recommend that the new version be used in clinical counseling, particularly in settings where families with CBC are common. (C) 2014 AACR. C1 [Mazzola, Emanuele; Chipman, Jonathan; Cheng, Su-Chun; Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Mazzola, E (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02115 USA. EM mazzola@jimmy.harvard.edu FU NIH/NCI [5R21CA177233-02, 5P30CA006516-49] FX This work has been supported by NIH/NCI awards 5R21CA177233-02 (to G. Parmigiani, PI) and 5P30CA006516-49 (to E. Benz, PI). NR 22 TC 5 Z9 5 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2014 VL 23 IS 8 BP 1689 EP 1695 DI 10.1158/1055-9965.EPI-13-1364 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AT9WJ UT WOS:000345274200027 PM 24891549 ER PT J AU Lin, DCC Diamandis, EP Januzzi, JL Maisel, A Jaffe, AS Clerico, A AF Lin, Danny C. C. Diamandis, Eleftherios P. Januzzi, James L., Jr. Maisel, Alan Jaffe, Allan S. Clerico, Aldo TI Natriuretic Peptides in Heart Failure SO CLINICAL CHEMISTRY LA English DT Editorial Material C1 [Lin, Danny C. C.] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Diamandis, Eleftherios P.] Univ Toronto, Dept Lab Med & Pathobiol, Div Clin Biochem, Toronto, ON, Canada. [Diamandis, Eleftherios P.] Univ Hlth Network, Dept Clin Biochem, Toronto, ON, Canada. [Diamandis, Eleftherios P.] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5T 3L9, Canada. [Januzzi, James L., Jr.] Massachusetts Gen Hosp, Coronary Care Unit, Boston, MA 02114 USA. [Januzzi, James L., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Maisel, Alan] Univ Calif San Diego, San Diego, CA 92103 USA. [Maisel, Alan] Univ Calif San Diego, Coronary Care Unit, San Diego, CA 92103 USA. [Maisel, Alan] Univ Calif San Diego, Vet Affairs San Diego Med Ctr, San Diego, CA 92103 USA. [Jaffe, Allan S.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. [Jaffe, Allan S.] Mayo Clin, Clin Core Lab Serv, Rochester, MN USA. [Clerico, Aldo] Scuola Superiore St Anna, Fdn CNR Toscana G Monasterio, Lab Cardiovasc Endocrinol & Cell Biol, Pisa, Italy. RP Diamandis, EP (reprint author), Mt Sinai Hosp, Dept Pathol & Lab Med, 6th Floor,Rm 6-201,Box 32,60 Murray St, Toronto, ON M5T 3L9, Canada. EM ediamandis@mtsinai.on.ca NR 0 TC 4 Z9 4 U1 1 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 EI 1530-8561 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2014 VL 60 IS 8 BP 1040 EP 1046 DI 10.1373/clinchem.2014.223057 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA AT2QL UT WOS:000344779100004 PM 24700774 ER PT J AU Charles, R Sakurai, T Takahashi, N Elder, GA Sosa, MAG Young, LJ Buxbaum, JD AF Charles, Rhonda Sakurai, Takeshi Takahashi, Nagahide Elder, Gregory A. Sosa, Miguel A. Gama Young, Larry J. Buxbaum, Joseph D. TI Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice SO DISEASE MODELS & MECHANISMS LA English DT Article DE AVPR1A; Humanized mouse; Social behavior; Species-specific; Microsatellite; Autism ID ANXIETY-RELATED BEHAVIOR; VASOPRESSIN RECEPTOR; KNOCKOUT MICE; PREPULSE INHIBITION; PROMOTER REGION; PSYCHIATRIC-DISORDERS; MONOGAMOUS VOLE; BINDING-SITES; MESSENGER-RNA; V-1A RECEPTOR AB Central arginine vasopressin receptor 1A(AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome(BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions. C1 [Charles, Rhonda; Sakurai, Takeshi; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. [Charles, Rhonda; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA. [Sakurai, Takeshi; Takahashi, Nagahide; Elder, Gregory A.; Sosa, Miguel A. Gama; Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Elder, Gregory A.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Elder, Gregory A.] James J Peters VA Med Ctr, Neurol Serv, Bronx, NY 10468 USA. [Sosa, Miguel A. Gama] James J Peters VA Med Ctr, Res & Dev Serv, Bronx, NY 10468 USA. [Young, Larry J.] Emory Univ, Yerkes Natl Primate Res Ctr, Dept Psychiat & Behav Sci, Ctr Translat Social Neurosci, Atlanta, GA 30329 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA. RP Buxbaum, JD (reprint author), Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA. EM joseph.buxbaum@mssm.edu OI Buxbaum, Joseph/0000-0001-8898-8313 FU Seaver Foundation; Autism Science Foundation; National Institutes of Health [MH056897, MH064692, P51OD11132] FX This work was supported by the Seaver Foundation and a predoctoral fellowship from the Autism Science Foundation to R. C. Additional support was provided by National Institutes of Health grants [MH056897 and MH064692 to L.J.Y. and P51OD11132 to Yerkes National Primate Research Center]. NR 55 TC 3 Z9 3 U1 2 U2 15 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 EI 1754-8411 J9 DIS MODEL MECH JI Dis. Model. Mech. PD AUG PY 2014 VL 7 IS 8 BP 1013 EP 1022 DI 10.1242/dmm.017053 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AT5TF UT WOS:000345004200009 PM 24924430 ER PT J AU Giardiello, FM Allen, JI Axilbund, JE Boland, CR Burke, CA Burt, RW Church, JM Dominitz, JA Johnson, DA Kaltenbach, T Levin, TR Lieberman, DA Robertson, DJ Syngal, S Rex, DK AF Giardiello, Francis M. Allen, John I. Axilbund, Jennifer E. Boland, C. Richard Burke, Carol A. Burt, Randall W. Church, James M. Dominitz, Jason A. Johnson, David A. Kaltenbach, Tonya Levin, Theodore R. Lieberman, David A. Robertson, Douglas J. Syngal, Sapna Rex, Douglas K. TI Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancere SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID NONPOLYPOSIS COLON-CANCER; MISMATCH-REPAIR GENES; REVISED BETHESDA GUIDELINES; COST-EFFECTIVENESS ANALYSIS; MSH2 MUTATION CARRIERS; MUIR-TORRE-SYNDROME; TUMOR MICROSATELLITE INSTABILITY; TESTING STRATEGIES; ENDOMETRIAL CANCER; GERMLINE MUTATIONS AB The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided. C1 [Giardiello, Francis M.; Axilbund, Jennifer E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Allen, John I.] Yale Univ, Sch Med, New Haven, CT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Burke, Carol A.; Church, James M.] Cleveland Clin, Cleveland, OH 44106 USA. [Burt, Randall W.] Univ Utah, Salt Lake City, UT USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Johnson, David A.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Kaltenbach, Tonya] Stanford Univ, Palo Alto, CA 94304 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Robertson, Douglas J.] White River Junct VA Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, White River Jct, VT USA. [Syngal, Sapna] Brigham & Womens Hosp, Boston, MA 02115 USA. [Syngal, Sapna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Giardiello, FM (reprint author), 1830 East Monument St,Room 431, Baltimore, MD 21205 USA. EM fgiardi@jhmi.edu OI Dominitz, Jason/0000-0002-8070-7086 FU Olympus American Inc. FX These authors disclose the following: C. Richard Boland and Randall W. Burt are consultants for Myriad Genetic. Jason A. Dominitz received resources in support of this work from the VA Puget Sound Health Care System, Seattle, Washington. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. David A. Johnson is a clinical investigator for EXACT Sciences, a consultant for Epigenomics, and on the advisory board for Given Imaging. Tonya Kaltenbach is a research grant recipient and consultant for Olympus American Inc. David A. Lieberman is on the advisory board for Given Imaging and Exact Sciences. Douglas J. Robertson is on the advisory board of Given Imaging. Sapna Syngal is an unpaid advisor/collaborator with Myriad genetics and a consultant for Archimedes, Inc. Douglas K. Rex is a consultant for Olympus America, Braintree Laboratories, Ferring Pharmaceuticals, Epigenomics, EXACT Sciences, Given Imaging, received research support from Olympus America; and is on the speaker's bureau for Olympus America and Boston Scientific. The remaining authors disclose no conflicts. NR 162 TC 69 Z9 70 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2014 VL 109 IS 8 BP 1159 EP 1179 DI 10.1038/ajg.2014.186 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS7UE UT WOS:000344459300008 PM 25070057 ER PT J AU Lochhead, P Chan, AT Giovannucci, E Fuchs, CS Wu, KN Nishihara, R O'Brien, M Ogino, S AF Lochhead, Paul Chan, Andrew T. Giovannucci, Edward Fuchs, Charles S. Wu, Kana Nishihara, Reiko O'Brien, Michael Ogino, Shuji TI Progress and Opportunities in Molecular Pathological Epidemiology of Colorectal Premalignant Lesions SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Review ID ISLAND METHYLATOR PHENOTYPE; RAS PROTOONCOGENE MUTATION; PARAFFIN-EMBEDDED TISSUES; BETA-CATENIN ALTERATIONS; UNIQUE TUMOR PRINCIPLE; LIFE-STYLE FACTORS; III COLON-CANCER; BODY-MASS INDEX; KRAS CODONS 12; MICROSATELLITE-INSTABILITY AB Molecular pathological epidemiology (MPE) is an integrative molecular and population health science that addresses the molecular pathogenesis and heterogeneity of disease processes. The MPE of colonic and rectal premalignant lesions (including hyperplastic polyps, tubular adenomas, tubulovillous adenomas, villous adenomas, traditional serrated adenomas, sessile serrated adenomas/sessile serrated polyps, and hamartomatous polyps) can provide unique opportunities for examining the influence of diet, lifestyle, and environmental exposures on specific pathways of carcinogenesis. Colorectal neoplasia can provide a practical model by which both malignant epithelial tumor (carcinoma) and its precursor are subjected to molecular pathological analyses. KRAS, BRAF, and PIK3CA oncogene mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation are commonly examined tumor biomarkers. Future opportunities include interrogation of comprehensive genomic, epigenomic, or panomic datasets, and the adoption of in vivo pathology techniques. Considering the colorectal continuum hypothesis and emerging roles of gut microbiota and host immunity in tumorigenesis, detailed information on tumor location is important. There are unique strengths and caveats, especially with regard to case ascertainment by colonoscopy. The MPE of colorectal premalignant lesions can identify etiologic exposures associated with neoplastic initiation and progression, help us better understand colorectal carcinogenesis, and facilitate personalized prevention, screening, and therapy. C1 [Lochhead, Paul] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Giovannucci, Edward; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Chan, Andrew T.; Giovannucci, Edward; Fuchs, Charles S.; Nishihara, Reiko; 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; Wu, Kana; Nishihara, Reiko] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Fuchs, Charles S.; Nishihara, Reiko; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [O'Brien, Michael] Boston Univ, Med Ctr, Dept Pathol, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Lochhead, P (reprint author), Univ Aberdeen, Inst Med Sci, Gastrointestinal Res Grp, Aberdeen AB25 2ZD, Scotland. EM paul.lochhead@abdn.ac.uk; shuji_ogino@dfci.harvard.edu FU USA National Institute of Health (NIH) [R01 CA137178, P50 CA127003, R01 CA151993, P01 CA87969] FX This work was supported by grants from USA National Institute of Health (NIH) (R01 CA137178 (to A.T.C.), P50 CA127003 (to C.S.F.), R01 CA151993 (to S.O.), and P01 CA87969 (to S.E. Hankinson)). P.L. is a Scottish Government Clinical Academic Fellow. A.T.C. is a Damon Runyon Clinical Investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the decision to submit the manuscript for publication, or in the writing of the manuscript. NR 174 TC 22 Z9 23 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 EI 1572-0241 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD AUG PY 2014 VL 109 IS 8 BP 1205 EP 1214 DI 10.1038/ajg.2014.153 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AS7UE UT WOS:000344459300011 PM 24935274 ER PT J AU Singh, AK Goralnick, E Velmahos, G Biddinger, PD Gates, J Sodickson, A AF Singh, Ajay K. Goralnick, Eric Velmahos, George Biddinger, Paul D. Gates, Jonathan Sodickson, Aaron TI Radiologic Features of Injuries From the Boston Marathon Bombing at Three Hospitals SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE blast injuries; Boston Marathon bombing; shrapnel; trauma ID BLAST INJURIES; EXPLOSIONS AB OBJECTIVE. The aim of this study is to describe the radiologic imaging findings of primary, secondary, tertiary, and quaternary blast injuries in patients injured in the Boston Marathon bombing on April 15, 2013. MATERIALS AND METHODS. A total of 43 patients presenting to three acute care hospitals and undergoing radiologic investigation within 7 hours of the time of the bombing on April 15, 2013, were included in this study. The radiographic and CT features of these patients were evaluated for imaging findings consistent with primary, secondary, tertiary, and quaternary blast injury. RESULTS. There were no pulmonary or gastrointestinal manifestations of the primary blast wave on imaging. Secondary blast injuries identified on imaging included a total of 189 shrapnel fragments identified in 32 of the 43 patients. The shrapnel was identified most often in the soft tissues of the leg (36.5%), thigh (31.2%), and pelvis (13.2%). Imaging identified 125 ball bearings, 10 nails, one screw, 44 metal fragments, and nine other (gravel, glass, etc.) foreign bodies. CONCLUSION. Injuries from the Boston Marathon bombing were predominantly from the secondary blast wave and resulted in traumatic injuries predominantly of the lower extremities. The most common shrapnel found on radiologic evaluation was the ball bearing. C1 [Singh, Ajay K.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, Boston, MA 02114 USA. [Goralnick, Eric] Harvard Univ, Brigham & Womens Hosp, Dept Emergency Med, Sch Med, Boston, MA 02114 USA. [Velmahos, George] Harvard Univ, Massachusetts Gen Hosp, Dept Trauma Surg, Sch Med, Boston, MA 02114 USA. [Biddinger, Paul D.] Harvard Univ, Massachusetts Gen Hosp, Dept Emergency Med, Sch Med, Boston, MA 02114 USA. [Gates, Jonathan] Harvard Univ, Brigham & Womens Hosp, Dept Trauma Surg, Sch Med, Boston, MA 02114 USA. [Sodickson, Aaron] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02114 USA. RP Singh, AK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, White 270,55 Fruit St, Boston, MA 02114 USA. EM asingh1@partners.org NR 16 TC 7 Z9 7 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP 235 EP 239 DI 10.2214/AJR.14.12549 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400018 PM 25055253 ER PT J AU Thipphavong, S Duigenan, S Schindera, ST Gee, MS Philips, S AF Thipphavong, Seng Duigenan, Shauna Schindera, Sebastian T. Gee, Michael S. Philips, Shaile TI Nonneoplastic, Benign, and Malignant Splenic Diseases: Cross-Sectional Imaging Findings and Rare Disease Entities SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE CT; MRI; neoplasm; spleen ID EXTRAMEDULLARY HEMATOPOIESIS; NONOPERATIVE MANAGEMENT; EXTRAOSSEOUS MYELOMA; PRIMARY ANGIOSARCOMA; HYDATID-DISEASE; SPLEEN; CT; MR; SPECTRUM; INJURY AB OBJECTIVE. Splenic lesions are commonly encountered and are often incidental in nature. Benign splenic vascular neoplasms include hemangioma, hamartoma, lymphangioma, extramedullary hematopoiesis (EMH), and sclerosing angiomatoid nodular transformation (SANT). Uncommonly encountered entities of the spleen include focal EMH, focal myeloma, angiomyolipoma, and SANT. Primary splenic angiosarcoma is the most common malignant nonhematolymphoid malignancy of the spleen. Lymphoma, myeloma, and metastases are the other malignant entities involving the spleen. The clinical presentation, key imaging findings, and associations of benign, neoplastic, and malignant diseases that can involve the spleen will be discussed. CONCLUSION. Radiologists can use multimodality imaging to diagnose entities involving the spleen by recognizing key imaging features and considering patient characteristics. However, biopsy may be warranted for definitive diagnosis when imaging findings are nonspecific. C1 [Thipphavong, Seng] Univ Toronto, Womens Coll Hosp, Joint Dept Med Imaging, Toronto, ON M5S 1B2, Canada. [Duigenan, Shauna] Ottawa Hosp, Dept Radiol, Ottawa, ON, Canada. [Schindera, Sebastian T.] Univ Basel Hosp, Clin Radiol & Nucl Med, CH-4031 Basel, Switzerland. [Gee, Michael S.] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Philips, Shaile] Univ Texas San Antonio, Hlth Sci Ctr, Dept Radiol, San Antonio, TX 78284 USA. RP Thipphavong, S (reprint author), Univ Toronto, Womens Coll Hosp, Joint Dept Med Imaging, 76 Grenville St,2nd Fl,Rm 2238, Toronto, ON M5S 1B2, Canada. EM seng.thipphavong@uhn.ca NR 30 TC 7 Z9 8 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP 315 EP 322 DI 10.2214/AJR.13.11777 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400030 PM 25055265 ER PT J AU Kong, CY Meng, L Omer, ZB Swan, JS Srouji, S Gazelle, GS Fennessy, FM AF Kong, Chung Y. Meng, Lesley Omer, Zehra B. Swan, J. Shannon Srouji, Serene Gazelle, G. Scott Fennessy, Fiona M. TI MRI-Guided Focused Ultrasound Surgery for Uterine Fibroid Treatment: A Cost-Effectiveness Analysis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE cost effectiveness; hysterectomy; MRI-guided focused ultrasound; uterine fibroids ID RANDOMIZED CONTROLLED-TRIAL; ARTERY EMBOLIZATION; UNITED-STATES; HYSTERECTOMY; LEIOMYOMAS; MYOMECTOMY; QUALITY; HEALTH; COMPLICATIONS; OUTCOMES AB OBJECTIVE. The purpose of this article is to evaluate the cost effectiveness of a treatment strategy for symptomatic uterine fibroids that uses MRI-guided focused ultrasound as a first-line therapy relative to uterine artery embolization (UAE) or hysterectomy. MATERIALS AND METHODS. We developed a decision-analytic model to compare the cost effectiveness of three first-line treatment strategies: MRI-guided focused ultrasound, UAE, and hysterectomy. Treatment-specific short- and long-term utilities, lifetime costs, and quality-adjusted life years (QALYs) were incorporated, allowing us to conduct an incremental cost-effectiveness analysis, using a societal willingness-to-pay (WTP) threshold of $50,000/QALY to designate a strategy as cost effective. Sensitivity analyses were subsequently performed on all key parameters. RESULTS. In the base-case analysis, UAE as a first-line treatment of symptomatic fibroids was the most effective and expensive strategy (22.75 QALYs; $22,968), followed by MRI-guided focused ultrasound (22.73 QALYs; $20,252) and hysterectomy (22.54 QALYs; $11,253). MRI-guided focused ultrasound was cost effective relative to hysterectomy, with an associated incremental cost-effectiveness ratio (ICER) of $47,891/QALY. The ICER of UAE relative to MRI-guided focused ultrasound was $234,565/QALY, exceeding the WTP threshold of $50,000/QALY, therefore rendering MRI-guided focused ultrasound also cost effective relative to UAE. In sensitivity analyses, results were robust to changes in most parameters but were sensitive to changes in probabilities of recurrence, symptom relief, and quality-of-life measures. CONCLUSION. First-line treatment of eligible women with MRI-guided focused ultrasound is a cost-effective noninvasive strategy. For those not eligible for MRI-guided focused ultrasound, UAE remains a cost-effective option. These recommendations integrate both the short- and long-term decrements in quality of life associated with the specific treatment modalities. C1 [Kong, Chung Y.; Meng, Lesley; Omer, Zehra B.; Swan, J. Shannon; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, Boston, MA 02114 USA. [Kong, Chung Y.; Swan, J. Shannon; Srouji, Serene; Gazelle, G. Scott; Fennessy, Fiona M.] Harvard Univ, Sch Med, Boston, MA USA. [Srouji, Serene] Brigham & Womens Hosp, Ctr Infertil & Reprod Surg, Boston, MA 02115 USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Fennessy, Fiona M.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Kong, CY (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, 101 Merrimac St,10th Fl, Boston, MA 02114 USA. EM joey@mgh-ita.org FU National Institutes of Health [K25-CA133141]; GE Healthcare AUR Radiology Research Academic Fellowship FX C. Y. Kong has received support from the National Institutes of Health (grant K25-CA133141). F. M. Fennessy has received a GE Healthcare AUR Radiology Research Academic Fellowship. G. S. Gazelle is a consultant for GE Healthcare. NR 51 TC 9 Z9 9 U1 1 U2 5 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP 361 EP 371 DI 10.2214/AJR.13.11446 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400037 PM 25055272 ER PT J AU Taneja, AK Kattapuram, SV Chang, CY Simeone, FJ Bredella, MA Torriani, M AF Taneja, Atul K. Kattapuram, Susan V. Chang, Connie Y. Simeone, F. Joseph Bredella, Miriam A. Torriani, Martin TI MRI Findings of Rotator Cuff Myotendinous Junction Injury SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE MRI; myotendinous junction; rotator cuff; strain; tear ID STEROID INJECTIONS; TENDON; RUPTURE; INFRASPINATUS; DENERVATION; LESION AB OBJECTIVE. The purpose of this article is to describe the MRI features of rotator cuff myotendinous junction injuries. MATERIALS AND METHODS. We retrospectively identified MRI cases with myotendinous junction injury of the rotator cuff muscles and reviewed clinical, imaging, and surgical records. MR images were reviewed independently by two musculoskeletal radiologists to grade myotendinous junction injuries (strain, partial tear, or complete tear) and to assess for concurrent tendon tears (partial or full thickness) and bone changes (fracture or contusion). RESULTS. The final study group comprised 16 subjects. The mean age was 38 years, with a majority of men (56%). The left shoulder was affected in 56% of subjects, with the dominant upper limb affected in 50%. The mean time between symptoms and MRI was 19 days. Subjects reported heavy lifting (19%), landing on the arm after a fall (19%), or prior shoulder therapeutic injection (25%). Myotendinous junction injuries affected the infraspinatus muscle (50%), followed by the supraspinatus (31%), subscapularis (25%), and teres minor (19%) muscles. About one fifth of subjects presented with more than one muscle affected, and 94% did not present with tears of the corresponding tendons. Most myotendinous junction injuries were strains (80%), followed by partial tears (20%). No complete tears were identified. There was no correlation between myotendinous junction injury and the presence of bone changes or the presence of tendon tears (p > 0.05). CONCLUSION. Rotator cuff myotendinous junction injuries affect mostly the infraspinatus and supraspinatus muscles, usually in a strain pattern and without tear of the corresponding tendon attachment. C1 [Taneja, Atul K.] Hosp Coracao HCor, Ctr Diagnost, Div Musculoskeletal Radiol, Sao Paulo, Brazil. [Taneja, Atul K.] Teleimagem, Sao Paulo, Brazil. [Taneja, Atul K.] Hosp Israelita Albert Einstein, Div Musculoskeletal Radiol, Dept Imaging, Sao Paulo, Brazil. [Kattapuram, Susan V.; Chang, Connie Y.; Simeone, F. Joseph; Bredella, Miriam A.; Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, Boston, MA 02114 USA. [Kattapuram, Susan V.; Chang, Connie Y.; Simeone, F. Joseph; Bredella, Miriam A.; Torriani, Martin] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Imaging & Intervent, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@mgh.harvard.edu RI Taneja, Atul/N-3133-2014 OI Taneja, Atul/0000-0002-4655-2033 NR 20 TC 4 Z9 4 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP 406 EP 411 DI 10.2214/AJR.13.11474 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400042 PM 25055277 ER PT J AU Wang, YB Ebuoma, L Saksena, M Liu, B Specht, M Rafferty, E AF Wang, Yingbing Ebuoma, Lilian Saksena, Mansi Liu, Bob Specht, Michelle Rafferty, Elizabeth TI Clinical Evaluation of a Mobile Digital Specimen Radiography System for Intraoperative Specimen Verification SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE lumpectomy; mobile specimen radiography; specimen radiography; specimen verification ID CARCINOMA IN-SITU; BREAST-CONSERVING THERAPY; RADIATION-THERAPY; MARGIN STATUS; SURGERY; MAMMOGRAPHY; MANAGEMENT; RECURRENCE; MASTECTOMY; STANDARDS AB OBJECTIVE. Use of mobile digital specimen radiography systems expedites intraoperative verification of excised breast specimens. The purpose of this study was to evaluate the performance of a such a system for verifying targets. MATERIALS AND METHODS. A retrospective review included 100 consecutive pairs of breast specimen radiographs. Specimens were imaged in the operating room with a mobile digital specimen radiography system and then with a conventional digital mammography system in the radiology department. Two expert reviewers independently scored each image for image quality on a 3-point scale and confidence in target visualization on a 5-point scale. A target was considered confidently verified only if both reviewers declared the target to be confidently detected. RESULTS. The 100 specimens contained a total of 174 targets, including 85 clips (49%), 53 calcifications (30%), 35 masses (20%), and one architectural distortion (1%). Although a significantly higher percentage of mobile digital specimen radiographs were considered poor quality by at least one reviewer (25%) compared with conventional digital mammograms (1%), 169 targets (97%), were confidently verified with mobile specimen radiography; 172 targets (98%) were verified with conventional digital mammography. Three faint masses were not confidently verified with mobile specimen radiography, and conventional digital mammography was needed for confirmation. One faint mass and one architectural distortion were not confidently verified with either method. CONCLUSION. Mobile digital specimen radiography allows high diagnostic confidence for verification of target excision in breast specimens across target types, despite lower image quality. Substituting this modality for conventional digital mammography can eliminate delays associated with specimen transport, potentially decreasing surgical duration and increasing operating room throughput. C1 [Wang, Yingbing; Ebuoma, Lilian; Saksena, Mansi; Liu, Bob; Rafferty, Elizabeth] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Specht, Michelle] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Wang, YB (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 216, Boston, MA 02114 USA. EM ywang34@partners.org NR 14 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP 457 EP 462 DI 10.2214/AJR.13.11408 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400051 PM 25055285 ER PT J AU Shyn, PB Mauri, G Alencar, RO Tatli, S Shah, SH Morrison, PR Catalano, PJ Silverman, SG AF Shyn, Paul B. Mauri, Giovanni Alencar, Raquel Oliva Tatli, Servet Shah, Shaan H. Morrison, Paul R. Catalano, Paul J. Silverman, Stuart G. TI Percutaneous Imaging-Guided Cryoablation of Liver Tumors: Predicting Local Progression on 24-Hour MRI SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ablation procedures; cancer; gastrointestinal imaging; hepatobiliary system; MRI; vascular and interventional imaging ID RADIOFREQUENCY ABLATION; HEPATOCELLULAR-CARCINOMA; HEPATIC-TUMORS; FOLLOW-UP; CONTRAST ENHANCEMENT; METASTASES; CT; CRYOTHERAPY; EXPERIENCE; SURVIVAL AB OBJECTIVE. The purpose of this study was to determine which MRI features observed 24 hours after technically successful percutaneous cryoablation of liver tumors predict subsequent local tumor progression and to describe the evolution of imaging findings after cryoablation. MATERIALS AND METHODS. Thirty-nine adult patients underwent technically successful imaging-guided percutaneous cryoablation of 54 liver tumors (hepatocellular carcinoma, 8; metastases, 46). MRI features pertaining to the tumor, ablation margin, and surrounding liver 24 hours after treatment were assessed independently by two readers. Fisher exact or Wilcoxon rank sum tests (significant p values < 0.05) were used to compare imaging features in patients with and without subsequent local tumor progression. Imaging features of the ablation margin, treated tumor, and surrounding liver were evaluated on serial MRI in the following year. RESULTS. A minimum ablation margin of 3 mm or less was observed in 11 (78.6%) of 14 tumors with and 15 of 40 (37.5%) without progression (p = 0.012). A blood vessel bridging the ablation margin was noted in 11 of 14 (78.6%) tumors with and nine of 40 (22.5%) without progression (p < 0.001). The incidence of tumor enhancement 24 hours after cryoablation was similar for tumors with (10/14, 71.4%) or without (25/40, 62.5%) local progression (p = 0.75). MRI enabled assessment of the entire cryoablation margin in 49 of 54 (90.7%) treated tumors. CONCLUSION. MRI features at 24 hours after liver cryoablation that were predictive of local tumor progression included a minimum ablation margin less than or equal to 3 mm and a blood vessel bridging the ablation margin. Persistent tumor enhancement is common after liver cryoablation and does not predict local tumor progression. C1 [Shyn, Paul B.; Mauri, Giovanni; Alencar, Raquel Oliva; Tatli, Servet; Shah, Shaan H.; Morrison, Paul R.; Silverman, Stuart G.] Harvard Univ, Brigham & Womens Hosp, Div Abdominal Imaging & Intervent, Dept Radiol,Med Sch, Boston, MA 02115 USA. [Catalano, Paul J.] Harvard Univ, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Sch Med, Boston, MA 02115 USA. RP Shyn, PB (reprint author), Harvard Univ, Brigham & Womens Hosp, Div Abdominal Imaging & Intervent, Dept Radiol,Med Sch, 75 Francis St, Boston, MA 02115 USA. EM pshyn@partners.org NR 42 TC 8 Z9 8 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP W181 EP W191 DI 10.2214/AJR.13.10747 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400008 PM 24555531 ER PT J AU Tran, LK Maturen, KE Feng, MU Wizauer, EJ Watcharotone, K Parker, RA Ellis, JH AF Tran, Linda K. Maturen, Katherine E. Feng, Mary U. Wizauer, Eric J. Watcharotone, Kuanwong Parker, Robert A. Ellis, James H. TI Renal Remodeling After Abdominal Radiation Therapy: Parenchymal and Functional Changes SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE abnormalities; radiation induced; radiation therapy; renal atrophy; side effects ID HUMAN KIDNEY; IRRADIATION; MALIGNANCIES; NEPHROPATHY; ABDOMEN; INJURY; CHEMORADIOTHERAPY; RADIOTHERAPY; SECONDARY; TISSUES AB OBJECTIVE. The purpose of this study was to quantify changes in renal length, volume, and function over time after upper abdominal radiation therapy. MATERIALS AND METHODS. Imaging and clinical data were retrospectively reviewed for 27 adults with abdominal radiation therapy between 2001 and 2012. All had two kidneys, radiation exposure to one kidney, and survival of at least 1 year after therapy. Mean prescribed dose was 52 +/- 9 Gy to extrarenal targets. Length and volume of exposed and unexposed kidneys were measured on CT scans before treatment (baseline) and at intervals 0-3, 3-6, 6-12, 12-24, 24-36, and more than 36 months after completion of radiotherapy. Serum creatinine was correlated at each interval. Mixed-models ANOVA was used to test renal length and volume, serum creatinine, and time against multiple models to assess for temporal effects; specific time intervals were compared in pairwise manner. RESULTS. Mean follow-up duration was 35 months (range, 5-94 months). Exposed kidney length and volume progressively decreased from baseline throughout follow-up, with mean loss of 23% (p < 0.001) and 47% (p < 0.001), respectively. Slight increase in unexposed kidney length was not significant. Mean serum creatinine increased from 0.86 +/- 0.18 mg/dL at baseline to 1.12 +/- 0.27 mg/dL at 12-24 months (p < 0.001), then stabilized. CONCLUSION. Kidneys exposed to radiation during therapy of adjacent malignancies exhibited continuous progressive atrophy for the entire follow-up period, nearly 8 years. Volume changes were twice as great as length changes. Renal function also declined. To accurately interpret follow-up studies in cancer survivors, radiologists should be aware of the potential for progressive renal atrophy, even many years after radiation therapy. C1 [Tran, Linda K.] Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. [Maturen, Katherine E.; Wizauer, Eric J.; Ellis, James H.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Feng, Mary U.] Univ Hosp, Dept Radiat Oncol, Ann Arbor, MI USA. [Watcharotone, Kuanwong; Parker, Robert A.] Michigan Inst Clin & Hlth Res, Biostat Core, Ann Arbor, MI USA. [Parker, Robert A.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. RP Tran, LK (reprint author), Univ Michigan, Sch Med, M4101 Med Sci Bldg,1-C Wing,1301 Catherine Rd, Ann Arbor, MI 48109 USA. EM lktran@umich.edu FU Association of University Radiologists FX K. E. Maturen receives research support from the General Electric Radiology Research Academic Fellowship from the Association of University Radiologists. NR 22 TC 0 Z9 0 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X EI 1546-3141 J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD AUG PY 2014 VL 203 IS 2 BP W192 EP W198 DI 10.2214/AJR.13.12149 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AS9GE UT WOS:000344550400009 PM 25055293 ER PT J AU Sher, L Landers, S AF Sher, Leo Landers, Sean TI Bipolar disorder, testosterone administration, and homicide: A case report SO INTERNATIONAL JOURNAL OF PSYCHIATRY IN CLINICAL PRACTICE LA English DT Article DE Bipolar disorder; testosterone; homicide ID STEROID USE; OFFENDERS AB Objective. Homicide is a major public health and social concern in the United States. Studies have found higher rates of psychiatric disorders in homicide off enders than in the general population. The aim of this article is to report and to discuss a case of a patient with bipolar disorder and hypogonadism who murdered his wife shortly aft er a testosterone injection. Methods. A case study and a review of the relevant literature. Results. Our case study as well as several case reports in the literature suggests that testosterone administration or high testosterone levels may be associated with homicidal behavior. Conclusion. Further studies of the role of testosterone in the neurobiology of violent and homicidal behavior may lead to improvements in the prevention of homicides. C1 [Sher, Leo] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. [Sher, Leo] James J Peters Vet Adm Med Ctr, New York, NY USA. [Landers, Sean] Ninth Judicial Circuit, Orlando, FL USA. RP Sher, L (reprint author), James J Peters Vet Adm, Icahn Sch Med Mt Sinai, Med Ctr, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM DrLeoSher@gmail.com NR 13 TC 1 Z9 1 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1365-1501 EI 1471-1788 J9 INT J PSYCHIAT CLIN JI Int. J. Psychiat. Clin. PD AUG PY 2014 VL 18 IS 3 BP 215 EP 216 DI 10.3109/13651501.2014.894075 PG 2 WC Psychiatry SC Psychiatry GA AS8AO UT WOS:000344473100011 PM 24527885 ER PT J AU Cover, KK Maeng, LY Lebron-Milad, K Milad, MR AF Cover, K. K. Maeng, L. Y. Lebron-Milad, K. Milad, M. R. TI Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology SO TRANSLATIONAL PSYCHIATRY LA English DT Review ID POSTTRAUMATIC-STRESS-DISORDER; ESTROGEN-RECEPTOR-ALPHA; FEMALE RAT-BRAIN; OBSESSIVE-COMPULSIVE DISORDER; NATIONAL COMORBIDITY SURVEY; MESSENGER-RIBONUCLEIC-ACID; MEDIAL PREFRONTAL CORTEX; CENTRAL-NERVOUS-SYSTEM; MENSTRUAL-CYCLE PHASE; ER-BETA AGONIST AB Over the past two decades, substantial knowledge has been attained about the mechanisms underlying the acquisition and subsequent extinction of conditioned fear. Knowledge gained on the biological basis of Pavlovian conditioning has led to the general acceptance that fear extinction may be a useful model in understanding the underlying mechanisms in the pathophysiology of anxiety disorders and may also be a good model for current therapies treating these disorders. Lacking in the current knowledge is how men and women may or may not differ in the biology of fear and its extinction. It is also unclear how the neural correlates of fear extinction may mediate sex differences in the etiology, maintenance, and prevalence of psychiatric disorders. In this review, we begin by highlighting the epidemiological differences in incidence rate. We then discuss how estradiol (E2), a primary gonadal hormone, may modulate the mechanisms of fear extinction and mediate some of the sex differences observed in psychiatric disorders. C1 [Cover, K. K.; Maeng, L. Y.; Lebron-Milad, K.; Milad, M. R.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Maeng, L. Y.; Lebron-Milad, K.; Milad, M. R.] Harvard Univ, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Milad, MR (reprint author), Harvard Univ, Sch Med, Dept Psychiat, 149 13th St,CNY 2614, Charlestown, MA 02129 USA. EM milad@nmr.mgh.harvard.edu FU [1R01MH097880-001] FX We thank members of the Behavioral Neuroscience Program in the Department of Psychiatry at Massachusetts General Hospital for helpful comments on this manuscript. MRM is supported by 1R01MH097880-001. NR 150 TC 19 Z9 19 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD AUG PY 2014 VL 4 AR e422 DI 10.1038/tp.2014.67 PG 9 WC Psychiatry SC Psychiatry GA AT3HR UT WOS:000344826900003 PM 25093600 ER PT J AU Duda, M Kosmicki, JA Wall, DP AF Duda, M. Kosmicki, J. A. Wall, D. P. TI Testing the accuracy of an observation-based classifier for rapid detection of autism risk SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID DIAGNOSTIC-OBSERVATION-SCHEDULE; SPECTRUM DISORDERS; REVISED ALGORITHMS; ADOS SCORES; SEVERITY; CHILDREN AB Current approaches for diagnosing autism have high diagnostic validity but are time consuming and can contribute to delays in arriving at an official diagnosis. In a pilot study, we used machine learning to derive a classifier that represented a 72% reduction in length from the gold-standard Autism Diagnostic Observation Schedule-Generic (ADOS-G), while retaining >97% statistical accuracy. The pilot study focused on a relatively small sample of children with and without autism. The present study sought to further test the accuracy of the classifier (termed the observation-based classifier (OBC)) on an independent sample of 2616 children scored using ADOS from five data repositories and including both spectrum (n = 2333) and non-spectrum (n = 283) individuals. We tested OBC outcomes against the outcomes provided by the original and current ADOS algorithms, the best estimate clinical diagnosis, and the comparison score severity metric associated with ADOS-2. The OBC was significantly correlated with the ADOS-G (r = -0.814) and ADOS-2 (r = -0.779) and exhibited >97% sensitivity and >77% specificity in comparison to both ADOS algorithm scores. The correspondence to the best estimate clinical diagnosis was also high (accuracy = 96.8%), with sensitivity of 97.1% and specificity of 83.3%. The correlation between the OBC score and the comparison score was significant (r = -0.628), suggesting that the OBC provides both a classification as well as a measure of severity of the phenotype. These results further demonstrate the accuracy of the OBC and suggest that reductions in the process of detecting and monitoring autism are possible. C1 [Duda, M.; Wall, D. P.] Stanford Univ, Div Syst Med, Dept Pediat, Stanford, CA 94305 USA. [Kosmicki, J. A.] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Kosmicki, J. A.] Harvard Univ, Sch Med, Boston, MA USA. [Kosmicki, J. A.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP Wall, DP (reprint author), Stanford Univ, Div Syst Med, Dept Pediat, 1265 Welch Rd, Stanford, CA 94305 USA. EM dpwall@stanford.edu FU Simons Foundation; Nancy Lurie Marks Family Foundation; Harvard Catalyst Program; National Institutes of Health [1R01MH090611-01A1] FX Work was supported in part by funds to DPW from the Simons Foundation, Nancy Lurie Marks Family Foundation, the Harvard Catalyst Program, and grant 1R01MH090611-01A1 from the National Institutes of Health. We thank the reviewers whose comments substantially improved the quality of the manuscript. We also thank the families who contributed the data that made this study possible. NR 21 TC 10 Z9 10 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD AUG PY 2014 VL 4 AR e424 DI 10.1038/tp.2014.65 PG 6 WC Psychiatry SC Psychiatry GA AT3HR UT WOS:000344826900005 PM 25116834 ER PT J AU Wang, JL Shamah, SM Sun, AX Waldman, ID Haggarty, SJ Perlis, RH AF Wang, J. L. Shamah, S. M. Sun, A. X. Waldman, I. D. Haggarty, S. J. Perlis, R. H. TI Label-free, live optical imaging of reprogrammed bipolar disorder patient-derived cells reveals a functional correlate of lithium responsiveness SO TRANSLATIONAL PSYCHIATRY LA English DT Article ID HUMAN FIBROBLASTS; PSA-NCAM; CONVERSION; EXPRESSION; PREVENTION; ADHESION; NEURONS; DISEASE AB Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n = 12), and healthy control subjects (n = 6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics. C1 [Wang, J. L.; Haggarty, S. J.; Perlis, R. H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Wang, J. L.; Haggarty, S. J.; Perlis, R. H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wang, J. L.; Haggarty, S. J.; Perlis, R. H.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Shamah, S. M.] X Body Biosci, Waltham, MA USA. [Sun, A. X.] Stanford Univ, Howard Hughes Med Inst, Sch Med, Stanford, CA 94305 USA. [Waldman, I. D.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Haggarty, S. J.] Harvard Univ, Dept Neurol, Chem Neurobiol Lab, Massachusetts Gen Hosp,Med Sch, Boston, MA 02114 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM rperlis@mgh.harvard.edu FU National Institute of Mental Health [R21MH093958, R33MH087896] FX We acknowledge the helpful discussion and feedback from members of the Perlis, Haggarty and Crabtree Laboratories and X-Body Biosciences. We also acknowledge Bob Weinberg and Didier Trono for the use of lentiviral packaging plasmids deposited with Addgene. This work was supported through funding from the National Institute of Mental Health (R21MH093958, R33MH087896). Biobank collection was further supported by the Stanley Center for Psychiatric Research. NR 35 TC 11 Z9 11 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2158-3188 J9 TRANSL PSYCHIAT JI Transl. Psychiatr. PD AUG PY 2014 VL 4 AR e428 DI 10.1038/tp.2014.72 PG 8 WC Psychiatry SC Psychiatry GA AT3HR UT WOS:000344826900009 PM 25158003 ER PT J AU Lytle, MC De Luca, SM Blosnich, JR AF Lytle, Megan C. De Luca, Susan M. Blosnich, John R. TI The Influence of Intersecting Identities on Self-Harm, Suicidal Behaviors, and Depression among Lesbian, Gay, and Bisexual Individuals SO SUICIDE AND LIFE-THREATENING BEHAVIOR LA English DT Article ID SEXUAL ORIENTATION; RISK-FACTORS; DISORDERS; IDEATION; ADULTS; LATINO AB Individuals with lesbian, gay, and bisexual (LGB) identities have higher prevalence of self-directed violence, but very little is known about racial/ethnic differences between LGB populations. This study aimed to examine racial/ethnic differences in self-harm, suicidal ideation, suicide attempt, and depression among LGB and heterosexual emerging adults. Data are compiled from the Fall 2008 and Spring 2009 National College Health Assessment and limited to respondents within emerging adulthood (ages 18-24) who indicated their sexual orientation and racial/ethnic identities (n = 89,199). Within each racial/ethnic group, LGB individuals were significantly more likely to report self-harm, suicidal ideation, suicide attempt, and depression than non-LGB individuals. C1 [Lytle, Megan C.] Univ Rochester, Med Ctr, Dept Psychiat, Rochester, NY 14642 USA. [De Luca, Susan M.] Univ Texas Austin, Sch Social Work, Austin, TX 78712 USA. [Blosnich, John R.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Lytle, MC (reprint author), Univ Rochester, Med Ctr, Dept Psychiat, 300 Crittenden Blvd, Rochester, NY 14642 USA. EM megan_lytle@urmc.rochester.edu FU NCATS NIH HHS [KL2 TR000095]; NIMH NIH HHS [T32 MH020061] NR 22 TC 5 Z9 5 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0363-0234 EI 1943-278X J9 SUICIDE LIFE-THREAT JI Suicide Life-Threat. Behav. PD AUG PY 2014 VL 44 IS 4 BP 384 EP 391 DI 10.1111/sltb.12083 PG 8 WC Psychiatry; Psychology, Multidisciplinary SC Psychiatry; Psychology GA AS3LI UT WOS:000344178900004 PM 25250405 ER PT J AU Kim, GE Shlyankevich, J Kimball, AB AF Kim, G. E. Shlyankevich, J. Kimball, A. B. TI The validity of the diagnostic code for hidradenitis suppurativa in an electronic database SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article ID PATIENT CLAIMS DATA; ADMINISTRATIVE DATA; UNITED-STATES; PREVALENCE; PSORIASIS AB Background Electronic claims and medical record databases are important sources of information for medical research. However, potential sources of error and bias, including inaccurate diagnoses, incomplete data, incorrect data entry and misclassification bias, necessitate studies that assess the validity of these databases. Objectives To assess the validity of the diagnostic code for hidradenitis suppurativa (HS), which is an increasingly studied disease. Methods In this retrospective study, the medical records of 1168 patients in the Massachusetts General Hospital database who had received at least two International Classification of Diseases, Ninth Revision 705.83 codes were manually screened. Results Of the screened patients, 1046 (89.6%) were confirmed as having HS. The mean age +/- SD was 44.0 +/- 15.7 years, the median age was 43.0 years and 748 (71.5%) were female. The majority were white (66.7%), while a significant minority were black (13.9%) or Hispanic (13.4%). An increasing number of codes and specific terms used to describe HS in the medical record, including 'hydradenitis', 'boil', 'draining', 'abscess', 'fistula', 'cyst' and 'nodule', could be used to improve the positive predictive value of the search. Conclusion Our results highlight the importance of establishing the validity of diagnostic codes in electronic databases, and allow for refinements of appropriate ways to design future searches. Given the potential for misclassification of patients with HS, establishing the validity of diagnostic codes and search strategies in electronic databases represents a crucial step for subsequent studies utilizing these databases. C1 [Kim, G. E.; Kimball, A. B.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Shlyankevich, J.; Kimball, A. B.] Massachusetts Gen Hosp, Clin Unit Res Trials & Outcomes Skin CURTIS, Boston, MA 02114 USA. RP Kimball, AB (reprint author), Harvard Univ, Sch Med, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM harvardskinstudies@partners.org FU NCATS NIH HHS [UL1 TR001102, 1UL1 TR001102-01] NR 11 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD AUG PY 2014 VL 171 IS 2 BP 338 EP 342 DI 10.1111/bjd.13041 PG 5 WC Dermatology SC Dermatology GA AS0ZL UT WOS:000344005200020 PM 24712395 ER PT J AU Thielen, AM Blouin, JL Piris, A Mihm, MC Kaya, G AF Thielen, A. -M. Blouin, J. -L. Piris, A. Mihm, M. C. Kaya, G. TI Multiple mantleomas: an unusual clinical presentation of an intriguing tumour SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Letter C1 [Thielen, A. -M.; Kaya, G.] Univ Hosp Geneva, Dept Dermatol, Geneva, Switzerland. [Blouin, J. -L.] Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland. [Piris, A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dermatopathol Unit, Boston, MA USA. [Mihm, M. C.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Kaya, G (reprint author), Univ Hosp Geneva, Dept Dermatol, Geneva, Switzerland. EM gkaya@hcuge.ch NR 4 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-0963 EI 1365-2133 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD AUG PY 2014 VL 171 IS 2 BP 417 EP 418 DI 10.1111/bjd.12924 PG 3 WC Dermatology SC Dermatology GA AS0ZL UT WOS:000344005200032 PM 25132573 ER PT J AU Mays, D DeMarco, TA Luta, G Peshkin, BN Patenaude, AF Schneider, KA Garber, JE Tercyak, KP AF Mays, Darren DeMarco, Tiffani A. Luta, George Peshkin, Beth N. Patenaude, Andrea F. Schneider, Katherine A. Garber, Judy E. Tercyak, Kenneth P. TI Distress and the Parenting Dynamic Among BRCA1/2 Tested Mothers and Their Partners SO HEALTH PSYCHOLOGY LA English DT Article DE breast/ovarian cancer; genetic testing; family communication; psychological distress ID BREAST-CANCER; PSYCHOLOGICAL DISTRESS; BREAST/OVARIAN CANCER; HEREDITARY BREAST; DECISION-MAKING; OVARIAN-CANCER; HIGH-RISK; CHILDREN; WOMEN; ADJUSTMENT AB Objective: To investigate the influence of dyadic parenting relationships on psychological distress among mothers tested for BRCA1/2 genetic mutations and their untested partners. Methods: Data were from a prospective study of mothers suspected to be at risk for hereditary breast/ovarian cancer who underwent genetic counseling and BRCA1/2 testing and their untested parenting partners (n = 109 parenting dyads). Participants completed assessments before and 1 month after genetic testing. Structural equation modeling was used to examine relationships among mothers' and partners' psychological distress, decisional conflict surrounding communication of test results to their offspring, and the parent-child communication relationship. Psychological distress was measured using items modified from the Brief Symptom Inventory. Results: Among mothers, greater psychological distress (B = 0.29, p < .001) and poorer parent-child communication (B = -0.12, p < .01) at baseline predicted greater distress at follow-up. Among partners, greater distress at baseline predicted greater distress at follow-up (B = 0.67, p < .001). Mother and partner decisional conflict at baseline were equally associated with the other dyad member's distress at follow-up (B = 1.17, p < .01), but not their own distress. Conclusions: Our findings indicate that conflicted decision-making over family communication of hereditary breast/ovarian cancer genetic test results for one member of a parenting dyad adversely affects the other dyad member's psychological well-being. Interventions to improve outcomes for mothers who may be at-risk for hereditary breast and ovarian cancer and undergoing BRCA1/2 genetic testing should attend to mothers' and their partners' preferences regarding family communication about hereditary cancer risk. C1 [Mays, Darren; DeMarco, Tiffani A.; Peshkin, Beth N.; Tercyak, Kenneth P.] Georgetown Univ Med Ctr, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Washington, DC 20007 USA. [Luta, George] Georgetown Univ Med Ctr, Lombardi Comprehens Canc Ctr, Canc Prevent & Control Program, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Patenaude, Andrea F.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02215 USA. [Patenaude, Andrea F.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Schneider, Katherine A.; Garber, Judy E.] Dana Farber Canc Inst, Ctr Canc Genet & Prevent, Boston, MA 02215 USA. [Garber, Judy E.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. RP Mays, D (reprint author), Georgetown Univ Med Ctr, Lombardi Comprehens Canc Ctr, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM dmm239@georgetown.edu OI Luta, George/0000-0001-9013-2207; Luta, George/0000-0002-4035-7632 FU National Human Genome Research Institute [R01 HG002686]; Biostatistics and Bioinformatics Shared Resource of Georgetown Lombardi Comprehensive Cancer Center through Comprehensive Cancer Center [P30CA051008] FX The authors thank the genetic counselors, physicians, and staff at study sites for their participation. This work was funded by Grant R01 HG002686 from the National Human Genome Research Institute to Dr. Tercyak. This work was also supported by the Biostatistics and Bioinformatics Shared Resource of Georgetown Lombardi Comprehensive Cancer Center through Comprehensive Cancer Center Support Grant P30CA051008. 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. Findings of this work were presented in part at the 2012 Annual Meeting of the American Society of Preventive Oncology, March 5, 2012, Washington, DC. NR 43 TC 4 Z9 4 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 EI 1930-7810 J9 HEALTH PSYCHOL JI Health Psychol. PD AUG PY 2014 VL 33 IS 8 BP 765 EP 773 DI 10.1037/a0033418 PG 9 WC Psychology, Clinical; Psychology SC Psychology GA AS3HA UT WOS:000344167100002 PM 23795707 ER PT J AU Walter, KH Varkovitzky, RL Owens, GP Lewis, J Chard, KM AF Walter, Kristen H. Varkovitzky, Ruth L. Owens, Gina P. Lewis, Jennifer Chard, Kathleen M. TI Cognitive Processing Therapy for Veterans With Posttraumatic Stress Disorder: A Comparison Between Outpatient and Residential Treatment SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE posttraumatic stress disorder; cognitive processing therapy; outpatient treatment; residential treatment; veterans ID ADMINISTERED PTSD SCALE; PSYCHOMETRIC PROPERTIES; BEHAVIORAL THERAPY; PROLONGED EXPOSURE; AFGHANISTAN; IRAQ; PROGRAM; TRIAL; CARE AB Objective: Across the Veterans Affairs (VA) Healthcare System, outpatient and residential posttraumatic stress disorder (PTSD) treatment programs are available to veterans of all ages and both genders; however, no research to date has compared these treatment options. This study compared veterans who received outpatient (n = 514) to those who received residential treatment (n = 478) within a VA specialty clinic on demographic and pretreatment symptom variables. Further, the study examined pre- to posttreatment symptom trajectories across the treatment programs. Method: All 992 veterans met diagnostic criteria for PTSD and attended at least 1 session of cognitive processing therapy (CPT) in either the outpatient or residential program. Bivariate analyses were utilized to investigate differences between samples on demographic variables and severity of pretreatment symptoms. Multilevel modeling (MLM) was used to investigate the change in symptomatology between the 2 samples from pre- to posttreatment. Results: Analyses indicated that the samples differed on all demographic and pretreatment symptom variables, with residential patients reporting higher scores on all assessment measures. MLM results demonstrated that symptom scores improved for all veterans across time, with outpatients consistently reporting fewer symptoms at both time points. The time by program interaction was significant for PTSD-related symptom trajectories, but not for the depression-related symptom trajectory. Conclusion: This is the 1st study to compare pretreatment characteristics and treatment outcome between veterans receiving outpatient and residential PTSD treatment. Findings may help clinicians select appropriate care for their patients by identifying relevant pretreatment characteristics and generally informing expectations of treatment outcome. C1 [Walter, Kristen H.] Vet Med Res Fdn, San Diego, CA 92161 USA. [Walter, Kristen H.] Vet Affairs San Diego Healthcare Syst, Res Serv, San Diego, CA USA. [Varkovitzky, Ruth L.] Vet Affairs Puget Sound Healthcare Syst, Amer Lake Div, PTSD Outpatient Clin, Tacoma, WA USA. [Owens, Gina P.] Univ Tennessee, Dept Psychol, Knoxville, TN 37996 USA. [Lewis, Jennifer; Chard, Kathleen M.] Cincinnati Vet Affairs Med Ctr, Trauma Recovery Ctr, Cincinnati, OH USA. [Chard, Kathleen M.] Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45221 USA. RP Walter, KH (reprint author), Vet Med Res Fdn, 3350 La Jolla Village Dr,111N-1,Bldg 13, San Diego, CA 92161 USA. EM Kristen.Walter@va.gov NR 37 TC 3 Z9 3 U1 3 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2014 VL 82 IS 4 BP 551 EP 561 DI 10.1037/a0037075 PG 11 WC Psychology, Clinical SC Psychology GA AS3FY UT WOS:000344164000001 PM 24911422 ER PT J AU Holowka, DW Marx, BP Gates, MA Litman, HJ Ranganathan, G Rosen, RC Keane, TM AF Holowka, Darren W. Marx, Brian P. Gates, Margaret A. Litman, Heather J. Ranganathan, Gayatri Rosen, Raymond C. Keane, Terence M. TI PTSD Diagnostic Validity in Veterans Affairs Electronic Records of Iraq and Afghanistan Veterans SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE PTSD; veterans; diagnosis; electronic medical record; electronic health record ID HEALTH INFORMATION-TECHNOLOGY; POSTTRAUMATIC-STRESS-DISORDER; TRAUMATIC BRAIN-INJURY; ADMINISTRATIVE DATA; PRIMARY-CARE; AMBULATORY-CARE; MEDICAL-CARE; QUALITY; SCALE; PREVALENCE AB Objective: Administrative planning and policy decisions frequently rely on diagnostic data extracted from large electronic databases. However, the accuracy of this diagnostic information is uncertain. The present study examined the degree to which various diagnoses of posttraumatic stress disorder (PTSD) within Department of Veterans Affairs (VA) electronic databases were concordant with PTSD diagnostic status determined by standardized diagnostic interview. Method: We interviewed 1,649 veterans of the Iraq and Afghanistan wars using the PTSD Module of the Structured Clinical Interview for DSM-IV (SCID). Participants also completed other interview-based and self-report measures of psychopathology and provided consent to access their electronic medical records (EMRs). Results: Concordance between database diagnosis and SCID diagnosis was 72.3% for current PTSD and 79.4% for lifetime PTSD. We observed associations between concordance status and combat exposure, PTSD symptom presentation, comorbid anxiety and depression, and psychosocial impairment. Veterans with false-negative PTSD diagnoses in the EMR were more likely to report lower levels of combat exposure, panic, and PTSD avoidance symptoms. Veterans with false-positive PTSD diagnoses in the EMR were more likely to report treatment seeking for emotional problems and less overall functional impairment. Conclusions: Although the majority of participants were concordant for PTSD status, over 25% of EMR diagnoses differed from those obtained in the diagnostic interview, with varying proportions of false positives and false negatives. Overall, those individuals with the most and least severe symptom presentations in the diagnostic interview were more likely to be accurately classified. C1 [Holowka, Darren W.; Marx, Brian P.; Keane, Terence M.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Holowka, Darren W.; Marx, Brian P.; Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Gates, Margaret A.; Litman, Heather J.; Ranganathan, Gayatri; Rosen, Raymond C.] New England Res Inst, Watertown, MA 02172 USA. RP Holowka, DW (reprint author), Rhode Isl Hosp, Dept Psychiat, Potter 2,593 Eddy St, Providence, RI 02903 USA. EM dholowka@lifespan.org NR 49 TC 10 Z9 10 U1 3 U2 12 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X EI 1939-2117 J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2014 VL 82 IS 4 BP 569 EP 579 DI 10.1037/a0036347 PG 11 WC Psychology, Clinical SC Psychology GA AS3FY UT WOS:000344164000003 PM 24731235 ER PT J AU Dibart, S Yee, C Surmenian, J Sebaoun, JD Baloul, S Goguet-Surmenian, E Kantarci, A AF Dibart, Serge Yee, Cynthia Surmenian, Jerome Sebaoun, Jean David Baloul, Susan Goguet-Surmenian, Emilie Kantarci, Alpdogan TI Tissue response during Piezocision-assisted tooth movement: a histological study in rats SO EUROPEAN JOURNAL OF ORTHODONTICS LA English DT Article ID ACID-PHOSPHATASE; BONE; CORTICISION; CLINICIANS; BIOLOGY AB OBJECTIVES: Piezocision is a novel, minimally invasive technique combining micro-incisions and decortications made by a piezotome in order to enhance the rate of orthodontic tooth movement. The combined technique allows simultaneous hard and/or soft tissue grafting via selective tunnelling to correct gingival recessions or bone deficiencies. The present study was designed to evaluate the effects of Piezocision on bone with or without tooth movement on a rat model. MATERIALS AND METHODS Ninety-four Sprague-Dawley rats were divided into four groups: no treatment (n = 3), TM (tooth movement alone; n = 21), PS (Piezocision alone; n = 35), and PS + TM (Piezocision and tooth movement; n = 35). In each group, seven time points were studied: 1, 3, 7, 14, 28, 42, and 56 days. After sacrifice, the maxillae were removed, defleshed, stained with haematoxylin and eosin for morphometric analyses and tartrate-resistant acid phosphatase for osteoclastic activity. RESULTS: Three days after the surgery, the bone content decreased significantly in the PS and PS + TM groups compared to baseline (P < 0.01) and the TM group (P < 0.05). This trend continued until Day 28 and was particularly evident in the PS + TM group. At Day 56, alveolar bone returned to its baseline levels in all groups. Osteoclastic activity followed similar change pattern found in the amount of bone, suggesting a strong role for the coupling of the resorptive and formative turnover of the bone. Osteoclastic activity increased as soon as Day 1 in the PS (29.0 +/- 3.0, P < 0.05) and PS + TM groups (39.0 +/- 6.0, P < 0.01) compared to baseline (22.0 +/- 4.0). The highest level of osteoclastic activity in TM group was observed at 3 days (64.3 +/- 8.0, P < 0.01) with a steady decrease thereafter. The Piezocision-induced osteoclastic activity showed a steady increase up to 7 days in both PS (39.0 +/- 7.0, P < 0.01) and PS + TM (51.8 +/- 7.0, P < 0.01) groups and decreased thereafter until Day 56. CONCLUSIONS: Within the limitations of our study (number of animals, duration in time, and limited data on the anabolic activity), our preliminary results suggest that Piezocision-facilitated orthodontic tooth movement increases the rate of movement of the teeth undergoing orthodontic treatment through the coupled remodelling of the alveolar bone. This process is initiated by the osteoclastic activity following surgery and extended via the synergistic relationship between Piezocision and tooth movement. C1 [Dibart, Serge; Yee, Cynthia; Surmenian, Jerome; Goguet-Surmenian, Emilie] Boston Univ, Dept Periodontol & Oral Biol, Boston, MA 02118 USA. [Sebaoun, Jean David; Baloul, Susan] Boston Univ, Dept Orthodont, Henry M Goldman Sch Dent Med, Boston, MA 02118 USA. [Kantarci, Alpdogan] Forsyth Inst, Ctr Periodontol, Dept Appl Oral Sci, Cambridge, MA USA. RP Dibart, S (reprint author), Boston Univ, Henry M Goldman Sch Dent Med, Dept Periodontol & Oral Biol, 100 East Newton St,G-217, Boston, MA 02118 USA. EM sdibart@bu.edu FU Satelec, Acteon group, Merignac, France FX Satelec, Acteon group, Merignac, France. NR 22 TC 6 Z9 6 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0141-5387 EI 1460-2210 J9 EUR J ORTHODONT JI Eur. J. Orthodont. PD AUG PY 2014 VL 36 IS 4 BP 457 EP 464 DI 10.1093/ejo/cjt079 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AR1DW UT WOS:000343323800015 PM 24253033 ER PT J AU Kim, LA Amarnani, D Gnanaguru, G Tseng, WA Vavvas, DG D'Amore, PA AF Kim, Leo A. Amarnani, Dhanesh Gnanaguru, Gopalan Tseng, Wen Allen Vavvas, Demetrios G. D'Amore, Patricia A. TI Tamoxifen Toxicity in Cultured Retinal Pigment Epithelial Cells Is Mediated by Concurrent Regulated Cell Death Mechanisms SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE apoptosis; necroptosis; pyroptosis; RPE; tamoxifen ID NLRP3 INFLAMMASOME ACTIVATION; MACULAR DEGENERATION; NALP3 INFLAMMASOME; CYSTEINE CATHEPSINS; ARPE-19 CELLS; RIP1 KINASE; TNF-ALPHA; IN-VITRO; NECROSIS; APOPTOSIS AB PURPOSE. To evaluate the mechanism of tamoxifen-induced cell death in human cultured RPE cells, and to investigate concurrent cell death mechanisms including pyroptosis, apoptosis, and necroptosis. METHODS. Human RPE cells were cultured until confluence and treated with tamoxifen; cell death was measured by detecting LDH release. Tamoxifen-induced cell death was further confirmed by 7-aminoactinomycin D (7-AAD) and annexin V staining. Lysosomal destabilization was assessed using lysosomal-associated membrane protein-1 (LAMP-1) and acridine orange staining. The roles of lysosomal enzymes cathepsin B and L were examined by blocking their activity. Caspase activity was evaluated by caspase-1, -3, -8, and -9 specific inhibition. Cells were primed with IL-1 alpha and treated with tamoxifen; mature IL-1 beta production was quantified via ELISA. Caspase activity was verified with the fluorochrome-labeled inhibitor of caspases (FLICA) probe specific for each caspase. Regulated cell necrosis or necroptosis was examined with 7-AAD and inhibition of receptor-interacting protein 1 (RIP1) kinase using necrostatin-1 (Nec-1). RESULTS. Cell death occurred within 2 hours of tamoxifen treatment of confluent RPE cells and was accompanied by lysosomal membrane permeabilization. Blockade of cathepsin B and L activity led to a significant decrease in cell death, indicating that lysosomal destabilization and cathepsin release occur prior to regulated cell death. Tamoxifen-induced toxicity was shown to occur through both caspase-dependent and caspase-independent cell death pathways. Treatment of RPE cells with caspase inhibitors and Nec-1 resulted in a near complete rescue from cell death. CONCLUSIONS. Tamoxifen-induced cell death occurs through concurrent regulated cell death mechanisms. Simultaneous inhibition of caspase-dependent and caspase-independent cell death pathways is required to protect cells from tamoxifen. Inhibition of upstream activators, such as the cathepsins, may represent a novel approach to block multiple cell death pathways. C1 [Kim, Leo A.; Amarnani, Dhanesh; Gnanaguru, Gopalan; Tseng, Wen Allen; Vavvas, Demetrios G.; D'Amore, Patricia A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kim, Leo A.; Amarnani, Dhanesh; Gnanaguru, Gopalan; Tseng, Wen Allen; D'Amore, Patricia A.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP D'Amore, PA (reprint author), 20 Staniford St, Boston, MA 02114 USA. EM patricia_damore@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU National Eye Institute/National Institutes of Health (NEI/NIH) [K12-EY16335]; Massachusetts Lions Eye Research Fund; NIH [GM07226, AG039245, EY015435]; NEI Grant [R21EY023079-01/A1]; Yeatts Family Foundation; Macula Society Research Grant Award; Research to Prevent Blindness (RPB) Physician-Scientist Award FX Supported by National Eye Institute/National Institutes of Health (NEI/NIH) Grant K12-EY16335 and by the Massachusetts Lions Eye Research Fund (LAK); NIH Grants GM07226 and AG039245 (WAT); NEI Grant R21EY023079-01/A1, the Yeatts Family Foundation, a 2013 Macula Society Research Grant Award, and an Research to Prevent Blindness (RPB) Physician-Scientist Award (DGV); and NIH Grant EY015435 (PAD). NR 63 TC 6 Z9 7 U1 0 U2 7 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2014 VL 55 IS 8 BP 4747 EP 4758 DI 10.1167/iovs.13-13662 PG 12 WC Ophthalmology SC Ophthalmology GA AQ9DV UT WOS:000343145500009 PM 24994868 ER PT J AU Arboleda-Velasquez, JF Primo, V Graham, M James, A Manent, J D'Amore, PA AF Arboleda-Velasquez, Joseph F. Primo, Vincent Graham, Mark James, Alexandra Manent, Jan D'Amore, Patricia A. TI Notch Signaling Functions in Retinal Pericyte Survival SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE diabetic retinopathy; survival; notch signaling; coculture; pericyte; small-vessel ID SMOOTH-MUSCLE-CELLS; ENDOTHELIAL-CELLS; GROWTH-FACTOR; MURAL CELL; VASCULAR MORPHOGENESIS; IN-VIVO; PATHWAY; DIFFERENTIATION; EXPRESSION; CADASIL AB PURPOSE. Pericytes, the vascular cells that constitute the outer layer of capillaries, have been shown to have a crucial role in vascular development and stability. Loss of pericytes precedes endothelial cell dysfunction and vascular degeneration in small-vessel diseases, including diabetic retinopathy. Despite their clinical relevance, the cellular pathways controlling survival of retinal pericytes remain largely uncharacterized. Therefore, we investigated the role of Notch signaling, a master regulator of cell fate decisions, in retinal pericyte survival. METHODS. A coculture system of ligand-dependent Notch signaling was developed using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing the Delta-like 1 Notch ligand. This model was used to examine the effect of Notch activity on pericyte survival using quantitative PCR (qPCR) and a light-induced cell death assay. The effect of Notch gain- and loss-of-function was analyzed in monocultures of retinal pericytes using antibody arrays to interrogate the expression of apoptosis-related proteins. RESULTS. Primary cultured retinal pericytes differentially expressed key molecules of the Notch pathway and displayed strong expression of canonical Notch/RBPJK (recombination signal-binding protein 1 for J-kappa) downstream targets. A gene expression screen using gain- and loss-of-function approaches identified genes relevant to cell survival as downstream targets of Notch activity in retinal pericytes. Ligand-mediated Notch activity protected retinal pericytes from light-induced cell death. CONCLUSIONS. Our results have identified signature genes downstream of Notch activity in retinal pericytes and suggest that tight regulation of Notch signaling is crucial for pericyte survival. C1 [Arboleda-Velasquez, Joseph F.; Primo, Vincent; Graham, Mark; James, Alexandra; D'Amore, Patricia A.] Harvard Univ, Sch Med, Mass Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02115 USA. [Arboleda-Velasquez, Joseph F.; Primo, Vincent; Graham, Mark; James, Alexandra; D'Amore, Patricia A.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. [Graham, Mark; James, Alexandra] Univ Exeter, Sch Med, Exeter, Devon, England. [Manent, Jan] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP D'Amore, PA (reprint author), 20 Staniford St, Boston, MA 02114 USA. EM patricia_damore@meei.harvard.edu FU National Institutes of Health (NIH; Bethesda, MD, USA) [EY005318, EY021624]; American Diabetes Association Innovation Award [7-12-IN-11]; American Heart Association Scientist Development Grant [12SDG8960025]; Undergraduate Research Fellowship [13-09-USF] FX Supported by National Institutes of Health (NIH; Bethesda, MD, USA) Grants EY005318 (PAD) and EY021624 (JFA-V), American Diabetes Association Innovation Award 7-12-IN-11 (PAD), American Heart Association Scientist Development Grant 12SDG8960025 (JFA-V), and Undergraduate Research Fellowship 13-09-USF (AJ). NR 58 TC 4 Z9 4 U1 1 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2014 VL 55 IS 8 BP 5191 EP 5199 DI 10.1167/iovs.14-14046 PG 9 WC Ophthalmology SC Ophthalmology GA AQ9DV UT WOS:000343145500066 PM 25015359 ER PT J AU Alt, C Runnels, JM Mortensen, LJ Zaher, W Lin, CP AF Alt, Clemens Runnels, Judith M. Mortensen, Luke J. Zaher, Walid Lin, Charles P. TI In Vivo Imaging of Microglia Turnover in the Mouse Retina After Ionizing Radiation and Dexamethasone Treatment SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article DE scanning laser ophthalmoscopy; radiation damage; anti-inflammatory agents; microglia; bone marrow-derived cells ID MARROW-DERIVED MICROGLIA; BONE-MARROW; BRAIN METASTASES; CELL-DEATH; MICROSCOPY; HEALTH; EYE; TRANSPLANTATION; INFLAMMATION; IRRADIATION AB PURPOSE. Gamma irradiation and bone marrow transplantation (BMT) are established clinical procedures for the treatment of hematologic malignancies. The radiation targets cells in the bone marrow, but injury to other tissues, including the central nervous system (CNS), have been reported. Here, we examine if anti-inflammatory treatment can mitigate the radiation-induced turnover of retinal microglia and the replacement by bone marrow-derived cells (BMDCs). METHODS. Two-color chimeric mice were generated by lethal irradiation of heterozygous CX3CR1-GFP mice that express GFP in microglial cells and bone marrow transplantation from universal DsRed donor mice. Mice were treated with the corticosteroid dexamethasone; a control group received no dexamethasone treatment. The populations of resident microglia (GFP+) and BMDCs (DsRed+) were quantified by serial in vivo imaging for 10 weeks after irradiation with a confocal scanning laser ophthalmoscope that we custom-built specifically for multicolor imaging of the murine retina. RESULTS. Ionizing radiation resulted in loss of 75% of the resident retinal microglia population after 70 days. Recruitment of BMDCs was delayed with respect to the microglia loss, resulting in a transient depletion of the total immune cell number in the retina. With dexamethasone treatment, both the loss of the resident microglia and the infiltration of BMDCs were suppressed by at least 50%. CONCLUSIONS. Anti-inflammatory treatment with the corticosteroidal agent dexamethasone preserves resident microglia and minimizes recruitment of BMDCs after ionizing radiation exposure and BMT. C1 [Alt, Clemens; Runnels, Judith M.; Mortensen, Luke J.; Zaher, Walid] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol,Adv Microscopy Program, Boston, MA 02115 USA. [Alt, Clemens; Runnels, Judith M.; Mortensen, Luke J.; Zaher, Walid; Lin, Charles P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02115 USA. Odense Univ Hosp, Dept Endocrinol, Endocrine Res KMEB, DK-5000 Odense, Denmark. Univ So Denmark, Odense, Denmark. [Zaher, Walid] King Saud Univ, Coll Med, Dept Anat, Stem Cell Unit, Riyadh 11451, Saudi Arabia. RP Lin, CP (reprint author), Massachusetts Gen Hosp, CPZN 8238,185 Cambridge St, Boston, MA 02114 USA. EM Charles_lin@hms.harvard.edu OI Mortensen, Luke/0000-0002-4331-4099 FU Department of Defense/Air Force [FA9550-11-1-0331] FX Supported by the Department of Defense/Air Force FA9550-11-1-0331. NR 42 TC 6 Z9 6 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 EI 1552-5783 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD AUG PY 2014 VL 55 IS 8 BP 5314 EP 5319 DI 10.1167/iovs.14-14254 PG 6 WC Ophthalmology SC Ophthalmology GA AQ9DV UT WOS:000343145500085 PM 25082884 ER PT J AU Ma, HJ Patti, ME AF Ma, Huijuan Patti, Mary Elizabeth TI Bile acids, obesity, and the metabolic syndrome SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Bile acids; FXR; TGR5; Obesity; Insulin resistance ID FARNESOID-X-RECEPTOR; Y GASTRIC BYPASS; TYPE-2 DIABETES-MELLITUS; PERIPHERAL INSULIN SENSITIVITY; IMPROVES GLUCOSE-HOMEOSTASIS; VERTICAL SLEEVE GASTRECTOMY; IMPROVED GLYCEMIC CONTROL; DIET-INDUCED OBESITY; NUCLEAR RECEPTOR; WEIGHT-LOSS AB Bile acids are increasingly recognized as key regulators of systemic metabolism. While bile acids have long been known to play important and direct roles in nutrient absorption, bile acids also serve as signalling molecules. Bile acid interactions with the nuclear hormone receptor farnesoid X receptor (FXR) and the membrane receptor G-protein-coupled bile acid receptor 5 (TGR5) can regulate incretin hormone and fibroblast growth factor 19 (FGF19) secretion, cholesterol metabolism, and systemic energy expenditure. Bile acid levels and distribution are altered in type 2 diabetes and increased following bariatric procedures, in parallel with reduced body weight and improved insulin sensitivity and glycaemic control. Thus, modulation of bile acid levels and signalling, using bile acid binding resins, TGR5 agonists, and FXR agonists, may serve as a potent therapeutic approach for the treatment of obesity, type 2 diabetes, and other components of the metabolic syndrome in humans. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ma, Huijuan] Hebei Gen Hosp, Dept Endocrinol & Metab, Shijiazhuang 050051, Hebei, Peoples R China. [Patti, Mary Elizabeth] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Patti, Mary Elizabeth] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Patti, ME (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Mary.Elizabeth.Patti@joslin.harvard.edu FU Hebei Health Department of Scientific Research Fund; American Diabetes Association; DRC (Joslin Diabetes Center) [P30DK036836] FX The authors gratefully acknowledge grant support from Hebei Health Department of Scientific Research Fund (to HM), P30DK036836 DRC (Joslin Diabetes Center), and the American Diabetes Association (to MEP). NR 101 TC 20 Z9 21 U1 5 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6918 EI 1532-1916 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD AUG PY 2014 VL 28 IS 4 BP 573 EP 583 DI 10.1016/j.bpg.2014.07.004 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AQ5VQ UT WOS:000342877100005 PM 25194176 ER PT J AU Gonzalez-Billalabeitia, E Seitzer, N Song, SJ Song, MS Patnaik, A Liu, XS Epping, MT Papa, A Hobbs, RM Chen, M Lunardi, A Ng, C Webster, KA Signoretti, S Loda, M Asara, JM Nardella, C Clohessy, JG Cantley, LC Pandolfi, PP AF Gonzalez-Billalabeitia, Enrique Seitzer, Nina Song, Su Jung Song, Min Sup Patnaik, Akash Liu, Xue-Song Epping, Mirjam T. Papa, Antonella Hobbs, Robin M. Chen, Ming Lunardi, Andrea Ng, Christopher Webster, Kaitlyn A. Signoretti, Sabina Loda, Massimo Asara, John M. Nardella, Caterina Clohessy, John G. Cantley, Lewis C. Pandolfi, Pier Paolo TI Vulnerabilities of PTEN-TP53-Deficient Prostate Cancers to Compound PARP-PI3K Inhibition SO CANCER DISCOVERY LA English DT Article ID TUMOR-SUPPRESSOR; CELL-SURVIVAL; PTEN; TUMORIGENESIS; BREAST; GENE AB Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer. SIGNIFICANCE: The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer. (C) 2014 AACR. C1 [Gonzalez-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung; Song, Min Sup; Liu, Xue-Song; Epping, Mirjam T.; Papa, Antonella; Hobbs, Robin M.; Chen, Ming; Lunardi, Andrea; Ng, Christopher; Webster, Kaitlyn A.; Nardella, Caterina; Clohessy, John G.; Pandolfi, Pier Paolo] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol & Med,Med Sch, Beth Israel Deaconess Canc Ctr,Canc Res Inst, Boston, MA 02215 USA. [Gonzalez-Billalabeitia, Enrique; Seitzer, Nina; Song, Su Jung; Song, Min Sup; Liu, Xue-Song; Epping, Mirjam T.; Papa, Antonella; Hobbs, Robin M.; Chen, Ming; Lunardi, Andrea; Ng, Christopher; Webster, Kaitlyn A.; Nardella, Caterina; Clohessy, John G.; Pandolfi, Pier Paolo] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Patnaik, Akash] Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA. [Patnaik, Akash; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA 02215 USA. [Signoretti, Sabina; Nardella, Caterina; Clohessy, John G.] Beth Israel Deaconess Med Ctr, Dept Med, Preclin Murine Pharmacogenet Facil, Boston, MA 02215 USA. [Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Patnaik, Akash; Asara, John M.; Cantley, Lewis C.] Harvard Univ, Dept Syst Biol, Boston, MA 02215 USA. [Loda, Massimo] Ctr Mol Oncol Pathol, Boston, MA USA. [Signoretti, Sabina; Loda, Massimo] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Loda, Massimo] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. RP Pandolfi, PP (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr,Dept Med, 330 Brookline Ave, Boston, MA 02215 USA. EM ppandolf@bidmc.harvard.edu RI Cantley, Lewis/D-1800-2014; OI Cantley, Lewis/0000-0002-1298-7653; Papa, Antonella/0000-0001-8653-7121 FU Mouse Models of Human Cancers Consortium/NCI [RC2 CA147940-01, R01 GM41890, P01 CA089021]; NIH [5P01CA120964-04]; NIH Dana-Farber/HCC Cancer Center [5P30CA006516-46]; Instituto de Salud Carlos III (Spain) FX This work has been supported through a Mouse Models of Human Cancers Consortium/NCI grant (RC2 CA147940-01), R01 GM41890, and P01 CA089021 (to P. P. Pandolfi and L. C. Cantley), and NIH grant 5P01CA120964-04 and NIH Dana-Farber/HCC Cancer Center Support Grant 5P30CA006516-46 (to J.M. Asara). E. Gonzalez-Billalabeitia has been supported by a Bolsa de ampliacion de estudios (BAE) from the Instituto de Salud Carlos III (Spain). NR 23 TC 19 Z9 20 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2014 VL 4 IS 8 BP 896 EP 904 DI 10.1158/2159-8290.CD-13-0230 PG 9 WC Oncology SC Oncology GA AQ8WW UT WOS:000343120400024 PM 24866151 ER PT J AU Yang, A Rajeshkumar, NV Wang, XX Yabuuchi, S Alexander, BM Chu, GC Von Hoff, DD Maitra, A Kimmelman, AC AF Yang, Annan Rajeshkumar, N. V. Wang, Xiaoxu Yabuuchi, Shinichi Alexander, Brian M. Chu, Gerald C. Von Hoff, Daniel D. Maitra, Anirban Kimmelman, Alec C. TI Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations SO CANCER DISCOVERY LA English DT Article ID DUCTAL ADENOCARCINOMA; CANCER; GENE; MICE; MOUSE; CELLS; HOMEOSTASIS; COOPERATE; BECLIN-1; DISEASE AB Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patientderived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. SIGNIFICANCE: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials. (C) 2014 AACR. C1 [Yang, Annan; Wang, Xiaoxu; Alexander, Brian M.; Kimmelman, Alec C.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02215 USA. [Chu, Gerald C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Rajeshkumar, N. V.; Yabuuchi, Shinichi; Maitra, Anirban] Johns Hopkins Univ, Dept Pathol & Oncol, Sch Med, Baltimore, MD USA. [Von Hoff, Daniel D.] Translat Genom Res Inst, Phoenix, AZ USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Maitra, Anirban] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. [Yabuuchi, Shinichi] Tohoku Univ, Grad Sch Med, Dept Surg, Sendai, Miyagi 980, Japan. RP Kimmelman, AC (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM alec_kimmelman@dfci.harvard.edu FU National Cancer Institute [R01CA157490]; American Cancer Society (ACS) Research Scholar grant [RSG-13-298-01-TBG]; Lustgarten Foundation; SU2C AACR Translational Research Dream Team [SU2C-AACR-DT0509] FX This work was supported by National Cancer Institute grant R01CA157490, American Cancer Society (ACS) Research Scholar grant RSG-13-298-01-TBG, and the Lustgarten Foundation (to A. C. Kimmelman), and an SU2C AACR Translational Research Dream Team SU2C-AACR-DT0509 grant (to A. Maitra, N.V. Rajesh-kumar, and D.D. Von Hoff). NR 34 TC 83 Z9 87 U1 4 U2 30 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2014 VL 4 IS 8 BP 905 EP 913 DI 10.1158/2159-8290.CD-14-0362 PG 9 WC Oncology SC Oncology GA AQ8WW UT WOS:000343120400025 PM 24875860 ER PT J AU Francis, JM Zhang, CZ Maire, CL Jung, J Manzo, VE Adalsteinsson, VA Homer, H Haidar, S Blumenstiel, B Pedamallu, CS Ligon, AH Love, JC Meyerson, M Ligon, KL AF Francis, Joshua M. Zhang, Cheng-Zhong Maire, Cecile L. Jung, Joonil Manzo, Veronica E. Adalsteinsson, Viktor A. Homer, Heather Haidar, Sam Blumenstiel, Brendan Pedamallu, Chandra Sekhar Ligon, Azra H. Love, J. Christopher Meyerson, Matthew Ligon, Keith L. TI EGFR Variant Heterogeneity in Glioblastoma Resolved through Single-Nucleus Sequencing SO CANCER DISCOVERY LA English DT Article ID GROWTH-FACTOR-RECEPTOR; TERT PROMOTER MUTATIONS; INTEGRATED GENOMIC ANALYSIS; LUNG-CANCER; INTRATUMOR HETEROGENEITY; COLORECTAL CARCINOMAS; KINASE INHIBITORS; HUMAN GLIOMAS; CELL-CYCLE; EVOLUTION AB Glioblastomas (GBM) with EGFR amplification represent approximately 50% of newly diagnosed cases, and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same tumor, which has implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here, we applied a population-based single-cell whole-genome sequencing methodology to characterize genomic heterogeneity in EGFR - amplified glioblastomas. Our analysis effectively identified clonal events, including a novel translocation of a super enhancer to the TERT promoter, as well as subclonal LOH and multiple EGFR mutational variants within tumors. Correlating the EGFR mutations onto the cellular hierarchy revealed that EGFR truncation variants (EGFRvII and EGFR carboxyl-terminal deletions) identified in the bulk tumor segregate into nonoverlapping subclonal populations. In vitro and in vivo functional studies show that EGFRvII is oncogenic and sensitive to EGFR inhibitors currently in clinical trials. Thus, the association between diverse activating mutations in EGFR and other subclonal mutations within a single tumor supports an intrinsic mechanism for proliferative and clonal diversification with broad implications in resistance to treatment. SIGNIFICANCE: We developed a novel single-cell sequencing methodology capable of identifying unique, nonoverlapping subclonal alterations from archived frozen clinical specimens. Using GBM as an example, we validated our method to successfully define tumor cell subpopulations containing distinct genetic and treatment resistance profiles and potentially mutually cooperative combinations of alterations in EGFR and other genes. (C) 2014 AACR. C1 [Francis, Joshua M.; Zhang, Cheng-Zhong; Jung, Joonil; Adalsteinsson, Viktor A.; Blumenstiel, Brendan; Pedamallu, Chandra Sekhar; Love, J. Christopher; Meyerson, Matthew] Broad Inst Harvard & MIT, Cambridge, MA USA. [Francis, Joshua M.; Maire, Cecile L.; Manzo, Veronica E.; Haidar, Sam; Pedamallu, Chandra Sekhar; Meyerson, Matthew; Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Adalsteinsson, Viktor A.; Love, J. Christopher] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Adalsteinsson, Viktor A.; Love, J. Christopher] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Homer, Heather; Ligon, Azra H.; Ligon, Keith L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02215 USA. [Ligon, Azra H.; Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ligon, Azra H.; Ligon, Keith L.] Boston Childrens Hosp, Dept Pathol, Boston, MA USA. [Ligon, Azra H.; Meyerson, Matthew; Ligon, Keith L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. RP Ligon, KL (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM Matthew_Meyerson@dfci.harvard.edu; Keith_Ligon@dfci.harvard.edu FU Bridge Project; David H. Koch Institute for Integrative Cancer Research at MIT; Dana-Farber/Harvard Cancer Center (DF/HCC); National Brain Tumor Society; NCI [R01CA170592, P01CA142536, R01CA116020]; Sontag Foundation FX This work was supported by the Bridge Project, a collaboration between The David H. Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC), and the National Brain Tumor Society (to J.C. Love, K.L. Ligon, and M. Meyerson). This work was supported in part by grants to K.L. Ligon from NCI R01CA170592, P01CA142536, and the Sontag Foundation, and to M. Meyerson from NCI R01CA116020. NR 55 TC 53 Z9 54 U1 2 U2 16 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 EI 2159-8290 J9 CANCER DISCOV JI Cancer Discov. PD AUG PY 2014 VL 4 IS 8 BP 956 EP 971 DI 10.1158/2159-8290.CD-13-0879 PG 16 WC Oncology SC Oncology GA AQ8WW UT WOS:000343120400029 PM 24893890 ER PT J AU Youngster, I Shenoy, ES Hooper, DC Nelson, SB AF Youngster, Ilan Shenoy, Erica S. Hooper, David C. Nelson, Sandra B. TI Comparative Evaluation of the Tolerability of Cefazolin and Nafcillin for Treatment of Methicillin-Susceptible Staphylococcus aureus Infections in the Outpatient Setting SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE nafcillin; cefazolin; MSSA; OPAT; tolerability ID PARENTERAL ANTIMICROBIAL THERAPY; PRACTICE GUIDELINES; TREATMENT FAILURE; BACTEREMIA; ENDOCARDITIS; MANAGEMENT; CEPHALOSPORINS; DIAGNOSIS; ASSOCIATION; STATEMENT AB Background. Nafcillin and cefazolin are considered first-line therapy for most infections with methicillin-susceptible Staphylococcus aureus (MSSA), and recent studies have suggested similar clinical efficacy. Limited data are available on the comparative tolerability of these agents. Methods. In this retrospective cohort analysis of patients treated with either nafcillin or cefazolin for MSSA infection in the outpatient parenteral antimicrobial therapy clinic at Massachusetts General Hospital from 2007 to 2011, the frequency of premature antimicrobial discontinuation (PAD) and drug-emergent events (DEEs) was calculated. Results. Three hundred sixty-six and 119 patients were treated with nafcillin or cefazolin, respectively. The median anticipated duration of therapy was comparable at 28 (interquartile range [IQR], 16-37) and 29 (IQR, 24-39) days, respectively, for those treated with nafcillin and cefazolin. Fewer patients completed the prespecified treatment course with nafcillin than with cefazolin (PAD rate, 33.8% vs 6.7%; P < .0001). The hazard ratio for PAD in the nafcillin vs cefazolin groups was 2.81 (95% confidence interval [CI], 1.26-3.68). More patients in the nafcillin group developed rash (13.9% vs 4.2%; P = .002), renal dysfunction (11.4% vs 3.3%; P = .006), and liver function abnormalities (8.1% vs 1.6%; P = .01). Overall rates of DEEs per 1000 patient-days were 16.9 (95% CI, 10.4-27.3) and 4.8 (95% CI, 1.1-10.2), respectively. In 9 cases of nafcillin discontinuation, treatment was changed to cefazolin; all 9 completed treatment with no further observed DEEs. Conclusions. Nafcillin treatment was associated with higher rates of both PAD as well as DEEs compared with cefazolin treatment. This difference in tolerability, in addition to efficacy and cost, should be considered when decisions for outpatient parenteral MSSA treatment are made. C1 [Youngster, Ilan; Shenoy, Erica S.; Hooper, David C.; Nelson, Sandra B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Youngster, Ilan; Shenoy, Erica S.; Hooper, David C.; Nelson, Sandra B.] Harvard Univ, Sch Med, Boston, MA USA. [Youngster, Ilan] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02445 USA. [Shenoy, Erica S.; Hooper, David C.] Massachusetts Gen Hosp, Infect Control Unit, Boston, MA 02114 USA. RP Youngster, I (reprint author), Boston Childrens Hosp, Div Infect Dis, 300 Longwood Ave, Boston, MA 02445 USA. EM ilan.youngster@childrens.harvard.edu OI Youngster, Ilan/0000-0001-5233-1213 FU National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000170-05]; Harvard University and its affiliated academic healthcare centers FX I. Y. received career support from Harvard Catalyst, The Harvard Clinical and Translational Science Center, funded by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (award number 8UL1TR000170-05), and financial contributions from Harvard University and its affiliated academic healthcare centers. NR 27 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2014 VL 59 IS 3 BP 369 EP 375 DI 10.1093/cid/ciu301 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AQ6KG UT WOS:000342919700008 PM 24785233 ER PT J AU Marcy, O Laureillard, D Madec, Y Chan, S Mayaud, C Borand, L Prak, N Kim, C Lak, KK Hak, C Dim, B Sok, T Delfraissy, JF Goldfeld, AE Blanc, FX AF Marcy, Olivier Laureillard, Didier Madec, Yoann Chan, Sarin Mayaud, Charles Borand, Laurence Prak, Narom Kim, Chindamony Lak, Kim Khemarin Hak, Chanroeurn Dim, Bunnet Sok, Thim Delfraissy, Jean-Francois Goldfeld, Anne E. Blanc, Francois-Xavier CA CAMELIA ANRS 1295-CIPRA KH001 TI Causes and Determinants of Mortality in HIV-Infected Adults With Tuberculosis: An Analysis From the CAMELIA ANRS 1295-CIPRA KH001 Randomized Trial SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE tuberculosis; HIV; mortality; cause of death; adult ID ACTIVE ANTIRETROVIRAL THERAPY; SUB-SAHARAN AFRICA; COTE-DIVOIRE; PULMONARY TUBERCULOSIS; CLINICAL-TRIAL; COHORT; COTRIMOXAZOLE; PROPHYLAXIS; MENINGITIS; PREDICTORS AB Background. Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival. Methods. We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count <= 200 cells/mu L and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial. Results. Six hundred sixty-one patients enrolled contributed to 1366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4-10.7) in the early-ART group and 13.8 deaths per 100 person-years (95% CI, 11.2-16.9) in the late-ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis. Conclusions. Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies. C1 [Marcy, Olivier; Laureillard, Didier; Chan, Sarin; Lak, Kim Khemarin; Dim, Bunnet; Sok, Thim; Goldfeld, Anne E.] Inst Pasteur Cambodge, Cambodian Hlth Comm, Phnom Penh, Cambodia. [Marcy, Olivier; Borand, Laurence] Inst Pasteur Cambodge, Epidemiol & Publ Hlth Unit, Phnom Penh, Cambodia. [Laureillard, Didier] ANRS, Ho Cho Minh City, Vietnam. [Madec, Yoann] Inst Pasteur, Emerging Dis Epidemiol Unit, Paris, France. [Chan, Sarin; Hak, Chanroeurn] Calmette Hosp, Phnom Penh, Cambodia. [Mayaud, Charles] Hop Tenon, AP HP, F-75970 Paris, France. [Prak, Narom] Khmer Soviet Friendship Hosp, Phnom Penh, Cambodia. [Kim, Chindamony] Donkeo Prov Hosp, Takeo, Cambodia. [Kim, Chindamony; Dim, Bunnet] Med Sans Frontieres, Phnom Penh, Cambodia. [Lak, Kim Khemarin] Svay Rieng Prov Hosp, Svay Rieng, Cambodia. [Dim, Bunnet] Siem Reap Prov Hosp, Siem Reap, Cambodia. [Delfraissy, Jean-Francois] Hop Bicetre, AP HP, Le Kremlin Bicetre, France. [Goldfeld, Anne E.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Blanc, Francois-Xavier] Univ Nantes, INSERM, CNRS, UMR 1087,UMR 6291,Inst Thorax,CHU Nantes, F-44035 Nantes, France. RP Blanc, FX (reprint author), CHU Nantes, Hop Laennec, Inst Thorax, Serv Pneumol, Blvd Jacques Monod, F-44093 Nantes 1, France. EM xavier.blanc@chu-nantes.fr RI Blanc, Francois-Xavier/D-7425-2015 FU French National Agency for Research on AIDS and Viral Hepatitis [ANRS 1295]; US National Institutes of Health (NIH), Division of AIDS [CIPRA KH001/DAID-ES ID 10425] FX This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS 1295) and the US National Institutes of Health (NIH), Division of AIDS (CIPRA KH001/DAID-ES ID 10425). NR 37 TC 12 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 1 PY 2014 VL 59 IS 3 BP 435 EP 445 DI 10.1093/cid/ciu283 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA AQ6KG UT WOS:000342919700020 PM 24759827 ER PT J AU Shah, A Carreno, FR Frazer, A AF Shah, Aparna Carreno, Flavia Regina Frazer, Alan TI Therapeutic Modalities for Treatment Resistant Depression: Focus on Vagal Nerve Stimulation and Ketamine SO CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE LA English DT Review DE Depression; Vagal nerve stimulation; Ketamine; TrkB ID D-ASPARTATE ANTAGONIST; PHARMACOLOGICALLY DIVERSE ANTIDEPRESSANTS; TRANSCRANIAL MAGNETIC STIMULATION; COGNITIVE-BEHAVIORAL THERAPY; NEUROTROPHIC FACTOR-RECEPTOR; DELTA-FOSB IMMUNOREACTIVITY; RANDOMIZED CONTROLLED-TRIAL; VAGUS NERVE; MAJOR DEPRESSION; RAT-BRAIN AB Treatment resistant depression (TRD) is a global health concern affecting a large proportion of depressed patients who then require novel therapeutic options. One such treatment option that has received some attention in the past several years. is vagal nerve stimulation (VNS). The present review briefly describes the relevance of this treatment in the light of other existing pharmacological and non-pharmacological options, It then summarizes clinical findings with respect to the efficacy of VNS. The anatomical rationale for its efficacy and other potential mechanisms of its antidepressant effects as compared to those employed by classical antidepressant drugs are discussed. VNS has been approved in some countries and has been used for patients with TRD for quite some time, A newer, fast-acting, non-invasive pharmacological option called ketamine is currently in the limelight with reference to TRD. This drug is currently in the investigational phase but shows promise. The clinical and preclinical findings related to ketamine have also been summarized and compared with those for VNS. The role of neurotrophin factors, specifically brain derived neurotrophic factor and its receptor, in the beneficial effects of both VNS and ketamine have been highlighted. It can be concluded that both these therapeutic modalities, while effective, need further research that can reveal specific targets for intervention by novel drugs and address concerns related to side-effects, especially those seen with ketamine. C1 [Shah, Aparna; Carreno, Flavia Regina; Frazer, Alan] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Shah, Aparna; Carreno, Flavia Regina; Frazer, Alan] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [Frazer, Alan] South Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Shah, A (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr,Mail Code 7764, San Antonio, TX 78229 USA. EM shahap@uthscsa.edu FU Lundbeck; Takeda Pharmaceuticals International, Inc.; Eli Lilly and Co. FX Dr. Frazer has served on advisory boards for Lundbeck and for Takeda Pharmaceuticals International, Inc. and Eli Lilly and Co. Previously, Dr. Frazer had received financial compensation as a consultant for Cyberonics Inc. and had also obtained grant support from them for a preclinical study. NR 126 TC 8 Z9 8 U1 1 U2 10 PU KOREAN COLL NEUROPSYCHOPHARMACOLOGY PI SEOUL PA RN 1003 OFFICETEL 40, 63-RO YEONGDEUNGPO-GU, SEOUL, 150-731, SOUTH KOREA SN 1738-1088 EI 2093-4327 J9 CLIN PSYCHOPHARM NEU JI Clin. Psychopharmacol. Neurosci. PD AUG PY 2014 VL 12 IS 2 BP 83 EP 93 DI 10.9758/cpn.2014.12.2.83 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA AQ5NK UT WOS:000342855700002 PM 25191499 ER PT J AU Rashid, A Jakobiec, FA Mandeville, JT AF Rashid, Alia Jakobiec, Frederick A. Mandeville, John T. TI Squamous Cell Carcinoma With Clear-Cell Features of the Palpebral Conjunctiva SO JAMA OPHTHALMOLOGY LA English DT Letter ID SEBACEOUS CARCINOMA C1 [Rashid, Alia; Jakobiec, Frederick A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA USA. [Mandeville, John T.] Eye Hlth Serv, Quincy, MA USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, David G Cogan Lab Ophthalm Pathol, 243 Charles St, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 8 TC 5 Z9 5 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6165 EI 2168-6173 J9 JAMA OPHTHALMOL JI JAMA Ophthalmol. PD AUG PY 2014 VL 132 IS 8 BP 1019 EP 1021 PG 4 WC Ophthalmology SC Ophthalmology GA AQ8EX UT WOS:000343058000020 PM 24852407 ER PT J AU Schwartz, DB DiTucci, A Goldman, B Gramigna, GD Cummings, B AF Schwartz, Denise Baird DiTucci, Angela Goldman, Babak Gramigna, Gary D. Cummings, Bernadette TI Achieving Patient-Centered Care in a Case of a Patient With Advanced Dementia SO NUTRITION IN CLINICAL PRACTICE LA English DT Article DE aged; nutritional support; patient self-determination act; geriatrics; ethics; critical care; surrogate decision maker; ethical principles AB An 83-year-old woman with a diagnosis of advanced dementia and aspiration transferred from a long-term care facility was intubated in the ambulance. As part of the hospital's proactive and systematic process, the patient received an interdisciplinary patient-centered care approach in accordance with her needs and cultural and religious beliefs. The purpose of this article is to present the use of a patient-centered interdisciplinary process by applying core ethical principles to a case study involving nutrition support. C1 [Schwartz, Denise Baird; Goldman, Babak] Providence St Joseph Med Ctr, Burbank, CA 91505 USA. [DiTucci, Angela; Gramigna, Gary D.; Cummings, Bernadette] VA Boston Healthcare Syst, West Roxbury, MA USA. RP Schwartz, DB (reprint author), Providence St Joseph Med Ctr, 501 South Buena Vista St, Burbank, CA 91505 USA. EM denisebairdschwartz@gmail.com NR 11 TC 5 Z9 5 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0884-5336 EI 1941-2452 J9 NUTR CLIN PRACT JI Nutr. Clin. Pract. PD AUG PY 2014 VL 29 IS 4 BP 556 EP 558 DI 10.1177/0884533614536588 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA AQ5LV UT WOS:000342851600018 PM 24913272 ER PT J AU Welch, M Uslan, DZ Greenspon, AJ Sohail, MR Baddour, LM Blank, E Carrillo, RG Danik, SB Del Rio, A Hellinger, W Le, KY Miro, JM Naber, C Peacock, JE Vikram, HR Tseng, CH Prutkin, JM AF Welch, Mariko Uslan, Daniel Z. Greenspon, Arnold J. Sohail, Muhammad R. Baddour, Larry M. Blank, Elisabeth Carrillo, Roger G. Danik, Stephan B. Del Rio, Ana Hellinger, Walter Le, Katherine Y. Miro, Jose M. Naber, Christoph Peacock, James E. Vikram, Holenarasipur R. Tseng, Chi-Hong Prutkin, Jordan M. CA MEDIC Investigators TI Variability in Clinical Features of Early Versus Late Cardiovascular Implantable Electronic Device Pocket Infections SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE cardiac implantable devices; endocarditis; device infection ID RISK-FACTORS; CARDIOVERTER-DEFIBRILLATORS; PACEMAKER IMPLANTATION; MEDICARE BENEFICIARIES; TEMPORAL TRENDS; UNITED-STATES; RATES; MANAGEMENT; REGISTRY; LEAD AB Background: Cardiovascular implantable electronic device (CIED) pocket infections are often related to recent CIED placement or manipulation, but these infections are not well characterized. The clinical presentation of CIED pocket infection, based on temporal onset related to last CIED procedure, deserves further study. Methods: The MEDIC (Multicenter Electrophysiologic Device Infection Cohort) prospectively enrolled subjects with CIED infection. Subjects were stratified into those whose infection occurred < 12 months (early) or >= 12 months (late) since their last CIED-related procedure. Results: There were 132 subjects in the early group and 106 in the late group. There were more females (P = 0.009) and anticoagulation use (P = 0.039) in the early group. Subjects with early infections were more likely to have had a generator change or lead addition as their last procedure (P = 0.03) and had more prior CIED procedures (P = 0.023). Early infections were more likely to present with pocket erythema (P < 0.001), swelling (P < 0.001), and pain (P = 0.007). Late infections were more likely to have pocket erosion (P = 0.005) and valvular vegetations (P = 0.009). In bacteremic subjects, early infections were more likely healthcare-associated (P < 0.001). In-hospital and 6-month mortality were equivalent. Conclusion: A total of 45% of patients with CIED pocket infection presented > 12 months following their last CIED-related procedure. Patients with early infection were more likely to be female, on anticoagulation, and present with localized inflammation, whereas those with late infection were more likely to have CIED erosion or valvular endocarditis. C1 [Welch, Mariko; Prutkin, Jordan M.] Univ Washington, Dept Med, Div Cardiol, Seattle, WA 98195 USA. [Uslan, Daniel Z.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Greenspon, Arnold J.] Thomas Jefferson Univ Hosp, Dept Med, Div Cardiol, Philadelphia, PA 19107 USA. [Sohail, Muhammad R.; Baddour, Larry M.; Le, Katherine Y.] Mayo Clin, Dept Med, Div Infect Dis, Rochester, MN USA. [Blank, Elisabeth; Naber, Christoph] Elisabeth Hosp, Essen, Germany. [Carrillo, Roger G.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Danik, Stephan B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv, Boston, MA USA. [Del Rio, Ana; Miro, Jose M.] Univ Barcelona, Hosp Clin IDIBAPS, Infect Dis Serv, Barcelona, Spain. [Hellinger, Walter] Mayo Clin, Dept Med, Div Infect Dis, Jacksonville, FL 32224 USA. [Peacock, James E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Med, Div Infect Dis, Winston Salem, NC 27103 USA. [Vikram, Holenarasipur R.] Mayo Clin, Dept Med, Div Infect Dis, Scottsdale, AZ USA. [Tseng, Chi-Hong] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biostat, Los Angeles, CA 90095 USA. RP Prutkin, JM (reprint author), Univ Washington, Dept Med, Div Cardiol, 1959 NE Pacific St,Box 356422, Seattle, WA 98195 USA. EM jprutkin@cardiology.washington.edu RI Sohail, Muhammad/K-1803-2016 OI Sohail, Muhammad/0000-0001-6355-0526 FU Significant; TyRx., Inc.; Modest; St. Jude Medical Corp.; Speakers Bureau; Medtronic; St. Jude Medical Corp; Sorin Group; Boston Scientific Corp. FX M. P. Welch, A. J. Greenspon, L. M. Baddour, E. Blank, S. B. Danik, A. del Rio, W. C. Hellinger, K. Y. Le, J. M. Miro, C. Naber, J. E. Peacock, C. Tseng, H. R. Vikram, J. M. Prutkin: None. D. Z. Uslan: Honoraria; Significant; Medtronic, BIOTRONIK. Consultant/Advisory Board; Significant; TyRx., Inc. M. R. Sohail: Research Grant; Significant; TyRx., Inc. R. G. Carrillo: Research Grant; Modest; St. Jude Medical Corp. Speakers Bureau; Modest; Medtronic, St. Jude Medical Corp, Sorin Group, Boston Scientific Corp. Consultant/Advisory Board; Significant; Spectranetics. NR 33 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0147-8389 EI 1540-8159 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD AUG PY 2014 VL 37 IS 8 BP 955 EP 962 DI 10.1111/pace.12385 PG 8 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA AQ5FL UT WOS:000342831900006 PM 24665867 ER PT J AU Shalaby, AA Brumberg, GE Pointer, L Bekelman, DB Rumsfeld, JS Yang, YF Pellegrini, CN Heidenreich, PA Keung, E Massie, BM Varosy, PD AF Shalaby, Alaa A. Brumberg, Genevieve E. Pointer, Lauren Bekelman, David B. Rumsfeld, John S. Yang, Yanfei Pellegrini, Cara N. Heidenreich, Paul A. Keung, Edmund Massie, Barry M. Varosy, Paul D. TI Depression and Outcome among Veterans with Implantable Cardioverter Defibrillators with or without Cardiac Resynchronization Therapy Capability SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE depression; implantable cardiac defibrillator; mortality; heart failure ID CHRONIC HEART-FAILURE; MYOCARDIAL-INFARCTION; COLLABORATIVE CARE; SYMPTOMS; RISK; MORTALITY; PREVALENCE; LIFE AB Background: The impact of depression on outcome in implantable cardioverter defibrillator (ICD) recipients has not been fully appreciated. We assessed the prevalence of depression and its association with heart failure (HF) outcome among veterans with ICDs. Methods and Results: Patients enrolled between January 2005 and January 2010 in the Outcomes among Veterans with Implantable Defibrillators Registry were studied. We examined the cross-sectional association of depression with severity of HF functional class as well as the association of depression with the composite outcome of mortality or HF hospitalization over a mean follow-up time of 2.7 years. There were 3,862 patients enrolled. Patients with depression (1,162, 43%) were younger (63.1 +/- 9.4 years vs 66.6 +/- 9.9 years, P<0.001), more likely to have a history of tobacco or alcohol abuse (P<0.0001) or atrial fibrillation (P=0.05) while having a higher ejection fraction (28.3% vs 27.4%, P=0.03). Depression was associated with advanced HF class at time of implant; odds ratio (OR; vs class I) for class III: 1.65 (confidence interval [CI] 1.17-2.33), class IV: 1.73 (95% CI 1.08-2.76). Death or HF hospitalization was more likely to occur in patients with depression (35.2% vs 32.0%, HR: 1.15 [95% CI 0.99-1.33]). The predictive value of depression was stronger after multivariable adjustment; HR: 1.25 (95% CI 1.05-1.49). Conclusion: Depression was prevalent among veterans with ICDs. Depression was associated with severity of HF. The predictive value of associated depression was significant after multivariable adjustment. C1 [Shalaby, Alaa A.; Brumberg, Genevieve E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15240 USA. [Shalaby, Alaa A.; Brumberg, Genevieve E.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Pointer, Lauren; Bekelman, David B.; Rumsfeld, John S.; Varosy, Paul D.] Vet Affairs Eastern Colorado Hlth Care Syst, Denver, CO USA. [Pointer, Lauren; Bekelman, David B.; Rumsfeld, John S.; Varosy, Paul D.] Univ Colorado, Colorado Cardiovasc Outcomes Res, Denver, CO 80202 USA. [Yang, Yanfei; Heidenreich, Paul A.] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Yang, Yanfei; Heidenreich, Paul A.] Stanford Univ, Palo Alto, CA 94304 USA. [Pellegrini, Cara N.; Keung, Edmund; Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Pellegrini, Cara N.; Keung, Edmund; Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Shalaby, AA (reprint author), Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Div Cardiol, 111 C Univ Dr, Pittsburgh, PA 15240 USA. EM Alaa.Shalaby@va.gov OI Heidenreich, Paul/0000-0001-7730-8490 NR 37 TC 2 Z9 2 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0147-8389 EI 1540-8159 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD AUG PY 2014 VL 37 IS 8 BP 994 EP 1001 DI 10.1111/pace.12361 PG 8 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA AQ5FL UT WOS:000342831900011 PM 24520992 ER PT J AU Sohn, K Lv, W Lee, K Galea, A Hirschman, G Barrett, C Cohen, RJ Armoundas, AA AF Sohn, Kwanghyun Lv, Wener Lee, Kichang Galea, Anna Hirschman, Gordon Barrett, Conor Cohen, Richard J. Armoundas, Antonis A. TI A Method to Noninvasively Identify Cardiac Bioelectrical Sources SO PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY LA English DT Article DE catheter ablation; single equivalent moving dipole; noninvasive; localization; arrhythmia ID RADIOFREQUENCY CATHETER ABLATION; CORONARY HEART-DISEASE; MOVING DIPOLE MODEL; VENTRICULAR-TACHYCARDIA; ELECTRICAL ACTIVATION; LOCAL ACTIVATION; MAPPING SYSTEM; TORSO MODEL; ELECTROPHYSIOLOGY; REPOLARIZATION AB Background: We have introduced a method to guide radiofrequency catheter ablation (RCA) procedures that estimates the location of a catheter tip used to pace the ventricles and the target site for ablation using the single equivalent moving dipole (SEMD). Objective: To investigate the accuracy of this method in resolving epicardial and endocardial electrical sources. Methods: Two electrode arrays, each of nine pacing electrodes at known distances from each other, sutured on the left-and right-ventricular (LV and RV) epicardial surfaces of swine, were used to pace the heart at multiple rates, while body surface potentials from 64 sites were recorded and used to estimate the SEMD location. A similar approach was followed for pacing from catheters in the LV and RV. Results: The overall (RV & LV) error in estimating the interelectrode distance of adjacent epicardial electrodes was 0.38 +/- 0.45 cm. The overall endocardial (RV & LV) interelectrode distance error, was 0.44 +/- 0.26 cm. Heart rate did not significantly affect the error of the estimated SEMD location (P > 0.05). The guiding process error became progressively smaller as the SEMD approached an epicardial target site and close to the target, the overall absolute error was similar to 0.28 cm. The estimated epicardial SEMD locations preserved their topology in image space with respect to their corresponding physical location of the epicardial electrodes. Conclusion: The proposed algorithm suggests one can efficiently and accurately resolve epicardial electrical sources without the need of an imaging modality. In addition, the error in resolving these sources is sufficient to guide RCA procedures. C1 [Sohn, Kwanghyun; Armoundas, Antonis A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Lv, Wener; Lee, Kichang; Cohen, Richard J.; Armoundas, Antonis A.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Galea, Anna; Hirschman, Gordon] Vivonics Inc, Waltham, MA USA. [Barrett, Conor] Massachusetts Gen Hosp, Div Cardiol, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org FU NIH [1RO1HL103961, R44 HL079726-04] FX The work was supported by NIH grants 1RO1HL103961 and R44 HL079726-04. NR 37 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0147-8389 EI 1540-8159 J9 PACE JI PACE-Pacing Clin. Electrophysiol. PD AUG PY 2014 VL 37 IS 8 BP 1038 EP 1050 DI 10.1111/pace.12380 PG 13 WC Cardiac & Cardiovascular Systems; Engineering, Biomedical SC Cardiovascular System & Cardiology; Engineering GA AQ5FL UT WOS:000342831900017 PM 24645803 ER PT J AU Dubois, MY Chen, L AF Dubois, Michel Y. Chen, Lucy TI Of Low Back Pain and Moxibustion SO PAIN MEDICINE LA English DT Editorial Material ID RANDOMIZED-CONTROLLED-TRIAL; ALTERNATIVE MEDICINE C1 [Dubois, Michel Y.] Midtown Pain Med, New York, NY 10022 USA. [Chen, Lucy] Massachusetts Gen Hosp, Dept Anaesthesia, Boston, MA 02114 USA. RP Dubois, MY (reprint author), Midtown Pain Med, New York, NY 10022 USA. NR 8 TC 0 Z9 0 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD AUG PY 2014 VL 15 IS 8 BP 1243 EP 1244 DI 10.1111/pme.12513 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2PW UT WOS:000342630800001 PM 25132305 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO PAIN MEDICINE LA English DT Article DE Low Back Pain; Chronic Low Back Pain; Research Standards; Minimum Dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Objective. Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific, and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Design. Expert panel and preliminary evaluation of key recommendations. Methods. The NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel developed a 3-stage process, each with a 2-day meeting. Results. The panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimal data set to describe research subjects (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. Conclusion. The RTF believes these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. We expect the RTF recommendations will be come a dynamic document, and undergo continual improvement. Perspective. A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Cook, Karon; Weiner, Debra K.] Northwestern Univ, Evanston, IL USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John] Johns Hopkins Univ, Baltimore, MD USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] NIAMSD, Bethesda, MD 20892 USA. [DeLitto, Anthony] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 126 TC 11 Z9 11 U1 8 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 EI 1526-4637 J9 PAIN MED JI Pain Med. PD AUG PY 2014 VL 15 IS 8 BP 1249 EP 1267 DI 10.1111/pme.12538 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA AQ2PW UT WOS:000342630800004 PM 25132307 ER PT J AU Allen, JL Kautz, SA Neptune, RR AF Allen, Jessica L. Kautz, Steven A. Neptune, Richard R. TI Forward propulsion asymmetry is indicative of changes in plantarflexor coordination during walking in individuals with post-stroke hemiparesis SO CLINICAL BIOMECHANICS LA English DT Article DE Forward dynamic simulations; Gait; Post-stroke hemiparesis; Rehabilitation ID GROUND REACTION FORCES; BODY-WEIGHT SUPPORT; MECHANICAL-PROPERTIES; STROKE SURVIVORS; GAIT ANALYSIS; PARETIC LEG; ENERGY-COST; MUSCLE; SPEED; PROGRESSION AB Background: A common measure of rehabilitation effectiveness post-stroke is self-selected walking speed, yet individuals may achieve the same speed using different coordination strategies. Asymmetry in the propulsion generated by each leg can provide insight into paretic leg coordination due to its relatively strong correlation with hemiparetic severity. Subjects walking at the same speed can exhibit different propulsion asymmetries, with some subjects relying more on the paretic leg and others on the nonparetic leg. The goal of this study was to assess whether analyzing propulsion asymmetry can help distinguish between improved paretic leg coordination versus nonparetic leg compensation. Methods: Three-dimensional forward dynamics simulations were developed for two post-stroke hemiparetic subjects walking at identical speeds before/after rehabilitation with opposite changes in propulsion asymmetry. Changes in the individual muscle contributions to forward propulsion were examined. Findings: The major source of increased forward propulsion in both subjects was from the ankle plantarflexors. How they were utilized differed and appears related to changes in propulsion asymmetry. Subject A increased propulsion generated from the paretic plantarflexors, while Subject B increased propulsion generated from the nonparetic plantarflexors. Each subject's strategy to increase speed also included differences in other muscle groups (e.g., hamstrings) that did not appear to be related to propulsion asymmetry. Interpretation: The results of this study highlight how speed cannot be used to elucidate underlying muscle coordination changes following rehabilitation. In contrast, propulsion asymmetry appears to provide insight into changes in plantarflexor output affecting propulsion generation and may be useful in monitoring rehabilitation outcomes. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Allen, Jessica L.; Neptune, Richard R.] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. [Kautz, Steven A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Neptune, RR (reprint author), Univ Texas Austin, Dept Mech Engn, 1 Univ Stn C2200, Austin, TX 78712 USA. EM rneptune@mail.utexas.edu FU NIH [R01 NS55380]; Rehabilitation Research & Development Service of the VA; NSF Graduate Research Fellowship Program FX The authors would like to thank Dr. Mark Bowden and the intervention research team for their contributions to the data collection and processing. This project was supported by NIH grant R01 NS55380, the Rehabilitation Research & Development Service of the VA, and the NSF Graduate Research Fellowship Program. The comments are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NICHD, VA or NSF. NR 42 TC 6 Z9 6 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 EI 1879-1271 J9 CLIN BIOMECH JI Clin. Biomech. PD AUG PY 2014 VL 29 IS 7 BP 780 EP 786 DI 10.1016/j.clinbiomech.2014.06.001 PG 7 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA AQ1GY UT WOS:000342531100010 PM 24973825 ER PT J AU Laubach, JP Faber, EA Voorhees, P Moslehi, J Varga, C Niculescu, L Anderson, KC Richardson, PG AF Laubach, Jacob P. Faber, Edward A., Jr. Voorhees, Peter Moslehi, Javid Varga, Cindy Niculescu, Liviu Anderson, Kenneth C. Richardson, Paul G. TI The challenge of cross-trial comparisons using limited data SO HAEMATOLOGICA LA English DT Letter DE cross-trial; data; challenge ID SINGLE-AGENT CARFILZOMIB; REFRACTORY MULTIPLE-MYELOMA; OPEN-LABEL; RANDOMIZED PHASE-3; BORTEZOMIB; DEXAMETHASONE; INDUCTION; ARM; THALIDOMIDE; THERAPY C1 [Laubach, Jacob P.; Varga, Cindy; Anderson, Kenneth C.; Richardson, Paul G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Faber, Edward A., Jr.] Oncol Hematol Care, Cincinnati, OH USA. [Voorhees, Peter] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Moslehi, Javid] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Niculescu, Liviu] Millennium Takeda Oncol Co, Cambridge, MA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu NR 15 TC 1 Z9 1 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOLOGICA JI Haematologica PD AUG 1 PY 2014 VL 99 IS 8 BP E145 EP E146 DI 10.3324/haematol.2013.103135 PG 2 WC Hematology SC Hematology GA AQ5GF UT WOS:000342834300007 PM 25082787 ER PT J AU Wu, G Zhu, J Yu, J Zhou, L Huang, JHZ Zhang, Z AF Wu, Gang Zhu, Jiang Yu, Jun Zhou, Lan Huang, Jianhua Z. Zhang, Zhang TI Evaluation of Five Methods for Genome-Wide Circadian Gene Identification SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Article DE circadian rhythms; comparison; circadian gene; ARSER; COSOPT; Fisher's G test; HAYSTACK; JTK_CYCLE ID KEY PATHWAYS; EXPRESSION; CLOCK; TIME; RHYTHMS; TRANSCRIPTION; METABOLOME; ALGORITHMS AB Identification of circadian-regulated genes based on temporal transcriptome data is important for studying the regulation mechanism of the circadian system. However, various computational methods adopting different strategies for the identification of cycling transcripts usually yield inconsistent results even for the same dataset, making it challenging to choose the optimal method for a specific circadian study. To address this challenge, we evaluate 5 popular methods, including ARSER (ARS), COSOPT (COS), Fisher's G test (FIS), HAYSTACK (HAY), and JTK_CYCLE (JTK), based on both simulated and empirical datasets. Our results show that increasing the number of total samples (through improving sampling frequency or lengthening the sampling time window) is beneficial for computational methods to accurately identify circadian transcripts and measure circadian phase. For a given number of total samples, higher sampling frequency is more important for HAY and JTK, and the longer sampling time window is more crucial for ARS and COS, as testified on simulated and empirical datasets from which circadian signals are computationally identified. In addition, the preference of higher sampling frequency or the longer sampling time window is also obvious for JTK, ARS, and COS in estimating circadian phases of simulated periodic profiles. Our results also indicate that attention should be paid to the significance threshold that is used for each method in selecting circadian genes, especially when analyzing the same empirical dataset with 2 or more methods. To summarize, for any study involving genome-wide identification of circadian genes from transcriptome data, our evaluation results provide suggestions for the selection of an optimal method based on specific goal and experimental design. C1 [Wu, Gang; Yu, Jun; Zhang, Zhang] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, Beijing 100101, Peoples R China. [Zhu, Jiang] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Zhu, Jiang] Harvard Univ, Sch Med, Boston, MA USA. [Zhou, Lan; Huang, Jianhua Z.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. RP Zhang, Z (reprint author), Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genome Sci & Informat, 1 Beichen West Rd, Beijing 100101, Peoples R China. EM zhangzhang@big.ac.cn FU National Programs for High Technology Research and Development (863 Program) [2012AA020409]; "100-Talent Program" of the Chinese Academy of Sciences FX The authors thank Dr. Michael Hughes and Dr. Rendong Yang for providing advice for using JTK_CYCLE and ARSER, respectively. They also thank all members in the Zhang Lab for valuable discussions on this work and anonymous reviewers for critical comments and helpful suggestions. This work was supported by grants from the National Programs for High Technology Research and Development (863 Program; 2012AA020409) and the "100-Talent Program" of the Chinese Academy of Sciences. NR 28 TC 8 Z9 8 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-7304 EI 1552-4531 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD AUG PY 2014 VL 29 IS 4 BP 231 EP 242 DI 10.1177/0748730414537788 PG 12 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA AQ3BV UT WOS:000342664600001 PM 25238853 ER PT J AU Trenor, CC Chaudry, G AF Trenor, Cameron C., III Chaudry, Gulraiz TI Complex lymphatic anomalies SO SEMINARS IN PEDIATRIC SURGERY LA English DT Article DE Gorham-Stout disease; Generalized lymphatic anomaly; Kaposiform lymphangiomatosis ID THORACIC-DUCT; KAPOSIFORM LYMPHANGIOMATOSIS; DIFFUSE LYMPHANGIOMATOSIS; TREATMENT OPTION; PROPRANOLOL; MANAGEMENT; SIROLIMUS; CHILDREN; LYMPHANGIOGRAPHY; MALFORMATIONS AB Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham-Stout disease have been segregated with distinctive bone lesions and pen-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies. (C) 2014 Elsevier Inc. All rights reserved. C1 [Trenor, Cameron C., III] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp,Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Chaudry, Gulraiz] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Intervent Radiol, Boston, MA 02115 USA. RP Trenor, CC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston Childrens Hosp,Div Pediat Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM Cameron.trenor@childrens.harvard.edu NR 26 TC 18 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1055-8586 EI 1532-9453 J9 SEMIN PEDIATR SURG JI Semin. Pediatr. Surg. PD AUG PY 2014 VL 23 IS 4 BP 186 EP 190 DI 10.1053/j.sempedsurg.2014.07.006 PG 5 WC Pediatrics; Surgery SC Pediatrics; Surgery GA AQ1OO UT WOS:000342550900007 PM 25241096 ER PT J AU Rassi, AN Theodos, G Franco, I AF Rassi, Andrew N. Theodos, Gus Franco, Irving TI Finding a Lost Coronary Stent Months Later with Use of Multimethod Imaging SO TEXAS HEART INSTITUTE JOURNAL LA English DT Editorial Material C1 [Rassi, Andrew N.; Theodos, Gus; Franco, Irving] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44195 USA. RP Rassi, AN (reprint author), Massachusetts Gen Hosp, Div Cardiol, Desk GRB 852K,55 Fruit St, Boston, MA 02114 USA. EM arassi@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU TEXAS HEART INST PI HOUSTON PA PO BOX 20345, HOUSTON, TX 77225-0345 USA SN 0730-2347 EI 1526-6702 J9 TEX HEART I J JI Tex. Heart Inst. J. PD AUG PY 2014 VL 41 IS 4 BP 445 EP 446 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AQ1MR UT WOS:000342546000021 PM 25120405 ER PT J AU Kathiresan, S AF Kathiresan, S. CA NHLBI Exome Sequencing Project HDL TI RARE LOSS-OF-FUNCTION MUTATIONS IN THE APOC3 GENE, PLASMA TRIGLYCERIDES, AND RISK FOR CORONARY HEART DISEASE SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Kathiresan, S.; NHLBI Exome Sequencing Project HDL] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-0190 BP E30 EP E31 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000057 ER PT J AU Zanoni, P Larach, DB Khetarpal, SA Hancock-Cerutti, WF Peloso, GM Rodrigues, A Tohyama, J Billheimer, JT Kathiresan, S Cuchel, M Rader, DJ AF Zanoni, P. Larach, D. B. Khetarpal, S. A. Hancock-Cerutti, W. F. Peloso, G. M. Rodrigues, A. Tohyama, J. Billheimer, J. T. Kathiresan, S. Cuchel, M. Rader, D. J. TI A LOSS-OF-FUNCTION MUTATION IN SCARB1 SEVERELY IMPAIRS SR-BI PROCESSING AND ACTIVITY IN HUMANS SO ATHEROSCLEROSIS LA English DT Meeting Abstract CT 82nd Congress of the European-Atherosclerosis-Society (EAS) CY MAY 31-JUN 03, 2014 CL Spanish Soc Atherosclerosis, Madrid, SPAIN SP European Atherosclerosis Soc HO Spanish Soc Atherosclerosis C1 [Zanoni, P.; Larach, D. B.; Khetarpal, S. A.; Hancock-Cerutti, W. F.; Rodrigues, A.; Tohyama, J.; Billheimer, J. T.; Cuchel, M.; Rader, D. J.] Univ Penn, Div Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Peloso, G. M.; Kathiresan, S.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 EI 1879-1484 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2014 VL 235 IS 2 MA EAS-0836 BP E22 EP E22 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AP9PF UT WOS:000342411000033 ER PT J AU Gandaglia, G Ravi, P Abdollah, F Abd-El-Barr, AM Becker, A Popa, I Briganti, A Karakiewicz, PI Trinh, QD Jewett, MA Sun, M AF Gandaglia, Giorgio Ravi, Praful Abdollah, Firas Abd-El-Barr, Abd-El-Rahman M. Becker, Andreas Popa, Ioana Briganti, Alberto Karakiewicz, Pierre I. Quoc-Dien Trinh Jewett, Michael A. Sun, Maxine TI Contemporary incidence and mortality rates of kidney cancer in the United States SO CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL LA English DT Article ID RENAL-CELL CARCINOMA; BODY-MASS INDEX; COMPETING-RISKS; CIGARETTE-SMOKING; RISING INCIDENCE; TRENDS; EPIDEMIOLOGY; SURVEILLANCE; METAANALYSIS; REGRESSION AB Introduction: This is a timely update of incidence and mortality for renal cell carcinoma (RCC) in the United States. Methods: Relying on the Surveillance, Epidemiology, and End Results (SEER) database, we computed age-adjusted incidence, mortality rates and 5-year cancer-specific survival (CSS) for patients with histologically confirmed kidney cancer between 1975 and 2009. Long-term (1975-2009) and short-term (2000-2009) trends were examined by joinpoint analysis, and quantified using the annual percent change (APC). The reported findings were stratified according to disease stage. Results: Age-adjusted incidence rates of RCC increased by +2.76%/year between 1975 and 2009 (from 6.5 to 17.1/100 000 person-years, p < 0.001), and by + 2.85%/year between 2000 and 2009 (p < 0.001). For the same time points, the corresponding APC for the incidence of localized stage were + 4.55%/year (from 3.0 to 12.2/100 000 person years, p < 0.001), and + 4.42%/year (p < 0.001), respectively. The incidence rates of regional stage increased by + 0.88%/year between 1975 and 2009 (p < 0.001), but stabilized in recent years (2000-2009: + 0.56%/year, p = 0.4). Incidence rates of distant stage remained unchanged in long-and short-term trends. Overall mortality rates increased by + 1.72%/year between 1975 and 2009 (from 1.2 to 5.0/100 000 person-years, P<0.001), but stabilized between 1994 and 2004 (p = 0.1). Shortterm mortality rates increased in a significant fashion by + 3.14%/year only for localized stage (p < 0.001). Interpretation: In contemporary years, there is a persisting upward trend in incidence and mortality of localized RCC. C1 [Gandaglia, Giorgio; Abdollah, Firas; Briganti, Alberto] Univ Vita Salute San Raffaele, Dept Urol, Milan, Italy. [Ravi, Praful] West Middlesex Univ Hosp, London, England. [Abd-El-Barr, Abd-El-Rahman M.] Henry Ford Hlth Syst, Vattikuti Urol Inst, Detroit, MI USA. [Popa, Ioana; Karakiewicz, Pierre I.; Sun, Maxine] Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ, Canada. [Becker, Andreas] Univ Hamburg Eppendorf, Prostate Canc Ctr, Dept Urol, Hamburg, Germany. [Quoc-Dien Trinh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Surg,Div Urol,Brigham & Womens Hosp, Boston, MA 02115 USA. [Jewett, Michael A.] Univ Hlth Network, Div Urol, Dept Surg Oncol, Toronto, ON, Canada. RP Sun, M (reprint author), Univ Montreal, Ctr Hlth, Canc Prognost & Hlth Outcomes Unit, Montreal, PQ, Canada. EM mcw.sun@umontreal.ca FU Intuitive Surgical Inc.; Novartis; GSK; Pfizer FX Dr. Becker, Dr. Ravi, Dr. Gandaglia, Dr. Karakiewicz, Dr. Sun, Dr. Abdollah, Dr. Abd-El-Barr, Dr. Popa and Dr. Briganti all declare no competing financial or personal interests. Dr. Trinh has received consultant fees from Intuitive Surgical Inc. Dr. Jewett is a member of the Advisory Board for Pfizer. He has also received grants from Novartis, GSK and Pfizer. Lastly, he has participated in clinical trials with Novartis, GSK and Pfizer. NR 27 TC 14 Z9 14 U1 0 U2 2 PU CANADIAN UROLOGICAL ASSOCIATION PI DORVAL PA 185 DORVAL AVENUE, STE 401, DORVAL, QC H9S 5J9, CANADA SN 1911-6470 EI 1920-1214 J9 CUAJ-CAN UROL ASSOC JI CUAJ-Can. Urol. Assoc. J. PD AUG PY 2014 VL 8 IS 7-8 BP 247 EP 252 DI 10.5489/cuaj.1760 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AQ0CT UT WOS:000342450400026 PM 25210548 ER PT J AU Ho, JM Anekonda, VT Thompson, BW Zhu, MY Curry, RW Hwang, BH Morton, GJ Schwartz, MW Baskin, DG Appleyard, SM Blevins, JE AF Ho, Jacqueline M. Anekonda, Vishwanath T. Thompson, Benjamin W. Zhu, Mingyan Curry, Robert W. Hwang, Bang H. Morton, Gregory J. Schwartz, Michael W. Baskin, Denis G. Appleyard, Suzanne M. Blevins, James E. TI Hindbrain Oxytocin Receptors Contribute to the Effects of Circulating Oxytocin on Food Intake in Male Rats SO ENDOCRINOLOGY LA English DT Article ID BRAIN-STEM NUCLEI; C-FOS EXPRESSION; HUMAN GASTROINTESTINAL-TRACT; PROLACTIN-RELEASING PEPTIDE; DORSAL VAGAL COMPLEX; PARAVENTRICULAR NUCLEUS; MESSENGER-RNA; CATECHOLAMINERGIC NEURONS; ADMINISTERED OXYTOCIN; GASTRIC-MOTILITY AB Oxytocin (OT)-elicited hypophagia has been linked to neural activity in the nucleus of the solitary tract (NTS). Because plasma OT levels increase after a meal, we hypothesized that circulating OT acts at both peripheral and hindbrain OT receptors (OTRs) to limit food intake. To initially determine whether circulating OT inhibits food intake by acting at hindbrain OTRs, we pretreated rats with an OTR antagonist administered into the fourth ventricle (4V) followed by either central or systemic OT administration. Administration of the OTR antagonist into the 4V blocked anorexia induced by either 4V or ip injection of OT. However, blockade of peripheral OTRs also weakened the anorectic response to ip OT. Our data suggest a predominant role for hindbrain OTRs in the hypophagic response to peripheral OT administration. To elucidate central mechanisms of OT hypophagia, we tested whether OT activates NTS catecholaminergic neurons. OT (ip) increased the number of NTS cells expressing c-Fos, of which 10%-15% were catecholaminergic. Furthermore, electrophysiological studies in mice revealed that OT stimulated 47% (8 of 17) of NTS catecholamine neurons through a presynaptic mechanism. However, OT-elicited hypophagia did not appear to require activation of alpha(1)-adrenoceptors, and blockade of glucagon-like peptide-1 receptors similarly did not attenuate anorexia induced by OT. These findings demonstrate that OT elicits satiety through both central and peripheral OTRs and that although catecholamine neurons are a downstream target of OT signaling in the NTS, the hypophagic effect is mediated independently of alpha(1)-adrenoceptor signaling. C1 [Ho, Jacqueline M.; Anekonda, Vishwanath T.; Thompson, Benjamin W.; Curry, Robert W.; Hwang, Bang H.; Baskin, Denis G.; Blevins, James E.] Vet Affairs Puget Sound Hlth Care Syst, Res & Dev Serv, Seattle, WA 98108 USA. [Ho, Jacqueline M.; Morton, Gregory J.; Schwartz, Michael W.; Baskin, Denis G.; Blevins, James E.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Morton, Gregory J.; Schwartz, Michael W.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Morton, Gregory J.; Schwartz, Michael W.] Univ Washington, Dept Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Zhu, Mingyan; Appleyard, Suzanne M.] Washington State Univ, Dept Integrat Physiol & Neurosci, Program Neurosci, Pullman, WA 99164 USA. RP Blevins, JE (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Res 151,1660 South Columbian Way, Seattle, WA 98108 USA. EM jeblevin@u.washington.edu FU Research and Development Service of the Department of Veterans Affairs; Cellular and Molecular Imaging Core of the Diabetes Research Center at the University of Washington; National Institutes of Health [P30DK017047, P30DK017047-31689, DK083452]; Department of Veterans Affairs Merit Review Research Program; Diabetes, Obesity, and Metabolism Training Grant [2T32DK007247]; Veterans Affairs Senior Research Career Scientist award FX This work was supported by the Research and Development Service of the Department of Veterans Affairs and the Cellular and Molecular Imaging Core of the Diabetes Research Center at the University of Washington and supported by National Institutes of Health Grant P30DK017047. The research in our laboratory has been supported by the Department of Veterans Affairs Merit Review Research Program as well as National Institutes of Health Grants P30DK017047-31689, DK083452 (to S.M.A.), and Diabetes, Obesity, and Metabolism Training Grant 2T32DK007247. D.G.B. is the recipient of a Veterans Affairs Senior Research Career Scientist award. NR 70 TC 10 Z9 10 U1 0 U2 8 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2014 VL 155 IS 8 BP 2845 EP 2857 DI 10.1210/en.2014-1148 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QL UT WOS:000342343800011 PM 24877632 ER PT J AU Calder, M Chan, YM Raj, R Pampillo, M Elbert, A Noonan, M Gillio-Meina, C Caligioni, C Berube, NG Bhattacharya, M Watson, AJ Seminara, SB Babwah, AV AF Calder, Michele Chan, Yee-Ming Raj, Renju Pampillo, Macarena Elbert, Adrienne Noonan, Michelle Gillio-Meina, Carolina Caligioni, Claudia Berube, Nathalie G. Bhattacharya, Moshmi Watson, Andrew J. Seminara, Stephanie B. Babwah, Andy V. TI Implantation Failure in Female Kiss1(-/-) Mice Is Independent of Their Hypogonadic State and Can Be Partially Rescued by Leukemia Inhibitory Factor SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR GPR54; EXPRESSION; KISS-1; BLASTOCYST; PREGNANCY; ESTROGEN; NEUROENDOCRINE; ORIENTATION; KISSPEPTIN; PHENOTYPES AB The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(-/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans. C1 [Calder, Michele; Pampillo, Macarena; Elbert, Adrienne; Gillio-Meina, Carolina; Berube, Nathalie G.; Watson, Andrew J.; Babwah, Andy V.] Childrens Hlth Res Inst, London, ON N6C 2V5, Canada. [Calder, Michele; Pampillo, Macarena; Elbert, Adrienne; Gillio-Meina, Carolina; Berube, Nathalie G.; Watson, Andrew J.; Babwah, Andy V.] Lawson Hlth Res Inst, London, ON N6C 2V5, Canada. [Calder, Michele; Pampillo, Macarena; Watson, Andrew J.; Babwah, Andy V.] Dept Obstet & Gynaecol, London, ON N6C 2V5, Canada. [Chan, Yee-Ming; Caligioni, Claudia; Seminara, Stephanie B.] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Reprod Endocrine Unit, Boston, MA 02114 USA. [Chan, Yee-Ming] Boston Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Raj, Renju] Univ Vermont, Coll Med, Dept Obstet & Gynecol & Reprod Sci, Burlington, VT 05405 USA. [Elbert, Adrienne; Berube, Nathalie G.] Univ Western Ontario, Dept Paediat, London, ON N6A 5C1, Canada. [Elbert, Adrienne; Berube, Nathalie G.] Univ Western Ontario, Dept Biochem, London, ON N6A 5C1, Canada. [Noonan, Michelle; Bhattacharya, Moshmi; Watson, Andrew J.; Babwah, Andy V.] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON N6A 5C1, Canada. [Bhattacharya, Moshmi] Univ Western Ontario, Dept Oncol, London, ON N6A 5C1, Canada. RP Babwah, AV (reprint author), Victoria Res Labs, Childrens Hlth Res Inst, A4-140,800 Commissioners Rd East, London, ON N6C 2V5, Canada. EM ababwah@uwo.ca RI Watson, Andrew/A-5636-2015 OI Watson, Andrew/0000-0002-2344-3061 FU Natural Sciences and Engineering Research Council of Canada [RGPIN/327334-2011]; Department of Obstetrics and Gynaecology, University of Western Ontario Academic Enrichment Fund; Canadian Institutes of Health Research; Canadian Institutes for Health Research [MOP 93697]; Canadian Institutes of Health Research [MOP107972]; Eunice Kennedy Shriver National Institute for Child Health and Human Development [R01 HD043341, U54 HD028138, K24 HD067388]; Boston Children's Hospital Career Development Award; Charles A. King Trust Postdoctoral Fellowship; National Institutes of Health Women's Reproductive Health Research [5K12HD063082-04]; Canadian Institutes for Health Research New Investigator's Award; Vanier Canada Graduate Scholarship FX This work was supported by Grant RGPIN/327334-2011 from the Natural Sciences and Engineering Research Council of Canada (to A.V.B.) and the Department of Obstetrics and Gynaecology, University of Western Ontario Academic Enrichment Fund (to A.V.B.); the Canadian Institutes of Health Research (to A.J.W.); Grant MOP 93697 from the Canadian Institutes for Health Research (to N.G.B.); Grant MOP107972 from the Canadian Institutes of Health Research (to M.B.); Grants R01 HD043341, U54 HD028138, and K24 HD067388 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (to S.B.S.); a Boston Children's Hospital Career Development Award and a Charles A. King Trust Postdoctoral Fellowship (to Y.-M.C.); and Training Grant 5K12HD063082-04 from the National Institutes of Health Women's Reproductive Health Research (to R.R.). M.B. and A.E. are currently supported by a Canadian Institutes for Health Research New Investigator's Award and a Vanier Canada Graduate Scholarship, respectively. NR 33 TC 17 Z9 18 U1 1 U2 6 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD AUG PY 2014 VL 155 IS 8 BP 3065 EP 3078 DI 10.1210/en.2013-1916 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8QL UT WOS:000342343800032 PM 24877624 ER PT J AU McMillan, KK Pugh, MJ Hamid, H Salinsky, M Pugh, J Noel, PH Finley, EP Leykum, LK Lanham, HJ LaFrance, WC AF McMillan, Katharine K. Pugh, Mary Jo Hamid, Hamada Salinsky, Martin Pugh, Jacqueline Noel, Polly H. Finley, Erin P. Leykum, Luci K. Lanham, Holly J. LaFrance, W. Curt, Jr. TI Providers' perspectives on treating psychogenic nonepileptic seizures: Frustration and hope SO EPILEPSY & BEHAVIOR LA English DT Article DE Nonepileptic seizures; Diagnosis; Treatment; Veterans; Practitioners; Cognitive behavioral therapy ID GROUP PSYCHOEDUCATION; EPILEPSY CENTER; CARE; DIAGNOSIS; VETERANS; PSYCHIATRISTS; PERCEPTIONS; MANAGEMENT; SYMPTOMS; OUTCOMES AB Recent diagnostic and treatment advances in psychogenic nonepileptic seizures (PNES) have the potential to improve care for patients, but little is known about the current state of PNES care delivery in the Veterans Health Administration (VA). We conducted semistructured interviews with 74 health-care clinicians and workers in the VA, eliciting provider perceptions of PNES care. Data were analyzed according to principles of Grounded Theory. The results revealed variation in care and two emergent domain themes of frustration and hope. Frustration was manifest in subthemes including Complexity, Patient Acceptance, Uncertainty About Treatment, Need for Evidence-based Treatment, and Failure of Cross-Disciplinary Collaboration between neurologists and mental health providers. Hope encompassed subthemes of Positive Attitudes, Developing Cross-Disciplinary Treatment, and Specific PNES Care. Increased resources for diagnosing, treating, and researching PNES have improved awareness of the disorder. More research is needed to understand patients' and caregivers' perceptions of PNES care. (C) 2014 Elsevier Inc. All rights reserved. C1 [McMillan, Katharine K.; Pugh, Mary Jo; Noel, Polly H.; Finley, Erin P.; Leykum, Luci K.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [McMillan, Katharine K.; Pugh, Mary Jo; Pugh, Jacqueline; Noel, Polly H.; Finley, Erin P.; Leykum, Luci K.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Pugh, Mary Jo; Hamid, Hamada] VA Epilepsy Ctr Excellence, San Antonio, TX USA. [Hamid, Hamada] VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. [Hamid, Hamada] Yale Univ, New Haven, CT USA. [Salinsky, Martin] Portland VA Med Ctr, Portland, OR USA. [Salinsky, Martin] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Lanham, Holly J.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. [LaFrance, W. Curt, Jr.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Providence Vet Affairs Med Ctr, Providence, RI 02903 USA. [LaFrance, W. Curt, Jr.] Brown Univ, Rhode Isl Hosp, Alpert Med Sch, Neuropsychiat & Behav Neurol Div, Providence, RI 02903 USA. [Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Finley, Erin P.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. RP McMillan, KK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, MSC 7933, San Antonio, TX 78229 USA. EM mcmillank@uthscsa.edu OI LaFrance, Jr., W Curt/0000-0002-4901-3852; Pugh, Jacqueline/0000-0003-4933-141X; Pugh, Mary Jo/0000-0003-4196-7763; Finley, Erin/0000-0003-4497-7721 FU VA Health Services Research and Development [IIR-067-11-2]; Implementation Research Institute (IRI) at the George Warren Brown School of Social Work, Washington University in St. Louis, through an award from the National Institute of Mental Health [R25 MH080916-01A2] FX VA Health Services Research and Development (IIR-067-11-2; Dr. MJ Pugh PI) funded this study. Dr. Finley is an investigator with the Implementation Research Institute (IRI) at the George Warren Brown School of Social Work, Washington University in St. Louis, through an award from the National Institute of Mental Health (R25 MH080916-01A2) and the Department of Veterans Affairs, Health Services Research & Development Service, Quality Enhancement Research Initiative (QUERI). The content of this article is solely the responsibility of the authors and does not necessarily reflect the official views of the Veterans' Health Administration. The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. NR 42 TC 13 Z9 13 U1 4 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 EI 1525-5069 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD AUG PY 2014 VL 37 BP 276 EP 281 DI 10.1016/j.yebeh.2014.07.001 PG 6 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA AP7MJ UT WOS:000342261100048 PM 25128685 ER PT J AU Blumenthal, SR Castro, VM Clements, CC Rosenfield, HR Murphy, SN Fava, M Weilburg, JB Erb, JL Churchill, SE Kohane, IS Smoller, JW Perlis, RH AF Blumenthal, Sarah R. Castro, Victor M. Clements, Caitlin C. Rosenfield, Hannah R. Murphy, Shawn N. Fava, Maurizio Weilburg, Jeffrey B. Erb, Jane L. Churchill, Susanne E. Kohane, Isaac S. Smoller, Jordan W. Perlis, Roy H. TI An Electronic Health Records Study of Long-term Weight Gain Following Antidepressant Use SO JAMA PSYCHIATRY LA English DT Article ID BODY-MASS INDEX; OBESITY; DEPRESSION; ASSOCIATION; OVERWEIGHT; ENTERPRISE; MORTALITY AB IMPORTANCE Short-term studies suggest antidepressants are associated with modest weight gain but little is known about longer-term effects and differences between individual medications in general clinical populations. OBJECTIVE To estimate weight gain associated with specific antidepressants over the 12 months following initial prescription in a large and diverse clinical population. DESIGN, SETTING, AND PARTICIPANTS We identified 22 610 adult patients who began receiving a medication of interest with available weight data in a large New England health care system, including 2 academic medical centers and affiliated outpatient primary and specialty care clinics. We used electronic health records to extract prescribing data and recorded weights for any patient with an index antidepressant prescription including amitriptyline hydrochloride, bupropion hydrochloride, citalopram hydrobromide, duloxetine hydrochloride, escitalopram oxalate, fluoxetine hydrochloride, mirtazapine, nortriptyline hydrochloride, paroxetine hydrochloride, venlafaxine hydrochloride, and sertraline hydrochloride. As measures of assay sensitivity, additional index prescriptions examined included the antiasthma medication albuterol sulfate and the antiobesity medications orlistat, phentermine hydrochloride, and sibutramine hydrochloride. Mixed-effects models were used to estimate rate of weight change over 12 months in comparison with the reference antidepressant, citalopram. MAIN OUTCOME AND MEASURE Clinician-recorded weight at 3-month intervals up to 12 months. RESULTS Compared with citalopram, in models adjusted for sociodemographic and clinical features, significantly decreased rate of weight gain was observed among individuals treated with bupropion (beta [SE]: -0.063 [0.027]; P = .02), amitriptyline (beta [SE]: -0.081[0.025]; P = .001), and nortriptyline (beta [SE]: -0.147 [0.034]; P < .001). As anticipated, differences were less pronounced among individuals discontinuing treatment prior to 12 months. CONCLUSIONS AND RELEVANCE Antidepressants differ modestly in their propensity to contribute to weight gain. Short-term investigations may be insufficient to characterize and differentiate this risk. C1 [Blumenthal, Sarah R.; Clements, Caitlin C.; Rosenfield, Hannah R.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Boston, MA 02114 USA. [Blumenthal, Sarah R.; Clements, Caitlin C.; Rosenfield, Hannah R.; Smoller, Jordan W.; Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Castro, Victor M.; Murphy, Shawn N.] Partners HealthCare Syst, Partners Res Comp, Boston, MA USA. [Castro, Victor M.; Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Comp Sci Lab, Boston, MA 02114 USA. [Fava, Maurizio; Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Dept Psychiat, Depress Clin, Boston, MA 02114 USA. [Fava, Maurizio; Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Dept Psychiat, Res Program, Boston, MA 02114 USA. [Erb, Jane L.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Churchill, Susanne E.] Partners HealthCare Syst, Informat Syst, Boston, MA USA. [Kohane, Isaac S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Ctr Expt Drugs & Diagnost, Psychiat & Neurodev Genet Unit, 185 Cambridge St,Simches Res Bldg MGH,6th Floor, Boston, MA 02114 USA. EM rperlis@partners.org FU National Institute of Mental Health [R01NH100286] FX The project was supported by grant R01NH100286 from the National Institute of Mental Health. NR 21 TC 25 Z9 25 U1 1 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-622X EI 2168-6238 J9 JAMA PSYCHIAT JI JAMA Psychiatry PD AUG PY 2014 VL 71 IS 8 BP 889 EP 896 DI 10.1001/jamapsychiatry.2014.414 PG 8 WC Psychiatry SC Psychiatry GA AP0SP UT WOS:000341774600007 PM 24898363 ER PT J AU Swanson, CM Nielson, CM Shrestha, S Lee, CG Barrett-Connor, E Jans, I Cauley, JA Boonen, S Bouillon, R Vanderschueren, D Orwoll, ES AF Swanson, Christine M. Nielson, Carrie M. Shrestha, Smriti Lee, Christine G. Barrett-Connor, Elizabeth Jans, Ivo Cauley, Jane A. Boonen, Steven Bouillon, Roger Vanderschueren, Dirk Orwoll, Eric S. CA Osteoporotic Fractures Men MrOS St TI Higher 25(OH)D-2 Is Associated With Lower 25(OH)D-3 and 1,25(OH)(2)D-3 SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VITAMIN-D DEFICIENCY; SERUM 25-HYDROXYVITAMIN D; OLDER MEN; OSTEOPOROTIC FRACTURES; D 25-HYDROXYLASE; D-2; SUPPLEMENTATION; CHOLECALCIFEROL; ERGOCALCIFEROL; CYP2R1 AB Context: Despite common use of supplemental vitamin D-2 in clinical practice, the associations of serum vitamin D-2 concentrations with other vitaminDmetabolites and total vitamin D are unclear. Objective: The aim of the study was to measure vitamin D-2 and D-3 levels and examine their associations with each other and with total vitamin D. Design: We performed a cross-sectional analysis of 679 randomly selected participants from the Osteoporotic Fractures in Men Study. 25-Hydroxyvitamin D-2 [ 25(OH)D-2], 25(OH)D-3, 1,25-dihydroxyvitamin D-2 [1,25(OH)(2)D-2], and 1,25(OH)(2)D-3 were measured using liquid chromatography-tandem mass spectrometry and were summed to obtain total 25(OH)D and 1,25(OH)(2)D. Associations between all metabolites (D-2, D-3, and total levels) were examined using Wilcoxon rank-sum tests and Spearman correlations. Results: 25(OH)D-2 and 1,25(OH)(2)D-2 were detectable in 189 (27.8%) and 178 (26.2%) of the men, respectively. Higher 25(OH)D-2 levels did not correlate with higher total 25(OH) D (r = 0.10; P = .17), although median total 25(OH)D was slightly higher in those with detectable vs undetectable 25(OH)D-2 (25.8 vs 24.3 ng/mL; P < .001). 25(OH)D-2 was not positively associated with total 1,25(OH)(2)D levels (r = -0.11; P = .13), and median 1,25(OH)(2)D level was not higher in those with detectable vs undetectable 25(OH)D-2. Higher 25(OH)D-2 was associated with lower 25(OH)D-3 (r = -0.35; P < .001) and 1,25(OH)(2)D-3 (r = -0.32; P < .001), with median levels of both D-3 metabolites 18-35% higher when D-2 metabolites were undetectable. Conclusions: In a cohort of older men, 25(OH)D-2 is associated with lower levels of 25(OH)D-3 and 1,25(OH)(2)D-3, suggesting that vitamin D-2 may decrease the availability of D-3 and may not increase calcitriol levels. C1 [Swanson, Christine M.; Lee, Christine G.; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Div Endocrinol, Portland, OR 97239 USA. [Swanson, Christine M.; Nielson, Carrie M.; Shrestha, Smriti; Lee, Christine G.; Orwoll, Eric S.] Oregon Hlth & Sci Univ, Bone & Mineral Unit, Portland, OR 97239 USA. [Nielson, Carrie M.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Lee, Christine G.] Portland VA Med Ctr, Res Serv, Portland, OR 97239 USA. [Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, Div Epidemiol, La Jolla, CA 92093 USA. [Jans, Ivo; Vanderschueren, Dirk] Univ Leuven, KU Leuven, Lab Diagnost Med, B-3000 Leuven, Belgium. [Cauley, Jane A.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Boonen, Steven] Univ Leuven, KU Leuven, Div Geriatr Med, B-3000 Leuven, Belgium. [Boonen, Steven] Univ Leuven, KU Leuven, Ctr Metab Bone Dis, B-3000 Leuven, Belgium. [Bouillon, Roger; Vanderschueren, Dirk] Univ Leuven, KU Leuven, Lab Clin & Expt Endocrinol, B-3000 Leuven, Belgium. RP Orwoll, ES (reprint author), 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM Orwoll@ohsu.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU National Institutes of Health; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Aging; National Center for Research Resources; NIH Roadmap for Medical Research [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, UL1 TR000128]; Merck Co, Inc. [SRA-12-009]; National Institute of Diabetes and Digestive and Kidney Diseases [T32DK007674-20]; University Hospital in Leuven FX The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on Aging, the National Center for Research Resources, and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01 AG027810, and UL1 TR000128.; This work was supported in part by an independent investigator grant (SRA-12-009) (to E.S.O.) from Merck & Co, Inc. C.M.S. is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant T32DK007674-20. D.V. is a senior clinical investigator supported by the University Hospital in Leuven. NR 30 TC 9 Z9 9 U1 1 U2 7 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP 2736 EP 2744 DI 10.1210/jc.2014-1069 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200046 PM 24828488 ER PT J AU Choi, HY Kim, S Park, JW Lee, NS Hwang, SY Huh, JY Hong, HC Yoo, HJ Baik, SH Youn, BS Mantzoros, CS Choi, KM AF Choi, Hae Yoon Kim, Sungeun Park, Ji Woo Lee, Nam Seok Hwang, Soon Young Huh, Joo Young Hong, Ho Cheol Yoo, Hye Jin Baik, Sei Hyun Youn, Byung-Soo Mantzoros, Christos S. Choi, Kyung Mook TI Implication of Circulating Irisin Levels with Brown Adipose Tissue and Sarcopenia in Humans SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FNDC5 GENE-EXPRESSION; SKELETAL-MUSCLE MASS; PREDICTING MORTALITY; PHYSICAL-ACTIVITY; ADULT HUMANS; EXERCISE; OBESITY; FAT; THERMOGENESIS; PGC-1-ALPHA AB Context: Irisin is an exercise-induced novel myokine that drives brown-fat-like conversion of white adipose tissue and has been suggested to be a promising target for the treatment of obesity-related metabolic disorders. Objective: To assess the association of circulating irisin concentrations with brown adipose tissue (BAT) and/or sarcopenia in humans. Setting and Design: We examined irisin levels in 40 BAT-positive and 40 BAT-negative women detected by F-18-fluorodeoxyglucose positron emission tomography ((18)FDG-PET). In a separate study, we also examined 401 subjects with or without sarcopenia defined by skeletal muscle mass index (SMMI) and appendicular skeletal muscle (ASM)/height(2) using dual-energy x-ray absorptiometry. Results: Among 6877 consecutive 18FDG-PET scans in 4736 subjects, 146 subjects (3.1%) had positive BAT scans. The BAT-detectable group and the matched BAT-undetectable group did not differ in circulating irisin levels measured using two different ELISA kits (P = .747 and P = .160, respectively). Serum irisin levels were not different between individuals with sarcopenia and those without sarcopenia using either kit (P = .305 and P = .569, respectively). Also, serum irisin levels were not different between groups defined by ASM/height(2) using either kit (P = .352 and P = .134, respectively). Although visceral fat area and skeletal muscle mass showed significant difference according to tertiles of SMMI levels, irisin concentrations did not differ. Conclusions: Circulating irisin levels were not different in individuals with detectable BAT or those with sarcopenia compared with control subjects and were not correlated with SMMI. C1 [Choi, Hae Yoon; Hong, Ho Cheol; Yoo, Hye Jin; Baik, Sei Hyun; Choi, Kyung Mook] Korea Univ, Coll Med, Dept Internal Med, Div Endocrinol & Metab, Seoul 136701, South Korea. [Kim, Sungeun] Korea Univ, Coll Med, Dept Nucl Med, Seoul 136701, South Korea. [Park, Ji Woo; Lee, Nam Seok; Youn, Byung-Soo] AdipoGen Inc, Inchon 406840, South Korea. [Hwang, Soon Young] Korea Univ, Coll Med, Dept Biostat, Seoul 136701, South Korea. [Huh, Joo Young; Mantzoros, Christos S.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Endocrinol Sect, Boston, MA 02130 USA. RP Choi, KM (reprint author), Korea Univ, Guro Hosp, Dept Internal Med, Div Endocrinol & Metab, 80 Guro Dong, Seoul 152050, South Korea. EM medica7@gmail.com FU Basic Science Research Program through the National Research Foundation of Korea - Ministry of Education, Science and Technology [2012006363]; Brain Korea 21 Project of the Ministry of Education and Human Resources Development, Republic of Korea [A102065-1011-1070100] FX This work was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2012006363) (K.M.C.) and by the Brain Korea 21 Project of the Ministry of Education and Human Resources Development, Republic of Korea (K.M.C. and S.H.B.) (A102065-1011-1070100). NR 37 TC 21 Z9 21 U1 2 U2 14 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP 2778 EP 2785 DI 10.1210/jc.2014-1195 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200051 PM 24780049 ER PT J AU Christensen, JD Lungu, AO Cochran, E Collins, MT Gafni, RI Reynolds, JC Rother, KI Gorden, P Brown, RJ AF Christensen, John D. Lungu, Andreea O. Cochran, Elaine Collins, Michael T. Gafni, Rachel I. Reynolds, James C. Rother, Kristina I. Gorden, Phillip Brown, Rebecca J. TI Bone Mineral Content in Patients With Congenital Generalized Lipodystrophy Is Unaffected by Metreleptin Replacement Therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID REVERSES INSULIN-RESISTANCE; DEFICIENT OB/OB MICE; LONG-TERM EFFICACY; GROWTH-FACTOR 23; LEPTIN-REPLACEMENT; BODY-COMPOSITION; RECOMBINANT LEPTIN; PLASMA ADIPONECTIN; OBESE GENE; CHILDREN AB Context: Leptin alters bone and mineral metabolism in rodents, but this has not been verified in humans. Patients with congenital generalized lipodystrophy (CGL) have low leptin due to deficient adipose mass and serve as models of leptin deficiency and replacement. Objective: To study the effects of recombinant human methionyl leptin (metreleptin) on bone mineral content (BMC) and mineral metabolism. Design and Setting: An open-label nonrandomized study at the National Institutes of Health. Patients: Thirty-one patients with CGL (ages 4.3 to 46.7 y). Intervention: Metreleptin (0.06 to 0.24 mg/kg/d) for 6 months to 11 years. Outcome Measures: BMC was assessed by dual-energy x-ray absorptiometry. SD scores (SDS) for BMC were calculated based on height, race, sex, and age using population normative data. Calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured at baseline and follow-up. Results: At baseline, patients demonstrated significantly increased total body less head BMC(mean SDS, 1.8 +/- 0.7), height (mean SDS, 1.3 +/- 1.3), and lean mass index, defined as lean body mass per height squared (mean SDS, 1.5 +/- 0.83), vs population normative data. No change in total body less head BMC was observed after metreleptin. Lean mass index decreased with metreleptin. Serum calcium decreased with metreleptin, but remained within normal limits. No changes were seen in phosphorus, PTH, or vitamin D. Conclusions: In contrast to rodent models, CGL patients have increased BMC in the leptin-deficient state, which does not change with leptin replacement. The high BMC in these patients is partially explained by high lean mass and tall stature. C1 [Christensen, John D.; Cochran, Elaine; Rother, Kristina I.; Gorden, Phillip; Brown, Rebecca J.] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA. [Collins, Michael T.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. [Lungu, Andreea O.] Joslin Diabet Ctr, Brookline, MA 02215 USA. RP Brown, RJ (reprint author), 10 Ctr Dr,MSC 1612,Room CRC 6-5942, Bethesda, MD 20892 USA. EM brownrebecca@niddk.nih.gov FU Intramural Research Programs of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Dental and Craniofacial Research FX This work was supported by Intramural Research Programs of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Dental and Craniofacial Research. NR 39 TC 11 Z9 12 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2014 VL 99 IS 8 BP E1493 EP E1500 DI 10.1210/jc.2014-1353 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8PO UT WOS:000342341200014 PM 25070319 ER PT J AU Li, J Li, FHR Wei, D Jia, W Kang, JX Stefanovic-Racic, M Dai, YF Zhao, AZ AF Li, Jie Li, Fanghong R. Wei, Dong Jia, Wei Kang, Jing X. Stefanovic-Racic, Maja Dai, Yifan Zhao, Allan Z. TI Endogenous omega-3 Polyunsaturated Fatty Acid Production Confers Resistance to Obesity, Dyslipidemia, and Diabetes in Mice SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID INDUCED INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE RISK; TRANSGENIC MICE; PPAR-GAMMA; FAT-1 MICE; FISH-OIL; PEROXISOME PROLIFERATOR; EVOLUTIONARY ASPECTS; ACTIVATED RECEPTORS; GLUCOSE-TOLERANCE AB Despite the well-documented health benefits of omega-3 polyunsaturated fatty acids (PUFAs), their use in clinical management of hyperglycemia and obesity has shown little success. To better define the mechanisms of omega-3 PUFAs in regulating energy balance and insulin sensitivity, we deployed a transgenic mouse model capable of endogenously producing omega-3 PUFAs while reducing omega-6 PUFAs owing to the expression of a Caenorhabditis elegans fat-1 gene encoding an omega-3 fatty acid desaturase. When challenged with high-fat diets, fat-1 mice strongly resisted obesity, diabetes, hypercholesterolemia, and hepatic steatosis. Endogenous elevation of omega-3 PUFAs and reduction of omega-6 PUFAs did not alter the amount of food intake but led to increased energy expenditure in the fat-1 mice. The requirements for the levels of omega-3 PUFAs as well as the omega-6/omega-3 ratios in controlling blood glucose and obesity are much more stringent than those in lipid metabolism. These metabolic phenotypes were accompanied by attenuation of the inflammatory state because tissue levels of prostaglandin E-2, leukotriene B4, monocyte chemoattractant protein-1, and TNF-alpha were significantly decreased. TNF-alpha-induced nuclear factor-kappa B signaling was almost completely abolished. Consistent with the reduction in chronic inflammation and a significant increase in peroxisome proliferator-activated receptor-alpha activity in the fat-1 liver tissue, hepatic insulin signaling was sharply elevated. The activities of prolipogenic regulators, such as liver X receptor, stearoyl-CoA desaturase-1, and sterol regulatory element binding protein-1 were sharply decreased, whereas the activity of peroxisome proliferator-activated receptor-alpha, a nuclear receptor that facilitates lipid beta-oxidation, was markedly increased. Thus, endogenous conversion of omega-6 to omega-3 PUFAs via fat-1 strongly protects against obesity, diabetes, inflammation, and dyslipidemia and may represent a novel therapeutic modality to treat these prevalent disorders. C1 [Li, Jie] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. [Stefanovic-Racic, Maja] Univ Pittsburgh, Div Endocrinol & Metab, Pittsburgh, PA 15261 USA. [Li, Fanghong R.] Nanjing Med Univ, Affiliated Hosp 1, Dept Pathol, Nanjing 210029, Jiangsu, Peoples R China. [Wei, Dong] Second Peoples Hosp Chengdu, Dept Endocrinol, Chengdu 610017, Peoples R China. [Jia, Wei] Sichuan Univ, West China Hosp, Chengdu 610041, Peoples R China. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Li, Fanghong R.; Dai, Yifan; Zhao, Allan Z.] Nanjing Med Univ, Ctr Metab Dis Res, Nanjing 210029, Jiangsu, Peoples R China. RP Zhao, AZ (reprint author), Nanjing Med Univ, Ctr Metab Dis Res, 140 HanZhong Rd, Nanjing 210029, Jiangsu, Peoples R China. EM daiyifan@njmu.edu.cn; azzhao@njmu.edu.cn FU National Program on Key Basic Research Project of China (973 Program) [2013CB945202]; National Natural Science Foundation of China [81170780, 81372798]; PhD Programs Foundation of the Ministry of Education of China [20113234110005]; High-Level Innovative Talents Reward from Jiangsu Province; Returned Overseas Chinese Scholar from The First Affiliated Hospital of Nanjing Medical University FX This work was supported by the grants from the National Program on Key Basic Research Project of China (973 Program) (Grant 2013CB945202 to A.Z.Z. and F.L.), the National Natural Science Foundation of China (Grant 81170780 to A.Z.Z. and 81372798 to F.L.), the PhD Programs Foundation of the Ministry of Education of China (Grant 20113234110005 to A.Z.Z.), the High-Level Innovative Talents Reward from Jiangsu Province, and the Returned Overseas Chinese Scholar from The First Affiliated Hospital of Nanjing Medical University (to F.L.). NR 61 TC 13 Z9 14 U1 1 U2 15 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2014 VL 28 IS 8 BP 1316 EP 1328 DI 10.1210/me.2014-1011 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8RF UT WOS:000342345800010 PM 24978197 ER PT J AU Gordon, FK Vallaster, CS Westerling, T Iyer, LK Brown, M Schnitzler, GR AF Gordon, Francesca K. Vallaster, Caroline S. Westerling, Thomas Iyer, Lakshmanan K. Brown, Myles Schnitzler, Gavin R. TI Research Resource: Aorta- and Liver-Specific ER alpha-Binding Patterns and Gene Regulation by Estrogen SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID NF-KAPPA-B; DIFFERENTIAL EXPRESSION ANALYSIS; ELEMENT ANNOTATION SYSTEM; GENOME-WIDE ANALYSIS; RECEPTOR-ALPHA; CHIP-SEQ; TRANSCRIPTIONAL ACTIVATION; ENDOTHELIAL-CELLS; BETA; PROLIFERATION AB Estrogen has vascular protective effects in premenopausal women and in women younger than 60 years who are receiving hormone replacement therapy. However, estrogen also increases the risks of breast and uterine cancers and of venous thromboses linked to up-regulation of coagulation factors in the liver. In mouse models, the vasculoprotective effects of estrogen are mediated by the estrogen receptor alpha (ER alpha) transcription factor. Here, through next-generation sequencing approaches, we show that almost all of the genes regulated by 17 beta-estradiol (E-2) differ between mouse aorta and mouse liver, ex vivo, and that this difference is associated with a distinct genome-wide distribution of ER alpha on chromatin. Bioinformatic analysis of E-2-regulated promoters and ER alpha binding site sequences identify several transcription factors that may determine the tissue specificity of ER alpha binding and E-2-regulated genes, including the enrichment of NF-kappa B, AML1, and AP1 sites in the promoters of E-2 down-regulated inflammatory genes in aorta but not liver. The possible vascular-specific functions of these factors suggest ways in which the protective effects of estrogen could be promoted in the vasculature without incurring negative effects in other tissues. C1 [Gordon, Francesca K.; Vallaster, Caroline S.; Iyer, Lakshmanan K.; Schnitzler, Gavin R.] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA. [Westerling, Thomas; Brown, Myles] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Schnitzler, GR (reprint author), Tufts Med Ctr, Mol Cardiol Res Inst, Tupper 13,800 Washington St,Box 80, Boston, MA 02111 USA. EM gschnitzler@tuftsmedicalcenter.org OI Brown, Myles/0000-0002-8213-1658 FU National Institutes of Health [HL107964, HL69770] FX This work was supported by the National Institutes of Health (Grant HL107964 to G.R.S. and T32 postdoctoral fellowship support to F.K.G. and C.V. [Grant HL69770, Richard H. Karas, Principal Investigator]). NR 60 TC 2 Z9 2 U1 0 U2 2 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD AUG PY 2014 VL 28 IS 8 BP 1337 EP 1351 DI 10.1210/me.2013-1395 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AP8RF UT WOS:000342345800012 PM 24992180 ER PT J AU Thiele, EA Granata, T Matricardi, S Chugani, HT AF Thiele, Elizabeth A. Granata, Tiziana Matricardi, Sara Chugani, Harry T. TI Transition into adulthood: Tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis SO EPILEPSIA LA English DT Article DE Tuberous sclerosis; Sturge Weber; Rasmussen's encephalitis ID BRAIN AB Children with tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen encephalitis all have complex but differing needs in the process of transition/transfer to adult care. All three may be associated with long-term normal intelligence or a varying degree of intellectual disability. In tuberous sclerosis complex, the emphasis of care in adulthood shifts from seizure control and developmental issues to renal and psychiatric disease and other issues. In Sturge-Weber syndrome, the emphasis shifts from seizure control and rehabilitation to management of disability and migraine. In Rasmussen encephalitis, transition may be particularly complex for those with adolescent onset. Those successfully operated on for childhood onset have a static problem and the potential to do well in life. C1 [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Granata, Tiziana; Matricardi, Sara] Natl Neurol Inst C Besta, Dept Pediat Neurosci, Milan, Italy. [Chugani, Harry T.] Wayne State Univ, Childrens Hosp Michigan, Detroit, MI USA. RP Thiele, EA (reprint author), Massachusetts Gen Hosp, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org OI granata, tiziana/0000-0002-0170-6836 NR 10 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0013-9580 EI 1528-1167 J9 EPILEPSIA JI Epilepsia PD AUG PY 2014 VL 55 SU 3 SI SI BP 29 EP 33 DI 10.1111/epi.12722 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA AP5OX UT WOS:000342129600008 PM 25209083 ER PT J AU Austin, TM Lam, HV Shin, NS Daily, BJ Dunn, PF Sandberg, WS AF Austin, Thomas M. Lam, Humphrey V. Shin, Naomi S. Daily, Bethany J. Dunn, Peter F. Sandberg, Warren S. TI Elective change of surgeon during the OR day has an operationally negligible impact on turnover time SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE Operating room efficiency; Surgeon swapping; Turnover times ID OPERATING-ROOM; COMPUTER-SIMULATION; CASE DURATION; SYSTEM; PERCEPTIONS; ANESTHESIA; THROUGHPUT; EFFICIENCY; TARDINESS; SCHEDULE AB Study Objective: To compare turnover times for a series of elective cases with surgeons following themselves with turnover times for a series of previously scheduled elective procedures for which the succeeding surgeon differed from the preceding surgeon. Design: Retrospective cohort study. Setting: University-affiliated teaching hospital. Measurements: The operating room (OR) statistical database was accessed to gather 32 months of turnover data from a large academic institution. Turnover time data for the same-surgeon and surgeon-swap groups were batched by month to minimize autocorrelation and achieve data normalization. Two-way analysis of variance (ANOVA) using the monthly batched data was performed with surgeon swapping and changes in procedure category as variables of turnover time. Similar analyses were performed using individual surgical services, hourly time intervals during the surgical day, and turnover frequency per OR as additional covariates to surgeon swapping. Main Results: The mean (95% confidence interval [CI]) same-surgeon turnover time was 43.6 (43.2 - 44.0) minutes versus 51.0 (50.5 - 51.6) minutes for a planned surgeon swap (P < 0.0001). This resulted in a difference (95% CI) of 7.4 (6.8 - 8.1) minutes. The exact increase in turnover time was dependent on surgical service, change in subsequent procedure type, time of day when the turnover occurred, and turnover frequency. Conclusions: The investigated institution averages 2.5 cases per OR per day. The cumulative additional turnover time (far less than one hour per OR per day) for switching surgeons definitely does not allow the addition of another elective procedure if the difference could be eliminated. A flexible scheduling policy allowing surgeon swapping rather than requiring full blocks incurs minimal additional staffed time during the OR day while allowing the schedule to be filled with available elective cases. (C) 2014 Elsevier Inc. All rights reserved. C1 [Austin, Thomas M.; Lam, Humphrey V.; Sandberg, Warren S.] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37232 USA. [Shin, Naomi S.; Dunn, Peter F.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Daily, Bethany J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dunn, Peter F.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. RP Austin, TM (reprint author), Vanderbilt Univ, Sch Med, Dept Anesthesiol, 2200 Childrens Way,Suite 3115, Nashville, TN 37232 USA. EM thomas.austin@vanderbilt.edu OI Sandberg, Warren/0000-0002-9246-777X FU Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, Boston, MA; Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN; B.H. Robbins Scholar; Foundation of Anesthesia Education and Research (FAER) Mentored Research Training Grant FX Supported by department funds of the Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, Boston, MA, and from the Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN. Thomas Austin, MD, is a B.H. Robbins Scholar and a recipient of the Foundation of Anesthesia Education and Research (FAER) Mentored Research Training Grant. NR 22 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 EI 1873-4529 J9 J CLIN ANESTH JI J. Clin. Anesth. PD AUG PY 2014 VL 26 IS 5 BP 343 EP 349 DI 10.1016/j.jclinane.2014.02.008 PG 7 WC Anesthesiology SC Anesthesiology GA AP5KW UT WOS:000342119100002 PM 25074630 ER PT J AU Tveito, TH Sembajwe, G Boden, LI Dennerlein, JT Wagner, GR Kenwood, C Stoddard, AM Reme, SE Hopcia, K Hashimoto, D Shaw, WS Sorensen, G AF Tveito, T. H. Sembajwe, G. Boden, L. I. Dennerlein, J. T. Wagner, G. R. Kenwood, C. Stoddard, A. M. Reme, S. E. Hopcia, K. Hashimoto, D. Shaw, W. S. Sorensen, G. TI Impact of Organizational Policies and Practices on Workplace Injuries in a Hospital Setting SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID PATIENT-CARE WORKERS; SAFETY CLIMATE; MUSCULOSKELETAL PAIN; SOCIOECONOMIC-STATUS; DISABILITY; MANAGEMENT; NURSES AB Objective: This study aimed to assess relationships between perceptions of organizational practices and policies (OPP), social support, and injury rates among workers in hospital units. Methods: A total of 1230 hospital workers provided survey data on OPP, job flexibility, and social support. Demographic data and unit injury rates were collected from the hospitals' administrative databases. Results: Injury rates were lower in units where workers reported higher OPP scores and high social support. These relationships were mainly observed among registered nurses. Registered nurses perceived coworker support and OPP as less satisfactory than patient care associates (PCAs). Nevertheless, because of the low number of PCAs at each unit, results for the PCAs are preliminary and should be further researched in future studies with larger sample sizes. Conclusions: Employers aiming to reduce injuries in hospitals could focus on good OPP and supportive work environment. C1 [Tveito, T. H.; Reme, S. E.] Uni Res Hlth, Bergen, Norway. [Tveito, T. H.; Sembajwe, G.; Dennerlein, J. T.; Wagner, G. R.; Reme, S. E.; Hashimoto, D.; Sorensen, G.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Sorensen, G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tveito, T. H.] Vestfold Hosp Trust, Stavern, Norway. [Sembajwe, G.] CUNY, Boston, MA USA. [Boden, L. I.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Dennerlein, J. T.] Northeastern Univ, Boston, MA 02115 USA. [Wagner, G. R.] NIOSH, Washington, DC USA. [Kenwood, C.; Stoddard, A. M.] New England Res Inst, Watertown, MA 02172 USA. [Hopcia, K.] Univ Illinois, Chicago, IL USA. [Hashimoto, D.] Partners Hlth Care, Boston, MA USA. [Hashimoto, D.] Boston Coll, Sch Law, Newton Ctr, Hopkinton, MA USA. [Shaw, W. S.] Liberty Mutual Res Inst Safety, Hopkinton, MA USA. RP Tveito, TH (reprint author), Uni Res Hlth, Krinkelkroken 1, Bergen, Norway. EM torill.tveito@uni.no OI Dennerlein, Jack/0000-0001-7703-643X FU National Institute for Occupational Safety and Health [U19 OH008861] FX This work was supported by a grant from the National Institute for Occupational Safety and Health (U19 OH008861) for the Harvard School of Public Health Center for Work, Health, and Well-being. NR 28 TC 7 Z9 7 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2014 VL 56 IS 8 BP 802 EP 808 DI 10.1097/JOM.0000000000000189 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AP1IU UT WOS:000341823200004 PM 25099405 ER PT J AU Calvert, JK Holt, SK Mossanen, M James, AC Wright, JL Porter, MP Gore, JL AF Calvert, Joshua K. Holt, Sarah K. Mossanen, Matthew James, Andrew C. Wright, Jonathan L. Porter, Michael P. Gore, John L. TI Use and Outcomes of Extended Antibiotic Prophylaxis in Urological Cancer Surgery SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; kidney neoplasms; urinary bladder neoplasms; antibiotic prophylaxis; cross infection ID CLOSTRIDIUM-DIFFICILE INFECTION; PROSTATE-CANCER; ANTIMICROBIAL-PROPHYLAXIS; BLADDER-CANCER; KIDNEY CANCER; RISK; METAANALYSIS; CARE; CYSTECTOMY; THERAPY AB Purpose: Although perioperative antibiotic prophylaxis prevents postoperative infectious complications, national guidelines recommend cessation of antibiotics within 24 hours after the procedure. Extended antibiotic prophylaxis beyond 24 hours may contribute to hospital acquired infections such as Clostridium difficile colitis. We evaluated practice patterns of antibiotic prophylaxis in genitourinary cancer surgery and assessed the impact of antibiotic prophylaxis on hospital acquired C. difficile infections. Materials and Methods: We identified 59,184 patients treated with radical prostatectomy, 27,921 who underwent partial or radical nephrectomy, and 5,425 treated with radical cystectomy for prostate, kidney and bladder cancers, respectively, from the Premier Perspective Database (Premier Inc., Charlotte, North Carolina) from 2007 to 2012. We constructed hierarchical linear regression models to identify patient and hospital factors associated with extended antibiotic prophylaxis. We evaluated the association between extended antibiotic prophylaxis and C. difficile infections for patients who underwent partial or radical nephrectomy and radical cystectomy with multivariate logistic regression. Results: Surgery specific models demonstrated that hospital identity was associated with a substantial proportion of the variation in extended antibiotic prophylaxis (20% to 35% for radical prostatectomy, partial or radical nephrectomy, and radical cystectomy). Postoperative C. difficile colitis occurred in 0.02% of patients treated with radical prostatectomy, 0.23% of those treated with partial or radical nephrectomy and 1.7% of those treated with radical cystectomy. On multivariate analysis extended antibiotic prophylaxis was associated with higher odds of C. difficile infection after partial or radical nephrectomy (OR 3.79, 95% CI 2.46-5.84) and radical cystectomy (OR 1.64, 95% CI 1.12-2.39). Conclusions: Antibiotics may be overused after genitourinary cancer surgery and this overuse is associated with hospital acquired C. difficile colitis. Efforts are needed to encourage greater compliance with evidence-based approaches to postoperative care. C1 [Calvert, Joshua K.; Holt, Sarah K.; Mossanen, Matthew; James, Andrew C.; Wright, Jonathan L.; Porter, Michael P.; Gore, John L.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Wright, Jonathan L.; Porter, Michael P.] VA Puget Sound Hlth Care Syst, Div Urol, Seattle, WA 98195 USA. RP Gore, JL (reprint author), 1959 NE Pacific St,Box 356510, Seattle, WA 98195 USA. EM jlgore@u.washington.edu NR 27 TC 17 Z9 18 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 EI 1527-3792 J9 J UROLOGY JI J. Urol. PD AUG PY 2014 VL 192 IS 2 BP 425 EP 429 DI 10.1016/j.juro.2014.02.096 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA AP5BT UT WOS:000342095400038 PM 24603103 ER PT J AU Liu, YJT Zehtabchi, S Liteplo, AS AF Liu, Yiju T. Zehtabchi, Shahriar Liteplo, Andrew S. TI Ultrasound and the Six Thinking Hats SO ACADEMIC EMERGENCY MEDICINE LA English DT Editorial Material C1 [Liu, Yiju T.] Kaiser Permanente Mid Atlantic, Rockville, MD 20852 USA. [Zehtabchi, Shahriar] Suny Downstate Med Ctr, Dept Emergency Med, Brooklyn, NY 11203 USA. [Liteplo, Andrew S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Liu, YJT (reprint author), Kaiser Permanente Mid Atlantic, Rockville, MD 20852 USA. EM shahriar.zehtabchi@downstate.edu NR 8 TC 1 Z9 1 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD AUG PY 2014 VL 21 IS 8 BP 920 EP 921 DI 10.1111/acem.12438 PG 2 WC Emergency Medicine SC Emergency Medicine GA AO8YC UT WOS:000341640800013 PM 25154709 ER PT J AU Goehler, A McMahon, PM Lumish, HS Wu, CC Munshi, V Gilmore, M Chung, JH Ghoshhajra, BB Mark, D Truong, QA Gazelle, GS Hoffmann, U AF Goehler, Alexander McMahon, Pamela M. Lumish, Heidi S. Wu, Carol C. Munshi, Vidit Gilmore, Michael Chung, Jonathan H. Ghoshhajra, Brian B. Mark, Daniel Truong, Quynh A. Gazelle, G. Scott Hoffmann, Udo TI Cost-Effectiveness of Follow-Up of Pulmonary Nodules Incidentally Detected on Cardiac Computed Tomographic Angiography in Patients With Suspected Coronary Artery Disease SO CIRCULATION LA English DT Article DE comparative effectiveness research; computer simulation; coronary artery disease; cost-benefit analysis; health policy; pulmonary nodules, solitary; tomography, x-ray computed ID QUALITY-OF-LIFE; CELL LUNG-CANCER; GROUND-GLASS OPACITY; ACUTE CHEST-PAIN; EXTRACARDIAC FINDINGS; CT ANGIOGRAPHY; UNITED-STATES; MORTALITY; OUTCOMES; HEALTH AB Background-Pulmonary nodules (PNs) are often detected incidentally during coronary computed tomographic (CT) angiography, which is increasingly being used to evaluate patients with chest pain symptoms. However, the efficiency of following up on incidentally detected PN is unknown. Methods and Results-We determined demographic and clinical characteristics of stable symptomatic patients referred for coronary CT angiography in whom incidentally detected PNs warranted follow-up. A validated lung cancer simulation model was populated with data from these patients, and clinical and economic consequences of follow-up per Fleischner guidelines versus no follow-up were simulated. Of the 3665 patients referred for coronary CT angiography, 591 (16%) had PNs requiring follow-up. The mean age of patients with PNs was 59 similar to 10 years; 66% were male; 67% had ever smoked; and 21% had obstructive coronary artery disease. The projected overall lung cancer incidence was 5.8% in these patients, but the majority died of coronary artery disease (38%) and other causes (57%). Follow-up of PNs was associated with a 4.6% relative reduction in cumulative lung cancer mortality (absolute mortality: follow-up, 4.33% versus non-follow-up, 4.54%), more downstream testing (follow-up, 2.34 CTs per patient versus non-follow-up, 1.01 CTs per patient), and an average increase in quality-adjusted life of 7 days. Costs per quality-adjusted life-year gained were $ 154 700 to follow up the entire cohort and $ 129 800 per quality-adjusted life-year when only smokers were included. Conclusions-Follow-up of PNs incidentally detected in patients undergoing coronary CT angiography for chest pain evaluation is associated with a small reduction in lung cancer mortality. However, significant downstream testing contributes to limited efficiency, as demonstrated by a high cost per quality-adjusted life-year, especially in nonsmokers. C1 [Goehler, Alexander] Yale Univ, Dept Radiol, New Haven, CT 06520 USA. [Goehler, Alexander; Lumish, Heidi S.; Ghoshhajra, Brian B.; Truong, Quynh A.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR, PET CT Program, Boston, MA 02114 USA. [Goehler, Alexander; McMahon, Pamela M.; Munshi, Vidit; Gilmore, Michael; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Truong, Quynh A.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Goehler, Alexander; McMahon, Pamela M.; Wu, Carol C.; Ghoshhajra, Brian B.; Truong, Quynh A.; Gazelle, G. Scott; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Wu, Carol C.] Harvard Univ, Sch Med, Dept Radiol, Div Thorac Imaging,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chung, Jonathan H.] Natl Jewish Hlth, Dept Radiol, Denver, CO USA. [Mark, Daniel] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Boston, MA 02115 USA. RP Goehler, A (reprint author), Yale Univ, Sch Med, Dept Radiol, 333 Cedar St,POB 208042, New Haven, CT 06520 USA. EM agoehler@post.harvard.edu FU National Institutes of Health Ruth Kirschstein National Research Award [5T32HL076136]; National Institutes of Health [K23HL098370, L30HL093896]; St. Jude Medical, the American College of Radiology Imaging Network, and the Duke Clinical Research Institute FX Drs Goehler, Chung, and Ghoshhajra received funding from the National Institutes of Health Ruth Kirschstein National Research Award T32 (5T32HL076136) training grant for this work. Drs McMahon and Gazelle acknowledge support from the National Cancer Institute Cancer Intervention and Surveillance Modeling Network consortium for past support of the Lung Cancer Policy Model. Dr Truong was supported by the National Institutes of Health (K23HL098370 and L30HL093896) and received grant support from St. Jude Medical, the American College of Radiology Imaging Network, and the Duke Clinical Research Institute. NR 44 TC 6 Z9 6 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG PY 2014 VL 130 IS 8 BP 668 EP + DI 10.1161/CIRCULATIONAHA.113.007306 PG 16 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO4IG UT WOS:000341300100015 PM 25015342 ER PT J AU von Elverfeldt, D Maier, A Duerschmied, D Braig, M Witsch, T Wang, XW Mauler, M Neudorfer, I Menza, M Idzko, M Zirlik, A Heidt, T Bronsert, P Bode, C Peter, K von zur Muhlen, C AF von Elverfeldt, Dominik Maier, Alexander Duerschmied, Daniel Braig, Moritz Witsch, Thilo Wang, Xiaowei Mauler, Maximilian Neudorfer, Irene Menza, Marius Idzko, Marco Zirlik, Andreas Heidt, Timo Bronsert, Peter Bode, Christoph Peter, Karlheinz von zur Muhlen, Constantin TI Dual-Contrast Molecular Imaging Allows Noninvasive Characterization of Myocardial Ischemia/Reperfusion Injury After Coronary Vessel Occlusion in Mice by Magnetic Resonance Imaging SO CIRCULATION LA English DT Article DE blood platelets; magnetic resonance imaging; reperfusion; thrombosis ID CONFORMATION-SPECIFIC BLOCKADE; SINGLE-CHAIN ANTIBODIES; SUDDEN CARDIAC DEATH; ACTIVATED PLATELETS; GLYCOPROTEIN IIB/IIIA; REPERFUSION INJURY; INFARCTION; THROMBOSIS; GPIIB/IIIA; THROMBOLYSIS AB Background-Inflammation and myocardial necrosis play important roles in ischemia/reperfusion injury after coronary artery occlusion and recanalization. The detection of inflammatory activity and the extent of myocardial necrosis itself are of great clinical and prognostic interest. We developed a dual, noninvasive imaging approach using molecular magnetic resonance imaging in an in vivo mouse model of myocardial ischemia and reperfusion. Methods and Results-Ischemia/reperfusion injury was induced in 10-week-old C57BL/6N mice by temporary ligation of the left anterior descending coronary artery. Activated platelets were targeted with a contrast agent consisting of microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody directed against a ligand-induced binding site (LIBS) on activated glycoprotein IIb/IIIa (LIBS-MPIOs). After injection and imaging of LIBS-MPIOs, late gadolinium enhancement was used to depict myocardial necrosis; these imaging experiments were also performed in P2Y(12) (-/-)mice. All imaging results were correlated to immunohistochemistry findings. Activated platelets were detectable by magnetic resonance imaging via a significant signal effect caused by LIBS-MPIOs in the area of left anterior descending coronary artery occlusion 2 hours after reperfusion. In parallel, late gadolinium enhancement identified the extent of myocardial necrosis. Immunohistochemistry confirmed that LIBS-MPIOs bound significantly to microthrombi in reperfused myocardium. Only background binding was found in P2Y(12) (-/-)mice. Conclusions-Dual molecular imaging of myocardial ischemia/reperfusion injury allows characterization of platelet-driven inflammation by LIBS-MPIOs and myocardial necrosis by late gadolinium enhancement. This noninvasive imaging strategy is of clinical interest for both diagnostic and prognostic purposes and highlights the potential of molecular magnetic resonance imaging for characterizing ischemia/reperfusion injury. C1 [von Elverfeldt, Dominik; Braig, Moritz; Menza, Marius] Univ Med Ctr Freiburg, Dept Radiol Med Phys, Freiburg, Germany. [Idzko, Marco] Univ Med Ctr Freiburg, Dept Pneumol, Freiburg, Germany. [Bronsert, Peter] Univ Med Ctr Freiburg, Inst Pathol, Freiburg, Germany. [Bronsert, Peter] Univ Med Ctr Freiburg, Ctr Comprehens Canc, Freiburg, Germany. [Maier, Alexander; Duerschmied, Daniel; Witsch, Thilo; Mauler, Maximilian; Neudorfer, Irene; Zirlik, Andreas; Heidt, Timo; Bode, Christoph; von zur Muhlen, Constantin] Univ Heart Ctr Freiburg, Dept Cardiol 1, D-79106 Freiburg, Germany. [Wang, Xiaowei; Peter, Karlheinz] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Mauler, Maximilian] Univ Freiburg, Fac Biol, D-79106 Freiburg, Germany. [Heidt, Timo] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP von zur Muhlen, C (reprint author), Univ Heart Ctr Freiburg, Hugstetter Str 55, D-79106 Freiburg, Germany. EM constantin.vonzurmuehlen@universitaets-herzzentrum.de OI /0000-0002-1178-9487 FU DFG [MU2727/3-1, MU2727/6-1, HE6382/1-1]; German Heart Research Foundation [F/09/12]; German Heart Foundation; National Health and Medical Research Council of Australia; Future Fellowship of the Australian Research Council FX This study was financed by DFG grants MU2727/3-1, MU2727/6-1 (both to Drs von Elverfeldt and von zur Muhlen) and HE6382/1-1 ( Dr Heidt). Drs Duerschmied and von Elverfeldt were supported by grant F/09/12 of the German Heart Research Foundation. Dr Maier was supported by a grant of the German Heart Foundation, Dr Wang by the National Health and Medical Research Council of Australia, and Dr Peter by a Future Fellowship of the Australian Research Council. NR 46 TC 15 Z9 15 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD AUG PY 2014 VL 130 IS 8 BP 676 EP + DI 10.1161/CIRCULATIONAHA.113.008157 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO4IG UT WOS:000341300100016 PM 24951772 ER PT J AU Yoon, J Choi, M Ku, T Choi, WJ Choi, C AF Yoon, Jonghee Choi, Myunghwan Ku, Taeyun Choi, Won Jong Choi, Chulhee TI Optical induction of muscle contraction at the tissue scale through intrinsic cellular amplifiers SO JOURNAL OF BIOPHOTONICS LA English DT Article DE Biophotonics; laser-tissue interaction; low-density plasma; femtosecond-pulsed lasers; muscle contraction ID SMOOTH-MUSCLE; IN-VIVO; URINARY-BLADDER; GENE-EXPRESSION; LASER-PULSES; CELLS; MECHANISMS; MICROSCOPY; EXCITATION; RELEASE AB The smooth muscle cell is the principal component responsible for involuntary control of visceral organs, including vascular tonicity, secretion, and sphincter regulation. It is known that the neurotransmitters released from nerve endings increase the intracellular Ca2+ level in smooth muscle cells followed by muscle contraction. We herein report that femtosecond laser pulses focused on the diffraction-limited volume can induce intracellular Ca2+ increases in the irradiated smooth muscle cell without neurotransmitters, and locally increased intracellular Ca2+ levels are amplified by calcium-induced calcium-releasing mechanisms through the ryanodine receptor, a Ca2+ channel of the endoplasmic reticulum. The laser-induced Ca2+ increases propagate to adjacent cells through gap junctions. Thus, ultrashort-pulsed lasers can induce smooth muscle contraction by controlling Ca2+, even with optical stimulation of the diffraction-limited volume. This [GRAPHICS] . optical method, which leads to reversible and reproducible muscle contraction, can be used in research into muscle dynamics, neuromuscular disease treatment, and nanorobot control. C1 [Yoon, Jonghee; Ku, Taeyun; Choi, Won Jong; Choi, Chulhee] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Taejon 305701, South Korea. [Yoon, Jonghee; Choi, Won Jong; Choi, Chulhee] Korea Adv Inst Sci & Technol, Inst Opt Sci & Technol, Taejon 305701, South Korea. [Choi, Myunghwan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Choi, Myunghwan] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Choi, Chulhee] Korea Adv Inst Sci & Technol, Inst BioCentury, Taejon 305701, South Korea. RP Choi, C (reprint author), Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Taejon 305701, South Korea. EM cchoi@kaist.ac.kr RI Choi, Chulhee/C-1642-2011; OI Choi, Chulhee/0000-0001-5542-9136; Choi, Myunghwan/0000-0002-4235-7003 FU National Research Foundation of Korea (NRF) - Korea government (MEST) [2012R1A2A4A01007108] FX This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012R1A2A4A01007108). NR 35 TC 2 Z9 2 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD AUG PY 2014 VL 7 IS 8 BP 597 EP 606 DI 10.1002/jbio.201200246 PG 10 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA AO9VY UT WOS:000341708600004 PM 23650149 ER PT J AU Huang, YY Nagata, K Tedford, CE Hamblin, MR AF Huang, Ying-Ying Nagata, Kazuya Tedford, Clark E. Hamblin, Michael R. TI Low-level laser therapy (810 nm) protects primary cortical neurons against excitotoxicity in vitro SO JOURNAL OF BIOPHOTONICS LA English DT Article DE low-level laser therapy; cultured cortical neurons; excitotoxicity; reactive oxygen species; mitochondrial membrane potential glutamate. NMDA; kainic acid ID TRAUMATIC BRAIN-INJURY; MITOCHONDRIAL PERMEABILITY TRANSITION; TERM NEUROLOGICAL DEFICITS; NITRIC-OXIDE; CELL-DEATH; CYTOCHROME-C; HIPPOCAMPAL-NEURONS; ISCHEMIC-STROKE; INFRARED LIGHT; SPINAL-CORD AB Excitotoxicity describes a pathogenic process whereby death of neurons releases large amounts of the excitatory neurotransmitter glutamate, which then proceeds to activate a set of glutamatergic receptors on neighboring neurons (glutamate, N-methyl-D-aspartate (NMDA), and kainate), opening ion channels leading to an influx of calcium ions producing mitochondrial dysfunction and cell death. Excitotoxicity contributes to brain damage after stroke, traumatic brain injury, and neurodegenerative diseases, and is also involved in spinal cord injury. We tested whether low level laser (light) therapy (LLLT) at 810 nm could protect primary murine cultured cortical neurons against excitotoxicity in vitro produced by addition of glutamate, NMDA or kainate. Although the prevention of cell death was modest but significant, LLLT (3 J/cm(2) delivered at 25 mW/cm(2) over 2 min) gave highly significant benefits in increasing ATP, raising mitochondrial membrane potential, reducing intracellular calcium concentrations, reducing oxidative stress and reducing nitric oxide. The action of LLLT in abrogating excitotoxicity may play a role in explaining its beneficial effects in diverse central nervous system pathologies. C1 [Huang, Ying-Ying; Nagata, Kazuya; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Huang, Ying-Ying; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Huang, Ying-Ying] Guangxi Med Univ, Dept Pathol, Nanning, Guangxi, Peoples R China. [Nagata, Kazuya] Univ Tokyo, Grad Sch Med, Tokyo 1138654, Japan. [Tedford, Clark E.] Photothera Inc, Carlsbad, CA USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, 40 Blossom St, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 FU Photothera Inc; NIH grant [R01AI050875]; Center for Integration of Medicine and Innovative Technology [DAMD17-02-2-0006]; CDMRP Program in TBI [W81XWH-09-1-0514]; Air Force Office of Scientific Research [FA9950-04-1-0079] FX This work was supported by sponsored research funding from Photothera Inc and by NIH grant R01AI050875, Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006), CDMRP Program in TBI (W81XWH-09-1-0514) and Air Force Office of Scientific Research (FA9950-04-1-0079). NR 52 TC 14 Z9 14 U1 0 U2 12 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1864-063X EI 1864-0648 J9 J BIOPHOTONICS JI J. Biophotonics PD AUG PY 2014 VL 7 IS 8 BP 656 EP 664 DI 10.1002/jbio.201300125 PG 9 WC Biochemical Research Methods; Biophysics; Optics SC Biochemistry & Molecular Biology; Biophysics; Optics GA AO9VY UT WOS:000341708600011 PM 24127337 ER PT J AU O'Donnell, TF Passman, MA Marston, WA Ennis, WJ Dalsing, M Kistner, RL Lurie, F Henke, PK Gloviczki, ML Eklof, BG Stoughton, J Raju, S Shortell, CK Raffetto, JD Partsch, H Pounds, LC Cummings, ME Gillespie, DL McLafferty, RB Murad, MH Wakefield, TW Gloviczki, P AF O'Donnell, Thomas F., Jr. Passman, Marc A. Marston, William A. Ennis, William J. Dalsing, Michael Kistner, Robert L. Lurie, Fedor Henke, Peter K. Gloviczki, Monika L. Eklof, Bo G. Stoughton, Julianne Raju, Sesadri Shortell, Cynthia K. Raffetto, Joseph D. Partsch, Hugo Pounds, Lori C. Cummings, Mary E. Gillespie, David L. McLafferty, Robert B. Murad, Mohammad Hassan Wakefield, Thomas W. Gloviczki, Peter TI Management of venous leg ulcers: Clinical practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; DEEP-VEIN THROMBOSIS; QUALITY-OF-LIFE; ELASTIC COMPRESSION STOCKINGS; MUSCLE PUMP FUNCTION; ENDOSCOPIC PERFORATOR SURGERY; ENDOVENOUS LASER-ABLATION; PLACEBO-CONTROLLED TRIAL; PURIFIED FLAVONOID FRACTION; INFERIOR VENA-CAVA C1 [O'Donnell, Thomas F., Jr.] Tufts Med Ctr, Ctr Cardiovasc, Boston, MA 02111 USA. [Passman, Marc A.] Univ Alabama Birmingham, Div Vasc Surg & Endovasc Therapy, Birmingham, AL USA. [Passman, Marc A.] Birmingham Vet Adm Med Ctr, Birmingham, AL USA. [Henke, Peter K.; Cummings, Mary E.; Wakefield, Thomas W.] Univ Michigan, Ann Arbor, MI 48109 USA. [Dalsing, Michael] Indiana Univ Sch Med, IU Hlth Care Syst, Indianapolis, IN 46202 USA. [Eklof, Bo G.] Lund Univ, S-22100 Lund, Sweden. [Ennis, William J.] Univ Illinois Hosp & Hlth Sci, Chicago, IL USA. [Gillespie, David L.] Southcoast Healthcare Syst, Cardiovasc Care Ctr, Dept Vasc Surg, Fall River, MA USA. [Gillespie, David L.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Gloviczki, Monika L.] Mayo Clin, Gonda Vasc Ctr, Rochester, MN USA. [Gloviczki, Peter] Mayo Clin, Div Vasc & Endovasc Surg, Rochester, MN USA. [Lurie, Fedor] Jobst Vasc Inst, Toledo, OH USA. [Marston, William A.] Univ N Carolina, Chapel Hill, NC USA. [McLafferty, Robert B.] Portland VA Med Ctr, Portland, OR USA. [McLafferty, Robert B.] Oregon Hlth & Sci Univ, Portland, OR USA. [Murad, Mohammad Hassan] Mayo Clin, Div Prevent Med, Rochester, MN USA. [Partsch, Hugo] Med Univ Vienna, Vienna, Austria. [Pounds, Lori C.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Raffetto, Joseph D.] Harvard Univ, Sch Med, Boston, MA USA. [Raffetto, Joseph D.] Vet Adm Boston Healthcare Syst, Boston, MA USA. [Raffetto, Joseph D.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Raju, Sesadri] Rane Ctr, Jackson, MS USA. [Shortell, Cynthia K.] Duke Univ, Med Ctr, Div Vasc Surg, Durham, NC USA. [Stoughton, Julianne] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP O'Donnell, TF (reprint author), Tufts Med Ctr, Ctr Cardiovasc, Boston, MA 02111 USA. NR 554 TC 52 Z9 54 U1 6 U2 16 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2014 VL 60 IS 2 SU S BP 3S EP 59S DI 10.1016/j.jvs.2014.04.049 PG 57 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AO8SU UT WOS:000341625500002 PM 24974070 ER PT J AU Hye, RJ Peden, EK O'Connor, TP Browne, BJ Dixon, BS Schanzer, AS Jensik, SC Dember, LM Jaff, MR Burke, SK AF Hye, Robert J. Peden, Eric K. O'Connor, Timothy P. Browne, Barry J. Dixon, Bradley S. Schanzer, Andres S. Jensik, Stephen C. Dember, Laura M. Jaff, Michael R. Burke, Steven K. TI Human type I pancreatic elastase treatment of arteriovenous fistulas in patients with chronic kidney disease SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID SMOOTH-MUSCLE CELLS; VASCULAR ACCESS; HEMODIALYSIS ACCESS; DIRECTED MIGRATION; PATENCY; GRAFTS; DIALYSIS; OUTCOMES; SALVAGE; SUCCESS AB Objective: This study explored the safety and efficacy of recombinant type I pancreatic elastase (PRT-201) topically applied once to the external surface of an arteriovenous fistula. Methods: This was a randomized, double-blind, placebo-controlled trial. Adults with kidney disease undergoing creation of a radiocephalic fistula (RCF) or brachiocephalic fistula were randomized to treatment with placebo (n = 51), PRT-201 at 10 mu g (n = 51), or PRT-201 at 30 mu g (n = 49). The primary efficacy measure was unassisted primary patency (PP) over 1 year. Secondary efficacy measures were secondary patency (SP), unassisted maturation by ultrasound interrogation, use for hemodialysis, and hemodynamically significant lumen stenosis. Results: Median PP was 224 days for placebo and > 365 days for the PRT-201 groups. At 1 year, 45%, 54%, and 53% of placebo, 10-mu g, and 30-mu g patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 mu g (hazard ratio [HR], 0.69; P = .19) and 30 mu g (HR, 0.67; P = .17) vs placebo. In the subset (44% of patients) with a RCF, the median PP was 125 days for placebo and > 365 days for the PRT-201 groups. At 1 year, 31%, 50%, and 63% of placebo, 10-mu g, and 30-mu g RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 mu g (HR, 0.59; P =.18) and significantly reduced by 30 mu g (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-mu g, and 30-mu g patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 mg (HR, 0.79; P = .61) and 30 mu g (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-mu g, and 30-mu g patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 mg (HR, 0.45; P = .19) and 30 mu g (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-mu g, and 30-mg group fistulas had unassisted maturation by ultrasound interrogation. At month 3 in the subset with an RCF, 47%, 74% (P = .17), and 93% (P < .01) of placebo, 10-mu g, and 30-mu g group fistulas had unassisted maturation by ultrasound interrogation. Adverse event reports were not meaningfully different between groups. Conclusions: PRT-201 appeared safe. The primary efficacy end point was not met. However, both PRT-201 doses were associated with improved unassisted maturation. The 30-mu g dose was associated with increased PP in the subset with RCF. C1 [Hye, Robert J.] Kaiser Permanente, San Diego, CA USA. [Peden, Eric K.] Methodist Hosp, Dept Cardiovasc Surg, Houston, TX 77030 USA. [O'Connor, Timothy P.] Renal Care Associates, Peoria, IL USA. [Browne, Barry J.] Calif Inst Renal Res, San Diego, CA USA. [Dixon, Bradley S.] Univ Iowa Hosp & Clin, Dept Med, Iowa City, IA 52242 USA. [Schanzer, Andres S.] Univ Massachusetts, Sch Med, Div Vasc & Endovasc Surg, Worcester, MA USA. [Jensik, Stephen C.] Rush Univ, Med Ctr, Transplant Program, Chicago, IL 60612 USA. [Dember, Laura M.] Univ Penn, Perelman Sch Med, Renal Elect & Hypertens Div, Philadelphia, PA 19104 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, VasCore, Vasc Ultrasound Core Lab, Boston, MA 02114 USA. [Burke, Steven K.] Proteon Therapeut Inc, Res & Dev, Waltham, MA USA. RP Burke, SK (reprint author), Proteon Therapeut Inc, 200 W St, Waltham, MA 02451 USA. EM sburke@proteontx.com OI Hye, Robert/0000-0002-7733-6173 FU Proteon Therapeutics Inc. FX This study was supported by Proteon Therapeutics Inc. NR 21 TC 15 Z9 15 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD AUG PY 2014 VL 60 IS 2 BP 454 EP U174 DI 10.1016/j.jvs.2014.02.037 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA AO8TK UT WOS:000341627600024 PM 24684771 ER PT J AU Olszewski, AJ Winer, ES Castillo, JJ AF Olszewski, Adam J. Winer, Eric S. Castillo, Jorge J. TI Improved survival with rituximab-based chemoimmunotherapy in older patients with extranodal diffuse large B-cell lymphoma SO LEUKEMIA RESEARCH LA English DT Article DE Diffuse large B-cell lymphoma; R-CHOP chemotherapy; Rituximab; SEER program; Comparative effectiveness researcha ID ELDERLY-PATIENTS; DES-LYMPHOMES; UNITED-STATES; MYD88; CHOP; CHEMOTHERAPY; ERA; MACROGLOBULINEMIA; INVOLVEMENT; POPULATION AB Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we investigated the relative benefits of adding rituximab to CHOP chemotherapy in diffuse large B-cell lymphoma (DLBCL) of extranodal origin, and found similar advantage for nodal and extranodal lymphomas. Hazard ratio for overall survival was 0.64 for nodal, and 0.70 for extranodal DLBCL. Hazard ratios for lymphoma-related death were 0.62 and 0.57, respectively. The advantage was largest for DLBCL of the spleen, liver and lung. Conversely, it was not evident for thyroid or testicular lymphomas. Compared with nodal DLBCL, spleen was the only site with significantly better prognosis after R-CHOP. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Olszewski, Adam J.] Brown Univ, Mem Hosp Rhode Isl, Ctr Canc, Pawtucket, RI 02860 USA. [Winer, Eric S.] Rhode Isl Hosp, Div Hematol & Oncol, Providence, RI 02903 USA. [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02215 USA. RP Olszewski, AJ (reprint author), Brown Univ, Mem Hosp Rhode Isl, Ctr Canc, 111 Brewster St, Pawtucket, RI 02860 USA. EM adam_olszewski@brown.edu OI Olszewski, Adam/0000-0002-6472-6658; Castillo, Jorge/0000-0001-9490-7532 FU California Department of Public Health; NCI's SEER Program [N01-PC-35136, N01-PC-35139, N02-PC-15105]; Centers for Disease Control and Prevention's National Program of Cancer Registries [U55/CCR921930-02] FX The collection of the California cancer incidence data used in this study was supported by the California Department of Public Health; the NCI's SEER Program under contract N01-PC-35136 (Northern California Cancer Center), contract N01-PC-35139 (University of Southern California) and contract N02-PC-15105 (Public Health Institute); and the Centers for Disease Control and Prevention's National Program of Cancer Registries, under agreement #U55/CCR921930-02 (Public Health Institute). The ideas and opinions expressed herein are those of the authors and endorsement by the State of California, Department of Public Health, the NCI, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors is not intended nor should be inferred. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the SEER Program tumor registries in the creation of the SEER-Medicare database. All authors designed the research study, wrote, revised and approved the paper; AJO and JJC performed the statistical analysis. NR 28 TC 6 Z9 6 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 EI 1873-5835 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2014 VL 38 IS 8 BP 866 EP 873 DI 10.1016/j.leukres.2014.04.009 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA AO4ZW UT WOS:000341350900003 PM 24837081 ER PT J AU Watts, JM Wang, XV Litzow, MR Luger, SM Lazarus, HM Cassileth, PA Fernandez, HF Douer, D Zickl, L Paietta, E Rowe, JM Tallman, MS AF Watts, Justin M. Wang, Xin Victoria Litzow, Mark R. Luger, Selina M. Lazarus, Hillard M. Cassileth, Peter A. Fernandez, Hugo F. Douer, Dan Zickl, Lynette Paietta, Elisabeth Rowe, Jacob M. Tallman, Martin S. TI Younger adults with acute myeloid leukemia in remission for >= 3 years have a high likelihood of cure: The ECOG experience in over 1200 patients SO LEUKEMIA RESEARCH LA English DT Article DE Acute myeloid leukemia; Late relapse; Outcomes; Clinical trials; Normal cytogeneticsa ID ACUTE MYELOGENOUS LEUKEMIA; 1ST REMISSION; THERAPY AB examined 1229 younger patients with acute myeloid leukemia who achieved CR1 on Eastern Cooperative Oncology Group trials. We defined late relapse as occurring after >= 3 years of CR1. With median follow-up of 11.3 years, there were 14 late relapses (1.1% of CR1 patients; 3.3% of 3-year CR1 patients). Eight achieved second CR and median overall survival after late relapse was 3.2 years. Most patients tested (9/11) had a normal karyotype at diagnosis; none had new cytogenetic abnormalities at relapse. Late relapse is rare and nearly all 3-year CR1 patients are cured. If late relapse occurs, outcomes are relatively favorable. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Watts, Justin M.; Douer, Dan; Tallman, Martin S.] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, Lukemia Serv, New York, NY USA. [Wang, Xin Victoria; Zickl, Lynette] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wang, Xin Victoria] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Luger, Selina M.] Univ Penn, Philadelphia, PA 19104 USA. [Lazarus, Hillard M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Cassileth, Peter A.] Univ Miami, Miami, FL USA. [Fernandez, Hugo F.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Paietta, Elisabeth] Albert Einstein Coll Med, Montefiore Med Ctr, Bronx, NY 10467 USA. [Rowe, Jacob M.] Share Zedek Med Ctr, Jerusalem, Israel. RP Watts, JM (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave,Box 8, New York, NY 10065 USA. EM wattsj@mskcc.org FU Eastern Cooperative Oncology Group (ECOG) Leukemia Committee FX This study was supported by the Eastern Cooperative Oncology Group (ECOG) Leukemia Committee. NR 13 TC 3 Z9 3 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD AUG PY 2014 VL 38 IS 8 BP 901 EP 906 DI 10.1016/j.leukres.2014.05.018 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA AO4ZW UT WOS:000341350900009 PM 24986381 ER PT J AU Mann, JK Barton, JP Ferguson, AL Omarjee, S Walker, BD Chakraborty, A Ndung'u, T AF Mann, Jaclyn K. Barton, John P. Ferguson, Andrew L. Omarjee, Saleha Walker, Bruce D. Chakraborty, Arup Ndung'u, Thumbi TI The Fitness Landscape of HIV-1 Gag: Advanced Modeling Approaches and Validation of Model Predictions by In Vitro Testing SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REPLICATION CAPACITY; EVOLUTIONARY; ESCAPE; MUTATIONS; INFECTION; CONTACTS; VACCINE; VIREMIA AB Viral immune evasion by sequence variation is a major hindrance to HIV-1 vaccine design. To address this challenge, our group has developed a computational model, rooted in physics, that aims to predict the fitness landscape of HIV-1 proteins in order to design vaccine immunogens that lead to impaired viral fitness, thus blocking viable escape routes. Here, we advance the computational models to address previous limitations, and directly test model predictions against in vitro fitness measurements of HIV-1 strains containing multiple Gag mutations. We incorporated regularization into the model fitting procedure to address finite sampling. Further, we developed a model that accounts for the specific identity of mutant amino acids (Potts model), generalizing our previous approach (Ising model) that is unable to distinguish between different mutant amino acids. Gag mutation combinations (17 pairs, 1 triple and 25 single mutations within these) predicted to be either harmful to HIV-1 viability or fitness-neutral were introduced into HIV-1 NL4-3 by site-directed mutagenesis and replication capacities of these mutants were assayed in vitro. The predicted and measured fitness of the corresponding mutants for the original Ising model (r = -0.74, p = 3.6x10(-6)) are strongly correlated, and this was further strengthened in the regularized Ising model (r = -0.83, p = 3.7x10(-12)). Performance of the Potts model (r = -0.73, p = 9.7x10(-9)) was similar to that of the Ising model, indicating that the binary approximation is sufficient for capturing fitness effects of common mutants at sites of low amino acid diversity. However, we show that the Potts model is expected to improve predictive power for more variable proteins. Overall, our results support the ability of the computational models to robustly predict the relative fitness of mutant viral strains, and indicate the potential value of this approach for understanding viral immune evasion, and harnessing this knowledge for immunogen design. C1 [Mann, Jaclyn K.; Omarjee, Saleha; Walker, Bruce D.; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Mann, Jaclyn K.; Omarjee, Saleha; Ndung'u, Thumbi] Univ KwaZulu Natal, Nelson R Mandela Sch Med, KwaZulu Natal Res Inst TB & HIV K RITH, Durban, South Africa. [Barton, John P.; Chakraborty, Arup] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Barton, John P.; Walker, Bruce D.; Chakraborty, Arup; Ndung'u, Thumbi] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. [Barton, John P.; Walker, Bruce D.; Chakraborty, Arup; Ndung'u, Thumbi] Harvard Univ, Boston, MA 02115 USA. [Ferguson, Andrew L.] Univ Illinois, Dept Mat Sci & Engn, Urbana, IL USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Chakraborty, Arup] MIT, Dept Chem, Boston, MA USA. [Chakraborty, Arup] MIT, Dept Phys, Boston, MA USA. [Ndung'u, Thumbi] Max Planck Inst Infect Biol, Berlin, Germany. RP Mann, JK (reprint author), Univ KwaZulu Natal, Nelson R Mandela Sch Med, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. EM arupc@mit.edu; ndungu@ukzn.ac.za OI Barton, John/0000-0003-1467-421X; Ndung'u, Thumbi/0000-0003-2962-3992; Ferguson, Andrew/0000-0002-8829-9726 FU Ragon Institute; National Institutes of Health Director's Pioneers Award; NIH Award [AI30914]; Howard Hughes Medical Institute; South African Department of Science and Technology/National Research Foundation Research Chairs Initiative; Victor Daitz Foundation FX Financial support was provided by the Ragon Institute (BDW, AKC, JKM, SO, TN), a National Institutes of Health Director's Pioneers Award (AKC), NIH Award AI30914 (BDW), the Howard Hughes Medical Institute (BDW, TN), the South African Department of Science and Technology/National Research Foundation Research Chairs Initiative and the Victor Daitz Foundation (JKM, SO, TN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 25 Z9 25 U1 3 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2014 VL 10 IS 8 AR e1003776 DI 10.1371/journal.pcbi.1003776 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AO8AE UT WOS:000341573600026 PM 25102049 ER PT J AU Miller, CA White, BS Dees, ND Griffith, M Welch, JS Griffith, OL Vij, R Tomasson, MH Graubert, TA Walter, MJ Ellis, MJ Schierding, W DiPersio, JF Ley, TJ Mardis, ER Wilson, RK Ding, L AF Miller, Christopher A. White, Brian S. Dees, Nathan D. Griffith, Malachi Welch, John S. Griffith, Obi L. Vij, Ravi Tomasson, Michael H. Graubert, Timothy A. Walter, Matthew J. Ellis, Matthew J. Schierding, William DiPersio, John F. Ley, Timothy J. Mardis, Elaine R. Wilson, Richard K. Ding, Li TI SciClone: Inferring Clonal Architecture and Tracking the Spatial and Temporal Patterns of Tumor Evolution SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MULTIPLE-MYELOMA; SEQUENCING DATA; BREAST CANCERS; MUTATIONS; GENOME; HETEROGENEITY; METASTASIS; DIVERSITY; DISCOVERY AB The sensitivity of massively-parallel sequencing has confirmed that most cancers are oligoclonal, with subpopulations of neoplastic cells harboring distinct mutations. A fine resolution view of this clonal architecture provides insight into tumor heterogeneity, evolution, and treatment response, all of which may have clinical implications. Single tumor analysis already contributes to understanding these phenomena. However, cryptic subclones are frequently revealed by additional patient samples (e. g., collected at relapse or following treatment), indicating that accurately characterizing a tumor requires analyzing multiple samples from the same patient. To address this need, we present SciClone, a computational method that identifies the number and genetic composition of subclones by analyzing the variant allele frequencies of somatic mutations. We use it to detect subclones in acute myeloid leukemia and breast cancer samples that, though present at disease onset, are not evident from a single primary tumor sample. By doing so, we can track tumor evolution and identify the spatial origins of cells resisting therapy. C1 [Miller, Christopher A.; White, Brian S.; Dees, Nathan D.; Griffith, Malachi; Griffith, Obi L.; Ley, Timothy J.; Mardis, Elaine R.; Wilson, Richard K.; Ding, Li] Washington Univ, Genome Inst, St Louis, MO 63130 USA. [White, Brian S.; Welch, John S.; Griffith, Obi L.; Vij, Ravi; Tomasson, Michael H.; Graubert, Timothy A.; Walter, Matthew J.; Ellis, Matthew J.; DiPersio, John F.; Ley, Timothy J.; Mardis, Elaine R.; Wilson, Richard K.; Ding, Li] Washington Univ, Sch Med, Dept Internal Med, Div Oncol, St Louis, MO 63110 USA. [Griffith, Malachi; Walter, Matthew J.; Ley, Timothy J.; Mardis, Elaine R.; Wilson, Richard K.; Ding, Li] Washington Univ, Dept Genet, St Louis, MO 63110 USA. [Welch, John S.; Vij, Ravi; Tomasson, Michael H.; Graubert, Timothy A.; Walter, Matthew J.; Ellis, Matthew J.; DiPersio, John F.; Ley, Timothy J.; Mardis, Elaine R.; Wilson, Richard K.; Ding, Li] Washington Univ, Sch Med, Siteman Canc Ctr, Barnes Jewish Hosp, St Louis, MO USA. [Graubert, Timothy A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schierding, William] Liggins Inst, Auckland, New Zealand. RP Miller, CA (reprint author), Washington Univ, Genome Inst, St Louis, MO 63130 USA. EM lding@genome.wustl.edu OI Griffith, Obi/0000-0002-0843-4271; Graubert, Timothy/0000-0002-7710-1171 FU NHGRI grant [U01HG006517]; NHGRI [U54HG003079]; International Myeloma Foundation Brian D. Novis research grant; Barnes-Jewish Hospital Foundation grant [7603-55]; NIH/NCI SPORE in Leukemia grant [P50CA171063]; NIH/NCI grant [1K12CA167540]; Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences grant [UL1 TR000448] FX This work was supported by NHGRI grant U01HG006517 to LD, NHGRI grant U54HG003079 to RKW, and an International Myeloma Foundation Brian D. Novis research grant, Barnes-Jewish Hospital Foundation grant 7603-55, NIH/NCI SPORE in Leukemia grant P50CA171063, NIH/NCI grant 1K12CA167540, and Clinical and Translational Award from the NIH National Center for Advancing Translational Sciences grant UL1 TR000448 to BSW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 55 Z9 55 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2014 VL 10 IS 8 AR e1003665 DI 10.1371/journal.pcbi.1003665 PG 15 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA AO8AE UT WOS:000341573600001 PM 25102416 ER PT J AU Yildirim, O Hung, JH Cedeno, RJ Weng, ZP Lengner, CJ Rando, OJ AF Yildirim, Ozlem Hung, Jui-Hung Cedeno, Ryan J. Weng, Zhiping Lengner, Christopher J. Rando, Oliver J. TI A System for Genome-Wide Histone Variant Dynamics In ES Cells Reveals Dynamic MacroH2A2 Replacement at Promoters SO PLOS GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; INACTIVE X-CHROMOSOME; NUCLEOSOME TURNOVER; SELF-RENEWAL; H3 EXCHANGE; CHROMATIN; REPLICATION; GENES; YEAST; MARKS AB Dynamic exchange of a subset of nucleosomes in vivo plays important roles in epigenetic inheritance of chromatin states, chromatin insulator function, chromosome folding, and the maintenance of the pluripotent state of embryonic stem cells. Here, we extend a pulse-chase strategy for carrying out genome-wide measurements of histone dynamics to several histone variants in murine embryonic stem cells and somatic tissues, recapitulating expected characteristics of the well characterized H3.3 histone variant. We extended this system to the less-studied MacroH2A2 variant, commonly described as a "repressive'' histone variant whose accumulation in chromatin is thought to fix the epigenetic state of differentiated cells. Unexpectedly, we found that while large intergenic blocks of MacroH2A2 were stably associated with the genome, promoter-associated peaks of MacroH2A2 exhibited relatively rapid exchange dynamics in ES cells, particularly at highly-transcribed genes. Upon differentiation to embryonic fibroblasts, MacroH2A2 was gained primarily in additional long, stably associated blocks across gene-poor regions, while overall turnover at promoters was greatly dampened. Our results reveal unanticipated dynamic behavior of the MacroH2A2 variant in pluripotent cells, and provide a resource for future studies of tissue-specific histone dynamics in vivo. C1 [Yildirim, Ozlem; Weng, Zhiping; Rando, Oliver J.] Univ Massachusetts, Sch Med, Dept Mol Pharmacol & Biochem, Worcester, MA USA. [Hung, Jui-Hung; Weng, Zhiping] Univ Massachusetts, Sch Med, Program Bioinformat & Integrat Biol, Worcester, MA USA. [Cedeno, Ryan J.; Lengner, Christopher J.] Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. [Cedeno, Ryan J.; Lengner, Christopher J.] Univ Penn, Inst Regenerat Med, Philadelphia, PA 19104 USA. RP Yildirim, O (reprint author), Harvard Univ, Sch Med, Dept Genet, Dept Mol Biol,Massachusetts Gen Hosp, Boston, MA 02163 USA. EM lengner@vet.upenn.edu; oliver.rando@umassmed.edu RI Hung, Jui-Hung/G-2673-2012; OI Hung, Jui-Hung/0000-0003-2208-9213; Lengner, Christopher/0000-0002-0574-5189 FU W.W. Smith Charitable Trust; Harold and Leila Mathers Foundation; [R01HD080224] FX Work in the Lengner lab was supported by the W.W. Smith Charitable Trust, work in the Rando lab was supported by the R01HD080224 and by the Harold and Leila Mathers Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 7 Z9 7 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7390 EI 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2014 VL 10 IS 8 AR e1004515 DI 10.1371/journal.pgen.1004515 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA AO8BQ UT WOS:000341577800018 PM 25102063 ER PT J AU Lankowski, AJ Tsai, AC Kanyesigye, M Bwana, M Haberer, JE Wenger, M Martin, JN Bangsberg, DR Hunt, PW Siedner, MJ AF Lankowski, Alexander J. Tsai, Alexander C. Kanyesigye, Michael Bwana, Mwebesa Haberer, Jessica E. Wenger, Megan Martin, Jeffrey N. Bangsberg, David R. Hunt, Peter W. Siedner, Mark J. TI Empiric Deworming and CD4 Count Recovery in HIV-Infected Ugandans Initiating Antiretroviral Therapy SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TRANSMITTED HELMINTH INFECTIONS; NEGLECTED TROPICAL DISEASES; SYSTEMIC IMMUNE ACTIVATION; T-CELL COUNT; DOUBLE-BLIND; VIRAL LOAD; ADULTS; COINFECTION; MORTALITY; IMMUNODEFICIENCY AB Background: There is conflicting evidence on the immunologic benefit of treating helminth co-infections ("deworming") in HIV-infected individuals. Several studies have documented reduced viral load and increased CD4 count in antiretroviral therapy (ART) naive individuals after deworming. However, there are a lack of data on the effect of deworming therapy on CD4 count recovery among HIV-infected persons taking ART. Methodology/Principal Findings: To estimate the association between empiric deworming therapy and CD4 count after ART initiation, we performed a retrospective observational study among HIV-infected adults on ART at a publicly operated HIV clinic in southwestern Uganda. Subjects were assigned as having received deworming if prescribed an anti-helminthic agent between 7 and 90 days before a CD4 test. To estimate the association between deworming and CD4 count, we fit multivariable regression models and analyzed predictors of CD4 count, using a time-by-interaction term with receipt or non-receipt of deworming. From 1998 to 2009, 5,379 subjects on ART attended 21,933 clinic visits at which a CD4 count was measured. Subjects received deworming prior to 668 (3%) visits. Overall, deworming was not associated with a significant difference in CD4 count in either the first year on ART (beta = 42.8; 95% CI, -22.1 to 87.7) or after the first year of ART (beta = -29.9; 95% CI, -24.1 to 4.4). However, in a sub-analysis by gender, during the first year of ART deworming was associated with a significantly greater rise in CD4 count (beta = 63.0; 95% CI, 6.0 to 120.1) in females. Conclusions/Significance: Empiric deworming of HIV-infected individuals on ART conferred no significant generalized benefit on subsequent CD4 count recovery. A significant association was observed exclusively in females and during the initial year on ART. Our findings are consistent with recent studies that failed to demonstrate an immunologic advantage to empirically deworming ART-naive individuals, but suggest that certain sub-populations may benefit. C1 [Lankowski, Alexander J.] Hosp Univ Penn, Dept Internal Med, Philadelphia, PA 19104 USA. [Lankowski, Alexander J.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Lankowski, Alexander J.; Tsai, Alexander C.; Haberer, Jessica E.; Bangsberg, David R.; Siedner, Mark J.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Tsai, Alexander C.] Massachusetts Gen Hosp, Dept Psychiat, Chester M Pierce MD Div Global Psychiat, Boston, MA 02114 USA. [Kanyesigye, Michael; Bwana, Mwebesa; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Wenger, Megan; Martin, Jeffrey N.; Hunt, Peter W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bangsberg, David R.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Siedner, Mark J.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. RP Lankowski, AJ (reprint author), Hosp Univ Penn, Dept Internal Med, 3400 Spruce St, Philadelphia, PA 19104 USA. EM alexlankowski@gmail.com OI Siedner, Mark/0000-0003-3506-842X; Tsai, Alexander/0000-0001-6397-7917 FU Doris Duke Charitable Foundation International Clinical Research Fellowship at Harvard Medical School; American Medical Association Foundation; U.S. National Institutes of Health [NIH] [R24TW007988, K23MH099916]; NIH [K23MH087228, K24MH087227, K23MH096620, U01 AI069911, P30 AI027763] FX This work was supported by the Doris Duke Charitable Foundation International Clinical Research Fellowship at Harvard Medical School and the American Medical Association Foundation Seed Grant Research Program (AJL); U.S. National Institutes of Health [NIH] R24TW007988 and K23MH099916 (MJS); NIH K23MH087228 (JEH); NIH K24MH087227 (DRB); NIH K23MH096620 (ACT); and NIH U01 AI069911 and P30 AI027763 (JNM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3036 DI 10.1371/journal.pntd.0003036 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700020 PM 25101890 ER PT J AU Leung, DT Bhuiyan, TR Nishat, NS Hoq, MR Aktar, A Rahman, MA Uddin, T Khan, AI Chowdhury, F Charles, RC Harris, JB Calderwood, SB Qadri, F Ryan, ET AF Leung, Daniel T. Bhuiyan, Taufiqur R. Nishat, Naoshin S. Hoq, Mohammad Rubel Aktar, Amena Rahman, M. Arifur Uddin, Taher Khan, Ashraful I. Chowdhury, Fahima Charles, Richelle C. Harris, Jason B. Calderwood, Stephen B. Qadri, Firdausi Ryan, Edward T. TI Circulating Mucosal Associated Invariant T Cells Are Activated in Vibrio cholerae O1 Infection and Associated with Lipopolysaccharide Antibody Responses SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID MEMORY B-CELL; IMMUNE-RESPONSES; MAIT CELLS; INFLAMMATORY MEDIATORS; BACTERIAL-INFECTION; HOUSEHOLD CONTACTS; BANGLADESH; CHILDREN; ADULTS; SUSCEPTIBILITY AB Background: Mucosal Associated Invariant T (MAIT) cells are innate-like T cells found in abundance in the intestinal mucosa, and are thought to play a role in bridging the innate-adaptive interface. Methods: We measured MAIT cell frequencies and antibody responses in blood from patients presenting with culture-confirmed severe cholera to a hospital in Dhaka, Bangladesh at days 2, 7, 30, and 90 of illness. Results: We found that MAIT (CD3(+) CD4(-) CD161(hi)Va7.2(+)) cells were maximally activated at day 7 after onset of cholera. In adult patients, MAIT frequencies did not change over time, whereas in child patients, MAITs were significantly decreased at day 7, and this decrease persisted to day 90. Fold changes in MAIT frequency correlated with increases in LPS IgA and IgG, but not LPS IgM nor antibody responses to cholera toxin B subunit. Conclusions: In the acute phase of cholera, MAIT cells are activated, depleted from the periphery, and as part of the innate response against V. cholerae infection, are possibly involved in mechanisms underlying class switching of antibody responses to T cell-independent antigens. C1 [Leung, Daniel T.; Bhuiyan, Taufiqur R.; Nishat, Naoshin S.; Hoq, Mohammad Rubel; Aktar, Amena; Rahman, M. Arifur; Uddin, Taher; Khan, Ashraful I.; Chowdhury, Fahima; Qadri, Firdausi] Bangladesh Icddr B, Int Ctr Diarrhoeal Dis Res, Ctr Vaccine Sci, Dhaka, Bangladesh. [Leung, Daniel T.; Charles, Richelle C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Leung, Daniel T.; Charles, Richelle C.; Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Harris, Jason B.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Leung, DT (reprint author), Univ Utah, Sch Med, Div Infect Dis, Salt Lake City, UT 84112 USA. EM Daniel.Leung@utah.edu OI leung, daniel/0000-0001-8401-0801 FU icddr,b; National Institutes of Health; National Institute of Allergy & Infectious Diseases [U01 AI058935, U01 AI077883, AI106878, R01AI03055, K08 AI089721, K08 AI100923]; Fogarty International Center, Training Grant in Vaccine Development and Public Health [TW005572]; Thrasher Research Fund Early Career Award; Postdoctoral Fellowship in Tropical Infectious Diseases from the American Society for Tropical Medicine & Hygiene - Burroughs Wellcome Fund FX This work was supported by the icddr,b and its donors, which provide unrestricted support to icddr,b for its operations and research. This study was also supported by grants from the National Institutes of Health, including the National Institute of Allergy & Infectious Diseases (U01 AI058935 (SBC, ETR), U01 AI077883 and AI106878 (ETR), R01AI03055 (JBH), K08 AI089721 (RCC), K08 AI100923 (DTL) and the Fogarty International Center, Training Grant in Vaccine Development and Public Health (TW005572 (TU, TRB, and FQ)), as well as by a Thrasher Research Fund Early Career Award (DTL), and a Postdoctoral Fellowship in Tropical Infectious Diseases from the American Society for Tropical Medicine & Hygiene - Burroughs Wellcome Fund (DTL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 16 Z9 16 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2014 VL 8 IS 8 AR e3076 DI 10.1371/journal.pntd.0003076 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA AO8AN UT WOS:000341574700040 PM 25144724 ER PT J AU Jones, RB O'Connor, R Mueller, S Foley, M Szeto, GL Karel, D Lichterfeld, M Kovacs, C Ostrowski, MA Trocha, A Irvine, DJ Walker, BD AF Jones, Richard Brad O'Connor, Rachel Mueller, Stefanie Foley, Maria Szeto, Gregory L. Karel, Dan Lichterfeld, Mathias Kovacs, Colin Ostrowski, Mario A. Trocha, Alicja Irvine, Darrell J. Walker, Bruce D. TI Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes SO PLOS PATHOGENS LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; VERSUS-HOST-DISEASE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; TIME-LAPSE MICROCINEMATOGRAPHY; IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; MRL-LPR/LPR MOUSE; IN-VITRO; HISTONE/PROTEIN DEACETYLASES; IMMUNE-RESPONSES AB Resting memory CD4(+) T-cells harboring latent HIV proviruses represent a critical barrier to viral eradication. Histone deacetylase inhibitors (HDACis), such as suberanilohydroxamic acid (SAHA), romidepsin, and panobinostat have been shown to induce HIV expression in these resting cells. Recently, it has been demonstrated that the low levels of viral gene expression induced by a candidate HDACi may be insufficient to cause the death of infected cells by viral cytopathic effects, necessitating their elimination by immune effectors, such as cytotoxic T-lymphocytes (CTL). Here, we study the impact of three HDACis in clinical development on T-cell effector functions. We report two modes of HDACi-induced functional impairment: i) the rapid suppression of cytokine production from viable T-cells induced by all three HDACis ii) the selective death of activated T-cells occurring at later time-points following transient exposures to romidepsin or, to a lesser extent, panobinostat. As a net result of these factors, HDACis impaired CTL-mediated IFN-c production, as well as the elimination of HIV-infected or peptide-pulsed target cells, both in liquid culture and in collagen matrices. Romidepsin exerted greater inhibition of antiviral function than SAHA or panobinostat over the dose ranges tested. These data suggest that treatment with HDACis to mobilize the latent reservoir could have unintended negative impacts on the effector functions of CTL. This could influence the effectiveness of HDACi-based eradication strategies, by impairing elimination of infected cells, and is a critical consideration for trials where therapeutic interruptions are being contemplated, given the importance of CTL in containing rebound viremia. C1 [Jones, Richard Brad; O'Connor, Rachel; Mueller, Stefanie; Karel, Dan; Trocha, Alicja; Irvine, Darrell J.; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Jones, Richard Brad; O'Connor, Rachel; Mueller, Stefanie; Karel, Dan; Trocha, Alicja; Irvine, Darrell J.; Walker, Bruce D.] Harvard Univ, Boston, MA 02115 USA. [Jones, Richard Brad; Mueller, Stefanie; Foley, Maria; Szeto, Gregory L.; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Foley, Maria; Szeto, Gregory L.; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lichterfeld, Mathias; Walker, Bruce D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kovacs, Colin; Ostrowski, Mario A.] Maple Leaf Med Clin, Toronto, ON, Canada. [Kovacs, Colin; Ostrowski, Mario A.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Ostrowski, Mario A.] St Michaels Hosp, Li Ka Shing Med Inst, Toronto, ON M5B 1W8, Canada. [Irvine, Darrell J.; Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Jones, RB (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. EM bwalker@partners.org OI Szeto, Gregory/0000-0001-7604-1333 FU Ragon Institute of MGH; MIT; Ruth L. Kirschstein National Research Service Award from the NIH FX This work was supported in part by the Ragon Institute of MGH, MIT, and Harvard. RBJ is a Banting Fellow of the Canadian Institute of Health Research and an Ontario HIV Treatment Network Junior Investigator. GLS is supported by a Ruth L. Kirschstein National Research Service Award from the NIH. BDW and DJI are investigators of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 53 Z9 53 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004287 DI 10.1371/journal.ppat.1004287 PG 19 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300017 PM 25122219 ER PT J AU Starkey, M Lepine, F Maura, D Bandyopadhaya, A Lesic, B He, JX Kitao, T Righi, V Milot, S Tzika, A Rahme, L AF Starkey, Melissa Lepine, Francois Maura, Damien Bandyopadhaya, Arunava Lesic, Biljana He, Jianxin Kitao, Tomoe Righi, Valeria Milot, Sylvain Tzika, Aria Rahme, Laurence TI Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity SO PLOS PATHOGENS LA English DT Article ID PSEUDOMONAS-QUINOLONE SIGNAL; INFECTIOUS-DISEASES SOCIETY; CYSTIC-FIBROSIS PATIENTS; BACTERIAL PERSISTERS; TRANSCRIPTIONAL REGULATORS; HYDROXYL RADICALS; MOUSE MODEL; AERUGINOSA; GENE; PATHOGENESIS AB Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections. C1 [Starkey, Melissa; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biljana; He, Jianxin; Kitao, Tomoe; Rahme, Laurence] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Starkey, Melissa; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biljana; He, Jianxin; Kitao, Tomoe; Rahme, Laurence] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Starkey, Melissa; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biljana; He, Jianxin; Kitao, Tomoe; Rahme, Laurence] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA USA. [Starkey, Melissa; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biljana; He, Jianxin; Kitao, Tomoe; Rahme, Laurence] Shriners Hosp Children Boston, Boston, MA USA. [Lepine, Francois; Milot, Sylvain] Univ Quebec, Inst Armand Frappier, INRS, Laval, PQ, Canada. [Righi, Valeria; Tzika, Aria] Harvard Univ, Sch Med, Dept Surg, NMR Surg Lab,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Righi, Valeria; Tzika, Aria] Harvard Univ, Sch Med, Dept Surg, NMR Surg Lab,Shriners Hosp, Boston, MA 02115 USA. [Righi, Valeria; Tzika, Aria] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Rahme, L (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM rahme@molbio.mgh.harvard.edu FU Shriners Postdoctoral Fellowships [8506, 84206]; Uehara Memorial Foundation; Shriners Grant [87700, 85300]; NIH [R21AI105902, R56AI063433-06A1]; Cystic Fibrosis Foundation [11P0]; [U54 AI057159] FX MS and DM were supported by Shriners Postdoctoral Fellowships #8506, #84206 respectively. TK was supported by International Research Fellowship from Uehara Memorial Foundation. LR was supported by Shriners Grant #87700 and #85300, NIH grants R21AI105902 and R56AI063433-06A1 and Cystic Fibrosis Foundation grant CFF#11P0. NERCE/NSRB was funded by U54 AI057159. The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. NR 86 TC 36 Z9 37 U1 3 U2 42 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7366 EI 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2014 VL 10 IS 8 AR e1004321 DI 10.1371/journal.ppat.1004321 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AO8BD UT WOS:000341576300039 PM 25144274 ER PT J AU Ripley, D Wierman, M Gerber, D Weintraub, A Newman, J AF Ripley, David Wierman, Margaret Gerber, Don Weintraub, Alan Newman, Jody TI Comment on The Decision to Provide Testosterone Supplementation to Patients With Traumatic Brain Injury SO PM&R LA English DT Letter C1 [Ripley, David] Rehabil Inst Chicago, Chicago, IL 60611 USA. [Wierman, Margaret] Univ Colorado, Sch Med, Aurora, CO USA. [Wierman, Margaret] Denver VA Med Ctr, Denver, CO USA. [Gerber, Don] Craig Hosp, Brain Injury Program, Englewood, CO USA. [Weintraub, Alan; Newman, Jody] Craig Hosp, Englewood, CO USA. RP Ripley, D (reprint author), Rehabil Inst Chicago, Chicago, IL 60611 USA. NR 3 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 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD AUG PY 2014 VL 6 IS 8 BP 761 EP 761 DI 10.1016/j.pmrj.2014.03.008 PG 1 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA AO8PN UT WOS:000341616800017 PM 25169710 ER PT J AU Ross, RJ AF Ross, Richard J. TI The Changing REM Sleep Signature of Posttraumatic Stress Disorder SO SLEEP LA English DT Editorial Material ID DEPENDENT PLASTICITY; COMBAT VETERANS; DISTURBANCE; PRAZOSIN; NIGHTMARES; MECHANISM; PTSD C1 [Ross, Richard J.] Philadelphia VA Med Ctr, Behav Hlth Serv, Philadelphia, PA 19104 USA. [Ross, Richard J.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Ross, RJ (reprint author), Philadelphia VA Med Ctr, Behav Hlth Serv, 116 MHC,Univ & Woodland Ave, Philadelphia, PA 19104 USA. EM rossri@mail.med.upenn.edu FU NIMHD NIH HHS [1P20MD006899-01] NR 22 TC 4 Z9 4 U1 6 U2 12 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2014 VL 37 IS 8 BP 1281 EP 1282 DI 10.5665/sleep.3912 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AO7DL UT WOS:000341512100004 PM 25083007 ER PT J AU Pellegrino, R Kavakli, IH Goel, N Cardinale, CJ Dinges, DF Kuna, ST Maislin, G Van Dongen, HPA Tufik, S Hogenesch, JB Hakonarson, H Pack, AI AF Pellegrino, Renata Kavakli, Ibrahim Halil Goel, Namni Cardinale, Christopher J. Dinges, David F. Kuna, Samuel T. Maislin, Greg Van Dongen, Hans P. A. Tufik, Sergio Hogenesch, John B. Hakonarson, Hakon Pack, Allan I. TI A Novel BHLHE41 Variant is Associated with Short Sleep and Resistance to Sleep Deprivation in Humans SO SLEEP LA English DT Article DE BHLHE41; delta power; genetics; sleep; sleep deprivation; sleep loss ID SLOW-WAVE ACTIVITY; VIGILANCE TEST PVT; E-BOX ELEMENTS; TRANSCRIPTION FACTOR; INTERINDIVIDUAL DIFFERENCES; GENE-EXPRESSION; 2-PROCESS MODEL; MOLECULAR CLOCK; LONG SLEEPERS; DEC2 AB Study Objectives: Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loop-helix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Design: Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. Results: We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. Conclusions: There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis. C1 [Pellegrino, Renata; Cardinale, Christopher J.; Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Pellegrino, Renata; Goel, Namni; Dinges, David F.; Kuna, Samuel T.; Maislin, Greg; Pack, Allan I.] Univ Penn, Perelman Sch Med, Ctr Sleep & Circadian Neurobiol, Philadelphia, PA 19104 USA. [Pellegrino, Renata; Tufik, Sergio] Univ Fed Sao Paulo, UNIFESP, Dept Psicobiol, Sao Paulo, Brazil. [Kavakli, Ibrahim Halil] Koc Univ, Dept Chem & Biol Engn, Sariyer, Turkey. [Kavakli, Ibrahim Halil] Koc Univ, Dept Mol Biol & Genet, Sariyer, Turkey. [Goel, Namni; Dinges, David F.] Univ Penn, Dept Psychiat, Perelman Sch Med, Div Sleep & Chronobiol, Philadelphia, PA 19104 USA. [Kuna, Samuel T.; Maislin, Greg; Pack, Allan I.] Univ Penn, Perelman Sch Med, Div Sleep Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA USA. [Van Dongen, Hans P. A.] Washington State Univ, Sleep & Performance Res Ctr, Pullman, WA 99164 USA. [Hakonarson, Hakon] Univ Penn, Dept Pharmacol, Perelman Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. RP Pellegrino, R (reprint author), Childrens Hosp Philadelphia, Ctr Appl Genom, Abramson Res Ctr, 3615 Civ Ctr Blvd,Suite 1014, Philadelphia, PA 19104 USA. EM renata.pellegrino@gmail.com RI Cardinale, Christopher/G-3351-2013 OI Cardinale, Christopher/0000-0001-7513-8977 FU NIH [P01 HL094307, NR004281]; Institutional Development Fund from the Center for Applied Genomics at The Children's Hospital of Philadelphia; National Space Biomedical Research Institute through NASA [NCC 9-58]; CTRC [UL1RR024134]; Department of the Navy, Office of Naval Research [N00014-11-1-0361]; Pulsar Informatics; Boeing Company; Battelle Center for Human Performance Safety; Institutes for Behavior Resources; FedEx Express FX This was not an industry supported study. This work was supported in part by NIH grant P01 HL094307 and Institutional Development Fund from the Center for Applied Genomics at The Children's Hospital of Philadelphia. Data analyzed from experiments on chronic partial sleep deprivation were supported by the National Space Biomedical Research Institute through NASA NCC 9-58, NIH NR004281, CTRC UL1RR024134 and the Department of the Navy, Office of Naval Research Award No. N00014-11-1-0361. Drs Pellegrino and Kavakli are co-first authors. Dr. Dinges is Editor-in-Chief of SLEEP. Dr. Van Dongen has received grant funding from Pulsar Informatics, Boeing Company, Battelle Center for Human Performance & Safety, and Institutes for Behavior Resources; has received consulting fees from Pulsar Informatics and FedEx Express; and has participated in a paid speaking engagement with the Ohio Sleep Medicine Institute. The other authors have indicated no financial conflicts of interest. NR 47 TC 13 Z9 13 U1 3 U2 26 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2014 VL 37 IS 8 BP 1327 EP U127 DI 10.5665/sleep.3924 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AO7DL UT WOS:000341512100010 PM 25083013 ER PT J AU Bhan, I AF Bhan, Ishir TI Breaking Down the Vitamin D-GFR Relationship SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; D DEFICIENCY; METABOLISM; CATABOLISM; DIALYSIS; CYP24A1 C1 [Bhan, Ishir] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bhan, I (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM ibhan@mgh.harvard.edu NR 14 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2014 VL 64 IS 2 BP 168 EP 170 DI 10.1053/j.ajkd.2014.05.004 PG 3 WC Urology & Nephrology SC Urology & Nephrology GA AO5BQ UT WOS:000341356400002 PM 25060002 ER PT J AU Allegretti, AS Nazarian, RM Goverman, J Nigwekar, SU AF Allegretti, Andrew S. Nazarian, Rosalynn M. Goverman, Jeremy Nigwekar, Sagar U. TI Calciphylaxis: A Rare But Fatal Delayed Complication of Roux-en-Y Gastric Bypass Surgery SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Calciphylaxis; gastric bypass; hypocalcemia; obesity; vitamin D ID CALCIFIC UREMIC ARTERIOLOPATHY; SODIUM THIOSULFATE; BARIATRIC SURGERY; RENAL-DISEASE; EMERGING ROLE; THERAPY; MORTALITY; WARFARIN; RAT AB Gastric bypass is a commonly used surgical procedure that has shown impressive health benefits for patients with morbid obesity. However, mineral bone abnormalities (hypocalcemia, hypovitaminosis D, and secondary hyperparathyroidism) and micronutrient (eg, iron) deficiencies are common complications after gastric bypass surgery due to alterations in the digestive anatomy. These abnormalities, their treatments, and a number of other factors associated with obesity can set up a perfect storm to induce calciphylaxis, a rare but highly fatal condition with severe comorbid conditions. We present a fatal case of nonuremic calciphylaxis coincident with symptomatic hypocalcemia in a morbidly obese man with a history of Roux-en-Y gastric bypass surgery. (C) 2014 by the National Kidney Foundation, Inc. C1 [Allegretti, Andrew S.; Nigwekar, Sagar U.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Nazarian, Rosalynn M.] Massachusetts Gen Hosp, Dermatopathol Unit, Boston, MA 02114 USA. [Goverman, Jeremy] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Nigwekar, SU (reprint author), Massachusetts Gen Hosp, Bulfinch 127, Boston, MA 02114 USA. EM sagarnigs@gmail.com FU Clinical Scientist in Nephrology Fellowship from the American Kidney Fund; Sanofi Nephrology Fellowship award FX Dr Nigwekar is supported by a Clinical Scientist in Nephrology Fellowship from the American Kidney Fund and a Sanofi Nephrology Fellowship award. The remaining authors declare that they have no relevant financial interests. NR 26 TC 3 Z9 3 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 EI 1523-6838 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2014 VL 64 IS 2 BP 274 EP 277 DI 10.1053/j.ajkd.2014.02.029 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA AO5BQ UT WOS:000341356400017 PM 24787764 ER PT J AU Bangalore, S Schwamm, L Smith, EE Singh, IM Liang, L Fonarow, GC Bhatt, DL AF Bangalore, Sripal Schwamm, Lee Smith, Eric E. Singh, Inder M. Liang, Li Fonarow, Gregg C. Bhatt, Deepak L. CA Guidelines-Stroke Steering Comm TI Secondary Prevention after Ischemic Stroke or Transient Ischemic Attack SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Secondary prevention; Stroke; Transient ischemic attacks ID HEALTH-CARE PROFESSIONALS; CARDIOVASCULAR EVENT RATES; AMERICAN-HEART-ASSOCIATION; STABLE OUTPATIENTS; GUIDELINES-STROKE; URGENT TREATMENT; BETA-BLOCKERS; MINOR STROKE; ATHEROTHROMBOSIS; DISEASE AB BACKGROUND: Patients with stroke or transient ischemic attack are at increased risk of recurrent stroke. Transient ischemic attack is a harbinger for stroke merely hours to days after the initial transient ischemic attack. There is thus a narrow window of opportunity to initiate evidence-based therapies for secondary prevention of stroke. Our objective was to assess hospital adherence at discharge to secondary prevention measures after transient ischemic attack or ischemic stroke. METHODS: Observational study of patients in the Get With The Guidelines-Stroke registry from 2007 to 2011. Patients were divided into 2 cohorts based on presentation: transient ischemic attack versus ischemic stroke. Adherence to evidence-based secondary prevention and other quality measures were assessed. RESULTS: Among the 858,835 patients with transient ischemic attack or ischemic stroke, 259,319 (30%) patients presented with a transient ischemic attack and 599,516 (70%) patients presented with an ischemic stroke. After adjusting for patient and hospital characteristics, adherence to secondary prevention measures was consistently lower for the transient ischemic attack cohort (vs ischemic stroke cohort), who had lower odds of being discharged on antithrombotics (odds ratio [OR] 0.63; 95% confidence interval [CI], 0.59-0.66; P <.0001), anticoagulants for atrial fibrillation (OR 0.65; 95% CI, 0.61-0.68; P <.0001), lipidlowering medication for LDL > 100 mg/dL (OR 0.52; 95% CI, 0.50-0.54; P <.0001), intensive statin therapy (OR 0.74; 95% CI, 0.72-0.76; P <.0001), LDL cholesterol measurement (OR 0.66; 95% CI, 0.64-0.68; P <.0001), smoking cessation counseling (OR 0.83; 95% CI, 0.78-0.89; P <.0001), stroke education (OR 0.71; 95% CI, 0.69-0.73; P <.0001), or weight loss recommendations (OR 0.88; 95% CI, 0.85-0.90; P <.0001). The adherence to evidence-based therapies increased significantly (P <.0001) over time (2007-2011) for both the cohorts, but the increasing trend was consistently lower for patients who presented with transient ischemic attack. CONCLUSIONS: In patients surviving an ischemic stroke or transient ischemic attack, adherence to evidence-based secondary prevention discharge measures were consistently less for patients with transient ischemic attack, thus representing a missed opportunity at instituting preventive measures to reduce the risk of recurrent stroke. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bangalore, Sripal] NYU, Med Ctr, New York, NY 10016 USA. [Schwamm, Lee] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Eric E.] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 1N4, Canada. [Singh, Inder M.] Mercy Heart & Vasc Inst, Sacramento, CA USA. [Liang, Li] Duke Clin Res Inst, Durham, NC USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Heart & Vasc Ctr, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Bangalore, S (reprint author), NYU, Sch Med, Cardiovasc Clin Res Ctr,Cardiovasc Outcomes Grp, Leon H Charney Div Cardiol,Cardiac Catheterizat L, New York, NY 10016 USA. EM sripalbangalore@gmail.com RI Smith, Eric/C-5443-2012; OI Smith, Eric/0000-0003-3956-1668; Schwamm, Lee/0000-0003-0592-9145; Bangalore, Sripal/0000-0001-9485-0652 FU Janssen Pharmaceutical Companies of Johnson Johnson; Boehringer Ingelheim; Merck; Bristol-Myers Squib/Sanofi Pharmaceutical Partnership; AHA Pharmaceutical Roundtable FX The GWTG-Stroke program is provided by the AHA/American Stroke Association. The GWTG-Stroke program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. GWTG-Stroke has been funded in the past through support from Boehringer Ingelheim, Merck, Bristol-Myers Squib/Sanofi Pharmaceutical Partnership, and the AHA Pharmaceutical Roundtable. The industry sponsors of GWTG-Stroke 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. NR 24 TC 8 Z9 9 U1 0 U2 17 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2014 VL 127 IS 8 BP 728 EP 738 DI 10.1016/j.amjmed.2014.03.011 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA AO6AO UT WOS:000341430000034 PM 24681258 ER PT J AU Chandler, PD Scott, JB Drake, BF Ng, K Forman, JP Chan, AT Bennett, GG Hollis, BW Giovannucci, EL Emmons, KM Fuchs, CS AF Chandler, Paulette D. Scott, Jamil B. Drake, Bettina F. Ng, Kimmie Forman, John P. Chan, Andrew T. Bennett, Gary G. Hollis, Bruce W. Giovannucci, Edward L. Emmons, Karen M. Fuchs, Charles S. TI Risk of Hypercalcemia in Blacks Taking Hydrochlorothiazide and Vitamin D SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Black; Hypercalcemia; Hypertension; Thiazide diuretics; Vitamin D ID D SUPPLEMENTATION; BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; POSTMENOPAUSAL WOMEN; 25-HYDROXYVITAMIN D; CALCIUM-ABSORPTION; AFRICAN-AMERICAN; PREVALENCE; EFFICACY; DISEASE AB INTRODUCTION: Hydrochlorothiazide, an effective antihypertensive medication commonly prescribed to blacks, decreases urinary calcium excretion. Blacks have significantly higher rates of hypertension and lower levels of 25-hydroxyvitamin D. Thus, they are more likely to be exposed to vitamin D supplementation and thiazide diuretics. The risk for hypercalcemia among blacks using vitamin D and hydrochlorothiazide is undefined. METHODS: We assessed the frequency of hypercalcemia in hydrochlorothiazide users in a post hoc analysis of a randomized, double-blind, dose-finding trial of 328 blacks (median age 51 years) assigned to either placebo, or 1000, 2000, or 4000 international units of cholecalciferol (vitamin D3) daily for 3 months during the winter (2007-2010). RESULTS: Of the 328 participants, 84 reported hydrochlorothiazide use and had serum calcium levels assessed. Additionally, a comparison convenience group of 44 enrolled participants who were not taking hydrochlorothiazide had serum calcium measurements at 3 months, but not at baseline. At 3 months, hydrochlorothiazide participants had higher calcium levels (0.2 mg/dL, P < .001) than nonhydrochlorothiazide participants, but only one participant in the hydrochlorothiazide group had hypercalcemia. In contrast, none of the nonhydrochlorothiazide participants had hypercalcemia. In a linear regression model adjusted for age, sex, 25-hydroxyvitamin D at 3 months, and other covariates, only hydrochlorothiazide use (Estimate [SE]: 0.05 [0.01], P = .01) predicted serum calcium at 3 months. CONCLUSION: In summary, vitamin D3 supplementation up to 4000 IU in hydrochlorothiazide users is associated with an increase in serum calcium but a low frequency of hypercalcemia. These findings suggest that participants of this population can use hydrochlorothiazide with up to 4000 IU of vitamin D3 daily and experience a low frequency of hypercalcemia. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chandler, Paulette D.] Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02215 USA. [Chandler, Paulette D.; Ng, Kimmie; Forman, John P.; Chan, Andrew T.; Giovannucci, Edward L.; Emmons, Karen M.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA USA. [Scott, Jamil B.] Michigan State Univ, Dept Epidemiol & Biostat, E Lansing, MI 48824 USA. [Drake, Bettina F.] Washington Univ, Sch Med, Dept Surg, Div Publ Hlth Sci, St Louis, MO 63110 USA. [Ng, Kimmie; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Forman, John P.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.; Bennett, Gary G.; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Hollis, Bruce W.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. [Giovannucci, Edward L.] Med Univ S Carolina, Div Pediat, Charleston, SC 29425 USA. [Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Chandler, PD (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM pchandler@partners.org OI Drake, Bettina/0000-0001-9340-5848 FU National Cancer Institute [P50CA127003, K07CA148894, K22CA126992, 5K05CA124415, U01CA138962]; Department of Defense Prostate Cancer Research Program [PC081669]; National Heart, Lung, and Blood Institute [5R01HL105440]; American Society of Clinical Oncology Career Development Award; Pharmavite LLC (Mission Hill, Calif) FX This trial was funded by the National Cancer Institute (P50CA127003; K07CA148894 [KN]; K22CA126992; 5K05CA124415 [KME]; U01CA138962 [PDC]), the Department of Defense Prostate Cancer Research Program (PC081669 [BFD]), the National Heart, Lung, and Blood Institute (5R01HL105440 [JPF]), the American Society of Clinical Oncology Career Development Award (KN), and Pharmavite LLC (Mission Hill, Calif). These funding sources had no role in the conception or conduct of the study, took no part in the data collection or analysis, and had no role in the drafting, review, or approval of the article. NR 49 TC 3 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2014 VL 127 IS 8 BP 772 EP 778 DI 10.1016/j.amjmed.2014.02.044 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AO6AO UT WOS:000341430000039 PM 24657333 ER PT J AU Simon, HB AF Simon, Harvey B. TI Literary Fiction and Medical Care: A Perfect Example SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Simon, Harvey B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Simon, Harvey B.] MIT, Hlth Sci Technol Fac, Cambridge, MA 02139 USA. [Simon, Harvey B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Simon, HB (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, 55 Fruit St, Boston, MA 02114 USA. EM hsimon@mgh.harvard.edu NR 4 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 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2014 VL 127 IS 8 BP 798 EP 799 DI 10.1016/j.amjmed.2014.04.006 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO6AO UT WOS:000341430000045 PM 24754970 ER PT J AU Clark, CR Pham, DD Grooms, KN Ommerborn, MJ Djousse, L AF Clark, Cheryl R. Pham, Do Quyen Grooms, Kya N. Ommerborn, Mark J. Djousse, Luc TI High Dietary Fiber Lowers Systemic Inflammation: Potential Utility in COPD and Lung Cancer Reply SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter ID DISEASE C1 [Clark, Cheryl R.; Pham, Do Quyen; Ommerborn, Mark J.] Brigham & Womens Hosp, Ctr Community Hlth & Hlth Equ, Boston, MA 02115 USA. [Clark, Cheryl R.; Pham, Do Quyen; Ommerborn, Mark J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Clark, Cheryl R.; Djousse, Luc] Harvard Univ, Sch Med, Boston, MA USA. [Clark, Cheryl R.] Brigham & Womens Faulkner Hospitalist Program, Div Gen Med & Primary Care, Boston, MA USA. [Grooms, Kya N.] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Djousse, Luc] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Djousse, Luc] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Djousse, Luc] Boston VA Healthcare Syst, Boston, MA USA. RP Clark, CR (reprint author), Brigham & Womens Hosp, Ctr Community Hlth & Hlth Equ, 75 Francis St, Boston, MA 02115 USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 EI 1555-7162 J9 AM J MED JI Am. J. Med. PD AUG PY 2014 VL 127 IS 8 BP E14 EP E14 DI 10.1016/j.amjmed.2014.01.037 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AO6AO UT WOS:000341430000008 ER PT J AU Manzo, CE Merrigan, MM Johnson, S Gerding, DN Riley, TV Silva, J Brazier, JS AF Manzo, Carl E. Merrigan, Michelle M. Johnson, Stuart Gerding, Dale N. Riley, Thomas V. Silva, Joseph, Jr. Brazier, Jon S. CA Int Clostridium Difficile Study Gr TI International typing study of Clostridium difficile SO ANAEROBE LA English DT Article DE Clostridium difficile; Genotypic typing; Phenotypic typing; PCR ribotyping; REA typing ID SYSTEMS; SCHEME; STRAIN AB We report the results of an international Clostridium difficile typing study to cross reference strain designations for seven typing methodologies and facilitate inter-laboratory communication. Four genotypic and three phenotypic methods were used to type 100 isolates and compare the results to 39 PCR ribotypes identified among the collection. Published by Elsevier Ltd. C1 [Manzo, Carl E.; Johnson, Stuart; Gerding, Dale N.] Loyola Univ, Chicago Stritch Sch Med, Maywood, IL 60153 USA. [Merrigan, Michelle M.; Johnson, Stuart; Gerding, Dale N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Riley, Thomas V.] Univ Western Australia, Perth, WA 6009, Australia. [Riley, Thomas V.] Queen Elizabeth II Med Ctr, Perth, WA, Australia. [Silva, Joseph, Jr.] Univ Calif Davis, Sacramento, CA 95817 USA. [Brazier, Jon S.] Univ Wales Hosp, Publ Hlth Lab, Anaerobe Reference Unit, Cardiff CF4 4XW, S Glam, Wales. RP Johnson, S (reprint author), Edward Hines Jr VA Hosp, Res Serv, 5000 S 5th St, Hines, IL 60141 USA. EM stuart.johnson2@va.gov; dale.gerding2@va.gov FU US Department of Veterans Affairs Research Service FX This work was supported in part by the US Department of Veterans Affairs Research Service Merit Review grants to DNG and SJ. NR 14 TC 3 Z9 3 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1075-9964 EI 1095-8274 J9 ANAEROBE JI Anaerobe PD AUG PY 2014 VL 28 BP 4 EP 7 DI 10.1016/j.anaerobe.2014.04.005 PG 4 WC Microbiology SC Microbiology GA AO4YT UT WOS:000341348000002 PM 24768986 ER PT J AU Moschetta, M Mishima, Y Sahin, I Manier, S Glavey, S Vacca, A Roccaro, AM Ghobrial, IM AF Moschetta, Michele Mishima, Yuji Sahin, Ilyas Manier, Salomon Glavey, Siobhan Vacca, Angelo Roccaro, Aldo M. Ghobrial, Irene M. TI Role of endothelial progenitor cells in cancer progression SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Endothelial progenitor cells; Cancers; Hematological malignancies; Vasculogenesis ID ACUTE MYELOID-LEUKEMIA; ACUTE MYOCARDIAL-INFARCTION; BONE-MARROW ANGIOGENESIS; AUTOIMMUNE RHEUMATIC-DISEASES; CHRONIC LYMPHOCYTIC-LEUKEMIA; HEMATOPOIETIC STEM-CELLS; CORONARY-ARTERY-DISEASE; MULTIPLE-MYELOMA; TUMOR ANGIOGENESIS; FUNCTIONAL-CHARACTERIZATION AB Tumor-associated neovasculature is a critical therapeutic target; however, despite significant progress made in the clinical efficacy of anti-vessel drugs, the effect of these agents remains transient: over time, most patients develop resistance, which inevitably leads to tumor progression. To develop more effective treatments, it is imperative that we better understand the mechanisms involved in tumor vessel formation, how they participate to the tumor progression and metastasis, and the best way to target them. Several mechanisms contribute to the formation of tumor-associated vasculature: i) neoangiogenesis; ii) vascular co-option; iii) mosaicism; iv) vasculogenic mimicry, and v) postnatal vasculogenesis. These mechanisms can also play a role in the development of resistance to anti-angiogenic drugs, and could serve as targets for designing new anti-vascular molecules to treat solid as well as hematological malignancies. Bone marrow-derived endothelial progenitor cell (EPC)-mediated vasculogenesis represents an important new target, especially at the early stage of tumor growth (when EPCs are critical for promoting the "angiogenic switch"), and during metastasis, when EPCs promote the transition from micro- to macro-metastases. In hematologic malignancies, the EPC population could be related to the neoplastic clone, and both may share a common ontogeny. Thus, characterization of tumor-associated EPCs in blood cancers may provide clues for more specific anti-vascular therapy that has both direct and indirect anti-tumor effects. Here, we review the role of vasculogenesis, mediated by bone marrow-derived EPCs, in the progression of cancer, with a particular focus on the role of these cells in promoting progression of hematological malignancies. (C) 2014 Elsevier B.V. All rights reserved. C1 [Moschetta, Michele; Mishima, Yuji; Sahin, Ilyas; Manier, Salomon; Glavey, Siobhan; Roccaro, Aldo M.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Moschetta, Michele; Vacca, Angelo] Univ Bari, Sch Med, Dept Biomed Sci & Human Oncol DIMO, Sect Internal Med & Clin Oncol, Bari, Italy. RP Ghobrial, IM (reprint author), Dana Farber Canc Inst, 450 Brookline Av, Boston, MA 02115 USA. EM irene_ghobrial@dfci.harvard.edu OI Roccaro, Aldo/0000-0002-1872-5128; Vacca, Angelo/0000-0002-4567-8216 FU NIH [R01CA154648]; Leukemia and Lymphoma Society (LLS); European Commission's Seventh Framework programme (EU FPT7) OVER-MyR [278706] FX Support was provided in part by NIH grant R01CA154648, the Leukemia and Lymphoma Society (LLS), and the European Commission's Seventh Framework programme (EU FPT7) OVER-MyR (number 278706 to AV). We thank Sonal Jhaveri (PGSAO, Dana Farber Cancer Institute) for editing the manuscript. NR 157 TC 31 Z9 32 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X EI 0006-3002 J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD AUG PY 2014 VL 1846 IS 1 BP 26 EP 39 DI 10.1016/j.bbcan.2014.03.005 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA AO6NM UT WOS:000341468800003 PM 24709008 ER PT J AU Kowalkowski, MA Mims, MA Day, RS Du, XL Chan, W Chiao, EY AF Kowalkowski, M. A. Mims, M. A. Day, R. S. Du, X. L. Chan, W. Chiao, E. Y. TI Longer duration of combination antiretroviral therapy reduces the risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans SO CANCER EPIDEMIOLOGY LA English DT Article DE Hodgkin lymphoma; HIV; Non-AIDS defining cancer; Epidemiology; Combined antiretroviral therapy ID UNITED-STATES; IN-VITRO; IMMUNE RECONSTITUTION; PROTEASE INHIBITOR; CARCINOMA-CELLS; AIDS; CANCER; NELFINAVIR; DISEASE; VIVO AB Background: Hodgkin lymphoma (HL) incidence has increased since combined antiretroviral therapy (cART) introduction. It is unclear how different cART classes (e.g., protease inhibitors (PI), non-nucleoside reverse transcription inhibitors (NNRTI)) influence HL. This study aimed to determine the effects of cART duration on HL incidence among HIV-infected veterans. Methods: We performed a retrospective cohort study utilizing the Veterans Affairs HIV Clinical Case Registry (1985-2010). HL cases were identified using ICD-9 codes (201.4-9). cART, PI, and NNRTI duration was the aggregate number of treatment days delivered. Incidence rates (IR) and rate ratios (IRR) were calculated from Poisson regression models to examine the effects of cART duration on HL. Results: 31,576 cART users contributed 288,736 person-years (PY) and 211 HL cases (IR = 7.3/10,000 person-years). HL incidence decreased from 25.1/10,000 PY (95%CI = 18.9-33.4) within the first year of cART to 0.6/10,000 PY (95%CI = 0.3-1.6) after >= 10 years. In multivariable models, each additional year of cART was associated with decreased HL incidence (IRR = 0.80; 95%CI = 0.75-0.86); similar effects were observed in models assessing HL incidence by PI and NNRTI. Conclusion: Our findings indicate long-term cART of any class is associated with decreased HL risk. High HL incidence directly following cART initiation supports a potential immune reconstitution mechanism in HIV-related HL. Further research is needed to evaluate the interaction between early cART, immune reconstitution, and HL. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Kowalkowski, M. A.] Levine Canc Inst, Carolinas HealthCare Syst, Charlotte, NC 28204 USA. [Kowalkowski, M. A.; Mims, M. A.; Chiao, E. Y.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Kowalkowski, M. A.; Chiao, E. Y.] Houston Hlth Serv Res & Dev Ctr Excellence, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Day, R. S.; Du, X. L.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Chan, W.] Univ Texas Houston, Sch Publ Hlth, Dept Biostat, Houston, TX USA. RP Kowalkowski, MA (reprint author), Levine Canc Inst, Carolinas HealthCare Syst, Charlotte, NC 28204 USA. EM marc.kowalkowski@carolinashealthcare.org FU Houston Health Services Research and Development Center of Innovation [HFP90-020]; Michael E. DeBakey Veterans Affairs Medical Center; Baylor College of Medicine Dan L. Duncan Cancer Center [P30CA125123-04S1]; Baylor-UTHouston Center for AIDS Research (CFAR); NIH [AI036211]; NCI [R01CA163103] FX This work was supported in part by resources and the use of facilities at the Houston Health Services Research and Development Center of Innovation (HFP90-020), Michael E. DeBakey Veterans Affairs Medical Center and the Baylor College of Medicine Dan L. Duncan Cancer Center (P30CA125123-04S1). This research was also supported by the Baylor-UTHouston Center for AIDS Research (CFAR), an NIH-funded program (AI036211). EYC (R01CA163103) also received support from the NCI. The funders had no role in study design, data collection and analysis, or preparation of this report. NR 33 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 EI 1877-783X J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD AUG PY 2014 VL 38 IS 4 BP 386 EP 392 DI 10.1016/j.canep.2014.05.009 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA AO5AI UT WOS:000341352100010 PM 24947588 ER PT J AU Liclican, EL Walser, TC Hazra, S Krysan, K Park, SJ Pagano, PC Gardner, BK Larsen, JE Minna, JD Dubinett, SM AF Liclican, Elvira L. Walser, Tonya C. Hazra, Saswati Krysan, Kostyantyn Park, Stacy J. Pagano, Paul C. Gardner, Brian K. Larsen, Jill E. Minna, John D. Dubinett, Steven M. TI Loss of miR125a Expression in a Model of K-ras-Dependent Pulmonary Premalignancy SO CANCER PREVENTION RESEARCH LA English DT Article ID CELL LUNG-CANCER; ACTIVATED RECEPTOR-GAMMA; MICRORNA EXPRESSION; EPITHELIAL-CELLS; CIGARETTE-SMOKE; DOWN-REGULATION; CHEMOPREVENTION; PIOGLITAZONE; ROSIGLITAZONE; ANGIOGENESIS AB Understanding the molecular pathogenesis of lung cancer is necessary to identify biomarkers/targets specific to individual airway molecular profiles and to identify options for targeted chemoprevention. Herein, we identify mechanisms by which loss of microRNA (miRNA) 125a-3p (miR125a) contributes to the malignant potential of human bronchial epithelial cells (HBEC) harboring an activating point mutation of the K-ras proto-oncogene (HBEC K-ras). Among other miRNAs, we identified significant miR125a loss in HBEC K-ras lines and determined that miR125a is regulated by the PEA3 transcription factor. PEA3 is upregulated in HBEC K-ras cells, and genetic knockdown of PEA3 restores miR125a expression. From a panel of inflammatory/angiogenic factors, we identified increased CXCL1 and vascular endothelial growth factor (VEGF) production by HBEC K-ras cells and determined that miR125a overexpression significantly reduces K-ras-mediated production of these tumorigenic factors. miR125a overexpression also abrogates increased proliferation of HBEC K-ras cells and suppresses anchorage-independent growth (AIG) of HBEC K-ras/P53 cells, the latter of which is CXCL1-dependent. Finally, pioglitazone increases levels of miR125a in HBEC K-ras cells via PEA3 downregulation. In addition, pioglitazone and miR125a overexpression elicit similar phenotypic responses, including suppression of both proliferation and VEGF production. Our findings implicate miR125a loss in lung carcinogenesis and lay the groundwork for future studies to determine whether miR125a is a possible biomarker for lung carcinogenesis and/or a chemoprevention target. Moreover, our studies illustrate that pharmacologic augmentation of miR125a in K-ras-mutated pulmonary epithelium effectively abrogates several deleterious downstream events associated with the mutation. (C)2014 AACR. C1 [Liclican, Elvira L.; Walser, Tonya C.; Hazra, Saswati; Krysan, Kostyantyn; Park, Stacy J.; Gardner, Brian K.; Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Dept Med, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Pagano, Paul C.; Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Liclican, Elvira L.; Walser, Tonya C.; Hazra, Saswati; Krysan, Kostyantyn; Park, Stacy J.; Gardner, Brian K.; Dubinett, Steven M.] Jonsson Comprehens Canc Ctr, Los Angeles, CA 90034 USA. [Dubinett, Steven M.] VA Greater Los Angeles Hlth Care Ctr, Los Angeles, CA USA. [Larsen, Jill E.; Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Larsen, Jill E.; Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. RP Dubinett, SM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Pulm & Crit Care Med, Ctr Hlth Sci 37 131, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM sdubinett@mednet.ucla.edu RI Larsen, Jill/G-3787-2010 OI Larsen, Jill/0000-0001-7806-3931 FU NIH/NHLBI [T32HL072752]; NCI [U01CA152751]; NIH/NCATS UCLA CTSI [UL1TR000124]; Department of Veteran Affairs [5I01BX000359]; NCI Lung Cancer SPORE [P50CA70907]; Cancer Prevention & Research Institute of Texas [RP120732] FX These studies were supported by funding from the following sources: NIH/NHLBI #T32HL072752 (to S.M. Dubinett, E.L. Liclican, T.C. Walser, S.J. Park), NCI #U01CA152751 (to S.M. Dubinett, T.C. Walser, K. Krysan, B.K. Gardner), NIH/NCATS UCLA CTSI #UL1TR000124 (to S.M. Dubinett), Department of Veteran Affairs #5I01BX000359 (S. M. Dubinett), NCI Lung Cancer SPORE #P50CA70907 (to J.D. Minna, J.E. Larsen), and Cancer Prevention & Research Institute of Texas #RP120732 (to J.D. Minna). NR 47 TC 1 Z9 1 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 EI 1940-6215 J9 CANCER PREV RES JI Cancer Prev. Res. PD AUG PY 2014 VL 7 IS 8 BP 845 EP 855 DI 10.1158/1940-6207.CAPR-14-0063 PG 11 WC Oncology SC Oncology GA AO9TU UT WOS:000341701200009 PM 24913817 ER PT J AU Hammond, SP Buckley, MW Petruzziello, G Koo, S Marty, FM Baden, LR AF Hammond, S. P. Buckley, M. W. Petruzziello, G. Koo, S. Marty, F. M. Baden, L. R. TI Clinical characteristics and outcomes of clostridial bacteraemia in cancer patients SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Article DE Cancer; Clostridia; Clostridium septicum; Clostridium tertium; neutropenia ID SEPTICUM; TERTIUM; SUSCEPTIBILITY; EPIDEMIOLOGY; PERFRINGENS; LEUKEMIA; SEPSIS AB Clostridial bacteraemia is usually associated with substantial morbidity and mortality in cancer patients. However, clinical characteristics and risk factors for early mortality in this population are poorly described. We retrospectively studied cancer patients with clostridial bacteraemia treated between January 1996 and December 2011. We compared clinical manifestations between patients with solid tumour and haematological malignancy and assessed risk factors for 7-day mortality. In all, 164 cancer patients developed clostridial bacteraemia during the study period-85 (52%) with solid tumour and 79 (48%) with haematological malignancy. Common isolates were Clostridium perfringens (27%), Clostridium septicum (19%) and Clostridium tertium (14%). Solid tumour malignancy patients were more likely to have a focal gastrointestinal source for bacteraemia and were more likely to undergo subsequent surgery. Haematological malignancy patients were more often neutropenic and more often had no focal source of bacteraemia. Seven-day mortality was 20% (33/164) and did not vary based on malignancy type. The adjusted odds ratio of dying within 7 days of clostridial bacteraemia among patients with hypotension (40/164) was 7.2 (95% CI, 2.9-18.1) and in patients with acute haemolysis (7/164) was 10.5 (95% CI, 1.3-85.2). Clostridial species also impacted mortality; no patient with C. tertium bacteraemia died within 7 days. In conclusion, clinical manifestations of clostridial bacteraemia differed between patients with solid tumour and haematological malignancy, but 7-day mortality was similar. Patients with hypotension and haemolysis at time of bacteraemia were at increased risk for early death. C1 [Hammond, S. P.; Buckley, M. W.; Petruzziello, G.; Koo, S.; Marty, F. M.; Baden, L. R.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Hammond, S. P.; Koo, S.; Marty, F. M.; Baden, L. R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hammond, S. P.; Koo, S.; Marty, F. M.; Baden, L. R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Hammond, SP (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St,PBB-A4, Boston, MA 02115 USA. EM shammond2@partners.org NR 17 TC 1 Z9 1 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1198-743X EI 1469-0691 J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD AUG PY 2014 VL 20 IS 8 BP 752 EP 757 DI 10.1111/1469-0691.12462 PG 6 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA AO7FC UT WOS:000341516600020 ER PT J AU Hawryluk, EB Tsao, H AF Hawryluk, Elena B. Tsao, Hensin TI Melanoma: Clinical Features and Genomic Insights SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID PRIMARY CUTANEOUS MELANOMA; BRAF INHIBITOR RESISTANCE; V600E MUTANT MELANOMA; UVEAL MELANOMA; MALIGNANT-MELANOMA; METASTATIC MELANOMA; MELANOCYTIC NEVI; MEK INHIBITION; MC1R VARIANTS; ULTRAVIOLET-RADIATION AB Recent efforts in genomic research have enabled the characterization of molecular mechanisms underlying many types of cancers, ushering novel approaches for diagnosis and therapeutics. Melanoma is a molecularly heterogeneous disease, as many genetic alterations have been identified and the clinical features can vary. Although discoveries of frequent mutations including BRAF have already made clinically significant impact on patient care, there is a growing body of literature suggesting a role for additional mutations, driver and passenger types, in disease pathophysiology. Although some mutations have been strongly associated with clinical phenotypes of melanomas (such as physical distribution or morphologic subtype), the function or implications of many of the recently identified mutations remains less clear. The phenotypic and clinical impact of genomic mutations in melanoma remains a promising opportunity for progress in the care of melanoma patients. C1 [Hawryluk, Elena B.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dermatol Program, Boston, MA 02114 USA. [Hawryluk, Elena B.; Tsao, Hensin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Tsao, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. EM htsao@partners.org FU Dermatology Foundation; [K24 CA149202] FX The authors gratefully acknowledge Dr. Matthew Hawryluk for his critical review and comments on this work. Funding for this effort is supported in part by K24 CA149202, the generous donors to the Massachusetts General Hospital Millennium Melanoma fund (both to H. T.), and the Dermatology Foundation Fellowship in Pediatric Dermatology (E. B. H.). NR 113 TC 0 Z9 0 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD AUG PY 2014 VL 6 IS 8 AR a015388 DI 10.1101/cshperspect.a015388 PG 17 WC Cell Biology SC Cell Biology GA AO8BE UT WOS:000341576400011 ER PT J AU Zietman, A AF Zietman, Anthony TI The Red Journal's Top Downloads of 2013 SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID CELL LUNG-CANCER; RADIATION-THERAPY; NORMAL TISSUE; BRACHIAL-PLEXUS; RADIOTHERAPY; ARTICLES; PROBABILITY; GUIDELINES; DELIVERY; ATLAS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Zietman, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM azietman@partners.org NR 27 TC 2 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 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2014 VL 89 IS 5 BP 937 EP 939 DI 10.1016/j.ijrobp.2014.04.054 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO6IK UT WOS:000341453600001 PM 25035194 ER PT J AU Jagsi, R Bennett, KE Griffith, KA DeCastro, R Grace, C Holliday, E Zietman, AL AF Jagsi, Reshma Bennett, Katherine Egan Griffith, Kent A. DeCastro, Rochelle Grace, Calley Holliday, Emma Zietman, Anthony L. TI Attitudes Toward Blinding of Peer Review and Perceptions of Efficacy Within a Small Biomedical Specialty SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review ID MASKING AUTHOR IDENTITY; ACCEPTANCE; JOURNALS; QUALITY; TRIAL AB Purpose: Peer reviewers' knowledge of author identity may influence review content, quality, and recommendations. Therefore, the International Journal of Radiation Oncology, Biology, Physics ("Red Journal") implemented double-blinded peer review in 2011. Given the relatively small size of the specialty and the high frequency of preliminary abstract presentations, we sought to evaluate attitudes, the efficacy of blinding, and the potential impact on the disposition of submissions. Methods and Materials: In May through August 2012, all Red Journal reviewers and 1 author per manuscript completed questionnaires regarding demographics, attitudes, and perceptions of success of blinding. We also evaluated correlates of the outcomes of peer review. Results: Questionnaires were received from 408 authors and 519 reviewers (100%). The majority of respondents favored double blinding; 6% of authors and 13% of reviewers disagreed that double blinding should continue in the Red Journal. In all, 50% of the reviewers did not suspect the identity of the author of the paper that they reviewed; 19% of reviewers believed that they could identify the author(s), and 31% suspected that they could. Similarly, 23% believed that they knew the institution(s) from which the paper originated, and 34% suspected that they did. Among those who at least suspected author identity, 42% indicated that prior presentations served as a clue, and 57% indicated that literature referenced did so. Of those who at least suspected origin and provided details (n = 133), 13% were entirely incorrect. Rejection was more common in 2012 than 2011, and submissions from last authors with higher H-indices (>21) were more likely to survive initial review, without evidence of interactions between submission year and author gender or H-index. Conclusions: In a relatively small specialty in which preliminary research presentations are common and occur in a limited number of venues, reviewers are often familiar with research findings and suspect author identity even when manuscript review is blinded. Nevertheless, blinding appears to be effective in many cases, and support for continuing blinding was strong. (C) 2014 Elsevier Inc. C1 [Jagsi, Reshma] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Bennett, Katherine Egan; Grace, Calley] Amer Soc Radiat Oncol ASTRO, Fairfax, VA USA. [Griffith, Kent A.] Univ Michigan, Sch Publ Hlth, Ctr Canc Biostat, Ann Arbor, MI 48109 USA. [DeCastro, Rochelle] Univ Michigan, Ctr Bioeth & Social Sci Med, Ann Arbor, MI 48109 USA. [DeCastro, Rochelle] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Holliday, Emma] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Jagsi, R (reprint author), Univ Michigan, Dept Radiat Oncol, UHB2C490,SPC 5010,1500 East Med Ctr Dr, Ann Arbor, MI 48109 USA. EM rjagsi@med.umich.edu OI Bennett, Katherine/0000-0001-8094-9176; Jagsi, Reshma/0000-0001-6562-1228 FU American Cancer Society [MRSG-09-145-01]; National Comprehensive Cancer Network; National Institutes of Health [5 R01 HL101997-04] FX Dr Zietman is Editor-in-Chief of the Red Journal; Ms. Bennett is Managing Editor, Scientific Publications, ASTRO; Ms. Grace is Assistant Managing Editor, Scientific Publications, ASTRO; Dr Jagsi is Senior Editor at the Red Journal. Dr Jagsi is a consultant for Eviti and receives grant funding from the National Institutes of Health, American Cancer Society, and National Comprehensive Cancer Network for unrelated work.; Dr Jagsi was supported by Grant 5 R01 HL101997-04 from the National Institutes of Health (for unrelated work).; Dr Jagsi was supported by a Mentored Research Scholar Grant from the American Cancer Society (MRSG-09-145-01). NR 16 TC 6 Z9 6 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2014 VL 89 IS 5 BP 940 EP 946 DI 10.1016/j.ijrobp.2014.04.021 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO6IK UT WOS:000341453600002 PM 25035195 ER PT J AU Bekelman, JE Epstein, AJ Emanuel, EJ AF Bekelman, Justin E. Epstein, Andrew J. Emanuel, Ezekiel J. TI Getting the Next Version of Payment Policy "Right" on the Road Toward Accountable Cancer Care SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material ID CLUSTER RANDOMIZED-TRIALS; HEALTH-CARE; QUALITY; PROVIDERS; BEHAVIOR C1 [Bekelman, Justin E.] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. [Bekelman, Justin E.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Bekelman, Justin E.; Emanuel, Ezekiel J.] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Univ Penn, Perelman Sch Med, Dept Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Emanuel, Ezekiel J.] Univ Penn, Wharton Sch Business, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Epstein, Andrew J.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Dept Vet Affairs, Philadelphia, PA USA. RP Bekelman, JE (reprint author), Univ Penn, Abramson Canc Ctr, Perelman Ctr Adv Med, Perelman Sch Med, 4 West,3400 Civic Ctr Blvd, Philadelphia, PA 19104 USA. EM bekelman@uphs.upenn.edu FU NCI NIH HHS [K07 CA163616, K07-CA163616] NR 19 TC 1 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2014 VL 89 IS 5 BP 954 EP 957 DI 10.1016/j.ijrobp.2014.04.022 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO6IK UT WOS:000341453600005 PM 25035198 ER PT J AU Greenberger, BA Pulsifer, MB Ebb, DH MacDonald, SM Jones, RM Butler, WE Huang, MS Marcus, KJ Oberg, JA Tarbell, NJ Yock, TI AF Greenberger, Benjamin A. Pulsifer, Margaret B. Ebb, David H. MacDonald, Shannon M. Jones, Robin M. Butler, William E. Huang, Mary S. Marcus, Karen J. Oberg, Jennifer A. Tarbell, Nancy J. Yock, Torunn I. TI Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID OPTIC PATHWAY GLIOMA; BRAIN-TUMORS; STEREOTACTIC RADIOTHERAPY; CONFORMAL RADIOTHERAPY; HYPOTHALAMIC GLIOMAS; MOYAMOYA SYNDROME; THERAPY; CHILDREN; ASTROCYTOMAS; CHILDHOOD AB Purpose/Objective(s): Primary low-grade gliomas are common brain tumors of childhood, many of which require radiation therapy (RT) as definitive treatment. Increased conformality of RT could decrease the incidence and severity of late effects. We report our experience with 32 pediatric patients treated with proton RT. Methods and Materials: Thirty-two pediatric patients with low-grade gliomas of the brain or spinal cord were treated with proton RT from 1995 to 2007. Sixteen patients received at least 1 regimen of chemotherapy before definitive RT. The median radiation dose was 52.2 Gy(RBE) (48.6-54 Gy(RBE)). Results: The median age at treatment was 11.0 years (range, 2.7-21.5 years), with a median follow-up time of 7.6 years (range, 3.2-18.2 years). The 6-year and 8-year rates of progression-free survival were 89.7% and 82.8%, respectively, with an 8-year overall survival of 100%. For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (P = .80), with a median neurocognitive testing interval of 4.5 years (range, 1.2-8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (<7 years) and those with significant dose to the left temporal lobe/hippocampus. The incidence of endocrinopathy correlated with a mean dose of >= 40 Gy(RBE) to the hypothalamus, pituitary, or optic chiasm. Stabilization or improvement of visual acuity was achieved in 83.3% of patients at risk for radiation-induced injury to the optic pathways. Conclusions: This report of late effects in children with low-grade gliomas after proton RT is encouraging. Proton RT appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis. (C) 2014 Elsevier Inc. C1 [Greenberger, Benjamin A.; Tarbell, Nancy J.] Harvard Univ, Sch Med, Boston, MA USA. [Pulsifer, Margaret B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ebb, David H.; Jones, Robin M.; Huang, Mary S.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [MacDonald, Shannon M.; Tarbell, Nancy J.; Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Jones, Robin M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Butler, William E.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Marcus, Karen J.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Oberg, Jennifer A.] Columbia Univ Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Suite 107,55 Fruit St, Boston, MA 02114 USA. EM tyock@partners.org NR 35 TC 18 Z9 19 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2014 VL 89 IS 5 BP 1060 EP 1068 DI 10.1016/j.ijrobp.2014.04.053 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA AO6IK UT WOS:000341453600020 PM 25035209 ER PT J AU Duda, DG Ancukiewicz, M Isakoff, SJ Krop, IE Jain, RK AF Duda, Dan G. Ancukiewicz, Marek Isakoff, Steven J. Krop, Ian E. Jain, Rakesh K. TI Seeds and Soil: Unraveling the Role of Local Tumor Stroma in Distant Metastasis SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID EARLY BREAST-CANCER; CELLS; ANGIOGENESIS; GROWTH C1 [Duda, Dan G.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab Tumor Biol, Boston, MA 02114 USA. [Isakoff, Steven J.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ancukiewicz, Marek] PAREXEL Int, Waltham, MA USA. [Krop, Ian E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02114 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab Tumor Biol, 100 Blossom St,Cox 734, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu NR 15 TC 2 Z9 2 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju187 DI 10.1093/jnci/dju187 PG 2 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800022 ER PT J AU Kerlikowske, K Hubbard, R Tosteson, ANA AF Kerlikowske, Karla Hubbard, Rebecca Tosteson, Anna N. A. TI Higher Mammography Screening Costs Without Appreciable Clinical Benefit: The Case of Digital Mammography SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BREAST-CANCER; COMMUNITY PRACTICE; STAGE; WOMEN; RISK; AGE C1 [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. [Hubbard, Rebecca] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Tosteson, Anna N. A.] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH USA. [Tosteson, Anna N. A.] Geisel Sch Med Dartmouth, Norris Cotton Canc Ctr, Lebanon, NH USA. RP Kerlikowske, K (reprint author), San Francisco VA Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM Karla.Kerlikowske@ucsf.edu NR 19 TC 2 Z9 2 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju191 DI 10.1093/jnci/dju191 PG 2 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800025 ER PT J AU Lochead, P Meyerhardt, JA Fuchs, CS Ogino, S AF Lochead, Paul Meyerhardt, Jefrey A. Fuchs, Charles S. Ogino, Shuji TI Re: Microsatellite Instability and BRAF Mutation Testing in Colorectal Cancer Prognostication Response SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID COLON-CANCER; MISMATCH REPAIR; TRIAL C1 [Lochead, Paul; Meyerhardt, Jefrey A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Lochead, Paul; Meyerhardt, Jefrey A.; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Lochead, Paul] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Room M422, Boston, MA 02215 USA. EM shuji_ogino@dfci.harvard.edu NR 6 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 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju181 DI 10.1093/jnci/dju181 PG 1 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800016 ER PT J AU Luke, JJ Oxnard, GR Paweletz, CP Camidge, DR Heymach, JV Solit, DB Johnson, BE AF Luke, Jason J. Oxnard, Geoffrey R. Paweletz, Cloud P. Camidge, D. Ross Heymach, John V. Solit, David B. Johnson, Bruce E. CA Cell Free DNA Working Grp TI Realizing the Potential of Plasma Genotyping in an Age of Genotype-Directed Therapies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CIRCULATING TUMOR DNA; FACTOR-RECEPTOR MUTATIONS; METASTATIC BREAST-CANCER; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; COLORECTAL-CANCER; COLD-PCR; PERIPHERAL-BLOOD; KRAS MUTATIONS; EGFR AB The identification of oncogenic driver mutations in cancer has led to the rapid rise of genotype-directed treatments such as EGFR and BRAF kinase inhibitors. Standard tumor biopsy remains a cumbersome and morbid procedure for patients, leading to a growing interest in noninvasive plasma genotyping approaches. Circulating tumor cells are of interest; however, the processing of specimens is complicated and time consuming. By comparison, cell-free DNA (cfDNA) genotyping has the potential to be convenient and relatively simple to process in a short time period. Several technologies are under development for cfDNA analysis, such as allele-specific polymerase chain reaction (PCR), coamplification at Lower Denaturation temperatures (COLD) PCR, emulsion PCR, and massively parallel sequencing. Broad clinical validity will need to be established for different assays, and clinical utility will need to be evaluated within prospective trials to determine which assays will best predict the efficacy of therapy and patient outcomes. In addition, assay standardization will be critical prior to widespread use in routine clinical practice. The Cell Free DNA Working Group, under the sponsorship of Transgenomic, was convened to evaluate the molecular assays in development and provide recommendations for application and interpretation of these tests in the context of future clinical research. The consensus commentary of the Cell Free DNA Working Group for the use of cfDNA plasma genotyping assays is presented here, including future steps in the development of these technologies. C1 [Luke, Jason J.; Oxnard, Geoffrey R.; Paweletz, Cloud P.; Johnson, Bruce E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Luke, Jason J.; Oxnard, Geoffrey R.; Paweletz, Cloud P.; Johnson, Bruce E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Solit, David B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Camidge, D. Ross] Univ Colorado, Ctr Canc, Denver, CO 80262 USA. [Heymach, John V.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave, Boston, MA 02115 USA. EM bejohnson@partners.org NR 39 TC 5 Z9 5 U1 0 U2 11 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju214 DI 10.1093/jnci/dju214 PG 5 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800037 ER PT J AU Sadow, PM Priolo, C Nanni, S Karreth, FA Duquette, M Martinelli, R Husain, A Clohessy, J Kutzner, H Mentzel, T Carman, CV Farsetti, A Henske, EP Palescandolo, E Macconaill, LE Chung, S Fadda, G Lombardi, CP De Angelis, AM Durante, O Parker, JA Pontecorvi, A Dvorak, HF Fletcher, C Pandolfi, PP Lawler, J Nucera, C AF Sadow, Peter M. Priolo, Carmen Nanni, Simona Karreth, Florian A. Duquette, Mark Martinelli, Roberta Husain, Amjad Clohessy, John Kutzner, Heinz Mentzel, Thomas Carman, Christopher V. Farsetti, Antonella Henske, Elizabeth Petri Palescandolo, Emanuele Macconaill, Laura E. Chung, Seum Fadda, Guido Lombardi, Celestino Pio De Angelis, Antonina M. Durante, Oreste Parker, John A. Pontecorvi, Alfredo Dvorak, Harold F. Fletcher, Christopher Pandolfi, Pier Paolo Lawler, Jack Nucera, Carmelo TI Role of BRAF(V600E) in the First Preclinical Model of Multifocal Infiltrating Myopericytoma Development and Microenvironment SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANAPLASTIC THYROID-CANCER; ORTHOTOPIC MOUSE MODEL; HAIRY-CELL LEUKEMIA; BRAF MUTATIONS; V600E MUTATION; TUMOR; VEMURAFENIB; SURVIVAL; ANGIOGENESIS; INHIBITION AB Myopericytoma (MPC) is a rare tumor with perivascular proliferation of pluripotent stem-cell-like pericytes. Although indolent, MPC may be locally aggressive with recurrent disease. The pathogenesis and diagnostic biomarkers of MPC are poorly understood. We discovered that 15% of benign MPCs (thyroid, skin; 3 of 20 samples) harbored BRAF(WT/V600E); 33.3% (1 of 3 samples) of BRAF(WT/V600E)-MPCs were multifocal/infiltrative/recurrent. Patient-MPC and primary MPC cells harbored BRAF(WT/V600E), were clonal and expressed pericytic-differentiation biomarkers crucial for its microenvironment. BRAF(WT/V600E)-positive thyroid MPC primary cells triggered in vitro (8.8-fold increase) and in vivo (3.6-fold increase) angiogenesis. Anti-BRAF(V600E) therapy with vemurafenib disrupted angiogenic and metabolic properties (similar to 3-fold decrease) with down-regulation (similar to 2.2-fold decrease) of some extracellular-matrix (ECM) factors and ECM-associated long noncoding RNA (LincRNA) expression, with no effects in BRAFWT-pericytes. Vemurafenib also inhibited (similar to 3-fold decrease) cell viability in vitro and in BRAF(WT/V600E)-positive thyroid MPC patient-derived xenograft (PDX) mice (n = 5 mice per group). We established the first BRAF(WT/V600E)-dependent thyroid MPC cell culture. Our findings identify BRAF(WT/V600E) as a novel genetic aberration in MPC pathogenesis and MPC-associated biomarkers and imply that anti-BRAF(V600E) agents may be useful adjuvant therapy in BRAF(WT/V600)-EMPC patients. Patients with BRAF(WT/V600E)-MPC should be closely followed because of the risk for multifocality/recurrence. C1 [Nucera, Carmelo] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Pathol, Div Canc Biol & Angiogenesis,Lab Human Thyroid Ca, Boston, MA 02215 USA. [Sadow, Peter M.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Priolo, Carmen; Henske, Elizabeth Petri] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Pulmonary & Crit Care Med, Boston, MA 02115 USA. [Nanni, Simona; Pontecorvi, Alfredo] Catholic Univ, Dept Med, Unit Endocrinol, Rome, Italy. [Karreth, Florian A.; Clohessy, John; Pandolfi, Pier Paolo] Harvard Univ, Sch Med, Dept Med, Canc Res Inst,Div Canc Genet, Boston, MA USA. [Duquette, Mark; Nucera, Carmelo] Harvard Univ,Sch Med, Div Canc Biol & Angiogenesis,Beth Israel Deacones, Lab Human Thyroid Canc Preclin & Translat Res, Ctr Vasc Biol Res,Canc Res Inst,Dept Pathol, Boston, MA USA. [Martinelli, Roberta; Carman, Christopher V.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Husain, Amjad; Dvorak, Harold F.; Lawler, Jack] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Kutzner, Heinz; Mentzel, Thomas] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02215 USA. [Mentzel, Thomas] Dermatopathol Gemeinschaftspraxis Siemensstr, Friedrichshafen, Germany. [Farsetti, Antonella] Regina Elena Inst Canc Res, Natl Res Council CNR IBCN, Rome, Italy. [Farsetti, Antonella] Regina Elena Inst Canc Res, Dept Expt Oncol, Rome, Italy. [Palescandolo, Emanuele; Macconaill, Laura E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Palescandolo, Emanuele; Macconaill, Laura E.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Chung, Seum] Ilsan Hosp, Natl Hlth Insurance Serv, Dept Plast & Reconstruct Surg, Ilsan, South Korea. [Fadda, Guido] Catholic Univ, Dept Pathol, Rome, Italy. [Lombardi, Celestino Pio] Catholic Univ, Dept Surg, Rome, Italy. [De Angelis, Antonina M.] Univ Catanzaro, Dept Expt & Clin Med, Catanzaro, Italy. [Durante, Oreste] Univ Catanzaro, Unit Radiotherapy, Catanzaro, Italy. [Parker, John A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Nucl Med, Sch Med, Boston, MA 02215 USA. [Fletcher, Christopher] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Nucera, C (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,Dept Pathol, Div Canc Biol & Angiogenesis,Lab Human Thyroid Ca, 99 Brookline Ave, Boston, MA 02215 USA. EM cnucera@bidmc.harvard.edu RI Carman, Christopher/L-8108-2016 OI Carman, Christopher/0000-0001-7358-2548 FU National Cancer Institute/National Institutes of Health [1R21CA165039-01A1, 1R01CA181183-01A1]; American Thyroid Association (ATA); ThyCa: Thyroid Cancer Survivors Association Inc. for Thyroid Cancer Research; Guido Berlucchi "Young Investigator" research award (Brescia, Italy); Roche; Tuberous Sclerosis Complex Research Program (TSCRP) of the USA Department of Defense (DOD) [W81XWH-13-1-0262] FX Carmelo Nucera (Principal Investigator, Human Thyroid Cancers Preclinical and Translational Research at the Beth Israel Deaconess Medical Center/Harvard Medical School) was awarded grants by the National Cancer Institute/National Institutes of Health (1R21CA165039-01A1 and 1R01CA181183-01A1) the American Thyroid Association (ATA), and ThyCa: Thyroid Cancer Survivors Association Inc. for Thyroid Cancer Research. Carmelo Nucera was also recipient of the Guido Berlucchi "Young Investigator" research award 2013 (Brescia, Italy). Beth Israel Deaconess Medical Center was recipient of a research grant by Roche (2011). CP was awarded a grant by the Tuberous Sclerosis Complex Research Program (TSCRP) of the USA Department of Defense (DOD) (W81XWH-13-1-0262). NR 33 TC 1 Z9 1 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju182 DI 10.1093/jnci/dju182 PG 7 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800017 ER PT J AU Van Loon, K Owzar, K Jiang, C Kindler, HL Mulcahy, MF Niedzwiecki, D O'Reilly, EM Fuchs, C Innocenti, F Venook, AP AF Van Loon, Katherine Owzar, Kouros Jiang, Chen Kindler, Hedy L. Mulcahy, Mary F. Niedzwiecki, Donna O'Reilly, Eileen M. Fuchs, Charles Innocenti, Federico Venook, Alan P. CA Alliance Clinical Trials Oncology TI 25-Hydroxyvitamin D Levels and Survival in Advanced Pancreatic Cancer: Findings From CALGB 80303 (Alliance) SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID VITAMIN-D-RECEPTOR; HYPOVITAMINOSIS-D; CARCINOMA CELLS; BREAST-CANCER; US POPULATION; D ANALOGS; IN-VITRO; EXPRESSION; D-3; D-3-1-ALPHA-HYDROXYLASE AB Background Data from animal and cell-line models suggest that vitamin D metabolism plays an important role in pancreatic tumor behavior. Although vitamin D deficiency has been implicated in numerous cancers, the vitamin D status of patients with advanced pancreatic cancer and the effect of baseline vitamin D levels on survival are unknown. Methods Participants in this correlative study (CALGB 151006) were enrolled in CALGB 80303, which was a randomized trial of patients with advanced pancreatic cancer that demonstrated no difference in overall survival (OS) among patients treated with gemcitabine plus placebo vs gemcitabine plus bevacizumab. We measured baseline serum 25-hydroxyvitamin D (25[OH] D) levels and examined associations between baseline 25(OH) D levels and progression-free survival and OS using the Cox rank score test. All statistical tests were two-sided. Results Of 256 patients with available serum, the median 25(OH) D level was 21.7 ng/mL (range 4 to 77). 44.5% of patients were vitamin D deficient (25[OH] D <20 ng/mL), and 32.4% were insufficient (25[OH] D >= 20 and <30 ng/mL). 25(OH) D levels were lower in black patients compared with white patients, and patients of other/undisclosed race (10.7 vs 22.4 vs 20.9 ng/mL, P < .001). Baseline 25(OH) D levels were not associated with PFS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .60) or OS (HR = 1.00, 95% CI = 0.99 to 1.01, P = .95). Conclusion Vitamin D deficiency was highly prevalent among patients with a new diagnosis of advanced pancreatic cancer. Black patients had statistically significantly lower 25(OH) D levels than white patients. In this cohort of patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy, baseline 25(OH) D levels were not associated with PFS or OS. C1 [Van Loon, Katherine; Venook, Alan P.] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Owzar, Kouros; Niedzwiecki, Donna] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Owzar, Kouros; Jiang, Chen; Niedzwiecki, Donna] Duke Univ, Alliance Stat & Data Ctr, Durham, NC USA. [Kindler, Hedy L.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Mulcahy, Mary F.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [O'Reilly, Eileen M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Fuchs, Charles] Dana Farber Canc Inst, Boston, MA 02115 USA. [Innocenti, Federico] Univ N Carolina, Lineberger Comprehens Canc Ctr, Inst Pharmacogen & Individualized Therapy, Eshelman Sch Pharm,Sch Med, Chapel Hill, NC 27599 USA. RP Van Loon, K (reprint author), UCSF Helen Diller Family, Ctr Comprehens Canc, 1600 Divisadero St,UCSF Box 1770, San Francisco, CA 94143 USA. EM katherine.vanloon@ucsf.edu FU Conquer Cancer Foundation of the American Society of Clinical Oncology; Agency for Healthcare Research and Quality (AHRQ) [K12HS021700]; National Cancer Institute (NCI) at the National Institutes of Health (NIH) [K07CA140390-01]; National Cancer Institute [CA31946, CA33601] FX This work was supported by a 2012 Young Investigator Award from The Conquer Cancer Foundation of the American Society of Clinical Oncology to Dr. Van Loon; the Agency for Healthcare Research and Quality (AHRQ) (grant number K12HS021700) to Dr. Van Loon; and the National Cancer Institute (NCI) at the National Institutes of Health (NIH) (grant number K07CA140390-01) to Dr. Innocenti.; The research for CALGB 80303 (Alliance) was supported, in part, by grants from the National Cancer Institute (CA31946) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, MD, Chair) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD, CA33601). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, AHRQ, or NIH. NR 44 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD AUG PY 2014 VL 106 IS 8 AR dju185 DI 10.1093/jnci/dju185 PG 8 WC Oncology SC Oncology GA AO8XB UT WOS:000341637800020 ER PT J AU Bauer, CM Heidary, G Koo, BB Killiany, RJ Bex, P Merabet, LB AF Bauer, Corinna M. Heidary, Gena Koo, Bang-Bon Killiany, Ronald J. Bex, Peter Merabet, Lotfi B. TI Abnormal white matter tractography of visual pathways detected by high-angular-resolution diffusion imaging (HARDI) corresponds to visual dysfunction in cortical/cerebral visual impairment SO JOURNAL OF AAPOS LA English DT Article AB Cortical (cerebral) visual impairment (CVI) is characterized by visual dysfunction associated with damage to the optic radiations and/or visual cortex. Typically it results from pre- or perinatal hypoxic damage to postchiasmal visual structures and pathways. The neuroanatomical basis of this condition remains poorly understood, particularly with regard to how the resulting maldevelopment of visual processing pathways relates to observations in the clinical setting. We report our investigation of 2 young adults diagnosed with CVI and visual dysfunction characterized by difficulties related to visually guided attention and visuospatial processing. Using high-angular-resolution diffusion imaging (NARDI), we characterized and compared their individual white matter projections of the extrageniculo-striate visual system with a normal-sighted control. Compared to a sighted control, both CVI cases revealed a striking reduction in association fibers, including the inferior frontal-occipital fasciculus as well as superior and inferior longitudinal fasciculi. This reduction in fibers associated with the major pathways implicated in visual processing may provide a neuroanatomical basis for the visual dysfunctions observed in these patients. C1 [Bauer, Corinna M.; Merabet, Lotfi B.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Lab Visual Neuroplast, Boston, MA 02114 USA. [Heidary, Gena] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Ophthalmol,Pediat Neuroophthalmol Serv, Boston, MA 02114 USA. [Koo, Bang-Bon; Killiany, Ronald J.] Boston Univ, Sch Med, Ctr Biomed Imaging, Boston, MA 02118 USA. [Bex, Peter] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst,Dept Ophthalmol, Boston, MA 02114 USA. RP Merabet, LB (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 20 Staniford St, Boston, MA 02114 USA. EM lotfi_merabet@meei.harvard.edu FU John W. Alden Trust; Massachusetts Lions Eye Research Fund; NIH/NEI [EY019924] FX Supported by grants from the John W. Alden Trust, the Massachusetts Lions Eye Research Fund, and NIH/NEI (R01 grant EY019924 to LBM). NR 5 TC 3 Z9 3 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1091-8531 EI 1528-3933 J9 J AAPOS JI J. AAPOS PD AUG PY 2014 VL 18 IS 4 BP 398 EP 401 DI 10.1016/j.jaapos.2014.03.004 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA AO5RZ UT WOS:000341404300023 PM 25087644 ER PT J AU Mulligan, JK Nagel, W O'Connell, BP Wentzel, J Atkinson, C Schlosser, RJ AF Mulligan, Jennifer K. Nagel, Whitney O'Connell, Brendan P. Wentzel, Jennifer Atkinson, Carl Schlosser, Rodney J. TI Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Vitamin D; secondhand smoke; sinusitis; epithelial cell ID ALLERGIC FUNGAL RHINOSINUSITIS; PRO-INFLAMMATORY CYTOKINE; REGULATORY T-CELLS; DENDRITIC CELLS; EPITHELIAL-CELLS; 2ND-HAND SMOKE; NASAL POLYPS; LIQUID-CHROMATOGRAPHY; 25-HYDROXYVITAMIN D; CHILDHOOD ASTHMA AB Background: Cigarette smoke (CS) plays a role in the exacerbation of chronic rhinosinusitis (CRS); however, the mechanism for this is unknown. We hypothesize that CS impairs human sinonasal epithelial cell (HSNEC) conversion of 25(OH) D3 (25VD3) to 1,25-dihydroxyvitamin D3 (1,25VD3) and, furthermore, that supplementation with 1,25VD3 will reverse smoke-induced inflammatory responses by HSNECs. Objective: We sought to determine the effect of CS on vitamin D3 (VD3) levels, conversion, and regulation of CS-induced inflammation in control subjects and patients with CRS. Methods: Blood and sinus tissue explants were collected at the time of surgery from control subjects, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic sinusitis with nasal polyps (CRSwNP). Expression of VD3 metabolizing enzymes were measured by using RT-PCR. Primary HSNECs were cultured from tissue explants. 25VD3 with and without cigarette smoke extract (CSE) was used to examine conversion of 25VD3 to 1,25VD3, as well as HSNEC production of proinflammatory cytokines. Results: CS exposure was associated with reduced circulating and sinonasal 25VD3 levels in all groups compared with those seen in CS-naive, disease-matched counterparts. CS exposure decreased expression of CYP27B1 and was especially pronounced in patients with CRSwNP. CSE impairs control HSNEC conversion of 25VD3. HSNECs from patients with CRSwNP also demonstrate an intrinsic reduction in conversion of 25VD3 to 1,25VD3. Exogenous 1,25VD3 reduces CSE-induced cytokine production by HSNECs. Conclusions: Exposure to CS is associated with reduced 25VD3 levels and an impaired ability of HSNECs to convert 25VD3 to 1,25VD3. Addition of 1,25VD3 reduces the proinflammatory effects of CS on HSNECs. Impaired VD3 conversion by CS exposure represents a novel mechanism through which CS induces its proinflammatory effects. C1 [Mulligan, Jennifer K.; Nagel, Whitney; O'Connell, Brendan P.; Wentzel, Jennifer; Schlosser, Rodney J.] Med Univ S Carolina, Dept Otolaryngol Head & Neck Surg, Charleston, SC USA. [Mulligan, Jennifer K.] Med Univ S Carolina, Dept Pediat, Charleston, SC USA. [Atkinson, Carl] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC USA. [Mulligan, Jennifer K.; Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Mulligan, JK (reprint author), 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM konopa@musc.edu FU Flight Attendant Medical Research Institute [092401, 113039]; National Institutes of Health [R01HL091944]; Department of Veterans Affairs FX Supported by grants from the Flight Attendant Medical Research Institute (092401 to J.K.M. and 113039 to R.J.S.), the National Institutes of Health (R01HL091944 to C. A.), and a grant from the Department of Veterans Affairs. NR 55 TC 18 Z9 18 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2014 VL 134 IS 2 BP 342 EP + DI 10.1016/j.jaci.2014.01.039 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA AO5GB UT WOS:000341370800013 PM 24698317 ER PT J AU Vendelbo, MH Moller, AB Treebak, JT Gormsen, LC Goodyear, LJ Wojtaszewski, JFP Jorgensen, JOL Moller, N Jessen, N AF Vendelbo, M. H. Moller, A. B. Treebak, J. T. Gormsen, L. C. Goodyear, L. J. Wojtaszewski, J. F. P. Jorgensen, J. O. L. Moller, N. Jessen, N. TI Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE AS160; TBC1D4; TBC1D1; endurance exercise; insulin sensitivity; skeletal muscle ID GTPASE-ACTIVATING-PROTEIN; INSULIN SENSITIVITY; GLUCOSE-TRANSPORT; BINDING-CAPACITY; CONTRACTION; METABOLISM; INCREASES; GLYCOGEN; KINASE; AICAR AB Background: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. Objective: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. Design: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. Results: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1. Conclusions: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle. C1 [Vendelbo, M. H.; Moller, A. B.; Jorgensen, J. O. L.; Moller, N.; Jessen, N.] Aarhus Univ Hosp, Dept Endocrinol & Internal Med, DK-8000 Aarhus, Denmark. [Vendelbo, M. H.; Gormsen, L. C.] Aarhus Univ Hosp, Dept Nucl Med, DK-8000 Aarhus, Denmark. [Vendelbo, M. H.; Gormsen, L. C.] Aarhus Univ Hosp, PET Ctr, DK-8000 Aarhus, Denmark. [Moller, A. B.; Jessen, N.] Aarhus Univ Hosp, Res Lab Biochem Pathol, DK-8000 Aarhus, Denmark. [Treebak, J. T.] Univ Copenhagen, Sect Integrat Physiol, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark. [Goodyear, L. J.] Brigham & Womens Hosp, Joslin Diabet Ctr, Boston, MA 02115 USA. [Goodyear, L. J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Goodyear, L. J.] Harvard Univ, Sch Med, Boston, MA USA. [Wojtaszewski, J. F. P.] Univ Copenhagen, August Krogh Ctr, Dept Nutr Exercise & Sports, Mol Physiol Grp, Copenhagen, Denmark. [Jessen, N.] Univ Aarhus, Dept Mol Med, Aarhus, Denmark. RP Jessen, N (reprint author), Aarhus Univ Hosp, Inst Clin Med, Res Lab Biochem Pathol, Norrebrogade 44, DK-8000 Aarhus C, Denmark. EM Niels.Jessen@ki.au.dk RI Treebak, Jonas/B-4521-2017; Gormsen, Lars Christian/C-6531-2017; Wojtaszewski, Jorgen /P-6583-2014; Moller, Niels/E-5091-2011 OI Treebak, Jonas/0000-0003-1488-7012; Gormsen, Lars Christian/0000-0002-0144-1305; Gormsen, Lars Christian/0000-0001-6937-704X; Jorgensen, Jens Otto Lunde/0000-0001-7408-1526; Jessen, Niels/0000-0001-5613-7274; Wojtaszewski, Jorgen /0000-0001-9785-6830; Moller, Niels/0000-0001-5627-7322 FU Danish Agency for Science Technology and Innovation [271-07-0719]; FOOD Study Group/Danish Ministry of Food, Agriculture, and Fisheries; Ministry of Family and Consumer Affairs [2101-05-0044] FX This work was supported by Danish Agency for Science Technology and Innovation Grant 271-07-0719 (to N.J.) and by the FOOD Study Group/Danish Ministry of Food, Agriculture, and Fisheries; and Ministry of Family and Consumer Affairs Grant 2101-05-0044 (to N. Moller). NR 42 TC 7 Z9 7 U1 1 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 EI 1522-1601 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD AUG 1 PY 2014 VL 117 IS 3 BP 289 EP 296 DI 10.1152/japplphysiol.00044.2014 PG 8 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA AO4LK UT WOS:000341309400012 PM 24876356 ER PT J AU Nwachukwu, BU McCormick, FM Schairer, WW Frank, RM Provencher, MT Roche, MW AF Nwachukwu, Benedict U. McCormick, Frank M. Schairer, William W. Frank, Rachel M. Provencher, Matthew T. Roche, Martin W. TI Unicompartmental Knee Arthroplasty Versus High Tibial Osteotomy: United States Practice Patterns for the Surgical Treatment of Unicompartmental Arthritis SO JOURNAL OF ARTHROPLASTY LA English DT Article DE high tibial osteotomy; unicompartmental knee arthroplasty; osteoarthritis; joint preservation ID FOLLOW-UP; 10-YEAR SURVIVAL; OSTEOARTHRITIS AB Both unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) produce satisfactory outcomes in the management of unicompartmental knee osteoarthritis (OA). The purpose of this study is to compare UKA and HTO practice patterns in a large US private payer insurance database. Utilization data for UKA and HTO were captured from the database between 2007 and 2011. Chi square analysis, parametric testing and Poisson regressions were performed where appropriate. Between 2007 and 2011, the compound annual growth rate in utilization of UKA was + 4.7%, while that for HTO was - 3.9%. Utilization of UKA and HTO were inversely correlated (P = 0.001). UKA utilization is increasing, while HTO utilization is decreasing in the management of OA. More work is required to understand specific indications and outcomes. (C) 2014 Elsevier Inc. All rights reserved. C1 [Nwachukwu, Benedict U.; Schairer, William W.; Roche, Martin W.] Hosp Special Surg, New York, NY 10021 USA. [McCormick, Frank M.] Holy Cross Orthoped Inst, Ft Lauderdale, FL USA. [Frank, Rachel M.] Rush Presbyterian St Lukes Med Ctr, Dept Sports Med, Chicago, IL 60612 USA. [Provencher, Matthew T.] Massachusetts Gen Hosp, Dept Sports Med, Boston, MA 02114 USA. RP McCormick, FM (reprint author), 5597 N Dixie Hwy, Ft Lauderdale, FL USA. OI Schairer, William/0000-0001-6162-9329 NR 25 TC 8 Z9 10 U1 1 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD AUG PY 2014 VL 29 IS 8 BP 1586 EP 1589 DI 10.1016/j.arth.2014.04.002 PG 4 WC Orthopedics SC Orthopedics GA AO5JI UT WOS:000341380000017 PM 24814891 ER PT J AU Abraham, KM Miller, CJ Birgenheir, DG Lai, ZS Kilbourne, AM AF Abraham, Kristen M. Miller, Christopher J. Birgenheir, Denis G. Lai, Zongshan Kilbourne, Amy M. TI Self-Efficacy and Quality of Life Among People With Bipolar Disorder SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Bipolar disorder; self-efficacy; self-management; health-related quality of life; medical comorbidities ID ALCOHOL SCREENING SCORES; CARDIOVASCULAR-DISEASE RISK; RANDOMIZED CONTROLLED-TRIAL; VETERANS AFFAIRS PATIENTS; IDENTIFICATION TEST AUDIT; HEALTH-CARE; DEPRESSIVE SYMPTOMS; MENTAL-ILLNESS; MANAGEMENT; MORTALITY AB People with bipolar disorders report a lower quality of life than the general population does, and few mutable factors associated with health-related quality of life (HRQoL) among people with bipolar disorders have been identified. Using a cross-sectional design, these analyses examined whether self-efficacy was associated with mental and physical HRQoL in a sample of 141 patients with bipolar disorder who completed baseline assessments for two randomized controlled trials. Multiple linear regression analyses indicated that higher levels of self-efficacy were associated with higher mental and physical HRQoL, after controlling for demographic factors and clinical factors (including mood symptoms, comorbid medical conditions, and substance use). Future research should examine whether targeted treatments that aim to improve self-efficacy (such as self-management interventions) lead to improvements in HRQoL among people with bipolar disorder and other serious mental illnesses. C1 [Abraham, Kristen M.] Univ Detroit Mercy, Dept Psychol, Detroit, MI 48221 USA. [Abraham, Kristen M.; Birgenheir, Denis G.; Lai, Zongshan; Kilbourne, Amy M.] VA Serious Mental Illness Treatment Resource & Ev, Ctr Clin Management Res, Ann Arbor, MI 48109 USA. [Miller, Christopher J.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Miller, Christopher J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Birgenheir, Denis G.; Lai, Zongshan; Kilbourne, Amy M.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI USA. RP Abraham, KM (reprint author), VA Serious Mental Illness Treatment Resource & Ev, 2800 Plymouth Rd,Bldg 16 Floor 2, Ann Arbor, MI 48109 USA. EM kristen.abraham2@va.gov FU Veterans Health Administration, Clinical Sciences Research and Development [CSRD S06]; VA Health Services Research and Development Center for Organization, Leadership, and Management Research (COLMR); National Institute of Mental Health [R34MH74509, R01 MH79994]; VA Office of Academic Affiliations, VA Advanced Psychology Fellowship FX This work was supported by the Veterans Health Administration, Clinical Sciences Research and Development (CSRD S06), the VA Health Services Research and Development Center for Organization, Leadership, and Management Research (COLMR), and the National Institute of Mental Health (R34MH74509 and R01 MH79994). Preparation of this manuscript was also supported by VA Office of Academic Affiliations, VA Advanced Psychology Fellowship. NR 52 TC 5 Z9 5 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2014 VL 202 IS 8 BP 583 EP 588 DI 10.1097/NMD.0000000000000165 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO6ZZ UT WOS:000341502900003 PM 25010107 ER PT J AU Robinaugh, DJ McNally, RJ LeBlanc, NJ Pentel, KZ Schwarz, NR Shah, RM Nadal-Vicens, MF Moore, CW Marques, L Bui, E Simon, NM AF Robinaugh, Donald J. McNally, Richard J. LeBlanc, Nicole J. Pentel, Kimberly Z. Schwarz, Noah R. Shah, Riva M. Nadal-Vicens, Mireya F. Moore, Cynthia W. Marques, Luana Bui, Eric Simon, Naomi M. TI Anxiety Sensitivity in Bereaved Adults With and Without Complicated Grief SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE Anxiety sensitivity; complicated grief; risk factors; bereavement ID PANIC DISORDER; PREVALENCE; PREDICTION; SYMPTOMS; ATTACKS AB Complicated grief (CG) is a bereavement-specific syndrome chiefly characterized by symptoms of persistent separation distress. Physiological reactivity to reminders of the loss and repeated acute pangs or waves of severe anxiety and psychological pain are prominent features of CG. Fear of this grief-related physiological arousal may contribute to CG by increasing the distress associated with grief reactions and increasing the likelihood of maladaptive coping strategies and grief-related avoidance. Here, we examined anxiety sensitivity (AS; i.e., the fear of anxiety-related sensations) in two studies of bereaved adults with and without CG. In both studies, bereaved adults with CG exhibited elevated AS relative to those without CG. In study 2, AS was positively associated with CG symptom severity among those with CG. These findings are consistent with the possibility that AS contributes to the development or maintenance of CG symptoms. C1 [Robinaugh, Donald J.; McNally, Richard J.; LeBlanc, Nicole J.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Robinaugh, Donald J.; Pentel, Kimberly Z.; Schwarz, Noah R.; Shah, Riva M.; Nadal-Vicens, Mireya F.; Moore, Cynthia W.; Marques, Luana; Bui, Eric; Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. RP Robinaugh, DJ (reprint author), Harvard Univ, Dept Psychol, 33 Kirkland St, Cambridge, MA 02138 USA. EM robinaug@fas.harvard.edu RI Schwarz, Noah/B-8525-2015; Bui, Eric/J-8347-2015 OI Schwarz, Noah/0000-0002-4604-1209; Bui, Eric/0000-0002-1413-6473 FU NIMH [5R01MH085308-04]; Highland Street Foundation FX This study was supported by NIMH grant 5R01MH085308-04 and a grant from the Highland Street Foundation to the Center for Anxiety and Traumatic Stress Disorders at Massachusetts General Hospital. NR 28 TC 2 Z9 2 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 EI 1539-736X J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2014 VL 202 IS 8 BP 620 EP 622 DI 10.1097/NMD.0000000000000171 PG 3 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AO6ZZ UT WOS:000341502900009 PM 25075646 ER PT J AU Chandra, RV Leslie-Mazwi, TM Orbach, DB Kaban, LB Rabinov, JD AF Chandra, Ronil V. Leslie-Mazwi, Thabele M. Orbach, Darren B. Kaban, Leonard B. Rabinov, James D. TI Transarterial Embolization of Mandibular Arteriovenous Malformations Using ONYX SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID VASCULAR MALFORMATIONS; MANAGEMENT; ANOMALIES; MAXILLA; REGION AB Purpose: To document the efficacy of ethylene vinyl alcohol copolymer (ONYX; ev3/Covidien, Irvine, CA) in the treatment of arteriovenous malformations (AVMs) of the mandible. Materials and Methods: A retrospective consecutive series of patients with facial AVMs isolated to the mandible and immediate perimandibular tissue was identified at 2 institutions. The primary treatment modality of transarterial embolization using ONYX was performed by way of the external carotid artery branches. Staged procedures were accomplished until no arteriovenous shunt remained. A 1-year follow-up angiogram was obtained for each patient. Results: Three patients, aged 8 (patient 1), 16 (patient 2), and 17 (patient 3) years presented with bleeding from facial AVMs isolated to the mandible. Patient 1 was female and patients 2 and 3 were male. The 2 older patients had loose molar or canine dentition. Transarterial embolization with ONYX achieved complete angiographic closure of the arteriovenous shunt in each patient. A total of 1, 6, and 3 staged embolization procedures were performed in the 3 patients. Patient 2 had mild transient facial numbness after embolization that completely resolved. Patient 3 had loose molars associated with the AVM that were extracted for treatment of intraprocedural bleeding. The 1-year angiographic follow-up data demonstrated durable closure of all 3 lesions. Conclusions: Transarterial embolization of high-flow intraosseus mandibular AVMs was safely accomplished with ONYX in our small retrospective cohort. Complete, durable occlusion was found on the angiogram at 1 year, with clinical stability extending to an average of 3 years. Surgical resection of the AVM was avoided in all 3 patients. (C) 2014 American Association of Oral and Maxillofacial Surgeons C1 [Chandra, Ronil V.] Monash Hlth, Monash Med Ctr, Dept Diagnost Imaging, Intervent Neuroradiol Unit, Melbourne, Vic, Australia. [Leslie-Mazwi, Thabele M.; Rabinov, James D.] Harvard Univ, Sch Med, Neurointervent Serv, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Leslie-Mazwi, Thabele M.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Orbach, Darren B.] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Chief Intervent & Neurointervent Radiol, Boston, MA 02114 USA. [Kaban, Leonard B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Head OMFS,Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Rabinov, James D.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rabinov, JD (reprint author), Harvard Univ, Sch Med, Neurointervent Serv, Massachusetts Gen Hosp, 55 Fruit St,Gray 241, Boston, MA 02114 USA. EM jrabinov@partners.org NR 19 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2014 VL 72 IS 8 BP 1504 EP 1510 DI 10.1016/j.joms.2014.02.025 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AO5CY UT WOS:000341361000011 PM 24704035 ER PT J AU Peacock, ZS Boulos, T Miller, JB Gardiner, MF Chuang, SK Troulis, MJ AF Peacock, Zachary S. Boulos, Toufic Miller, John B. Gardiner, Matthew F. Chuang, Sung-Kiang Troulis, Maria J. TI Orbital Fractures and Ocular Injury: Is a Postoperative Ophthalmology Examination Necessary? SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID MIDFACIAL FRACTURES; COMPLEX FRACTURES; FACIAL FRACTURES; TRAUMA; EYE AB Purpose: To determine whether formal ophthalmology evaluation is necessary after operative repair of orbital fractures and the association of an ocular injury to the severity of facial injury. Patients and Methods: This was a retrospective cohort study of patients with orbital fractures undergoing operative repair from 2005 to 2013. Subjects were included if they had undergone reconstruction of orbital floor fractures and had data from pre- and postoperative examinations by the oral and maxillofacial surgery and ophthalmology services available. The predictor variables included the service performing the ocular examination (oral and maxillofacial surgery or ophthalmology) and the number of fractures present. The outcome variables were the presence of pre- and postoperative ocular injuries. Logistic regression models were used to determine the relationship of the fracture number to ocular injury. Results: A total of 28 subjects had undergone repair of orbital fractures with preoperative and postoperative examinations performed by both services. Preoperative ocular injuries were found in 17 of the 28 subjects. Those detected by oral and maxillofacial surgeons were limited to changes in visual acuity, pupillary response, and extraocular muscle dysfunction in 11 subjects. Two subjects had new postoperative ocular findings that were considered minor and did not alter management. An increasing number of facial fractures was associated with an increased risk of ocular trauma. Those with 3 or more fractures had an odds ratio of 14.625 (95% confidence interval, 2.191 to 97.612, P = .006) for the presence of ocular injury. Conclusions: Operative repair of orbital fractures did not lead to new ocular injuries that would change the management. Thus, those without preoperative ocular injuries will not require a formal postoperative ophthalmology examination. However, the subjects with more fractures had an increased likelihood of ocular injuries. (C) 2014 American Association of Oral and Maxillofacial Surgeons. C1 [Peacock, Zachary S.; Boulos, Toufic; Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Miller, John B.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Gardiner, Matthew F.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Ophthalmol Emergency Dept, Boston, MA 02114 USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Peacock, ZS (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, WRN 1201, Boston, MA 02114 USA. EM zpeacock@partners.org OI Gardiner, Matthew/0000-0002-8864-2379 NR 14 TC 4 Z9 4 U1 2 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 EI 1531-5053 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD AUG PY 2014 VL 72 IS 8 BP 1533 EP 1540 DI 10.1016/j.joms.2014.03.008 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA AO5CY UT WOS:000341361000017 PM 24780607 ER PT J AU Harrell, KM Wilkins, SS Connor, MK Chodosh, J AF Harrell, Kathryn M. Wilkins, Stacy S. Connor, Megan K. Chodosh, Joshua TI Telemedicine and the Evaluation of Cognitive Impairment: The Additive Value of Neuropsychological Assessment SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Telemedicine; telehealth; neuropsychology; dementia; cognitive assessment ID TELEMENTAL HEALTH-SERVICES; MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; SCREENING TOOL; PRIMARY-CARE; IN-PERSON; DEMENTIA; TELEHEALTH; RELIABILITY; DIAGNOSIS AB Introduction: The number of people in the United States living with dementia is projected to rise to over 7.1 million in the next 12 years, representing a 40% increase from current levels. This anticipated "dementia tsunami" has led to a recent state and national policy emphasis on early detection, improved care quality, reduced caregiver burden, and increased access to care. The ability to achieve these objectives is limited by few dementia specialists in rural and small communities and the challenges of travel to and within congested urban regions for dementia patients and their caregivers. Telemedicine is one such means for responding to this lack of access to subspecialty assessment and care. We describe our early experiences with this technology applied to neuropsychological assessments, with data from 31 patients. Methods: As part of an interdisciplinary dementia care demonstration project, clinical video teleconferencing provides real-time high resolution video interactions between dementia subspecialists in a major metropolitan medical center and patients in 3 outlying clinics located 180, 150, and 100 miles away. Comprehensive neuropsychological assessments, designed to address referral questions related to neurocognitive disorders via clinical video teleconferencing, are conducted as one component of interdisciplinary care. Outcomes: Eighty-seven percent of patients referred for neuropsychological assessment had an inaccurate neurocognitive diagnosis at the time of referral. Unmet and unrecognized mental health treatment needs were identified in over 77% of patients. In addition, acceptance was good for patients, caregivers, and clinicians. Discussion: Teleneuropsychology is proving to be an excellent resource for clarifying cognitive and psychiatric diagnoses, and integrating individual strengths, weaknesses, and preferences into treatment and care plans used by other health care providers, patients, and caregivers. Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. C1 [Harrell, Kathryn M.; Wilkins, Stacy S.; Connor, Megan K.; Chodosh, Joshua] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Wilkins, Stacy S.; Chodosh, Joshua] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Harrell, KM (reprint author), VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd 11G, Los Angeles, CA 90073 USA. EM kathryn.harrell@va.gov OI Chodosh, Joshua/0000-0001-7784-4306 FU US Department of Veterans Affairs, Office of Rural Health (ORH) [N22-FY13Q1-S1-P00555] FX Funding for this clinical demonstration project was provided by the US Department of Veterans Affairs, Office of Rural Health (ORH Project ID Number: N22-FY13Q1-S1-P00555). NR 51 TC 11 Z9 11 U1 2 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 EI 1538-9375 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD AUG PY 2014 VL 15 IS 8 BP 600 EP 606 DI 10.1016/j.jamda.2014.04.015 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AO2PL UT WOS:000341167400014 PM 24913209 ER PT J AU van Rhee, F Wong, RS Munshi, N Rossi, JF Ke, XY Fossa, A Simpson, D Capra, M Liu, T Hsieh, RK Goh, YT Zhu, J Cho, SG Ren, HY Cavet, J Bandekar, R Rothman, M Puchalski, TA Reddy, M van de Velde, H Vermeulen, J Casper, C AF van Rhee, Frits Wong, Raymond S. Munshi, Nikhil Rossi, Jean-Francois Ke, Xiao-Yan Fossa, Alexander Simpson, David Capra, Marcelo Liu, Ting Hsieh, Ruey Kuen Goh, Yeow Tee Zhu, Jun Cho, Seok-Goo Ren, Hanyun Cavet, James Bandekar, Rajesh Rothman, Margaret Puchalski, Thomas A. Reddy, Manjula van de Velde, Helgi Vermeulen, Jessica Casper, Corey TI Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial SO LANCET ONCOLOGY LA English DT Article ID ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODY; LYMPH-NODE HYPERPLASIA; RITUXIMAB; SPECTRUM AB Background Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. Methods We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2: 1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. Findings We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34 0%, 95% CI 11.1-54.8, p=0.0012). The incidence of grade 3 or more adverse events (25 [47%]vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). Interpretation Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. C1 [van Rhee, Frits] Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. [Wong, Raymond S.] Chinese Univ Hong Kong, Prince Wales Hosp, Hong Kong, Hong Kong, Peoples R China. [Munshi, Nikhil] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rossi, Jean-Francois] CHU Montpellier, Hop St Eloi, Montpellier, France. [Ke, Xiao-Yan] Peking Univ, Hosp 3, Beijing 100871, Peoples R China. [Fossa, Alexander] Oslo Univ Hosp, Oslo, Norway. [Simpson, David] North Shore Hosp, Takapuna Auckland, New Zealand. [Capra, Marcelo] Hosp Mae de Deus, Porto Alegre, RS, Brazil. [Liu, Ting] Sichuan Univ, West China Hosp, Chengdu 610064, Peoples R China. [Hsieh, Ruey Kuen] Mackay Mem Hosp, Taipei, Taiwan. [Goh, Yeow Tee] Singapore Gen Hosp, Singapore, Singapore. [Zhu, Jun] Beijing Canc Hosp, Beijing, Peoples R China. [Cho, Seok-Goo] Seoul St Marys Hosp, Seoul, South Korea. [Ren, Hanyun] Peking Univ, Hosp 1, Beijing 100871, Peoples R China. [Cavet, James] Christie NHS Fdn Trust, Manchester, Lancs, England. [Cavet, James] Univ Manchester, Manchester, Lancs, England. [Bandekar, Rajesh; Puchalski, Thomas A.; Reddy, Manjula] Janssen Res & Dev, Spring House, PA USA. [Rothman, Margaret] Janssen Res & Dev, Washington, GA USA. [van de Velde, Helgi] Janssen Res & Dev, Beerse, Belgium. [Vermeulen, Jessica] Janssen Res & Dev, Leiden, Netherlands. [Casper, Corey] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP van Rhee, F (reprint author), Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. EM vanrheefrits@uams.edu OI Cho, Seok-Goo/0000-0002-5429-4839; Wong, Raymond/0000-0002-9011-4268 FU Janssen Research Development FX Janssen Research & Development. NR 26 TC 67 Z9 68 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 EI 1474-5488 J9 LANCET ONCOL JI Lancet Oncol. PD AUG PY 2014 VL 15 IS 9 BP 966 EP 974 DI 10.1016/S1470-2045(14)70319-5 PG 9 WC Oncology SC Oncology GA AO4MA UT WOS:000341311600041 PM 25042199 ER PT J AU Xu, L Hunter, ZR Yang, G Cao, Y Liu, X Manning, R Tripsas, C Chen, J Patterson, CJ Kluk, M Kanan, S Castillo, J Lindeman, N Treon, SP AF Xu, L. Hunter, Z. R. Yang, G. Cao, Y. Liu, X. Manning, R. Tripsas, C. Chen, J. Patterson, C. J. Kluk, M. Kanan, S. Castillo, J. Lindeman, N. Treon, S. P. TI Detection of MYD88 L265P in peripheral blood of patients with Waldenstrom's Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance SO LEUKEMIA LA English DT Article ID CELL LYMPHOPROLIFERATIVE DISORDERS; CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; SOMATIC MUTATION; BONE-MARROW; MULTIPLE-MYELOMA; LEUKEMIA; DIAGNOSIS; MGUS AB MYD88 L265P is highly prevalent in Waldenstrom's Macroglobulinemia (WM) and IgM monoclonal gammopathy of unknown significance (MGUS). We investigated whether MYD88 L265P could be identified by peripheral blood (PB) allele-specific PCR. MYD88 L265P was detected in untreated WM (114/118; 96.6%); previously treated WM (63/102; 61.8%); and IgM MGUS (5/12; 41.7%) but in none of 3 hyper-IgM or 40 healthy individuals. Median PB MYD88 L265P Delta Ct was 3.77, 7.24, 10.89, 12.33 and 14.07 for untreated WM, previously treated WM, IgM MGUS, hyper-IgM and healthy individuals, respectively (P<0.0001). For the 232 IgM MGUS and WM patients, PB MYD88 L265P Delta Ct moderately correlated to bone marrow (BM) disease (r= -0.3553; P<0.0001), serum IgM (r= -0.3262; P< 0.0001) and hemoglobin (r=0.3005; P< 0.0001) levels. PB MYD88 L265P Delta Ct and serum IgM correlated similarly with BM disease burden. For positive patients, PB MYD88 L265P Delta Ct was <6.5 in 100/114 (88%) untreated WM, and >6.5 in 4/5 (80%) IgM MGUS patients (P=0.0034). Attainment of a negative PB MYD88 L265P mutation status was associated with lower BM disease (P=0.001), serum IgM (P=0.019) and higher hemoglobin (P=0.004) levels in treated patients. These studies show the feasibility for detecting MYD88 L265P by PB examination, and the potential for PB MYD88 L265P Delta Ct use in the diagnosis and management of WM patients. C1 [Xu, L.; Hunter, Z. R.; Yang, G.; Cao, Y.; Liu, X.; Manning, R.; Tripsas, C.; Chen, J.; Patterson, C. J.; Kanan, S.; Castillo, J.; Treon, S. P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Xu, L.; Hunter, Z. R.; Yang, G.; Cao, Y.; Liu, X.; Kluk, M.; Castillo, J.; Lindeman, N.; Treon, S. P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kluk, M.; Lindeman, N.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M548,450 Brookline Ave, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532; Hunter, Zachary/0000-0002-1689-1691 FU Peter and Helen Bing Foundation; Coyote Fund for WM; International Waldenstrom's Macroglobulinemia Foundation; Waldenstrom's Cancer Fund; Bailey Family Fund for WM; D'Amato Family Fund for Genomic Discovery; Edward and Linda Nelson Fund for WM Research; Bauman Family Trust; Tannenhauser Family Foundation FX We acknowledge the generous support of the Peter and Helen Bing Foundation, the Coyote Fund for WM, the International Waldenstrom's Macroglobulinemia Foundation, the Waldenstrom's Cancer Fund, the Bailey Family Fund for WM, the D'Amato Family Fund for Genomic Discovery, the Edward and Linda Nelson Fund for WM Research, the Bauman Family Trust, the Tannenhauser Family Foundation and the WM patients who provided their samples in support of these studies. NR 32 TC 16 Z9 17 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD AUG PY 2014 VL 28 IS 8 BP 1698 EP 1704 DI 10.1038/leu.2014.65 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA AO4TP UT WOS:000341334600013 PM 24509637 ER PT J AU Ray, A Tian, Z Das, DS Coffman, RL Richardson, P Chauhan, D Anderson, KC AF Ray, A. Tian, Z. Das, D. S. Coffman, R. L. Richardson, P. Chauhan, D. Anderson, K. C. TI A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib SO LEUKEMIA LA English DT Article DE myeloma; immunotherapy; dendritic cells; pDC; TLR-9; CpG-ODN-C792; interferons ID HUMAN MULTIPLE-MYELOMA; CPG DNA; NUCLEIC-ACIDS; HUMAN BLOOD; IN-VITRO; T-CELLS; INTERFERON; INDUCTION; DIFFERENTIATION; IDENTIFICATION AB Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM), which both contribute to immune dysfunction as well as promote tumor cell growth, survival and drug resistance. Here we show that a novel Toll-like receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T-cell proliferation. Coculture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-alpha and interferon-lambda, secretion and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, SAHA or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM. C1 [Ray, A.; Tian, Z.; Das, D. S.; Richardson, P.; Chauhan, D.; Anderson, K. C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Dept Med Oncol, Boston, MA 02215 USA. [Ray, A.; Tian, Z.; Das, D. S.; Richardson, P.; Chauhan, D.; Anderson, K. C.] Harvard Univ, Sch Med, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA 02215 USA. [Coffman, R. L.] Dynavax Technol, Berkeley, CA USA. RP Chauhan, D (reprint author), Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Dept Med Oncol, M561,450 Brookline Ave, Boston, MA 02215 USA. EM Dharminder_Chauhan@dfci.harvard.edu; Kenneth_Anderson@dfci.harvard.edu FU National Institutes of Health Specialized Programs of Research Excellence (SPORE) [P50100707, PO1-CA078378, RO1 CA050947] FX This investigation was supported by National Institutes of Health Specialized Programs of Research Excellence (SPORE) grants P50100707, PO1-CA078378, and RO1 CA050947. KCA is an American Cancer Society Clinical Research Professor, NR 54 TC 11 Z9 11 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD AUG PY 2014 VL 28 IS 8 BP 1716 EP 1724 DI 10.1038/leu.2014.46 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA AO4TP UT WOS:000341334600015 PM 24476765 ER PT J AU Becker, H Maharry, K Mrozek, K Volinia, S Eisfeld, AK Radmacher, MD Kohlschmidt, J Metzeler, KH Schwind, S Whitman, SP Mendler, JH Wu, YZ Nicolet, D Paschka, P Powell, BL Carter, TH Wetzler, M Kolitz, JE Carroll, AJ Baer, MR Caligiuri, MA Stone, RM Marcucci, G Bloomfield, CD AF Becker, H. Maharry, K. Mrozek, K. Volinia, S. Eisfeld, A-K Radmacher, M. D. Kohlschmidt, J. Metzeler, K. H. Schwind, S. Whitman, S. P. Mendler, J. H. Wu, Y-Z Nicolet, D. Paschka, P. Powell, B. L. Carter, T. H. Wetzler, M. Kolitz, J. E. Carroll, A. J. Baer, M. R. Caligiuri, M. A. Stone, R. M. Marcucci, G. Bloomfield, C. D. TI Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8 SO LEUKEMIA LA English DT Letter ID MYELODYSPLASTIC SYNDROMES; CYTOGENETICS; FLT3 C1 [Becker, H.; Maharry, K.; Mrozek, K.; Volinia, S.; Eisfeld, A-K; Radmacher, M. D.; Kohlschmidt, J.; Metzeler, K. H.; Schwind, S.; Whitman, S. P.; Mendler, J. H.; Wu, Y-Z; Nicolet, D.; Paschka, P.; Caligiuri, M. A.; Marcucci, G.; Bloomfield, C. D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Maharry, K.; Kohlschmidt, J.] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN USA. [Maharry, K.; Kohlschmidt, J.] Mayo Clin, Ctr Data, Rochester, MN USA. [Powell, B. L.] Wake Forest Univ, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. [Carter, T. H.] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Wetzler, M.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Kolitz, J. E.] Hofstra North Shore Long Isl Jewish Sch Med, Monter Canc Ctr, Lake Success, NY USA. [Carroll, A. J.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Baer, M. R.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Baer, M. R.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Stone, R. M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Becker, H (reprint author), Univ Freiburg, Med Ctr, Dept Internal Med 1, Freiburg, Germany. EM guido.marcucci@osumc.edu; clara.bloomfield@osumc.edu RI Mrozek, Krzysztof/A-3142-2008; Metzeler, Klaus/C-2118-2009; OI Metzeler, Klaus/0000-0003-3920-7490; Mendler, Jason/0000-0001-5605-5324; Volinia, Stefano/0000-0003-0910-3893 FU NCI NIH HHS [CA114725, CA129657, CA140158, CA101140, CA16058, CA31946, CA33601, CA77658, P30 CA016058, P50 CA140158, R21 CA129657, U10 CA031946, U10 CA033601, U10 CA077658, U10 CA101140, U10 CA180861, U24 CA114725] NR 17 TC 8 Z9 9 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD AUG PY 2014 VL 28 IS 8 BP 1754 EP 1758 DI 10.1038/leu.2014.114 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA AO4TP UT WOS:000341334600024 PM 24651097 ER PT J AU Steensma, DP Rayson, D Shampo, MA Kyle, RA AF Steensma, David P. Rayson, Daniel Shampo, Marc A. Kyle, Robert A. TI Terry Fox: Canadian Cancer Research Activist Whose "Marathon of Hope" Inspired Millions SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material C1 [Steensma, David P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rayson, Daniel] Dalhousie Univ, Halifax, NS, Canada. [Shampo, Marc A.; Kyle, Robert A.] Mayo Clin, Rochester, MN USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 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 0025-6196 EI 1942-5546 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD AUG PY 2014 VL 89 IS 8 BP E75 EP E76 DI 10.1016/j.mayocp.2013.10.037 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AO5UQ UT WOS:000341411200001 PM 25092373 ER PT J AU Dizon, DS AF Dizon, Don S. TI Narratives in Oncology SO ONCOLOGIST LA English DT Editorial Material C1 [Dizon, Don S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dizon, DS (reprint author), 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM ddizon@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2014 VL 19 IS 8 BP 789 EP 789 DI 10.1634/theoncologist.2014-0225 PG 1 WC Oncology SC Oncology GA AO5UV UT WOS:000341411700003 PM 24969161 ER PT J AU Trivers, KF Fink, AK Partridge, AH Oktay, K Ginsburg, ES Li, CY Pollack, LA AF Trivers, Katrina F. Fink, Aliza K. Partridge, Ann H. Oktay, Kutluk Ginsburg, Elizabeth S. Li, Chunyu Pollack, Lori A. TI Estimates of Young Breast Cancer Survivors at Risk for Infertility in the U. S. SO ONCOLOGIST LA English DT Article DE Breast neoplasms; Infertility; Fertility preservation; Survivors; Reproductive behavior; Pregnancy ID CARCINOMA IN-SITU; QUALITY-OF-LIFE; FERTILITY PRESERVATION; RECEPTOR STATUS; REPRODUCTIVE HEALTH; WOMEN; CHEMOTHERAPY; PREGNANCY; DIAGNOSIS; ESTROGEN AB Background. Standard treatments for breast cancer can impair fertility. It is unknown how many U. S. survivors are at risk for infertility. We estimated the population at risk for infertility secondary to treatment among reproductive-aged breast cancer survivors. Methods. We combined data from three sources: the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results cancer registry data on incident breast cancers diagnosed in women aged 15-44 years between 2004 and 2006; treatment data from NPCR's 2004 Breast and Prostate Cancer Data Quality and Patterns of Care (PoC) study; and data on women's intentions to have children from the 2006-2010 National Survey of Family Growth (NSFG). Results. In the cancer registry data, an average of 20,308 women with breast cancer aged,45 years were diagnosed annually. Based on estimates from PoC data, almost all of these survivors (97%, 19,416 women) were hormone receptor positive or received chemotherapy and would be at risk for infertility. These women need information about the impact of treatments on fertility. Estimates based on NSFG data suggest approximately half of these survivors (9,569 women) might want children and could benefit from fertility counseling and fertility preservation. Conclusion. Nearly all young breast cancer survivors in the U. S. are at risk for infertility. Physicians should discuss the potential impact of treatment on fertility. A smaller but sizeable number of at-risk survivors may be interested in having children. Given the magnitude of potential infertility and its quality-of-life implications, these survivors should have access to and potential coverage for fertility services. The Oncologist 2014; 19: 814-822 C1 [Trivers, Katrina F.; Li, Chunyu; Pollack, Lori A.] Natl Ctr Chron Dis Prevent & Hlth Promot, Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Fink, Aliza K.] ICF Int, Rockville, MD USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Partridge, Ann H.; Ginsburg, Elizabeth S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Oktay, Kutluk] New York Med Coll, Div Reprod Med, Valhalla, NY 10595 USA. [Oktay, Kutluk] New York Med Coll, Lab Fertil Preservat & Mol Reprod, Valhalla, NY 10595 USA. [Oktay, Kutluk] Innovat Inst Fertil Preservat, New York, NY USA. RP Trivers, KF (reprint author), 4770 Buford Highway,NE,MS F76, Atlanta, GA 30341 USA. EM fph1@cdc.gov FU Centers for Disease Control and Prevention (CDC) [200-2008-27957] FX This project was partially funded by the Centers for Disease Control and Prevention (CDC) through a contract (#200-2008-27957) to ICF International. The Breast and Prostate Cancer Data Quality and Patterns of Care (PoC) data were provided based on a collaborative effort through cooperative agreements provided by the CDC. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC or any of the seven collaborating PoC states. A. K. F. is currently affiliated with the Cystic Fibrosis Foundation, Bethesda, MD. NR 44 TC 12 Z9 12 U1 1 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2014 VL 19 IS 8 BP 814 EP 822 DI 10.1634/theoncologist.2014-0016 PG 9 WC Oncology SC Oncology GA AO5UV UT WOS:000341411700007 PM 24951610 ER PT J AU Tanguturi, SK Wo, JY Zhu, AX Dawson, LA Hong, TS AF Tanguturi, Shyam K. Wo, Jennifer Y. Zhu, Andrew X. Dawson, Laura A. Hong, Theodore S. TI Radiation Therapy for Liver Tumors: Ready for Inclusion in Guidelines? SO ONCOLOGIST LA English DT Article DE Hepatobiliary cancer; Stereotactic body radiation therapy; Radiation therapy; Cholangiocarcinoma ID STEREOTACTIC BODY RADIOTHERAPY; ADVANCED HEPATOCELLULAR-CARCINOMA; PORTAL-VEIN THROMBOSIS; 3-DIMENSIONAL CONFORMAL RADIOTHERAPY; ACTIVE BREATHING CONTROL; LOCAL SALVAGE TREATMENT; LINEAR-QUADRATIC MODEL; PROTON-BEAM THERAPY; LONG-TERM OUTCOMES; PHASE-II TRIAL AB Despite the historically limited role of radiotherapy in the management of primary hepatic malignancies, modern advances in treatment design and delivery have renewed enthusiasm for radiation as a potentially curative treatment modality. Surgical resection and/ or liver transplantation are traditionally regarded as the most effective forms of therapy, although the majority of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma present with locally advanced or unresectable disease on the basis of local vascular invasion or inadequate baseline hepatobiliary function. In this context, many efforts have focused on nonoperative treatment approaches including novel systemic therapies, transarterial chemoembolization, ethanol ablation, radiofrequency ablation, and stereotactic body radiation therapy (SBRT). This review aims to summarize modern advances in radiotherapy, particularly SBRT, in the treatment of primary hepatic malignancies. The Oncologist 2014; 19: 868-879 C1 [Tanguturi, Shyam K.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [Wo, Jennifer Y.; Zhu, Andrew X.; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Dawson, Laura A.] Univ Toronto, Princess Margaret Canc Ctr, Dept Radiat Oncol, Toronto, ON, Canada. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 32 Fruit St,Yawkey 7, Boston, MA 02114 USA. EM TSHong1@partners.org NR 112 TC 9 Z9 10 U1 0 U2 6 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 EI 1549-490X J9 ONCOLOGIST JI Oncologist PD AUG PY 2014 VL 19 IS 8 BP 868 EP 879 DI 10.1634/theoncologist.2014-0097 PG 12 WC Oncology SC Oncology GA AO5UV UT WOS:000341411700013 PM 25001265 ER PT J AU Awh, CC Lane, AM Hawken, S Zanke, B Kim, IK AF Awh, Carl C. Lane, Anne Marie Hawken, Steven Zanke, Brent Kim, Ivana K. TI Re: Awh et al.: CFH and ARMS2 Genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration (Ophthalmology 2013;120:2317-23) reply SO OPHTHALMOLOGY LA English DT Letter C1 [Awh, Carl C.] Tennessee Retina PC, Nashville, TN 37203 USA. [Lane, Anne Marie; Kim, Ivana K.] Harvard Univ, Sch Med, Dept Ophthalmol, Retina Serv,Massachusetts Eye & Ear Infirm, Boston, MA USA. [Hawken, Steven] Ottawa Hosp Res Inst Clin Epidemiol Program, Ottawa, ON, Canada. [Zanke, Brent] Univ Ottawa, Dept Med, Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Zanke, Brent] Univ Ottawa, Dept Med, Div Hematol, Ottawa, ON, Canada. [Zanke, Brent] Arctic Grp Co, Toronto, ON, Canada. RP Awh, CC (reprint author), Tennessee Retina PC, Nashville, TN 37203 USA. NR 5 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD AUG PY 2014 VL 121 IS 8 BP E39 EP E39 PG 1 WC Ophthalmology SC Ophthalmology GA AO2KR UT WOS:000341151100002 PM 24793507 ER PT J AU Dransfield, MT Feldman, G Korenblat, P LaForce, CF Locantore, N Pistolesi, M Watkins, ML Crim, C Martinez, FJ AF Dransfield, Mark T. Feldman, Gregory Korenblat, Phillip LaForce, Craig F. Locantore, Nicholas Pistolesi, Massimo Watkins, Michael L. Crim, Courtney Martinez, Fernando J. TI Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients SO RESPIRATORY MEDICINE LA English DT Article DE Chronic obstructive pulmonary disease; Head-to-head; Inhaled corticosteroid; Long-acting beta(2)-agonist; Lung function ID MU-G; RANDOMIZED-TRIAL; PERSISTENT ASTHMA; LUNG-FUNCTION; FUROATE; EXACERBATIONS; SALMETEROL; VILANTEROL; AGONIST AB Background: Fluticasone furoate/vilanterol (FF/VI) is an inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA), recently approved as once-daily maintenance therapy for COPD. We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol (FP/SAL). Methods: Three 12 week studies comparing FF/VI and FP/SAL were conducted. Patients aged >= 40 years with moderate-to-very severe COPD were randomized to receive double-blind, double-dummy FF/VI 100/25 mcg once-daily, or FP/SAL 250/50 nncg twice-daily for 12 weeks following a 2 week placebo run-in period. The primary endpoint of each study was change from baseline trough in 0-24 h weighted mean FEV1 (wmFEV(1)) on Day 84. Safety was also assessed. Results: In Study 1 (HZC113109) (intent-to-treat n: FF/VI = 260; FP/SAL = 259), the increase from baseline in 0-24 h wmFEVi was significantly greater with FF/VI than FP/SAL (A80 mL, P < 0.001). In Study 2 (HZC112352) (intent-to-treat n: FF/VI = 259; FP/SAL = 252) and Study 3 (RLV116974) (intent-to-treat n: FF/VI = 412; FP/SAL = 416), the increase from baseline in 0 24 h wmFEVi was not significantly greater with FF/VI than FP/SAL (A29 mL, P = 0.267; A25 mL, P = 0.137). The treatment difference was statistically but not clinically significant in a pooled analysis (6,41 mL, P < 0.001). Pooled adverse events (FF/VI 27%; FP/SAL 28%) and serious adverse events (FF/VI 2%; FP/SAL 3%) were similar between treatments. Conclusions: Our data suggest that once-daily FF/VI 100/25 mcg provides FEV, improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg, although interpretation is limited by differences in individual study outcomes. The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Dransfield, Mark T.] Univ Alabama Birmingham, UAB Lung Hlth Ctr, Birmingham, AL 35294 USA. [Dransfield, Mark T.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. [Feldman, Gregory] S Carolina Pharmaceut Res, Spartanburg, SC 29303 USA. [Korenblat, Phillip] Clin Res Ctr LLB, St Louis, MO 63141 USA. [LaForce, Craig F.] North Carolina Clin Res, Raleigh, NC 27607 USA. [Locantore, Nicholas; Watkins, Michael L.; Crim, Courtney] GlaxoSmithKline, Res Triangle Pk, NC 27709 USA. [Pistolesi, Massimo] Univ Florence, I-50121 Florence, Italy. [Martinez, Fernando J.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Dransfield, MT (reprint author), Univ Alabama Birmingham, UAB Lung Hlth Ctr, Div Pulm Allergy & Crit Care Med, 1900 Univ Blvd,THT-422, Birmingham, AL 35294 USA. EM mdrans99@uab.edu FU GlaxoSmithKline (GSK) [HZC113109, HZC112352, RLV116974]; GlaxoSmithKline FX This study was funded by GlaxoSmithKline (GSK study numbers HZC113109, HZC112352, RLV116974). NL, an employee of the sponsor (GlaxoSmithKline), performed the statistical analysis; all authors (MTD, GE, PK, CFL, NL, MP, MLW, CC, FJM) contributed to the study design, interpreted the data and developed the manuscript. All authors had full access to the data and were responsible for the decision to publish the paper. The authors acknowledge the contribution of Anna Ellsworth, who performed the statistical analysis of Study 3 and of the pooled analysis, and thank all patients and investigators involved in the study. Editorial support, in the form of development of a draft outline in consultation with the authors, development of a manuscript first draft in consultation with the authors, editorial suggestions to draft versions of this paper, assembling tables and figures, collating author comments, copyediting, fact checking, referencing and graphic services, was provided by Geoff Weller, PhD, and Ian Grieve, PhD, at Gardiner-Caldwell Communications (Macclesfield, UK) and was funded by GlaxoSmithKline. NR 25 TC 18 Z9 19 U1 2 U2 9 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 EI 1532-3064 J9 RESP MED JI Respir. Med. PD AUG PY 2014 VL 108 IS 8 BP 1171 EP 1179 DI 10.1016/j.rmed.2014.05.008 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA AO4YU UT WOS:000341348100012 PM 24998880 ER PT J AU Minzenberg, MJ Lesh, TA Niendam, TA Yoon, JH Rhoades, RN Carter, CS AF Minzenberg, Michael J. Lesh, Tyler A. Niendam, Tara A. Yoon, Jong H. Rhoades, Remy N. Carter, Cameron S. TI Frontal cortex control dysfunction related to long-term suicide risk in recent-onset schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Suicide; Cognitive control; fMRI; Frontal cortex ID COGNITIVE CONTROL; PREFRONTAL CORTEX; 1ST EPISODE; PREMOTOR AREAS; WORST-POINT; BEHAVIOR; PSYCHOSIS; MOTOR; PREVENTION; VOLUME AB Objective: Suicide is highly-prevalent and the most serious outcome in schizophrenia, yet the disturbances in neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in psychotic disorders, and various PFC changes are observed in post-mortem studies of completed suicide. We tested whether PFC activity during goal-representation (an important component of cognitive control) relates to long-term suicide risk in recent-onset schizophrenia. Method: 35 patients with recent-onset of DSM-IV-TR-defined schizophrenia (SZ) were evaluated for long-term suicide risk (using the Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models associating control-related brain activation with suicide risk controlled for depression, psychosis and impulsivity. Results: Within this group, past suicidal ideation was associated with lower activation with goal-representation demands in multiple PFC sectors. Among those with past suicidal ideation (n = 18), reported suicidal behavior was associated with lower control-related activation in premotor cortex ipsilateral to the active primary motor cortex. Conclusions: This study provides unique evidence that suicide risk directly relates to PFC-based circuit dysfunction during goal-representation, in a major mental illness with significant suicide rates. Among those with suicidal ideation, the overt expression in suicidal behavior may stem from impairments in premotor cortex support of action-planning as an expression of control. Furtherwork should address how PFC-based control function changes with risk over time, whether this brain-behavior relationship is specific to schizophrenia, and address its potential utility as a biomarker for interventions to mitigate suicide risk. Published by Elsevier B.V. C1 [Minzenberg, Michael J.; Rhoades, Remy N.] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Minzenberg, Michael J.; Rhoades, Remy N.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Lesh, Tyler A.; Niendam, Tara A.; Carter, Cameron S.] Univ Calif Davis, Sch Med, Dept Psychiat, Sacramento, CA 95817 USA. [Carter, Cameron S.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Yoon, Jong H.] Stanford Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA USA. [Yoon, Jong H.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. RP Minzenberg, MJ (reprint author), San Francisco VA Med Ctr, 116C,4150 Clement St, San Francisco, CA 94121 USA. EM Michael.minzenberg@ucsf.edu RI Niendam, Tara/K-8475-2015 OI Niendam, Tara/0000-0003-2285-5002 FU American Foundation for Suicide Prevention Young Investigator Award; Doris Duke Charitable Foundation Grant [2009045, MH059883] FX This work was supported by an American Foundation for Suicide Prevention Young Investigator Award, and the Doris Duke Charitable Foundation Grant # 2009045, both to MJM, and MH059883 to CSC. NR 41 TC 10 Z9 12 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 19 EP 25 DI 10.1016/j.schres.2014.05.039 PG 7 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100004 PM 24972755 ER PT J AU McCleery, A Ventura, J Kern, RS Subotnik, KL Gretchen-Doorly, D Green, MF Hellemann, GS Nuechterlein, KH AF McCleery, A. Ventura, J. Kern, R. S. Subotnik, K. L. Gretchen-Doorly, D. Green, M. F. Hellemann, G. S. Nuechterlein, K. H. TI Cognitive functioning in first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) Profile of Impairment SO SCHIZOPHRENIA RESEARCH LA English DT Article DE MCCB; First-episode schizophrenia; Cognition; Profile analysis; First episode schizophrenia ID FIRST-EPISODE SCHIZOPHRENIA; FACIAL AFFECT RECOGNITION; 1ST EPISODE; ONSET SCHIZOPHRENIA; WORKING-MEMORY; PSYCHOSIS; DEFICITS; DISORDERS; DETERIORATION; RELIABILITY AB Background: Although many studies have assessed cognitive functioning in first-episode schizophrenia (FESz), the pattern and severity of impairment across cognitive domains remain unclear. Moreover, few studies have directly compared the pattern of cognitive performance between FESz and chronic schizophrenia (CSz). In this study we examined the cognitive impairment profile in FESz using a standardized neurocognitive battery (MATRICS Consensus Cognitive Battery; MCCB). Methods: MCCB data were compared from 105 FESz patients, 176 CSz patients and 300 non-psychiatric (NP) participants. Mixed model analysis evaluated group differences in MCCB profiles and relative strengths and weaknesses in the MCCB profiles of patients. Clinical implications of MCCB performance were also examined; we compared the proportion of participants from each group who exhibited clinically-significant global cognitive impairment based on the MCCB Overall Composite score. Results: FESz and CSz showed impaired performance across all MCCB domains relative to NP. With the exception of relative preservation of working memory and social cognition in FESz, the MCCB domain scores were similar in FESz and CSz. The distribution of impairment on the Overall Composite score did not significantly differ between FESz and CSz; compared to NP, both patient groups were over represented in moderate and severe impairment categories. Conclusion: The pattern, magnitude, and distribution of severity of impairment in FESz were similar to that observed in CSz. However, early in the illness, there may be relative sparing of working memory and social cognition. (C) 2014 Elsevier B.V. All rights reserved. C1 [McCleery, A.; Ventura, J.; Kern, R. S.; Subotnik, K. L.; Gretchen-Doorly, D.; Green, M. F.; Hellemann, G. S.; Nuechterlein, K. H.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Kern, R. S.; Green, M. F.] Greater Los Angeles VA Healthcare Syst, VISN Mental Illness Res Educ & Clin Ctr MIRECC 22, Los Angeles, CA USA. [Nuechterlein, K. H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP McCleery, A (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Dept Psychiat, 300 Med Plaza,Room 2213, Los Angeles, CA 90095 USA. EM amccleery@mednet.ucla.edu RI McCleery, Amanda/D-5471-2016 OI McCleery, Amanda/0000-0003-2714-6897 FU MATRICS Assessment, Inc.; Janssen Scientific Affairs [R092670SCH4005, RIS-NAP-4009]; Genentech [ML28264]; Posit Science [BPI-1000-11]; Genentech, Inc. [C4-150335]; Janssen Scientific Affairs, LLC; Genentech, Inc.; Amgen Foundation [20130132] FX M.F. Green and K.H. Nuechterlein are officers within MATRICS Assessment, Inc., the publisher of the MCCB, but do not receive any financial remuneration for their respective roles. R.S. Kern is an officer for MATRICS Assessment, Inc. and receives financial compensation for his role within the non-profit organization. K. H. Nuechterlein has received unrelated research grants from Janssen Scientific Affairs (R092670SCH4005; RIS-NAP-4009), Genentech (ML28264), and Posit Science (BPI-1000-11) and has been a consultant to Otsuka and Genentech. J. Ventura has received funding from Genentech, Inc. (C4-150335). He has served as a consultant to Brain Plasticity, Inc., and Boehringer-Ingelheim GmbH. K.L. Subotnik and D. Gretchen-Doorly have received research funding from Janssen Scientific Affairs, LLC, and Genentech, Inc., through grants to K. H. Nuechterlein and J. Ventura. K. L. Subotnik is a consultant to Otsuka America Pharmaceutical, Inc. M. F. Green has been a consultant to AbbVie, Biogen, DSP, FORUM Pharmaceuticals, and Roche, and he is on the scientific advisory board of Mnemosyne. He has received research funds from Amgen Foundation (20130132). All other authors declare they have no conflicts of interest. NR 60 TC 13 Z9 14 U1 7 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 33 EP 39 DI 10.1016/j.schres.2014.04.039 PG 7 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100006 PM 24888526 ER PT J AU Walsh-Messinger, J Ramirez, PM Wong, P Antonius, D Aujero, N McMahon, K Opler, LA Malaspina, D AF Walsh-Messinger, Julie Ramirez, Paul Michael Wong, Philip Antonius, Daniel Aujero, Nicole McMahon, Kevin Opler, Lewis A. Malaspina, Dolores TI Impairment in emotional modulation of attention and memory in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Emotion; Cognition; Negative symptoms ID SERIAL VISUAL PRESENTATION; AFFECTIVE-PICTURE-SYSTEM; HUMAN AMYGDALA; BLINK; WORDS; PERCEPTION; BEHAVIOR; STIMULI; AROUSAL; INFORMATION AB Emotion plays a critical role in cognition and goal-directed behavior via complex interconnections between the emotional and motivational systems. It has been hypothesized that the impairment in goal-directed behavior widely noted in schizophrenia may result from defects in the interaction between the neural (ventral) emotional system and (rostral) cortical processes. The present study examined the impact of emotion on attention and memory in schizophrenia. Twenty-five individuals with schizophrenia related psychosis and 25 healthy control subjects were administered a computerized task in which they were asked to search for target images during a Rapid Serial Visual Presentation of pictures. Target stimuli were either positive or negative, or neutral images presented at either 200 ms or 700 ms lag. Additionally, a visual hedonic task was used to assess differences between the schizophrenia group and controls on ratings of valence and arousal from the picture stimuli. Compared to controls, individuals with schizophrenia detected fewer emotional images under both the 200 ms and 700 ms lag conditions. Multivariate analyses showed that the schizophrenia group also detected fewer positive images under the 700 ms lag condition and fewer negative images under the 200 ms lag condition. Individuals with schizophrenia reported higher pleasantness and unpleasantness ratings than controls in response to neutral stimuli, while controls reported higher arousal ratings for neutral and positive stimuli compared to the schizophrenia group. These results highlight dysfunction in the neural modulation of emotion, attention, and cortical processing in schizophrenia, adding to the growing but mixed body of literature on emotion processing in the disorder. Published by Elsevier B.V. C1 [Walsh-Messinger, Julie; Ramirez, Paul Michael; Wong, Philip] Long Isl Univ, Dept Psychol, Brooklyn, NY USA. [Walsh-Messinger, Julie; Antonius, Daniel; Aujero, Nicole; McMahon, Kevin; Malaspina, Dolores] NYU, Sch Med, Dept Psychiat, InSPIRES, New York, NY USA. [Antonius, Daniel] SUNY Buffalo, Buffalo, NY 14260 USA. [Antonius, Daniel] Erie Cty Forens Mental Hlth Serv, Buffalo, NY USA. [Opler, Lewis A.] Columbia Univ, Dept Psychiat, New York, NY USA. [Malaspina, Dolores] NY State Off Mental Hlth, Creedmoor Psychiat Ctr, Queens, NY USA. RP Walsh-Messinger, J (reprint author), James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr MIRECC, 130 West Kingsbridge Rd,6th Floor,Suite 6A-41C, Bronx, NY 10468 USA. EM julie.walshmessinger@mssm.edu FU National Institute of Mental Health [RC1MH088843, 2K24MH00169] FX This work was supported by the National Institute of Mental Health grants RC1MH088843 (DM) and 2K24MH00169 (DM). NR 58 TC 4 Z9 4 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 63 EP 69 DI 10.1016/j.schres.2014.05.014 PG 7 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100011 PM 24910446 ER PT J AU Walder, DJ Faraone, SV Glatt, SJ Tsuang, MT Seidman, LJ AF Walder, Deborah J. Faraone, Stephen V. Glatt, Stephen J. Tsuang, Ming T. Seidman, Larry J. TI Genetic liability, prenatal health, stress and family environment: Risk factors in the Harvard Adolescent Family High Risk for Schizophrenia Study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Stress; Psychosis; Relatives; Obstetric complications; Neurodevelopment; Family environment ID OBSTETRIC COMPLICATIONS; LIFE EVENTS; MATERNAL RECALL; YOUNG RELATIVES; CHILDREN BORN; PSYCHOSIS; DISORDERS; METAANALYSIS; PSYCHOPATHOLOGY; INDIVIDUALS AB Objectives: The familial ("genetic") high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. Methods: We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13-25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. 'Genetic load' indexed number of affected family members relative to pedigree size. Results: PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. Conclusions: Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed 'polygenic neurodevelopmental diathesis-stress model' whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies. (C) 2014 Elsevier B.V. All rights reserved. C1 [Walder, Deborah J.] Brooklyn Coll, Dept Psychol, Brooklyn, NY 11210 USA. [Walder, Deborah J.] CUNY, Grad Ctr, New York, NY USA. [Walder, Deborah J.; Seidman, Larry J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Psychiat, Cambridge, MA 02138 USA. [Faraone, Stephen V.; Glatt, Stephen J.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Faraone, Stephen V.; Glatt, Stephen J.] SUNY Upstate Med Univ, Ctr Neuropsychiat Genet, Program Biomed Sci, Syracuse, NY 13210 USA. [Tsuang, Ming T.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Tsuang, Ming T.] Univ Calif San Diego, Inst Genom Med, Dept Psychiat, La Jolla, CA 92093 USA. [Tsuang, Ming T.] Harvard Univ, Sch Publ Hlth, Harvard Inst Psychiat Epidemiol & Genet, Cambridge, MA 02138 USA. [Seidman, Larry J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. RP Walder, DJ (reprint author), Brooklyn Coll, Dept Psychol, Rm 5315 James Hall,2900 Bedford Ave, Brooklyn, NY 11210 USA. EM DWalder@brooklyn.cuny.edu; lseidman@bidmc.harvard.edu OI Glatt, Stephen/0000-0002-0360-7567; Faraone, Stephen/0000-0002-9217-3982 FU Fellowship Leave, The City University of New York; Stanley Medical Research Institute; National Association for Research on Schizophrenia and Depression (NARSAD); Mental Illness and Neuroscience Discovery (MIND) Institute; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006]; [MH 43518]; [MH 65562]; [MH 63951]; [MH 46318] FX This work was supported by the following: Fellowship Leave, The City University of New York (DJW); Stanley Medical Research Institute (LJS); National Association for Research on Schizophrenia and Depression (NARSAD; LJS, MTT); Mental Illness and Neuroscience Discovery (MIND) Institute (LJS); MH 43518 and MH 65562 (MTT, LJS); MH 63951 (LJS); MH 46318 (MTT); The Commonwealth Research Center of the Massachusetts Department of Mental Health, SCDMH82101008006 (LJS). NR 64 TC 12 Z9 12 U1 7 U2 35 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 142 EP 148 DI 10.1016/j.schres.2014.04.015 PG 7 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100023 PM 24836971 ER PT J AU Brent, BK Seidman, LJ Coombs, G Keshavan, MS Moran, JM Holt, DJ AF Brent, Benjamin K. Seidman, Larry J. Coombs, Garth, III Keshavan, Matcheri S. Moran, Joseph M. Holt, Daphne J. TI Neural responses during social reflection in relatives of schizophrenia patients: Relationship to subclinical delusions SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Social reflection; Schizophrenia; Delusions; Genetic risk; Relatives ID DEFAULT-MODE NETWORK; METACOGNITIVE EVALUATION; PERSECUTORY DELUSIONS; 1ST-DEGREE RELATIVES; PREFRONTAL CORTEX; SELF-REFLECTION; HIGH-RISK; MIND; FMRI; DYSFUNCTION AB Background: Deficits in the capacity to reflect about the self and others ("social reflection" [SR]) have been identified in schizophrenia, as well as in people with a genetic or clinical risk for the disorder. However, the neural underpinnings of these abnormalities are incompletely understood. Methods: Responses of a network of brain regions known to be involved in self and other processing (e. g., medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and superior temporal gyrus (STG)) were measured during SR in 16 first-degree, non-psychotic relatives (RELS) of schizophrenia patients and 16 healthy controls (CONS). Because of prior evidence linking dysfunction in this network and delusions, associations between SR-related responses of this network and subclinical delusions (measured using the Peters et al. Delusions Inventory) were also examined. Results: Compared with CONS, RELS showed significantly less SR-related activity of the right and left PCC and STG. Moreover, response magnitudes were negatively correlated with levels of delusional thinking across both groups. Conclusions: These findings suggest that aberrant function of the neural circuitry underpinning SR is associated with the genetic liability to schizophrenia and confers vulnerability to delusional beliefs. (C) 2014 Elsevier B. V. All rights reserved. C1 [Brent, Benjamin K.; Seidman, Larry J.; Keshavan, Matcheri S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Psychiat, Sch Med, Boston, MA 02215 USA. [Holt, Daphne J.] HST MIT Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Brent, Benjamin K.; Seidman, Larry J.; Holt, Daphne J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Coombs, Garth, III] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Moran, Joseph M.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Moran, Joseph M.] US Army Natick Soldier Res Dev & Engn Ctr, Natick, MA USA. RP Brent, BK (reprint author), Massachusetts Mental Hlth Ctr, 75 Fenwood Rd,Room 618, Boston, MA 02115 USA. EM bbrent@bidmc.harvard.edu FU Harvard Catalyst and the Harvard Clinical and Translational Science Center; NIH [KL2 RR 025757, T32 16259]; Harvard Medical School's Stuart T. Hauser Clinical Research Training Program; Commonwealth Research Center of the Massachusetts Department of Mental Health [SCDMH82101008006]; National Institute of Mental Health [K23MH076054] FX This work was supported by a KL2 Medical Research Investigator Training (MeRIT) award from the Harvard Catalyst and the Harvard Clinical and Translational Science Center, NIH KL2 RR 025757 (BKB), Harvard Medical School's Stuart T. Hauser Clinical Research Training Program, NIH T32 16259 (BKB), the Commonwealth Research Center of the Massachusetts Department of Mental Health (SCDMH82101008006; BKB, LJS), and by the National Institute of Mental Health grant no. K23MH076054 (DJH). NR 68 TC 3 Z9 3 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 292 EP 298 DI 10.1016/j.schres.2014.05.033 PG 7 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100045 PM 24951401 ER PT J AU Tabak, NT Granholm, E AF Tabak, Naomi T. Granholm, Eric TI Mindful cognitive enhancement training for psychosis: A pilot study SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID MEDITATION; ATTENTION C1 [Tabak, Naomi T.; Granholm, Eric] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Granholm, Eric] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. RP Tabak, NT (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, MIRECC, Bldg 210,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ntabak@ucla.edu RI Granholm, Eric/P-7680-2014 FU NIMH NIH HHS [T32 MH096682, T32MH09668] NR 10 TC 2 Z9 2 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 EI 1573-2509 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2014 VL 157 IS 1-3 BP 312 EP 313 DI 10.1016/j.schres.2014.06.002 PG 2 WC Psychiatry SC Psychiatry GA AO4MR UT WOS:000341314100049 PM 24968738 ER PT J AU Mendelsohn, J Bertagnolli, MM AF Mendelsohn, John Bertagnolli, Monica M. TI The 2010 Institute of Medicine Consensus Statement "A National Clinical Trials Network for the 21st Century": Progress and Challenges SO SEMINARS IN ONCOLOGY LA English DT Editorial Material C1 [Mendelsohn, John] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bertagnolli, Monica M.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Mendelsohn, J (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. EM jmendelsohn@mdanderson.org; mbertagnolli@partners.org RI Mendelsohn, John/K-6864-2016 NR 1 TC 2 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2014 VL 41 IS 4 BP 435 EP 436 DI 10.1053/j.seminoncol.2014.06.003 PG 2 WC Oncology SC Oncology GA AO3KS UT WOS:000341228700001 PM 25173135 ER PT J AU Gedeon, PC Riccione, KA Fecci, PE Sampson, JH AF Gedeon, Patrick C. Riccione, Katherine A. Fecci, Peter E. Sampson, John H. TI Antibody-Based Immunotherapy for Malignant Glioma SO SEMINARS IN ONCOLOGY LA English DT Review ID EPIDERMAL-GROWTH-FACTOR; REGULATORY T-CELLS; ENHANCES ANTITUMOR IMMUNITY; PRIMARY INTRACRANIAL TUMORS; FACTOR RECEPTOR EGFRVIII; NON-HODGKINS-LYMPHOMA; PRIMARY BRAIN-TUMORS; I CLINICAL-TRIAL; MONOCLONAL-ANTIBODIES; TGF-BETA AB Conventional therapy for malignant glioma (MG) fails to specifically eliminate tumor cells, resulting in toxicity that limits therapeutic efficacy. In contrast, antibody-based immunotherapy uses the immune system to eliminate tumor cells with exquisite specificity. Increased understanding of the pathobiology of MG and the profound immunosuppression present among patients with MG has revealed several biologic targets amenable to antibody-based immunotherapy. Novel antibody engineering techniques allow for the production of fully human antibodies or antibody fragments with vastly reduced antigen-binding dissociation constants, increasing safety when used clinically as therapeutics. In this report, we summarize the use of antibody-based immunotherapy for MG. Approaches currently under investigation include the use of antibodies or antibody fragments to: (1) redirect immune effector cells to target tumor mutations, (2) inhibit immunosuppressive signals and thereby stimulate an immunological response against tumor cells, and (3) provide costimulatory signals to evoke immunologic targeting of tumor cells. These approaches demonstrate highly compelling safety and efficacy for the treatment of MG, providing a viable adjunct to current standard-of-care therapy for MG. (C) 2014 Elsevier Inc. All rights reserved. C1 [Gedeon, Patrick C.; Riccione, Katherine A.; Sampson, John H.] Duke Univ, Med Ctr, Duke Brain Tumor Immunotherapy Program, Div Neurosurg,Dept Surg, Durham, NC 27710 USA. [Gedeon, Patrick C.; Riccione, Katherine A.; Sampson, John H.] Duke Univ, Dept Biomed Engn, Durham, NC 27710 USA. [Gedeon, Patrick C.; Riccione, Katherine A.; Sampson, John H.] Duke Univ, Med Ctr, Preston Robert Tisch Brain Tumor Ctr, Durham, NC 27710 USA. [Fecci, Peter E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA USA. RP Gedeon, PC (reprint author), Duke Univ, Med Ctr, Box 3050, Durham, NC 27710 USA. EM patrick.gedeon@duke.edu RI Gedeon, Patrick/G-6563-2013 OI Gedeon, Patrick/0000-0002-5387-1833 FU NCI NIH HHS [P30 CA014236]; NIGMS NIH HHS [T32 GM007171]; NINDS NIH HHS [R01 NS085412] NR 174 TC 4 Z9 4 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD AUG PY 2014 VL 41 IS 4 BP 496 EP 510 DI 10.1053/j.seminoncol.2014.06.004 PG 15 WC Oncology SC Oncology GA AO3KS UT WOS:000341228700008 PM 25173142 ER PT J AU Deyo, RA Dworkin, SF Amtmann, D Andersson, G Borenstein, D Carragee, E Carrino, J Chou, R Cook, K DeLitto, A Goertz, C Khalsa, P Loeser, J Mackey, S Panagis, J Rainville, J Tosteson, T Turk, D Von Korff, M Weiner, DK AF Deyo, Richard A. Dworkin, Samuel F. Amtmann, Dagmar Andersson, Gunnar Borenstein, David Carragee, Eugene Carrino, John Chou, Roger Cook, Karon DeLitto, Anthony Goertz, Christine Khalsa, Partap Loeser, John Mackey, Sean Panagis, James Rainville, James Tosteson, Tor Turk, Dennis Von Korff, Michael Weiner, Debra K. TI Report of the NIH Task Force on Research Standards for Chronic Low Back Pain SO SPINE JOURNAL LA English DT Article DE Low back pain; chronic low back pain; research standards; minimum dataset; NIH Task Force ID CLINICAL-PRACTICE GUIDELINE; DEFINING CHRONIC PAIN; INFORMATION-SYSTEM PROMIS; FUNCTION ITEM BANK; QUALITY-OF-LIFE; PRIMARY-CARE; PROGNOSTIC APPROACH; SCREENING TOOL; START BACK; OUTCOME MEASURES AB Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses'' in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. PERSPECTIVE: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes. This guideline article was first reported in the The Journal of Pain. (C) 2014 by the American Pain Society. C1 [Deyo, Richard A.; Chou, Roger] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Dworkin, Samuel F.; Amtmann, Dagmar; Loeser, John; Turk, Dennis] Univ Washington, Seattle, WA 98195 USA. [Andersson, Gunnar] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Borenstein, David] George Washington Univ, Washington, DC USA. [Carragee, Eugene; Mackey, Sean] Stanford Univ, Stanford, CA 94305 USA. [Carrino, John; Weiner, Debra K.] Johns Hopkins Univ, Baltimore, MD USA. [Cook, Karon] Northwestern Univ, Evanston, IL USA. [DeLitto, Anthony] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [DeLitto, Anthony] Univ Pittsburgh, Pittsburgh, PA USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Khalsa, Partap] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. [Panagis, James] Natl Inst Arthritis Musculoskeletal & Skin Dis, Bethesda, MD USA. [Rainville, James] New England Baptist Hosp, Roxbury Crossing, MA USA. [Tosteson, Tor] Dartmouth Coll, Hanover, NH USA. [Von Korff, Michael] Grp Hlth Res Inst, Seattle, WA USA. RP Deyo, RA (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd,Mail Code FM, Portland, OR 97239 USA. EM deyor@ohsu.edu FU National Center for Complementary and Alternative Medicine; National Institute for Arthritis, Musculoskeletal, and Skin Diseases FX This study was supported by the National Center for Complementary and Alternative Medicine and the National Institute for Arthritis, Musculoskeletal, and Skin Diseases. NR 124 TC 6 Z9 6 U1 8 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD AUG PY 2014 VL 14 IS 8 BP 1375 EP 1391 DI 10.1016/j.spinee.2014.05.002 PG 17 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AO4JT UT WOS:000341304300002 PM 24950669 ER PT J AU Do Kim, S Melikian, R Ju, KL Zurakowski, D Wood, KB Bono, CM Harris, MB AF Do Kim, Sang Melikian, Rojeh Ju, Kevin L. Zurakowski, David Wood, Kirkham B. Bono, Christopher M. Harris, Mitchel B. TI Independent predictors of failure of nonoperative management of spinal epidural abscesses SO SPINE JOURNAL LA English DT Article DE Spinal epidural abscess; Nonoperative Treatment; Outcomes; Infection; Risk factors; Decompression ID EXPERIENCE AB BACKGROUND CONTEXT: The notion that all patients with spinal epidural abscess (SEA) require surgical decompression has been recently challenged by reports of successful medical management of select patients with SEA. PURPOSE: The purpose of this study was to identify the independent variables that determine success or failure of medical management of SEA. STUDY DESIGN/SETTING: This was a retrospective, case-control study. PATIENT SAMPLE: Patients 18 years or older with diagnosis of SEA admitted to our institution during the study period were included in the sample. OUTCOME MEASURES: The outcome measure was successful management of SEA by eradication of the infection without worsening of neurologic deficits. METHODS: All patients admitted to our health-care system with a diagnosis of SEA from 1993 to 2011 were identified and the data were retrospectively collected. Patients 18 years or older diagnosed with SEA were included. Excluded were those with postsurgical SEA or phlegmon without an abscess and those with a complete spinal cord injury from SEA for longer than 48 hours. RESULTS: A total of 355 patients with average age of 60 years met our inclusion criteria. Of the patients who initially underwent nonoperative treatment, 54 patients failed medical management and 73 patients were successfully treated without surgery. Univariate and multivariate analysis identified incomplete or complete spinal cord deficits as the most significant risk factor for failure of medical management. Age older than 65 years, diabetes, and methicillin-resistant Staphylococcus aureus (MRSA) were also independent risk factors for failure. An algorithm for probability of failed antibiotic management of spinal epidural abscess predicted 99% probability of failure for patients with all four of these risk factors. CONCLUSIONS: SEA treated with medical management alone has a very high risk for failure if the patient is older than 65 years with diabetes, MRSA infection, or neurologic compromise. In the absence of these risk factors, nonoperative management of spinal epidural abscess may be considered as the initial line of treatment with close monitoring. (C) 2014 Elsevier Inc. All rights reserved. C1 [Do Kim, Sang] Cedars Sinai Med Ctr, Spine Ctr Excellence, Los Angeles, CA 90048 USA. [Melikian, Rojeh; Ju, Kevin L.; Wood, Kirkham B.] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Zurakowski, David] Boston Childrens Hosp, Dept Orthopaed, Boston, MA 02115 USA. [Bono, Christopher M.; Harris, Mitchel B.] Brigham & Womens Hosp, Dept Orthopaed, Boston, MA 02115 USA. RP Do Kim, S (reprint author), Cedars Sinai Med Ctr, Spine Ctr Excellence, 444 S San Vicente Blvd Suite 901, Los Angeles, CA 90048 USA. EM sangdkim@gmail.com FU Globus; K2M; NIH; AOSpine; Depuy; OREF FX SDK: Nothing to disclose. RM: Nothing to disclose. KLJ: Nothing to disclose. DZ: Nothing to disclose. KBW: Stock Ownership: Trans 1 (B, Paid directly to employer); Consulting: Depuy (D, Paid directly to employer); Research Support (Investigator Salary, Staff/Materials): Globus (E, Paid to institution), K2M (F, Paid to institution); Grants: NIH (F, Paid to institution); Fellowship Support: Globus (E, Paid to institution), AOSpine (E, Paid to institution), Depuy (D, Paid to institution), OREF (E, Paid to institution). CMB: Royalties: Wolters Kluwer (A); Consulting: United Health Care (B), Intrinsic therapeutics NR 36 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 EI 1878-1632 J9 SPINE J JI Spine Journal PD AUG PY 2014 VL 14 IS 8 BP 1673 EP 1679 DI 10.1016/j.spinee.2013.10.011 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA AO4JT UT WOS:000341304300038 ER PT J AU Romero, JM Madan, N Betancur, I Ciobanu, A Murphy, E McCullough, D Grant, PE AF Romero, Javier M. Madan, Neil Betancur, Ilda Ciobanu, Adrian Murphy, Erin McCullough, Danielle Grant, P. Ellen TI TIME EFFICIENCY AND DIAGNOSTIC AGREEMENT OF 2-D VERSUS 3-D ULTRASOUND ACQUISITION OF THE NEONATAL BRAIN SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE 3-D ultrasound; Neonatal brain; Volume imaging; Time efficiency ID BIRTH-WEIGHT INFANTS; 3-DIMENSIONAL ULTRASOUND; PRETERM INFANTS; CRANIAL ULTRASOUND; VOLUMETRIC-ANALYSIS; LATERAL VENTRICLES; PREMATURE-INFANT; INJURY; RECONSTRUCTION; OUTCOMES AB The purpose of this study was to compare acquisition time efficiency and diagnostic agreement of neonatal brain ultrasound (US) scans obtained with a 3-D volume US acquisition protocol and the conventional 2-D acquisition protocol. Ninety-one consecutive premature neonatal brain ultrasound scans were prospectively performed on 59 neonates with the conventional 2-D acquisition protocol. Immediately after the 2-D study, a coronal 3-D ultrasound volume was acquired and later reconstructed into axial and sagittal planes. All 59 neonates were imaged in the neonatal intensive care unit to rule out intracranial hemorrhage. Total time for 2-D and 3-D acquisition protocols was recorded, and a two-tailed t-test was used to determine if study durations differed significantly. One pediatric neuroradiologist reviewed the reformatted 3-D images, tomographic ultrasound images. Results were compared with the clinical interpretation of the 2-D conventional study. The mean scanning time for the 2-D US acquisition protocol was 10.56 min (standard deviation [SD] = 7.11), and that for the 3-D volume US acquisition protocol was 1.48 min (SD = 0.59) (p <= 0.001). Inter-observer agreement revealed k values of 0.84 for hydrocephalus, 0.80 for germinal matrix hemorrhage/intraventricular hemorrhage, 0.74 for periventricular leukomalacia and 0.91 for subdural collection, hence near-perfect to substantial agreement between imaging protocols. There was a significant decrease in acquisition time for the 3-D volume ultrasound acquisition protocol compared with the conventional 2-D US protocol (p = <0.001), without compromising the diagnostic quality compared with a conventional 2-D US imaging protocol. (E-mail: Jmromero@partners.org) (C) 2014 World Federation for Ultrasound in Medicine & Biology. C1 [Romero, Javier M.; Ciobanu, Adrian; Murphy, Erin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Madan, Neil] Tufts Med Ctr, Dept Radiol, Boston, MA USA. [McCullough, Danielle] New York Presbyterian Hosp, Dept Anesthesiol, New York, NY USA. [Grant, P. Ellen] Childrens Hosp, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Betancur, Ilda] Lowell Community Hlth Ctr, Dept Internal Med, Lowell, MA USA. RP Romero, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, GRB, 55 Fruit St,Off 279, Boston, MA 02114 USA. EM Jmromero@partners.org NR 30 TC 2 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 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD AUG PY 2014 VL 40 IS 8 BP 1804 EP 1809 DI 10.1016/j.ultrasmedbio.2014.03.013 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA AO6KM UT WOS:000341460100007 PM 24798394 ER PT J AU Mahal, BA Aizer, AA Ziehr, DR Hyatt, AS Sammon, JD Schmid, M Choueiri, TK Hu, JC Sweeney, CJ Beard, CJ D'Amico, AV Martin, NE Kim, SP Trinh, QD Nguyen, PL AF Mahal, Brandon A. Aizer, Ayal A. Ziehr, David R. Hyatt, Andrew S. Sammon, Jesse D. Schmid, Marianne Choueiri, Toni K. Hu, Jim C. Sweeney, Christopher J. Beard, Clair J. D'Amico, Anthony V. Martin, Neil E. Kim, Simon P. Trinh, Quoc-Dien Nguyen, Paul L. TI Trends in Disparate Treatment of African American Men With Localized Prostate Cancer Across National Comprehensive Cancer Network Risk Groups SO UROLOGY LA English DT Article ID TERM ANDROGEN DEPRIVATION; RADICAL PROSTATECTOMY; RACIAL-DIFFERENCES; ACTIVE SURVEILLANCE; RADIATION-THERAPY; PHASE-3 TRIAL; CARE; RADIOTHERAPY; ASSOCIATION; OUTCOMES AB OBJECTIVE To determine whether African Americans (AAs) with intermediate-to high-risk prostate cancer (PCa) receive similar treatment as white patients and whether any observed disparities are narrowing with time. METHODS We used Surveillance, Epidemiology, and End Results to identify 128,189 men with localized intermediate-to high-risk PCa (prostate-specific antigen >= 10 ng/mL, Gleason score >= 7, or T stage >= T2b) diagnosed from 2004 to 2010. We used multivariate logistic regression analyses to determine the impact of race on the receipt of definitive treatment. RESULTS AA men were significantly less likely to receive curative-intent treatment than white men (adjusted odds ratio [AOR], 0.82; 95% confidence interval [CI], 0.79-0.86; P <.001). There was no evidence of this disparity narrowing over time (P-interaction 2010 vs 2004 = .490). Disparities in the receipt of treatment between AA and white men were significantly larger in high-risk (AOR, 0.60; 95% CI, 0.56-0.64; P <.001) than in intermediate-risk disease (AOR, 0.92; 95% CI, 0.88-0.97; P = .04; P-interaction <.001). After adjusting for treatment, demographics, and prognostic factors, AA men had a higher risk of prostate cancer-specific mortality (adjusted hazard ratio, 1.12; 95% CI, 1.01-1.25; P = .03). CONCLUSION AA men with intermediate-to high-risk PCa are less likely to be treated with curative intent than white men. This disparity is worse in high-risk disease and is not improving over time. Factors underlying this treatment disparity should be urgently studied as it is a potentially correctable contributor to excess PCa mortality among AA patients. (C) 2014 Elsevier Inc. C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Radiat Oncol Program, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Henry Ford Hosp, Vattikuti Urol Inst, Detroit, MI 48202 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Urol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. Yale Univ, Canc Outcomes & Publ Policy Effectiveness Res Ctr, Dept Urol, New Haven, CT USA. RP Nguyen, PL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst,Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu RI Martin, Neil/E-2193-2014 OI Martin, Neil/0000-0002-8164-8516 FU Prostate Cancer Foundation; Fitz's Cancer Warriors FX This work is supported by David and Cynthia Chapin, the Prostate Cancer Foundation, Fitz's Cancer Warriors, Hugh Simons in honor of Frank and Anne Simons, and a grant from an anonymous family foundation. NR 29 TC 21 Z9 23 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD AUG PY 2014 VL 84 IS 2 BP 386 EP 392 DI 10.1016/j.urology.2014.05.009 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AO5EH UT WOS:000341365500046 PM 24975710 ER PT J AU Talab, SS McDougal, WS Wu, CL Tabatabaei, S AF Talab, Saman Shafaat McDougal, W. Scott Wu, Chin-Lee Tabatabaei, Shahin TI Mucosa-sparing, KTP Laser Coagulation of Submucosal Telangiectatic Vessels in Patients With Radiation-induced Cystitis: A Novel Approach SO UROLOGY LA English DT Article ID REFRACTORY HEMORRHAGIC CYSTITIS; ALUM IRRIGATION; VOCAL FOLD AB INTRODUCTION This study aimed evaluate the safety and feasibility of endoscopic potassium titanyl phosphate (KTP) laser application in the management of patients with radiation-induced hemorrhagic cystitis (RHC). TECHNICAL CONSIDERATIONS We retrospectively reviewed the records of 20 patients with RHC who underwent endoscopic KTP laser ablation of telangiectatic bladder vessels between October 2005 and January 2013. After initial cystoscopy, KTP laser was used to ablate the submucosal vasculature while preserving the overlying mucosa. The surgical outcome was evaluated by duration of hematuria-free interval, number of episodes of hematuria, and number of required medical and/or surgical interventions after initial treatment. Overall, 20 patients underwent 26 sessions of KTP laser ablation of bladder vessels. The procedure was able to stop bleeding 92% of the time and the average hematuria-free interval after ablation was 11.8 months, with a range of 1-37 months. In 13 patients (65%) hematuria resolved after 1 session of KTP laser treatment, whereas 5 patients (25%) required multiple sessions. Two patients (10%) with severe hematuria continued to have bleeding after laser treatment, which necessitated proximal diversion of urine with percutaneous nephrostomy tubes to control bleeding. CONCLUSION This study suggests that KTP laser, with its unique photoselectivity property, is a safe, effective, and durable treatment with minimal side effects for ablation of submucosal bladder vessels in patients with RHC. (C) 2014 Elsevier Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Tabatabaei, S (reprint author), Massachusetts Gen Hosp, Dept Urol, GRB-1102,15 Parkman St, Boston, MA 02114 USA. EM stabatabaei@partners.org NR 22 TC 2 Z9 2 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD AUG PY 2014 VL 84 IS 2 BP 478 EP 483 DI 10.1016/j.urology.2014.03.029 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA AO5EH UT WOS:000341365500070 PM 24929946 ER PT J AU Balvers, RK Belcaid, Z van den Hengel, SK Kloezeman, J de Vrij, J Wakimoto, H Hoeben, RC Debets, R Leenstra, S Dirven, C Lamfers, MLM AF Balvers, Rutger K. Belcaid, Zineb van den Hengel, Sanne K. Kloezeman, Jenneke de Vrij, Jeroen Wakimoto, Hiroaki Hoeben, Rob C. Debets, Reno Leenstra, Sieger Dirven, Clemens Lamfers, Martine L. M. TI Locally-Delivered T-Cell-Derived Cellular Vehicles Efficiently Track and Deliver Adenovirus Delta24-RGD to Infiltrating Glioma SO VIRUSES-BASEL LA English DT Article DE glioblastoma; oncolytic; cellular vehicles; GSC; T-cell therapy; virotherapy; Delta24-RGD ID CONDITIONALLY REPLICATIVE ADENOVIRUS; ANTIGLIOMA ONCOLYTIC VIROTHERAPY; MESENCHYMAL STEM-CELLS; GENE-TRANSFER; BRAIN-TUMORS; MALIGNANT GLIOMAS; TGF-BETA; IN-VIVO; THERAPY; GLIOBLASTOMA AB Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma. Recent publications have demonstrated the advantages of shielding viral particles within cellular vehicles (CVs), which can be targeted towards the tumor microenvironment. Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma. The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro. The effect of intraparenchymal and tail vein injections on intratumoral virus distribution and overall survival was addressed in an orthotopic glioma stem cell (GSC)-based xenograft model. Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs. Delta24-RGD dosing and incubation time were found to influence the migratory ability of T-cells towards GSCs. Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones. This occurred after injection into the ipsilateral hemisphere, as well as into the non-tumor-bearing hemisphere. We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007). Systemic administration of virus-loaded T-cells resulted in intratumoral viral delivery, albeit at low levels. Based on these findings, we conclude that T-cell-based CVs are a feasible approach to local Delta24-RGD delivery in glioblastoma, although efficient systemic targeting requires further improvement. C1 [Balvers, Rutger K.; Belcaid, Zineb; Kloezeman, Jenneke; de Vrij, Jeroen; Leenstra, Sieger; Dirven, Clemens; Lamfers, Martine L. M.] Erasmus MC, Brain Tumor Ctr, Dept Neurosurg, NL-3015 GE Rotterdam, Netherlands. [van den Hengel, Sanne K.; de Vrij, Jeroen; Hoeben, Rob C.] Leiden Univ, Dept Mol Cell Biol, Med Ctr, NL-2333 ZC Leiden, Netherlands. [Wakimoto, Hiroaki] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Mol Neurosurg Lab, Boston, MA 02114 USA. [Debets, Reno] Erasmus MC Canc Inst, Dept Med Oncol, Lab Expt Tumor Immunol, NL-3015 GE Rotterdam, Netherlands. RP Lamfers, MLM (reprint author), Erasmus MC, Brain Tumor Ctr, Dept Neurosurg, Dr Molewaterpl 50,Ee2236, NL-3015 GE Rotterdam, Netherlands. EM r.balvers@erasmusmc.nl; z.belcaid@erasmusmc.nl; sanne.vandenhengel@wetsus.nl; j.kloezeman@erasmusmc.nl; j.devrij@erasmusmc.nl; HWakimoto@partners.org; r.c.hoeben@lumc.nl; j.debets@erasmusmc.nl; s.leenstra@erasmusmc.nl; c.dirven@erasmusmc.nl; m.lamfers@erasmusmc.nl RI Hoeben, Rob/A-5771-2008; Lamfers, Martine/C-6246-2016; OI Hoeben, Rob/0000-0001-9443-8377; Lamfers, Martine/0000-0001-7745-9029 NR 48 TC 3 Z9 3 U1 0 U2 6 PU MDPI AG PI BASEL PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD AUG PY 2014 VL 6 IS 8 BP 3080 EP 3096 DI 10.3390/v6083080 PG 17 WC Virology SC Virology GA AO6AS UT WOS:000341430400007 PM 25118638 ER PT J AU Rucevic, M Boucau, J Dinter, J Kourjian, G Le Gall, S AF Rucevic, Marijana Boucau, Julie Dinter, Jens Kourjian, Georgio Le Gall, Sylvie TI Mechanisms of HIV Protein Degradation into Epitopes: Implications for Vaccine Design SO VIRUSES-BASEL LA English DT Review DE HIV; antigen processing; protein degradation; proteasome; aminopeptidase; peptidase; immunogen; vaccine vector; dendritic cells; T cells; viral evolution ID MHC CLASS-I; T-CELL RESPONSES; IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN DENDRITIC CELLS; MODULATES PROTEASOME ACTIVITY; CROSS-PRESENTATION PATHWAY; HIGHLY PATHOGENIC SIV; 20 S PROTEASOMES; ANTIGEN PRESENTATION; ENDOPLASMIC-RETICULUM AB The degradation of HIV-derived proteins into epitopes displayed by MHC-I or MHC-II are the first events leading to the priming of HIV-specific immune responses and to the recognition of infected cells. Despite a wealth of information about peptidases involved in protein degradation, our knowledge of epitope presentation during HIV infection remains limited. Here we review current data on HIV protein degradation linking epitope production and immunodominance, viral evolution and impaired epitope presentation. We propose that an in-depth understanding of HIV antigen processing and presentation in relevant primary cells could be exploited to identify signatures leading to efficient or inefficient epitope presentation in HIV proteomes, and to improve the design of immunogens eliciting immune responses efficiently recognizing all infected cells. C1 [Le Gall, Sylvie] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Cambridge, MA 02139 USA. RP Le Gall, S (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Cambridge, MA 02139 USA. EM Rucevic.Marijana@mgh.harvard.edu; jnoucau@mgh.harvard.edu; jdinter@mgh.harvard.edu; gkourjian@mgh.harvard.edu; sylvie_legall@hms.harvard.edu FU NIAID [R01 A1084753, R01 A1084106, R01 AI112493]; Ernst-Schering-Foundation FX The authors acknowledge financial support from NIAID R01 A1084753, R01 A1084106 and R01 AI112493 and thank Matthew Berberich for critical reading the manuscript. Jens Dinter is a Ph.D. student supported by a fellowship from the Ernst-Schering-Foundation. NR 160 TC 4 Z9 4 U1 4 U2 13 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD AUG PY 2014 VL 6 IS 8 BP 3271 EP 3292 DI 10.3390/v6083271 PG 22 WC Virology SC Virology GA AO6AS UT WOS:000341430400015 PM 25196483 ER PT J AU Yokoe, DS Anderson, DJ Berenholtz, SM Calfee, DP Dubberke, ER Ellingson, KD Gerding, DN Haas, JP Kaye, KS Klompas, M Lo, E Marschall, J Mermel, LA Nicolle, LE Salgado, CD Bryant, K Classen, D Crist, K Deloney, VM Fishman, NO Foster, N Goldmann, DA Humphreys, E Jernigan, JA Padberg, J Perl, TM Podgorny, K Septimus, EJ VanAmringe, M Weaver, T Weinstein, RA Wise, R Maragakis, LL AF Yokoe, Deborah S. Anderson, Deverick J. Berenholtz, Sean M. Calfee, David P. Dubberke, Erik R. Ellingson, Katherine D. Gerding, Dale N. Haas, Janet P. Kaye, Keith S. Klompas, Michael Lo, Evelyn Marschall, Jonas Mermel, Leonard A. Nicolle, Lindsay E. Salgado, Cassandra D. Bryant, Kristina Classen, David Crist, Katrina Deloney, Valerie M. Fishman, Neil O. Foster, Nancy Goldmann, Donald A. Humphreys, Eve Jernigan, John A. Padberg, Jennifer Perl, Trish M. Podgorny, Kelly Septimus, Edward J. VanAmringe, Margaret Weaver, Tom Weinstein, Robert A. Wise, Robert Maragakis, Lisa L. TI A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals: 2014 Updates SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID CLOSTRIDIUM-DIFFICILE INFECTIONS; RESISTANT STAPHYLOCOCCUS-AUREUS; SURGICAL SITE INFECTIONS; BLOOD-STREAM INFECTIONS; TRANSMISSION AB Since the publication of "A Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals" in 2008, prevention of healthcare-associated infections (HAIs) has become a national priority. Despite improvements, preventable HAIs continue to occur. The 2014 updates to the Compendium were created to provide acute care hospitals with up-to-date, practical, expert guidance to assist in prioritizing and implementing their HAI prevention efforts. They are the product of a highly collaborative effort led by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), the American Hospital Association (AHA), the Association for Professionals in Infection Control and Epidemiology (APIC), and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise, including the Centers for Disease Control and Prevention (CDC), the Institute for Healthcare Improvement (IHI), the Pediatric Infectious Diseases Society (PIDS), the Society for Critical Care Medicine (SCCM), the Society for Hospital Medicine (SHM), and the Surgical Infection Society (SIS). C1 [Yokoe, Deborah S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yokoe, Deborah S.; Goldmann, Donald A.] Harvard Univ, Sch Med, Boston, MA USA. [Anderson, Deverick J.] Duke Univ, Med Ctr, Durham, NC USA. [Berenholtz, Sean M.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Berenholtz, Sean M.; Perl, Trish M.; Maragakis, Lisa L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Calfee, David P.] Weill Cornell Med Coll, New York, NY USA. [Dubberke, Erik R.] Washington Univ, Sch Med, St Louis, MO USA. [Ellingson, Katherine D.; Jernigan, John A.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Gerding, Dale N.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Gerding, Dale N.] Loyola Univ Chicago, Stritch Sch Med, Chicago, IL USA. [Haas, Janet P.] Westchester Med Ctr, Valhalla, NY USA. [Haas, Janet P.] New York Med Coll, Valhalla, NY 10595 USA. [Kaye, Keith S.] Detroit Med Ctr, Detroit, MI USA. [Kaye, Keith S.] Wayne State Univ, Detroit, MI USA. [Klompas, Michael] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Lo, Evelyn] St Boniface Gen Hosp, Winnipeg, MB R2H 2A6, Canada. [Lo, Evelyn; Nicolle, Lindsay E.] Univ Manitoba, Winnipeg, MB, Canada. [Marschall, Jonas] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Marschall, Jonas] Univ Bern, Bern, Switzerland. [Mermel, Leonard A.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Mermel, Leonard A.] Rhode Isl Hosp, Providence, RI USA. [Nicolle, Lindsay E.] Hlth Sci Ctr, Winnipeg, MB, Canada. [Salgado, Cassandra D.] Med Univ S Carolina, Charleston, SC 29425 USA. [Bryant, Kristina] Univ Louisville, Louisville, KY 40292 USA. [Classen, David] Univ Utah, Sch Med, Salt Lake City, UT USA. [Crist, Katrina; Weaver, Tom] Assoc Profess Infect Control & Epidemiol, Washington, DC USA. [Deloney, Valerie M.; Humphreys, Eve] Soc Healthcare Epidemiol Amer, Arlington, VA USA. [Fishman, Neil O.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Foster, Nancy] Amer Hosp Assoc, Washington, DC USA. [Goldmann, Donald A.] Inst Healthcare Improvement, Cambridge, MA USA. [Goldmann, Donald A.] Boston Childrens Hosp, Boston, MA USA. [Jernigan, John A.] Emory Univ, Sch Med, Atlanta, GA USA. [Padberg, Jennifer] Infect Dis Soc Amer, Arlington, VA USA. [Podgorny, Kelly; VanAmringe, Margaret; Wise, Robert] Joint Commiss, Oak Brook Terrace, IL USA. [Septimus, Edward J.] Texas A&M Hlth Sci Ctr, Coll Med, Houston, TX USA. [Septimus, Edward J.] Hosp Corp Amer, Nashville, TN USA. [Weinstein, Robert A.] Stroger Hosp, Chicago, IL USA. [Weinstein, Robert A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. RP Yokoe, DS (reprint author), 181 Longwood Ave, Boston, MA 02115 USA. EM dyokoe@partners.org FU Society for Healthcare Epidemiology of America FX Support for this Compendium was provided by the Society for Healthcare Epidemiology of America. NR 21 TC 0 Z9 0 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2014 VL 35 IS 8 BP 967 EP 977 DI 10.1086/677216 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AL3RQ UT WOS:000339046900005 ER PT J AU Le, MTN Hamar, P Lieberman, J AF Le, M. T. N. Hamar, P. Lieberman, J. TI miR-200 in extracellular vesicles promotes metastasis of breast cancer cells SO ACTA PHYSIOLOGICA LA English DT Meeting Abstract C1 [Le, M. T. N.; Hamar, P.; Lieberman, J.] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Hamar, P.] Semmelweis Univ, Inst Pathophysiol, H-1085 Budapest, Hungary. RI Lieberman, Judy/A-2717-2015 NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1748-1708 EI 1748-1716 J9 ACTA PHYSIOL JI Acta Physiol. PD AUG PY 2014 VL 211 SU 697 SI SI MA S5-E4 BP 54 EP 54 PG 1 WC Physiology SC Physiology GA AN4VO UT WOS:000340586900140 ER PT J AU Batki, SL Pennington, DL Lasher, B Neylan, TC Metzler, T Waldrop, A Delucchi, K Herbst, E AF Batki, Steven L. Pennington, David L. Lasher, Brooke Neylan, Thomas C. Metzler, Thomas Waldrop, Angela Delucchi, Kevin Herbst, Ellen TI Topiramate Treatment of Alcohol Use Disorder in Veterans with Posttraumatic Stress Disorder: A Randomized Controlled Pilot Trial SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Topiramate; Clinical Trial; Alcohol Use Disorder; Posttraumatic Stress Disorder; Cognition ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; COGNITIVE FUNCTION; DEPENDENT PATIENTS; OPEN-LABEL; ADD-ON; EFFICACY; PTSD; NALTREXONE; THERAPY AB Background: The course of posttraumatic stress disorder (PTSD) is frequently and severely complicated by co-occurring alcohol use disorder (AUD), yet there are few reports of pharmacologic treatments for these comorbid conditions. The objective of this pilot study was to obtain a preliminary assessment of the efficacy and safety of topiramate in reducing alcohol use and PTSD symptoms in veterans with both disorders. Methods: This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot trial of flexible-dose topiramate up to 300 mg/d in 30 veterans with PTSD and AUD. The primary outcome measure was frequency of drinking. Secondary outcomes consisted of other measures of alcohol use and PTSD symptom severity. Results: Within-group analyses showed that topiramate treatment was associated with significant reductions in frequency and amount of alcohol use and alcohol craving from baseline through week 12. Between-group analyses showed that topiramate reduced frequency of alcohol use and alcohol craving significantly more than placebo and tended to reduce drinking amount. Topiramate treatment was also associated with decreased PTSD symptom severity and tended to reduce hyperarousal symptoms compared with placebo. Topiramate transiently impaired learning and memory, with significant recovery by the end of treatment. Conclusions: These preliminary results indicate that in veterans with co-occurring PTSD and AUD, topiramate may be effective in reducing alcohol consumption, alcohol craving, and PTSD symptom severity-particularly hyperarousal symptoms. Topiramate was associated with transient cognitive impairment but was otherwise well tolerated. C1 [Batki, Steven L.; Pennington, David L.; Lasher, Brooke; Neylan, Thomas C.; Metzler, Thomas; Waldrop, Angela; Herbst, Ellen] San Francisco VA Med Ctr, San Francisco, CA USA. [Batki, Steven L.; Pennington, David L.; Lasher, Brooke; Neylan, Thomas C.; Metzler, Thomas; Waldrop, Angela; Herbst, Ellen] NCIRE, Addict Res Program, San Francisco, CA USA. [Batki, Steven L.; Neylan, Thomas C.; Metzler, Thomas; Waldrop, Angela; Delucchi, Kevin; Herbst, Ellen] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Batki, SL (reprint author), San Francisco VA Med Ctr 116E, Dept Psychiat, Subst Abuse Programs, 4150 Clement St, San Francisco, CA 94121 USA. EM steven.batki@ucsf.edu FU Department of Defense [W81XWH-05-2-0094, W81XWH-12-2-0137, W81XWH-11-2-0245]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health UCSF-CTSI [UL1 RR024131] FX This work was supported by grants from the Department of Defense W81XWH-05-2-0094, W81XWH-12-2-0137, and W81XWH-11-2-0245 (SLB), National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health UCSF-CTSI UL1 RR024131, which were administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, California. NR 43 TC 15 Z9 16 U1 9 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2014 VL 38 IS 8 BP 2169 EP 2177 DI 10.1111/acer.12496 PG 9 WC Substance Abuse SC Substance Abuse GA AO2UQ UT WOS:000341181900005 PM 25092377 ER PT J AU Gavini, A Reagan, JL Winer, ES Castillo, JJ AF Gavini, Aruna Reagan, John L. Winer, Eric S. Castillo, Jorge J. TI Primary refractory Hodgkin lymphoma: Limited options and poor survival-but not always SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID STEM-CELL TRANSPLANTATION; TUMOR-ASSOCIATED MACROPHAGES; INTERNATIONAL PROGNOSTIC SCORE; POSITRON-EMISSION-TOMOGRAPHY; BRENTUXIMAB VEDOTIN; MARROW-TRANSPLANTATION; RANDOMIZED-TRIAL; 1ST RELAPSE; DISEASE; CHEMOTHERAPY AB Our patient is a 32-year-old woman of Cape Verdean descent, who initially presented in February of 2010 with 1-month course of non-productive cough. She also stated that she had a few swollen lymph nodes on the right side of her neck for the past 6 months, which were initially sore, but never painful. She endorsed drenching night sweats and a 20-pound weight loss over the last 6 months, but denied any fever or chills. Her past medical history and family history were non-contributory. She is a cigarette smoker with a 10 pack-year history of cumulative smoking. After a course of antibiotics that had no effect on her lymphadenopathy, she had a cervical lymph node excisional biopsy. (C) 2014 Wiley Periodicals, Inc. C1 [Gavini, Aruna; Reagan, John L.; Winer, Eric S.] Roger Williams Med Ctr, Div Hematol & Oncol, Providence, RI USA. [Reagan, John L.; Winer, Eric S.] Miriam Hosp, Providence, RI 02906 USA. [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Castillo, JJ (reprint author), 450 Brookline Ave,M221, Boston, MA 02215 USA. EM jorgej_castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 NR 46 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2014 VL 89 IS 8 BP 853 EP 857 DI 10.1002/ajh.23660 PG 5 WC Hematology SC Hematology GA AN5YW UT WOS:000340670000015 PM 24382755 ER PT J AU Fircanis, S Merriam, P Khan, N Castillo, JJ AF Fircanis, Sophia Merriam, Priscilla Khan, Naushaba Castillo, Jorge J. TI The relation between cigarette smoking and risk of acute myeloid leukemia: An updated meta-analysis of epidemiological studies SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; ADULT LEUKEMIA; CYTOGENETIC ABNORMALITIES; MYELODYSPLASTIC SYNDROMES; MULTIPLE-MYELOMA; ALCOHOL-DRINKING; TOBACCO SMOKING; COHORT; ASSOCIATIONS; MALIGNANCIES AB Smoking has been postulated as an environmental risk factor for acute myeloid leukemia (AML). The primary objective of this meta-analysis of observational studies was to evaluate the epidemiologic relationship between smoking and the risk of development of AML. Twenty-three studies published between January 1993 and December 2013 were included in our analysis, and accounted for 7,746 cases of AML. The outcome of interest was the relative risk (RR) with 95% confidence interval (CI) of developing AML in adult cigarette smokers in comparison with non-smokers, and was estimated using the random-effects model. Our results showed that current and ever smokers have 40% (RR 1.40, 95% CI 1.22-1.60; P < 0.001) and 25% (RR 1.25, 95% CI 1.15-1.36; P < 0.001) increased risk of developing AML when compared with non-smokers. The increased RR of AML was increased regardless of sex, study design, geographical region, and quality of the studies. Intensity of smoking of < 10, 10-20, 20-30, and >30 cigarettes per day was associated with RRs of AML of 1.27, 1.36, 1.55, and 1.77, respectively (P < 0.001 for trend). Duration of smoking of <20 and >20 years was associated with RRs of 1.07 and 1.44, respectively (P < 0.001 for trend). Cumulative smoking of < 10, 10-20, 20-30, and >30 pack-years was associated with RRs of 1.13, 1.23, 1.39, and 1.71, respectively (P < 0.001 for trend). Overall, cigarette smoking proves to be a significant risk factor for the development of AML in adults. (C) 2014 Wiley Periodicals, Inc. C1 [Fircanis, Sophia; Merriam, Priscilla] Miriam Hosp, Div Hematol & Oncol, Providence, RI 02906 USA. [Khan, Naushaba] Miriam Hosp, Dept Med, Providence, RI 02906 USA. [Castillo, Jorge J.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Castillo, JJ (reprint author), 450 Brookline Ave,M221, Boston, MA 02215 USA. EM JorgeJ_Castillo@dfci.harvard.edu OI Castillo, Jorge/0000-0001-9490-7532 NR 49 TC 15 Z9 16 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0361-8609 EI 1096-8652 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2014 VL 89 IS 8 BP E125 EP E132 DI 10.1002/ajh.23744 PG 8 WC Hematology SC Hematology GA AN5YW UT WOS:000340670000005 PM 24753145 ER PT J AU Hill, JN Hogan, TP Cameron, KA Guihan, M Goldstein, B Evans, ME Evans, CT AF Hill, Jennifer N. Hogan, Timothy P. Cameron, Kenzie A. Guihan, Marylou Goldstein, Barry Evans, Martin E. Evans, Charlesnika T. TI Perceptions of methicillin-resistant Staphylococcus aureus and hand hygiene provider training and patient education: Results of a mixed method study of health care providers in Department of Veterans Affairs spinal cord injury and disorder units SO AMERICAN JOURNAL OF INFECTION CONTROL LA English DT Article DE Provider training; Patient education; Methicillin-resistant Staphylococcus aureus; Spinal cord injury and disorders ID INFECTIONS; KNOWLEDGE; PREVENTION; BELIEFS; ATTITUDES; AWARENESS; STAFF; MRSA AB Background: The goal of this study was to assess current practices for training of spinal cord injury and disorder (SCI/D) health care workers and education of veterans with SCI/D in Department of Veterans Affairs (VA) spinal cord injury (SCI) centers on methicillin-resistant Staphylococcus aureus (MRSA) prevention. Methods: Mixed methods. A Web-based survey was distributed to 673 VA SCI/D providers across 24 SCI centers; 21 acute care and 1 long-term care facility participated. There were 295 that responded, 228 had complete data and were included in this analysis. Semistructured interviews were conducted with 30 SCI/D providers across 9 SCI centers. Results: Nurses, physicians, and therapists represent most respondents (92.1%, n = 210); over half (56.6%, n = 129) were nurses. Of providers, 75.9% (n = 173) reported receiving excellent or good training on how to educate patients about MRSA. However, nurses were more likely to report having excellent or good training for how to educate patients about MRSA (P = .005). Despite this, only 63.6% (n = 82) of nurses perceived the education they provide patients on how MRSA is transmitted as excellent or good. Conclusion: Despite health care workers reporting receiving excellent or good training on MRSA-related topics, this did not translate to excellent or good education for patients, suggesting that health care workers need additional training for educating patients. Population-specific MRSA prevention educational materials may also assist providers in educating patients about MRSA prevention for individuals with SCI/D. Published by Elsevier Inc. on behalf of the Association for Professionals in Infection Control and Epidemiology, Inc. C1 [Hill, Jennifer N.; Guihan, Marylou; Evans, Charlesnika T.] Edward Hines Jr VA Hosp, Vet Hlth Adm, Dept Vet Affairs, Spinal Cord Injury Qual Enhancement Res Initiat, Hines, IL 60141 USA. [Hill, Jennifer N.; Guihan, Marylou; Evans, Charlesnika T.] Edward Hines Jr VA Hosp, Ctr Innovat Complex Chron Healthcare, Hines, IL 60141 USA. [Hogan, Timothy P.] Edith Nourse Rogers Mem Vet Hosp, US Dept Vet Affairs, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Hogan, Timothy P.] Edith Nourse Rogers Mem Vet Hosp, US Dept Vet Affairs, Natl EHlth Qual Enhancement Res Initiat Coordinat, EHlth Qual Enhancement Res Initiat, Bedford, MA USA. [Hogan, Timothy P.] Univ Massachusetts, Sch Med, Dept Quantitat Hlth Sci, Div Hlth Informat & Implementat Sci, Worcester, MA USA. [Hogan, Timothy P.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Gen Internal Med & Geriatr, Chicago, IL 60611 USA. [Cameron, Kenzie A.; Evans, Charlesnika T.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA. [Cameron, Kenzie A.; Evans, Charlesnika T.] Northwestern Univ, Feinberg Sch Med, Ctr Healthcare Studies, Chicago, IL USA. [Goldstein, Barry] Dept Vet Affairs, Patient Care Serv, Spinal Cord Injury Disorders Serv, Seattle, WA USA. [Goldstein, Barry] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Evans, Martin E.] Dept Vet Affairs, Vet Hlth Adm Methicillin Resistant Staphylococcus, Natl Infect Dis Serv, Cent Off, Lexington, KY USA. [Evans, Martin E.] Lexington VA Med Ctr, Lexington, KY USA. [Evans, Martin E.] Univ Kentucky, Sch Med, Dept Internal Med, Div Infect Dis, Lexington, KY 40536 USA. RP Hill, JN (reprint author), Edward Hines Jr VA Hosp, Vet Hlth Adm, Dept Vet Affairs, 5000 S 5th Ave 151H, Hines, IL 60141 USA. EM jennifer.hill3@va.gov OI Cameron, Kenzie/0000-0002-3535-6459 FU United States Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service, and Quality Enhancement Research Initiative [RRP09-163] FX This study was supported by the United States Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service, and Quality Enhancement Research Initiative (Grant: RRP09-163). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 25 TC 1 Z9 1 U1 2 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-6553 EI 1527-3296 J9 AM J INFECT CONTROL JI Am. J. Infect. Control PD AUG PY 2014 VL 42 IS 8 BP 834 EP 840 DI 10.1016/j.ajic.2014.04.026 PG 7 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA AO4KN UT WOS:000341306700004 PM 24950922 ER PT J AU Chen, JW Galloway, JL AF Chen, Jessica W. Galloway, Jenna L. TI The development of zebrafish craniofacial tendon and ligament progenitors SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 22, 2013 CL Boston, MA SP Soc Craniofacial Genet & Dev Biol C1 [Chen, Jessica W.; Galloway, Jenna L.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Harvard Stem Cell Inst, Ctr Regenerat Med, Boston, MA 02114 USA. [Chen, Jessica W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2014 VL 164 IS 8 MA 14 BP 1879 EP 1880 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA AN5YD UT WOS:000340667900017 ER PT J AU Kong, YW Grimaldi, M Hoyos, T Liao, EC AF Kong, Yawei Grimaldi, Michael Hoyos, Tatiana Liao, Eric C. TI Functional analysis of connective tissue growth factor (ctgf) in neural crest and craniofacial development SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-of-Craniofacial-Genetics-and-Developmental-Biology (SCGDB) CY OCT 22, 2013 CL Boston, MA SP Soc Craniofacial Genet & Dev Biol C1 [Kong, Yawei; Grimaldi, Michael; Hoyos, Tatiana; Liao, Eric C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Regenerat Med,Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Kong, Yawei; Grimaldi, Michael; Liao, Eric C.] Shriners Hosp Children, Boston, MA 02114 USA. [Liao, Eric C.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG PY 2014 VL 164 IS 8 MA 26 BP 1883 EP 1883 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA AN5YD UT WOS:000340667900029 ER PT J AU Pang, CE Shah, VP Sarraf, D Freund, KB AF Pang, Claudine E. Shah, Vinnie P. Sarraf, David Freund, K. Bailey TI Ultra-Widefield Imaging With Autofluorescence and Indocyanine Green Angiography in Central Serous Chorioretinopathy SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID UVEAL EFFUSION SYNDROME; FUNDUS AUTOFLUORESCENCE; SURGICAL-TREATMENT; CLINICAL-FEATURES; PATHOGENESIS; HYPOTHESIS AB PURPOSE: To describe the spectrum of ultra-widefield autofluorescence (AF) and indocyanine green (ICG) angiographic findings in central serous chorioretinopathy (CSC). DESIGN: Retrospective observational case series. METHODS: In 37 patients, 65 eyes with CSC from 2 vitreoretinal clinical practices were imaged using ultra-widefield AF and 24 of these eyes with ultra-widefield ICG angiography. Images were correlated with clinical findings and spectral-domain optical coherence tomography (OCT). RESULTS: In 37 (57%) eyes, a variety of altered AF patterns, including gravitational tracts, extended beyond the posterior 50 degrees of retina. Hyper-AF corresponded to areas of subretinal fluid (SRF) on spectral-domain OCT and was found to persist in 44 (70%) eyes for up to 8 years despite resolution of SRF. These areas corresponded to outer retinal atrophy with viable retinal pigment epithelium (RPE) on spectral-domain OCT and may be explained by the unmasking of normal background RPE AF. Ultra-widefield ICG angiography revealed dilated choroidal vessels and choroidal hyperpermeability in areas corresponding to altered AF on ultra-widefield AF in all 24 eyes. In 20 (83.3%) eyes, dilated vessels were observed in association with 1 or more congested vortex veins ampullas, suggesting that outflow congestion may be a contributing factor to the pathogenesis of CSC. CONCLUSIONS: Ultra-widefield AF and ICG angiography in CSC revealed more widespread disease in a single image than with standard field imaging and may be useful for identifying peripheral areas of previous or ongoing SRF and choroidal hyperpermeability that can assist in the diagnosis of CSC, surveillance of recurrent disease and treatment of active disease. (C) 2014 by Elsevier Inc. All rights reserved. C1 [Pang, Claudine E.; Shah, Vinnie P.; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY 10022 USA. [Pang, Claudine E.; Freund, K. Bailey] Manhattan Eye Ear & Throat Hosp, LuEsther T Mertz Retinal Res Ctr, New York, NY 10021 USA. [Shah, Vinnie P.; Freund, K. Bailey] NYU, Sch Med, Dept Ophthalmol, New York, NY 10003 USA. [Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA 90024 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. RP Freund, KB (reprint author), Vitreous Retina Macula Consultants New York, 460 Pk Ave,Fifth Floor, New York, NY 10022 USA. EM kbfnyf@aol.com OI Shah, Vinnie/0000-0003-1325-7019; Freund, K. Bailey/0000-0002-7888-9773 FU Macula Foundation, Inc., New York, NY, USA; Regeneron; Heidelberg FX ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST, and the following were reported. Financial support was received from the Macula Foundation, Inc., New York, NY, USA. The funding organization had no role in the design or conduct of this research. Dr Freund is a consultant to Genentech, Regeneron, Optos, Heidelberg Engineering, and Bayer. Dr Sarraf received research support from Regeneron and financial support from Heidelberg. Dr Pang and Dr Shah have no financial disclosures. Design and conduct of study (C.E.P., V.P.S., K.B.F., D.S.); Collection, management, analysis, and interpretation of data (C.E.P., V.P.S., K.B.F., D.S.); and Preparation, review, or approval of the manuscript (C.E.P., V.P.S., K.B.F., D.S.). NR 36 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 EI 1879-1891 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD AUG PY 2014 VL 158 IS 2 BP 362 EP 371 DI 10.1016/j.ajo.2014.04.021 PG 10 WC Ophthalmology SC Ophthalmology GA AN6EB UT WOS:000340686600021 PM 24794091 ER PT J AU Sayadi, O Weiss, EH Merchant, FM Puppala, D Armoundas, AA AF Sayadi, Omid Weiss, Eric H. Merchant, Faisal M. Puppala, Dheeraj Armoundas, Antonis A. TI An optimized method for estimating the tidal volume from intracardiac or body surface electrocardiographic signals: implications for estimating minute ventilation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE tidal volume; percent modulation; body surface; intracardiac electrograms; minute ventilation ID RESPIRATORY-DISTRESS-SYNDROME; CHEYNE-STOKES RESPIRATION; CONGESTIVE-HEART-FAILURE; ACUTE LUNG INJURY; REPOLARIZATION ALTERNANS; SLEEPING INFANTS; NEWBORN-INFANTS; PRESSURE; PLETHYSMOGRAPH; PREVENTION AB The ability to accurately monitor tidal volume (TV) from electrocardiographic (ECG) signals holds significant promise for improving diagnosis treatment across a variety of clinical settings. The objective of this study was to develop a novel method for estimating the TV from ECG signals. In 10 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the coronary sinus (CS), left ventricle (LV), and right ventricle (RV), as well as body surface electrograms, while TV was varied between 0 and 750 ml at respiratory rates of 7-14 breaths/min. We devised an algorithm to determine the optimized respirophasic modulation of the amplitude of the ECG-derived respiratory signal. Instantaneous measurement of respiratory modulation showed an absolute error of 72.55, 147.46, 85.68, 116.62, and 50.89 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. Minute TV estimation demonstrated a more accurate estimation with an absolute error of 69.56, 153.39, 79.33, 122.16, and 48.41 ml for body surface, CS, LV, RV, and RV-CS leads, respectively. The RV-CS and body surface leads provided the most accurate estimations that were within 7 and 10% of the true TV, respectively. Finally, the absolute error of the bipolar RV-CS lead was significantly lower than any other lead configuration (P < 0.0001). In conclusion, we have demonstrated that ECG-derived respiratory modulation provides an accurate estimation of the TV using intracardiac or body surface signals, without the need for additional hardware. C1 [Sayadi, Omid; Puppala, Dheeraj; Armoundas, Antonis A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Weiss, Eric H.; Armoundas, Antonis A.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org FU Scientist Development [0635127N]; American Heart Association [12POST9310001]; Heart Rhythm Society [13-FA-32-HRS]; Center for Integration of Medicine and Innovative Technology (CIMIT); Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; Cardiovascular Research Society; Harvard Catalyst; Harvard Clinical and Translational Science Center; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000170-05]; Harvard University; [0815767D] FX The work was supported by a Scientist Development Grant (No. 0635127N), a Pre-Doctoral Fellowship (No. 0815767D), a Founders Affiliate Post-Doctoral Fellowship (No. 12POST9310001) from the American Heart Association, the Kenneth M. Rosen Fellowship in Cardiac Pacing and Electrophysiology (No. 13-FA-32-HRS) from the Heart Rhythm Society, and grants from the Center for Integration of Medicine and Innovative Technology (CIMIT), the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke and the Cardiovascular Research Society. This work was conducted with support from Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic health care centers). NR 36 TC 3 Z9 3 U1 2 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG 1 PY 2014 VL 307 IS 3 BP H426 EP H436 DI 10.1152/ajpheart.00038.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AO1NR UT WOS:000341080300018 PM 24906917 ER PT J AU Weiss, EH Sayadi, O Ramaswamy, P Merchant, FM Sajja, N Foley, L Laferriere, S Armoundas, AA AF Weiss, Eric H. Sayadi, Omid Ramaswamy, Priya Merchant, Faisal M. Sajja, Naveen Foley, Lori Laferriere, Shawna Armoundas, Antonis A. TI An optimized method for the estimation of the respiratory rate from electrocardiographic signals: implications for estimating minute ventilation SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE respiratory rate; estimation; intracardiac; body surface; electrograms; minute ventilation ID CHEYNE-STOKES RESPIRATION; CONGESTIVE-HEART-FAILURE; FREQUENCY; PRESSURE; SLEEP; VARIABILITY; ALTERNANS AB It is well-known that respiratory activity influences electrocardiographic (ECG) morphology. In this article we present a new algorithm for the extraction of respiratory rate from either intracardiac or body surface electrograms. The algorithm optimizes selection of ECG leads for respiratory analysis, as validated in a swine model. The algorithm estimates the respiratory rate from any two ECG leads by finding the power spectral peak of the derived ratio of the estimated root-mean-squared amplitude of the QRS complexes on a beat-by-beat basis across a 32-beat window and automatically selects the lead combination with the highest power spectral signal-to-noise ratio. In 12 mechanically ventilated swine, we collected intracardiac electrograms from catheters in the right ventricle, coronary sinus, left ventricle, and epicardial surface, as well as body surface electrograms, while the ventilation rate was varied between 7 and 13 breaths/min at tidal volumes of 500 and 750 ml. We found excellent agreement between the estimated and true respiratory rate for right ventricular (R-2 = 0.97), coronary sinus (R-2 = 0.96), left ventricular (R-2 = 0.96), and epicardial (R-2 = 0.97) intracardiac leads referenced to surface lead ECGII. When applied to intracardiac right ventricular-coronary sinus bipolar leads, the algorithm exhibited an accuracy of 99.1% (R-2 = 0.97). When applied to 12-lead body surface ECGs collected in 4 swine, the algorithm exhibited an accuracy of 100% (R-2 = 0.93). In conclusion, the proposed algorithm provides an accurate estimation of the respiratory rate using either intracardiac or body surface signals without the need for additional hardware. C1 [Weiss, Eric H.; Sayadi, Omid; Sajja, Naveen; Foley, Lori; Laferriere, Shawna; Armoundas, Antonis A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Weiss, Eric H.; Armoundas, Antonis A.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Ramaswamy, Priya] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org FU Scientist Development [0635127N]; American Heart Association [12POST9310001]; Center for Integration of Medicine and Innovative Technology (CIMIT); Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; Cardiovascular Research Society; Harvard Catalyst; Harvard Clinical and Translational Science Center; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health Award [8UL1TR000170-05]; Harvard University; [0815767D] FX The work was supported by a Scientist Development Grant (No. 0635127N), a Predoctoral Fellowship (No. 0815767D), a Founders Affiliate Postdoctoral Fellowship (No. 12POST9310001) from the American Heart Association, and grants from the Center for Integration of Medicine and Innovative Technology (CIMIT), the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke, and the Cardiovascular Research Society. This work was conducted with support from Harvard Catalyst and The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic health care centers). NR 32 TC 2 Z9 2 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 EI 1522-1539 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG 1 PY 2014 VL 307 IS 3 BP H437 EP H447 DI 10.1152/ajpheart.00039.2014 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA AO1NR UT WOS:000341080300019 PM 24858847 ER PT J AU Fisichella, PM AF Fisichella, Piero Marco TI The puzzling argument of antireflux surgery in obese patients with gastroesophageal reflux disease: can the excellent perioperative safety of antireflux surgery make up for better comprehensive long-term outcomes of bariatric surgery? SO AMERICAN JOURNAL OF SURGERY LA English DT Editorial Material ID BARRETTS-ESOPHAGUS; GASTRIC BYPASS; MORBID-OBESITY; CARDIA; RISK C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg,Boston VA Healthcare Syst, West Roxbury, MA 02215 USA. RP Fisichella, PM (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg,Boston VA Healthcare Syst, 1400 VFW Pkwy 112, West Roxbury, MA 02215 USA. EM piero.fisichella@va.gov OI Fisichella, P. Marco/0000-0002-7697-7884 NR 11 TC 2 Z9 2 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 EI 1879-1883 J9 AM J SURG JI Am. J. Surg. PD AUG PY 2014 VL 208 IS 2 BP 169 EP 170 DI 10.1016/j.amjsurg.2014.03.001 PG 2 WC Surgery SC Surgery GA AO2KC UT WOS:000341149400002 PM 24881022 ER PT J AU Hyman, BT Sorger, P AF Hyman, Bradley T. Sorger, Peter TI Failure Analysis of Clinical Trials to Test the Amyloid Hypothesis SO ANNALS OF NEUROLOGY LA English DT Editorial Material ID ALZHEIMERS-DISEASE; THERAPEUTICS; BETA C1 [Hyman, Bradley T.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. [Sorger, Peter] Harvard Univ, Sch Med, Lab Syst Pharmacol, Boston, MA USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. NR 15 TC 5 Z9 5 U1 4 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2014 VL 76 IS 2 BP 159 EP 161 DI 10.1002/ana.24227 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN8XT UT WOS:000340890000003 PM 25044380 ER PT J AU Paschou, P Yu, DM Gerber, G Evans, P Tsetsos, F Davis, LK Karagiannidis, I Chaponis, J Gamazon, E Mueller-Vahl, K Stuhrmann, M Schloegelhofer, M Stamenkovic, M Hebebrand, J Noethen, M Nagy, P Barta, C Tarnok, Z Rizzo, R Depienne, C Worbe, Y Hartmann, A Cath, DC Budman, CL Sandor, P Barr, C Wolanczyk, T Singer, H Chou, IC Grados, M Posthuma, D Rouleau, GA Aschauer, H Freimer, NB Pauls, DL Cox, NJ Mathews, CA Scharf, JM AF Paschou, Peristera Yu, Dongmei Gerber, Gloria Evans, Patrick Tsetsos, Fotis Davis, Lea K. Karagiannidis, Iordanis Chaponis, Jonathan Gamazon, Eric Mueller-Vahl, Kirsten Stuhrmann, Manfred Schloegelhofer, Monika Stamenkovic, Mara Hebebrand, Johannes Noethen, Markus Nagy, Peter Barta, Csaba Tarnok, Zsanett Rizzo, Renata Depienne, Christel Worbe, Yulia Hartmann, Andreas Cath, Danielle C. Budman, Cathy L. Sandor, Paul Barr, Cathy Wolanczyk, Thomas Singer, Harvey Chou, I-Ching Grados, Marco Posthuma, Danielle Rouleau, Guy A. Aschauer, Harald Freimer, Nelson B. Pauls, David L. Cox, Nancy J. Mathews, Carol A. Scharf, Jeremiah M. TI Genetic Association Signal Near NTN4 in Tourette Syndrome SO ANNALS OF NEUROLOGY LA English DT Article ID GENOMEWIDE ASSOCIATION; HISTIDINE-DECARBOXYLASE; VARIANTS; SLITRK1; SAMPLE; SCANS AB Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3)) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 x 10 (-4)) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 x 10 (7)). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p - 0.042), suggesting that many of these variants are true TS risk alleles. C1 [Paschou, Peristera; Tsetsos, Fotis; Karagiannidis, Iordanis] Democritus Univ Thrace, Dept Mol Biol & Genet, Alexandroupolis 68100, Greece. [Yu, Dongmei; Gerber, Gloria; Chaponis, Jonathan; Pauls, David L.; Scharf, Jeremiah M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Human Genet Res, Psychiat & Neurodev Genet Unit,Dept Psychiat, Boston, MA USA. [Yu, Dongmei; Scharf, Jeremiah M.] Broad Inst Harvard & Massachusetts Inst Technol, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Evans, Patrick; Davis, Lea K.; Gamazon, Eric; Cox, Nancy J.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Mueller-Vahl, Kirsten] Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany. [Stuhrmann, Manfred] Hannover Med Sch, Dept Human Genet, Hannover, Germany. [Schloegelhofer, Monika; Stamenkovic, Mara; Aschauer, Harald] Med Univ Vienna, Dept Psychiat & Psychotherapy, Div Biol Psychiat, Vienna, Austria. [Hebebrand, Johannes] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, Essen, Germany. [Noethen, Markus] Univ Bonn, Inst Human Genet, Life & Brain Ctr, Dept Genom, Bonn, Germany. [Nagy, Peter; Tarnok, Zsanett] Vadaskert Child & Adolescent Psychiat Hosp, Budapest, Hungary. [Barta, Csaba] Semmelweis Univ, Inst Med Chem Mol Biol & Pathobiochem, H-1085 Budapest, Hungary. [Rizzo, Renata] Univ Catania, Dept Med & Pediat Sci, Catania, Italy. [Depienne, Christel] Brain & Spinal Cord Inst, Res Ctr, Paris, France. [Depienne, Christel] Hop La Pitie Salpetriere, Brain & Spinal Cord Inst, Res Ctr, Natl Inst Hlth & Med Res,Res Unit 975, Paris, France. [Depienne, Christel] Univ Paris 06, Res Unit S 975, Paris, France. [Worbe, Yulia; Hartmann, Andreas] Natl Rare Dis Reference Ctr Gilles de la Tourette, Paris, France. [Worbe, Yulia; Hartmann, Andreas] Brain & Spinal Cord Inst, Res Ctr, Dept Neurol, Paris, France. [Cath, Danielle C.] Univ Utrecht, Dept Clin & Hlth Psychol, Utrecht, Netherlands. [Cath, Danielle C.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Budman, Cathy L.] Hofstra Univ, Sch Med, Hempstead, NY 11550 USA. [Budman, Cathy L.] North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA. [Sandor, Paul; Barr, Cathy] Univ Hlth Network, Toronto Western Res Inst, Toronto, ON, Canada. [Sandor, Paul] Youthdale Treatment Ctr, Toronto, ON, Canada. [Wolanczyk, Thomas] Med Univ Warsaw, Dept Child Psychiat, Warsaw, Poland. [Singer, Harvey] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Chou, I-Ching] China Med Univ Hosp, Dept Pediat, Taichung, Taiwan. [Chou, I-Ching] China Med Univ, Grad Inst Integrated Med, Taichung, Taiwan. [Grados, Marco] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Posthuma, Danielle] Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Posthuma, Danielle] Erasmus Univ, Sophia Childs Hosp, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Rouleau, Guy A.] McGill Univ, Dept Neurol & Neurosurg, Montreal Neurol Inst & Hosp, Montreal, PQ, Canada. [Freimer, Nelson B.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. [Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Scharf, Jeremiah M.] Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA. RP Scharf, JM (reprint author), Massachusetts Gen Hosp, Genet Unit, Simches Res Bldg,6th Floor,185 Cambridge St, Boston, MA 02114 USA. EM ppaschou@mbg.duth.gr; jscharf@partners.org OI Paschou, Peristera/0000-0002-9783-1024; Barr, Cathy/0000-0003-0361-0106; Rizzo, Renata/0000-0002-3997-1328; Tsetsos, Fotis/0000-0001-5521-846X; Nothen, Markus/0000-0002-8770-2464; Gamazon, Eric/0000-0003-4204-8734 FU NIH/NINDS grant [NS040024]; Tourette Syndrome Association International Consortium for Genetics; NIH/NINDS [NS016648, NS037484]; American Recovery and Reinvestment Act grants [NS040024-07S1, NS016648-29S1]; NIH/NIMH [MH085057]; Tourette Syndrome Association USA; Tourette Syndrome Association Canada; COST Action grant [BM0905]; Deutsche Forschungsgemeinschaft FX This work was supported by NIH/NINDS grant NS040024 to D.L.P., J.M.S., and the Tourette Syndrome Association International Consortium for Genetics; NIH/NINDS grant NS016648 to D. L. P.; American Recovery and Reinvestment Act grants NS040024-07S1 and NS016648-29S1 to D. L. P.; NIH/NINDS grant NS037484 to N.B.F.; and NIH/NIMH grant MH085057 to J.M.S. The study was also supported by the Tourette Syndrome Association USA, Tourette Syndrome Association Canada, COST Action grant BM0905, and Deutsche Forschungsgemeinschaft (M.N.). NR 21 TC 10 Z9 10 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 EI 1531-8249 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2014 VL 76 IS 2 BP 310 EP 315 DI 10.1002/ana.24215 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA AN8XT UT WOS:000340890000018 PM 25042818 ER PT J AU Herzog, EL Mathur, A Tager, AM Feghali-Bostwick, C Schneider, F Varga, J AF Herzog, Erica L. Mathur, Aditi Tager, Andrew M. Feghali-Bostwick, Carol Schneider, Frank Varga, John TI Interstitial Lung Disease Associated With Systemic Sclerosis and Idiopathic Pulmonary Fibrosis How Similar and Distinct? SO ARTHRITIS & RHEUMATOLOGY LA English DT Review ID MUC5B PROMOTER POLYMORPHISM; STEM-CELL TRANSPLANTATION; PLACEBO-CONTROLLED TRIAL; HIGH-RESOLUTION CT; GROWTH-FACTOR-BETA; SCLERODERMA LUNG; MYCOPHENOLATE-MOFETIL; OPEN-LABEL; INCREASED FREQUENCY; PROFILING REVEALS C1 [Herzog, Erica L.; Mathur, Aditi] Yale Sch Med, New Haven, CT USA. [Tager, Andrew M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tager, Andrew M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Feghali-Bostwick, Carol] Med Univ S Carolina, Charleston, IL USA. [Schneider, Frank] Univ Pittsburgh, Pittsburgh, PA USA. [Varga, John] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Varga, J (reprint author), Northwestern Univ, Feinberg Sch Med, McGaw Pavil,Suite M300,240 East Huron St, Chicago, IL 60611 USA. EM j-varga@northwestern.edu FU NIH [HL-109033, HL-108975, AR-42309] FX Supported by the NIH (grant HL-109033 to Dr. Herzog, grant HL-108975 to Dr. Tager, and grant AR-42309 to Dr. Varga). NR 78 TC 24 Z9 24 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2014 VL 66 IS 8 BP 1967 EP 1978 DI 10.1002/art.38702 PG 12 WC Rheumatology SC Rheumatology GA AN1WV UT WOS:000340375600001 PM 24838199 ER PT J AU Londono, D Cadavid, D Drouin, EE Strle, K McHugh, G Aversa, JM Steere, AC AF Londono, Diana Cadavid, Diego Drouin, Elise E. Strle, Klemen McHugh, Gail Aversa, John M. Steere, Allen C. TI Antibodies to Endothelial Cell Growth Factor and Obliterative Microvascular Lesions in the Synovium of Patients With Antibiotic-Refractory Lyme Arthritis SO ARTHRITIS & RHEUMATOLOGY LA English DT Article ID SPIROCHETE BORRELIA-BURGDORFERI; RHEUMATOID SYNOVIUM; ADHESION MOLECULES; DISEASE; INFECTION; CHEMOKINES; RESPONSES; ANTIGENS; THERAPY; TISSUE AB Objective. Endothelial cell growth factor (ECGF) was recently identified as the first autoantigen known to be a target of T cell and B cell responses in similar to 20% of patients with antibiotic-refractory Lyme arthritis. The goal of the current study was to look for a pathologic correlate between ECGF autoantibody responses and histologic findings in synovial tissue. Methods. Synovial tissue was examined from 14 patients with antibiotic-refractory Lyme arthritis and 6 patients with other forms of chronic inflammatory arthritis, primarily rheumatoid arthritis. The tissue sections were subjected to chemical and immunostaining, and IgG antibody responses to ECGF were determined by enzyme-linked immunosorbent assay (ELISA). Each finding was ranked for statistical analysis. Results. In each disease, synovial tissue showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, among the 14 patients with antibiotic-refractory arthritis, 8 (57%) had obliterative microvascular lesions in the tissue, compared with none of the 6 patients with other forms of chronic inflammatory arthritis (P = 0.04). Among the patients with Lyme arthritis, 5 (36%) had autoantibody responses to ECGF, and all 5 had obliterative lesions, as compared with only 3 of 9 patients who lacked ECGF antibody responses (P = 0.009). Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative lesions (P = 0.02) and with greater vascularity in the tissue (P = 0.05). Conclusion. The correlations of ECGF autoantibody reactivity with obliterative microvascular lesions imply that these autoantibodies may be involved in the obliterative process, suggesting that anti-ECGF antibodies have specific pathologic consequences in the synovial tissue of patients with antibiotic-refractory Lyme arthritis. C1 [Drouin, Elise E.; Strle, Klemen; McHugh, Gail; Steere, Allen C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Drouin, Elise E.; Strle, Klemen; McHugh, Gail; Steere, Allen C.] Harvard Univ, Sch Med, Boston, MA USA. [Aversa, John M.] Yale Univ, Sch Med, New Haven, CT USA. RP Steere, AC (reprint author), Massachusetts Gen Hosp, CNY 149-8301,55 Fruit St, Boston, MA 02114 USA. EM asteere@partners.org FU NIH [AI-101175, K01-AR-062098]; Mathers Foundation; English, Bonter, Mitchell Foundation; Ounsworth-Fitzgerald Foundation; Littauer Foundation; Eshe Fund; Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital; Arthritis Foundation FX Supported by the NIH (grant AI-101175), the Mathers Foundation, the English, Bonter, Mitchell Foundation, the Ounsworth-Fitzgerald Foundation, the Littauer Foundation, the Eshe Fund, and the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital. Dr. Strle's work was supported by the Arthritis Foundation and the NIH (grant K01-AR-062098). NR 35 TC 9 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2326-5191 EI 2326-5205 J9 ARTHRITIS RHEUMATOL JI Arthritis Rheumatol. PD AUG PY 2014 VL 66 IS 8 BP 2124 EP 2133 DI 10.1002/art.38618 PG 10 WC Rheumatology SC Rheumatology GA AN1WV UT WOS:000340375600018 PM 24623727 ER PT J AU Garcia-Perez, MA Peli, E AF Garcia-Perez, Miguel A. Peli, Eli TI The bisection point across variants of the task SO ATTENTION PERCEPTION & PSYCHOPHYSICS LA English DT Article DE Bisection task; Landmark task; Method of single stimuli; Single-presentation method; Two-alternative forced-choice; Response bias; Indecision ID LINE BISECTION; PSYCHOMETRIC FUNCTIONS; VISUAL NEGLECT; LANDMARK TASK; HEMISPATIAL NEGLECT; TEMPORAL BISECTION; DIFFERENCE LIMEN; PREMOTOR NEGLECT; RESPONSE BIAS; INTERVAL BIAS AB Bisection tasks are used in research on normal space and time perception and to assess the perceptual distortions accompanying neurological disorders. Several variants of the bisection task are used, which often yield inconsistent results, prompting the question of which variant is most dependable and which results are to be trusted. We addressed this question using theoretical and experimental approaches. Theoretical performance in bisection tasks is derived from a general model of psychophysical performance that includes sensory components and decisional processes. The model predicts how performance should differ across variants of the task, even when the sensory component is fixed. To test these predictions, data were collected in a within-subjects study with several variants of a spatial bisection task, including a two-response variant in which observers indicated whether a line was transected to the right or left of the midpoint, a three-response variant (which included the additional option to respond "midpoint"), and a paired-comparison variant of the three-response format. The data supported the model predictions, revealing that estimated bisection points were least dependable with the two-response variant, because this format confounds perceptual and decisional influences. Only the three-response paired-comparison format can separate out these influences. Implications for research in basic and clinical fields are discussed. C1 [Garcia-Perez, Miguel A.] Univ Complutense, Fac Psicol, Dept Metodol, Madrid 28223, Spain. [Peli, Eli] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. RP Garcia-Perez, MA (reprint author), Univ Complutense, Fac Psicol, Dept Metodol, Campus Somosaguas, Madrid 28223, Spain. EM miguel@psi.ucm.es RI Garcia-Perez, Miguel Angel/F-7043-2011 OI Garcia-Perez, Miguel Angel/0000-0003-2669-4429 FU Ministerio de Ciencia e Innovacion [PSI2009-08800]; Ministerio de Economia y Competitividad [PSI2012-32903]; NIH [R01EY05957, R01EY12890] FX This research was supported by Grant Nos. PSI2009-08800, from Ministerio de Ciencia e Innovacion, and PSI2012-32903, from Ministerio de Economia y Competitividad, to M. A. G.-P., and by NIH Grant Nos. R01EY05957 and R01EY12890 to E. P. We thank Zachary Reynolds for his help in participant recruitment and data collection. NR 55 TC 10 Z9 10 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1943-3921 EI 1943-393X J9 ATTEN PERCEPT PSYCHO JI Atten. Percept. Psychophys. PD AUG PY 2014 VL 76 IS 6 BP 1671 EP 1697 DI 10.3758/s13414-014-0672-9 PG 27 WC Psychology; Psychology, Experimental SC Psychology GA AN5JS UT WOS:000340627400012 PM 24811039 ER PT J AU Baek, JH Nierenberg, AA Kinrys, G AF Baek, Ji Hyun Nierenberg, Andrew A. Kinrys, Gustavo TI Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Review DE Herbal medicine; anxiety; insomnia; bipolar disorder; adjunctive treatment ID ST-JOHNS-WORT; PLACEBO-CONTROLLED TRIAL; CHAMOMILE MATRICARIA-RECUTITA; HUMAN CYTOCHROME-P450 ENZYMES; RANDOMIZED CONTROLLED-TRIAL; LABORATORY-INDUCED STRESS; OFFICINALIS LEMON BALM; EXTRACT EGB 761(R); GENERALIZED ANXIETY; DOUBLE-BLIND AB Objectives: Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines. Methods: We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder. Results: Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder. Conclusions: Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments. C1 [Baek, Ji Hyun; Nierenberg, Andrew A.; Kinrys, Gustavo] Massachusetts Gen Hosp, Bipolar Clin, Boston, MA 02114 USA. [Baek, Ji Hyun; Nierenberg, Andrew A.; Kinrys, Gustavo] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. [Baek, Ji Hyun] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. [Nierenberg, Andrew A.; Kinrys, Gustavo] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. RP Nierenberg, AA (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Bipolar Clin,Massachusetts Gen Hosp, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM anierenberg@partners.org FU American Psychiatric Association; MGH from National Institute of Mental Health (NIMH); Agency for Healthcare Research and Quality's (AHRQ); Forest Research Institute; PamLabs; Pfizer Pharmaceuticals; Shire; Astra Zeneca; Eli Lilly; Janssen Pharmaceuticals; Bristol-Myers Squibb; Bristol-Myers Squibb Company; Cephalon; Elan Pharmaceuticals; Eli Lilly Company; Forest Pharmaceuticals Inc.; GlaxoSmithkline; Sanofi/Synthelabo; SepracorInc.; Pfizer Inc; UCB Pharma; Wyeth-Ayerst Laboratories FX AA Nierenberg served as a consultant to American Psychiatric Association (only travel expenses paid), Appliance Computing Inc. (Mindsite), Basliea, Brain Cells, Inc., Brandeis University, Bristol-Myers Squibb, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo, Eli Lilly and Company, EpiQ, Forest Research Institute, LP/Mylan Inc., Novartis, PGx Health, Ridge Diganostics, Shire, Schering-Plough, Sunovian, Takeda Pharmaceuticals, Targacept; consulted for, through the Massachusetts General Hospital (MGH) Clinical Trials Network and Institute (CTNI), Astra Zeneca, Brain Cells, Inc., Dianippon Sumitomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept, and Takeda/Lundbeck Pharmaceuticals. He received grant/research support through MGH from National Institute of Mental Health (NIMH), Agency for Healthcare Research and Quality's (AHRQ), Forest Research Institute, PamLabs, Pfizer Pharmaceuticals, Shire; received honoraria from Belvoir Publishing, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, Controlled Risk Insurance Company (CRICO), Dartmouth Medical School, Imedex, Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Publishing, National Association of Continuing Education, Physicians Postgraduate Press, SUNY Buffalo, University of Wisconsin, University of Pisa, University of Michigan, University of Miami, American Professional Society of ADHD and Related Disorders (APSARD), International Society for Bipolar Disorder (ISBD), SciMed, Slack Publishing, WoltersKlower Publishing; 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; (was) on the advisory boards of Appliance Computing, Inc., Brain Cells, Inc., Eli Lilly and Company, Johnson and Johnson, Takeda/Lundbeck, Targacept, InfoMedic; owns stock options in Appliance Computing, Inc. and Brain Cells, Inc; through MGH, AA Nierenberg 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, AA Nierenberg has a patent extension application for the combination of buspirone, bupropion, and melatonin for the treatment of depression.; G Kinrys served as a consultant to Astra-Zeneca, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Janssen Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma and Wyeth-Ayerst Laboratories; is a presenter for Astra-Zeneca, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Janssen Pharmaceutica, Pfizer Inc, Sepracor Inc., UCB Pharma and Wyeth-Ayerst Laboratories; received research support from Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Elan Pharmaceuticals, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Sanofi/Synthelabo, SepracorInc., Pfizer Inc, UCB Pharma and Wyeth-Ayerst Laboratories. G Kinrys reports no equity holding and no royalty/patent. NR 102 TC 4 Z9 5 U1 6 U2 33 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0004-8674 EI 1440-1614 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD AUG PY 2014 VL 48 IS 8 BP 705 EP 715 DI 10.1177/0004867414539198 PG 11 WC Psychiatry SC Psychiatry GA AN4SN UT WOS:000340578900004 PM 24947278 ER PT J AU Sanders, K Jung, JH Loeken, MR AF Sanders, Kaitlyn Jung, Jin Hyuk Loeken, Mary R. TI Use of a Murine Embryonic Stem Cell Line That Is Sensitive to High Glucose Environment to Model Neural Tube Development in Diabetic Pregnancy SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article; Proceedings Paper CT 8th International Neural Tube Defects Conference CY OCT 07-10, 2013 CL Austin, TX DE embryonic stem cells; Scl2a2; Glut2; hyperglycemia; neural tube defect; pregestational diabetic pregnancy; Pax3 ID GENE-EXPRESSION; PHYSIOLOGICAL-GLUCOSE; DEFECTS; APOPTOSIS; MALFORMATIONS; POLARITY AB Background: Neural tube defects (NTDs) are significantly increased by maternal diabetes. Embryonic stem cells (ESC) that can differentiate into neuroepithelium and can sense supraphysiological glucose concentrations would be very valuable to simulate the effects of maternal diabetes on molecular and cellular processes during neural tube formation. Methods: LG-ESC, a recently established ESC line that expresses the glucose transporter, Scl2a2, and is sensitive to elevated glucose concentrations, were grown for up to 8 days in a three-dimensional culture to form neural cysts. We tested whether high glucose media inhibits expression of Pax3, a gene that is required for neural tube closure and whose expression is inhibited in embryos of diabetic mice, and inhibits formation of neural cysts. Results: Pax3 expression was detected after 4 days of culture and increased with time. Pax3 expression was inhibited by high glucose media, but not if cells had been cultured in low glucose media for the first 4 days of culture. Pax7, which is also expressed in dorsal neural tube, was not detected. Pax6, which is expressed in the ventral neural tube, was detected only after 8 days of culture, but was not inhibited by high glucose. High glucose media did not inhibit formation of neural cysts. Conclusion: LG-ESC can be used as a model of embryonic exposure to a diabetic environment during neural tube development. While high glucose exposure inhibits expression of a gene required for neural tube closure, it may not inhibit all of the processes involved in formation of a neural tube-like structure. C1 [Sanders, Kaitlyn; Jung, Jin Hyuk; Loeken, Mary R.] Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol, Boston, MA 02215 USA. [Jung, Jin Hyuk; Loeken, Mary R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Loeken, MR (reprint author), Joslin Diabet Ctr, One Joslin Pl, Boston, MA 02215 USA. EM mary.loeken@joslin.harvard.edu OI Loeken, Mary/0000-0002-8056-9816 FU NIH [RO1DK052865, RO1DK058300, P30DK036836] FX This work was funded by NIH RO1DK052865 (to M. R. L.), NIH RO1DK058300 (to M. R. L.), and NIH P30DK036836 (to the Joslin Diabetes Center). NR 30 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD AUG PY 2014 VL 100 IS 8 SI SI BP 584 EP 591 DI 10.1002/bdra.23281 PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA AO2XN UT WOS:000341191000004 PM 25124397 ER PT J AU Zareba, P Wu, C Agzarian, J Rodriguez, D Kearon, C AF Zareba, P. Wu, C. Agzarian, J. Rodriguez, D. Kearon, C. TI Meta-analysis of randomized trials comparing combined compression and anticoagulation with either modality alone for prevention of venous thromboembolism after surgery SO BRITISH JOURNAL OF SURGERY LA English DT Review ID MOLECULAR-WEIGHT HEPARIN; DEEP-VEIN THROMBOSIS; INTERMITTENT PNEUMATIC COMPRESSION; TOTAL HIP-REPLACEMENT; ABDOMINAL-SURGERY; PULMONARY-EMBOLISM; ELECTIVE HIP; KNEE SURGERY; STOCKINGS; PROPHYLAXIS AB Background: Although venous thromboembolism (VTE) is an important cause of postoperative morbidity and mortality, there is still no consensus on the optimal strategy for VTE prevention after major surgery. The objective of this review was to determine the benefits and risks of thromboprophylaxis with both compression and anticoagulation, compared with either modality alone. Methods: A systematic review of MEDLINE, CENTRAL and Embase databases was performed to identify eligible randomized trials. The literature search and data extraction were carried out independently by two reviewers. Outcomes of interest were deep vein thrombosis (DVT), pulmonary embolism, bleeding, limb injury and mortality. Results: Twenty-five studies were eligible for inclusion. Adding compression to anticoagulation decreased the risk of DVT by 49 per cent (risk ratio (RR) 0.51, 95 per cent confidence interval 0.36 to 0.73). The corresponding funnel plot suggested publication bias and, overall, the evidence for this comparison was judged to be of low quality. Adding anticoagulation to compression decreased the risk of DVT by 44 per cent (RR 0.56, 0.45 to 0.69) while increasing the risk of bleeding (RR 1.74, 1.29 to 2.34). There was no suggestion of publication bias and the evidence for this comparison was judged to be of moderate quality. Conclusion: Combined compression and anticoagulation is more effective at preventing postoperative DVT than either modality alone. However, adding anticoagulation to compression increases the risk of bleeding, and the evidence that adding compression to anticoagulation reduces VTE risk is of low quality. C1 [Zareba, P.; Wu, C.] McMaster Univ, Div Urol, Hamilton, ON, Canada. [Agzarian, J.] McMaster Univ, Div Gen Surg, Hamilton, ON, Canada. [Kearon, C.] McMaster Univ, Dept Med, Hamilton, ON, Canada. [Rodriguez, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. RP Zareba, P (reprint author), St Josephs Healthcare Hamilton, McMaster Inst Urol, 50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada. EM piotr.zareba@medportal.ca NR 43 TC 9 Z9 9 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1323 EI 1365-2168 J9 BRIT J SURG JI Br. J. Surg. PD AUG PY 2014 VL 101 IS 9 BP 1053 EP 1062 DI 10.1002/bjs.9527 PG 10 WC Surgery SC Surgery GA AN5XJ UT WOS:000340665200003 PM 24916118 ER PT J AU Hatzis, C Bedard, PL Birkbak, NJ Beck, AH Aerts, HJWL Stern, DF Shi, LM Clarke, R Quackenbush, J Haibe-Kains, B AF Hatzis, Christos Bedard, Philippe L. Birkbak, Nicolai J. Beck, Andrew H. Aerts, Hugo J. W. L. Stern, David F. Shi, Leming Clarke, Robert Quackenbush, John Haibe-Kains, Benjamin TI Enhancing Reproducibility in Cancer Drug Screening: How Do We Move Forward? SO CANCER RESEARCH LA English DT Review ID MICROARRAY DATA; CYTOTOXICITY; INHIBITION; DISCOVERY; SENSITIVITY; STANDARDS; MELANOMA; STRATEGY; IMPACT; TARGET AB Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories. (C)2014 AACR. C1 [Hatzis, Christos] Yale Univ, Sch Med, Sect Med Oncol, New Haven, CT USA. [Stern, David F.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Hatzis, Christos; Stern, David F.] Yale Univ, Yale Canc Ctr, New Haven, CT USA. [Beck, Andrew H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Biostat & Computat Bio, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.; Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Canc Computat Biol, Boston, MA 02215 USA. [Quackenbush, John] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02215 USA. [Aerts, Hugo J. W. L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol & Radiol, Boston, MA 02215 USA. [Shi, Leming] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Clarke, Robert] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Bedard, Philippe L.; Haibe-Kains, Benjamin] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Bedard, Philippe L.] Univ Toronto, Fac Med, Toronto, ON, Canada. [Haibe-Kains, Benjamin] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Birkbak, Nicolai J.] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Shi, Leming] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Shi, Leming] Fudan Univ, Sch Pharm, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Shi, Leming] Zhanjiang Ctr Translat Med, Shanghai, Peoples R China. RP Haibe-Kains, B (reprint author), Univ Hlth Network, Princess Margaret Canc Ctr, 101 Coll St, Toronto, ON M5G 1L7, Canada. EM bhaibeka@uhnresearch.ca RI Clarke, Robert/A-6485-2008; Hatzis, Christos/M-3867-2015; Aerts, Hugo/P-6350-2015; Haibe-Kains, Benjamin/D-3702-2011 OI Clarke, Robert/0000-0002-9278-0854; Hatzis, Christos/0000-0002-8120-2290; Aerts, Hugo/0000-0002-2122-2003; Haibe-Kains, Benjamin/0000-0002-7684-0079 FU Yale University; United States National Institute of Health [UM1 CA186644]; Villum Kann Rasmussen Foundation; Klarman Family Foundation; US National Institutes of Health (NIH) [CA087969]; NIH National Cancer Institute (NCI) [R01CA80065]; NIH [U54 CA149147, R01 CA131465]; NCI GAME-ON Cancer Post-GWAS initiative [5U19 CA148065]; NHLBI [5R01HL111759]; Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre FX C. Hatzis was supported by Yale University. P.L. Bedard was supported by a grant from the United States National Institute of Health (UM1 CA186644). N. Juul Birkbak was funded by The Villum Kann Rasmussen Foundation. A.H. Beck was supported by an award from the Klarman Family Foundation and by support from US National Institutes of Health (NIH) grant CA087969. D.F. Stern was supported by the NIH National Cancer Institute (NCI) under award number R01CA80065. R. Clarke was supported by Public Health Service grants (U54 CA149147 and R01 CA131465) from the NIH. J. Quackenbush was supported by grants from the NCI GAME-ON Cancer Post-GWAS initiative (5U19 CA148065) and the NHLBI (5R01HL111759). B. Haibe-Kains was supported by the Gattuso Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre. NR 41 TC 16 Z9 16 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2014 VL 74 IS 15 BP 4016 EP 4023 DI 10.1158/0008-5472.CAN-14-0725 PG 8 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400003 PM 25015668 ER PT J AU Kuruppu, D Brownell, AL Shah, K Mahmood, U Tanabe, KK AF Kuruppu, Darshini Brownell, Anna-Liisa Shah, Khalid Mahmood, Umar Tanabe, Kenneth K. TI Molecular Imaging with Bioluminescence and PET Reveals Viral Oncolysis Kinetics and Tumor Viability SO CANCER RESEARCH LA English DT Article ID HERPES-SIMPLEX-VIRUS; HSV1-TK GENE-EXPRESSION; LIVER METASTASES; COLON-CARCINOMA; CANCER-THERAPY; IN-VIVO; VECTORS; INFECTION; MICE; REPLICATION AB Viral oncolysis, the destruction of cancer cells by replicating virus, is an experimental cancer therapy that continues to be explored. The treatment paradigm for this therapy involves successive waves of lytic replication in cancer cells. At present, monitoring viral titer at sites of replication requires biopsy. However, repeat serial biopsies are not practically feasible for temporal monitoring of viral replication and tumor response in patients. Molecular imaging provides a noninvasive method to identify intracellular viral gene expression in real time. We imaged viral oncolysis and tumor response to oncolysis sequentially with bioluminescence and positron emission tomography (PET), revealing the kinetics of both processes in tumor xenografts. We demonstrate that virus replication cycles can be identified as successive waves of reporter expression that occur similar to 2 days after the initial viral tumor infection peak. These waves correspond to virions that are released following a replication cycle. The viral and cellular kinetics were imaged with Fluc and Rluc bioluminescence reporters plus two 18F-labeled PET reporters FHBG [9-(4-18F-fluoro-3-[hydroxymethyl] butyl) guanine] and FLT (18F-3'-deoxy-3-'fluorothymidine), respectively. Correlative immunohistochemistry on tumor xenograft sections confirmed in vivo results. Our findings show how PET can be used to identify virus replication cycles and for real-time measurements of intratumoral replicating virus levels. This noninvasive imaging approach has potential utility for monitoring viral oncolysis therapy in patients. (C)2014 AACR. C1 [Kuruppu, Darshini; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Brownell, Anna-Liisa; Shah, Khalid; Mahmood, Umar] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. FU NIH [5R01CA076183, 5R21CA119600, U01CA084301, P50CA127003, 5R01 EB001850, 1R01EB012864, 1S10RR023452]; Department of Defense (DOD) [W81XWH-11-1-0388] FX This work was supported by NIH grants 5R01CA076183 and 5R21CA119600 (K.K. Tanabe), U01CA084301 and P50CA127003 (U. Mahmood), 5R01 EB001850, 1R01EB012864, and 1S10RR023452 (A.-L. Brownell), and Department of Defense (DOD) grant W81XWH-11-1-0388 (D. Kuruppu). NR 37 TC 5 Z9 5 U1 1 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2014 VL 74 IS 15 BP 4111 EP 4121 DI 10.1158/0008-5472.CAN-13-3472 PG 11 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400012 PM 24876106 ER PT J AU Wilson, BJ Saab, KR Ma, J Schatton, T Putz, P Zhan, Q Murphy, GF Gasser, M Waaga-Gasser, AM Frank, NY Frank, MH AF Wilson, Brian J. Saab, Karim R. Ma, Jie Schatton, Tobias Puetz, Pablo Zhan, Qian Murphy, George F. Gasser, Martin Waaga-Gasser, Ana Maria Frank, Natasha Y. Frank, Markus H. TI ABCB5 Maintains Melanoma-Initiating Cells through a Proinflammatory Cytokine Signaling Circuit SO CANCER RESEARCH LA English DT Article ID BINDING CASSETTE TRANSPORTER; MALIGNANT-MELANOMA; TUMOR-GROWTH; BREAST-CANCER; STEM-CELLS; IN-VIVO; INTERLEUKIN-8; CHEMORESISTANCE; PROGRESSION; CXCR1 AB The drug efflux transporter ABCB5 identifies cancer stem-like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells, ABCB5 controls IL1 beta secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1 beta/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth. (C)2014 AACR. C1 [Wilson, Brian J.; Saab, Karim R.; Ma, Jie; Schatton, Tobias; Frank, Markus H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Wilson, Brian J.; Saab, Karim R.; Ma, Jie; Schatton, Tobias; Puetz, Pablo; Frank, Natasha Y.; Frank, Markus H.] Harvard Univ, Sch Med, Boston Childrens Hosp, Transplant Res Program, Boston, MA USA. [Wilson, Brian J.; Frank, Natasha Y.] VA Boston Healthcare Syst, Dept Med, Boston, MA USA. [Zhan, Qian; Murphy, George F.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Program Dermatopathol, Boston, MA 02115 USA. [Gasser, Martin; Waaga-Gasser, Ana Maria] Univ Wurzburg, Dept Surg, D-97070 Wurzburg, Germany. [Frank, Natasha Y.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. RP Frank, MH (reprint author), Boston Childrens Hosp, Enders Res Bldg Room 507,300 Longwood Ave, Boston, MA 02115 USA. EM markus.frank@childrens.harvard.edu RI Frank, Markus/O-1625-2014 OI Frank, Markus/0000-0002-1312-0488 FU NIH/NCI [1R01CA113796, 1R01CA138231, 2P50CA093683, 1R01CA158467]; U.S. Department of Veterans Affairs (BLR&D VA Merit Award) [10688354] FX This work was supported by the NIH/NCI (grants 1R01CA113796 and 1R01CA138231 to M.H. Frank and grants 2P50CA093683 and 1R01CA158467 to M.H. Frank and G.F. Murphy), and the U.S. Department of Veterans Affairs (BLR&D VA Merit Award 10688354 to N.Y. Frank). NR 50 TC 21 Z9 24 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2014 VL 74 IS 15 BP 4196 EP 4207 DI 10.1158/0008-5472.CAN-14-0582 PG 12 WC Oncology SC Oncology GA AO2VM UT WOS:000341184400019 PM 24934811 ER PT J AU Krolewski, AS Gohda, T Niewczas, MA AF Krolewski, Andrzej S. Gohda, Tomohito Niewczas, Monika A. TI Progressive renal decline as the major feature of diabetic nephropathy in type 1 diabetes SO CLINICAL AND EXPERIMENTAL NEPHROLOGY LA English DT Review DE Type 1 diabetes; Kidney complications; Proteinuria; Progressive renal decline ID TNF RECEPTORS 1; NORMOTENSIVE PATIENTS; CHEMOKINE RECEPTORS; ALBUMIN EXCRETION; KIDNEY-DISEASE; BLOOD-PRESSURE; IDDM PATIENTS; MICROALBUMINURIA; RISK; PROTEINURIA AB Despite almost universal implementation of renoprotective therapies over the past 25 years, the risk of end-stage renal disease (ESRD) in type 1 diabetes (T1D) is not decreasing, and ESRD remains the major cause of excess morbidity and premature mortality [1]. Such a state of affairs prompts a call to action. In this review we re-evaluated the proteinuria-centric model of diabetic nephropathy and showed its deficiencies. On the basis of extensive studies that we have been conducting on the patients attending the Joslin Clinic, we propose that progressive renal decline, not abnormalities in urinary albumin excretion, should be considered as the major feature of disease processes leading to ESRD in T1D. The etiology of diabetic nephropathy should be reconsidered in light of our new findings so our perspective can be broadened regarding new therapeutic targets available for interrupting the progressive renal decline in T1D. Reduction in the loss of glomerular filtration rate, not reduction of albumin excretion rate, should become the measure for evaluating the effectiveness of new therapeutic interventions. We need new accurate methods for early diagnosis of patients at risk of progressive renal decline or, better still, for detecting in advance which patients will have rapid, moderate or minimal rate of progression to ESRD. C1 [Krolewski, Andrzej S.; Gohda, Tomohito; Niewczas, Monika A.] Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Krolewski, Andrzej S.; Gohda, Tomohito; Niewczas, Monika A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gohda, Tomohito] Juntendo Univ, Sch Med, Dept Internal Med, Div Nephrol, Tokyo 113, Japan. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Div Res, Sect Genet & Epidemiol, 1 Joslin Pl, Boston, MA 02215 USA. EM andrzej.krolewski@joslin.harvard.edu FU NIH [DK-41526, DK676381]; JDRF [1-2008-1018, 17-2013-8]; Diabetes Research Center-Joslin, Pilot and Feasibility Grant [P30DK036836] FX This study was supported by the following grants: NIH grants DK-41526 and DK676381 and JDRF grants 1-2008-1018 and 17-2013-8 to A. S. Krolewski; and Diabetes Research Center-Joslin, Pilot and Feasibility Grant, P30DK036836 to M.A. Niewczas. NR 59 TC 6 Z9 7 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1342-1751 EI 1437-7799 J9 CLIN EXP NEPHROL JI Clin. Exp. Nephrol. PD AUG PY 2014 VL 18 IS 4 BP 571 EP 583 DI 10.1007/s10157-013-0900-y PG 13 WC Urology & Nephrology SC Urology & Nephrology GA AN9MJ UT WOS:000340930700003 PM 24218296 ER PT J AU Ananthakrishnan, AN Cheng, SC Cai, TX Cagan, A Gainer, VS Szolovits, P Shaw, SY Churchill, S Karlson, EW Murphy, SN Kohane, I Liao, KP AF Ananthakrishnan, Ashwin N. Cheng, Su-Chun Cai, Tianxi Cagan, Andrew Gainer, Vivian S. Szolovits, Peter Shaw, Stanley Y. Churchill, Susanne Karlson, Elizabeth W. Murphy, Shawn N. Kohane, Isaac Liao, Katherine P. TI Serum Inflammatory Markers and Risk of Colorectal Cancer in Patients With Inflammatory Bowel Diseases SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Crohn's Disease; Ulcerative Colitis; C-reactive Protein; ESR; Colorectal Cancer ID C-REACTIVE PROTEIN; ULCERATIVE-COLITIS; CROHNS-DISEASE; NEOPLASIA; DIAGNOSIS; THERAPY; COLON; CARCINOGENESIS; DYSPLASIA; CARCINOMA AB BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBDs) (Crohn's disease, ulcerative colitis) are at increased risk of colorectal cancer (CRC). Persistent inflammation is hypothesized to increase risk of CRC in patients with IBD; however, the few studies in this area have been restricted to cross-sectional assessments of histologic severity. No prior studies have examined association between C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) elevation and risk of CRC in an IBD cohort. METHODS: From a multi-institutional validated IBD cohort, we identified all patients with at least one measured CRP or ESR value. Patients were stratified into quartiles of severity of inflammation on the basis of their median CRP or ESR value, and subsequent diagnosis of CRC was ascertained. Logistic regression adjusting for potential confounders was used to identify the independent association between CRP or ESR elevation and risk of CRC. RESULTS: Our study included 3145 patients with at least 1 CRP value (CRP cohort) and 4008 with at least 1 ESR value (ESR cohort). Thirty-three patients in the CRP cohort and 102 patients in the ESR cohort developed CRC during a median follow-up of 5 years at a median age of 55 years. On multivariate analysis, there was a significant increase in risk of CRC across quartiles of CRP elevation (P-trend = .017; odds ratio for quartile 4 vs quartile 1, 2.72; 95% confidence interval, 0.95-7.76). Similarly higher median ESR was also independently associated with risk of CRC across the quartiles (odds ratio, 2.06; 95% confidence interval, 1.14-3.74) (P-trend = .007). CONCLUSIONS: An elevated CRP or ESR is associated with increased risk of CRC in patients with IBD. C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Shaw, Stanley Y.; Karlson, Elizabeth W.; Murphy, Shawn N.; Kohane, Isaac; Liao, Katherine P.] Harvard Univ, Sch Med, Boston, MA USA. [Cheng, Su-Chun; Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Cagan, Andrew; Gainer, Vivian S.; Murphy, Shawn N.] Partners HealthCare, Res IS & Comp, Charlestown, MA USA. [Murphy, Shawn N.] MIT, Dept Neurol, Cambridge, MA 02139 USA. [Szolovits, Peter] MIT, Dept Neurol, Cambridge, MA 02139 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Churchill, Susanne; Kohane, Isaac] Brigham & Womens Hosp, Natl Ctr Biomed Comp I2b2, Boston, MA 02115 USA. [Karlson, Elizabeth W.; Liao, Katherine P.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Kohane, Isaac] Childrens Hosp Boston, Boston, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org OI Szolovits, Peter/0000-0001-8411-6403 FU NIH [U54-LM008748, K08 AR060257, K24 AR052403, P60 AR047782, R01 AR049880]; American Gastroenterological Association; U.S. National Institutes of Health [K23 DK097142]; Harold and Duval Bowen Fund FX Supported by NIH U54-LM008748. A.N.A is supported by funding from the American Gastroenterological Association and from the U.S. National Institutes of Health (K23 DK097142). K.P.L. is supported by NIH K08 AR060257 and the Harold and Duval Bowen Fund. E.W.K is supported by grants from the NIH (K24 AR052403, P60 AR047782, R01 AR049880). NR 43 TC 13 Z9 13 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD AUG PY 2014 VL 12 IS 8 BP 1342 EP + DI 10.1016/j.cgh.2013.12.030 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2BG UT WOS:000341119700023 PM 24407106 ER PT J AU Ioannou, GN Beste, LA Green, PK AF Ioannou, George N. Beste, Lauren A. Green, Pamela K. TI Similar Effectiveness of Boceprevir and Telaprevir Treatment Regimens for Hepatitis C Virus Infection on the Basis of a Nationwide Study of Veterans SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE DAA; Antiviral Therapy; Population; APRI; Outcome; LDL ID HEPATOCELLULAR-CARCINOMA; CIRRHOSIS; PREDICTORS; PREVALENCE; FIBROSIS AB BACKGROUND & AIMS: We investigated the real-world effectiveness of triple therapy regimens against hepatitis C virus (HCV) and compared rates of sustained virologic response (SVR) between telaprevir-based and boceprevir-based regimens in a population-based study. METHODS: We analyzed data on all patients in the Veterans Administration healthcare system who were infected with HCV genotype 1 and began treatment with pegylated interferon, ribavirin, and either boceprevir (n = 3696,83%) or telaprevir (n = 759,17%) from June 2011 to February 2013. RESULTS: Patients treated with telaprevir were more likely to have baseline characteristics associated with not achieving SVR than patients treated with boceprevir. Fewer than half of patients eligible for short-duration regimens (28 weeks for boceprevir, 24 weeks for telaprevir) successfully completed treatment (37% for boceprevir, 27.5% for telaprevir); similar to 25% discontinued early, and the remaining patients were treated for longer durations. Of the patients who were supposed to complete 48-week regimens, only 35% of boceprevir-treated and 34% of telaprevir-treated patients completed >44 weeks. The rate of SVR was 51.5% overall, 42.7% among patients with cirrhosis, 56.8% among treatment-naive patients, 64.2% among prior relapsers, 31.7% among prior partial responders, and 29.8% among prior null responders. There were no significant differences in rate of SVR between patients given boceprevir or telaprevir in the entire population or among subgroups. The most important predictors of failure to achieve SVR were IL28B genotype, high viral load, black race, diabetes, high aspartate aminotransferase to platelet ratio index or FIB-4 scores, low platelet counts, or low levels of low-density lipoprotein cholesterol. Erythropoietin use was not associated with SVR. CONCLUSIONS: In a nationwide analysis of veterans with HCV genotype 1 infection, rates of SVR were similar for those treated with boceprevir vs telaprevir. However, rates of treatment completion and SVR in real clinical practice were substantially lower than those in clinical trials. C1 [Ioannou, George N.] Vet Affairs Puget Sound Hlth Care Syst, Div Gastroenterol, Seattle, WA 98108 USA. [Ioannou, George N.; Green, Pamela K.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98108 USA. [Beste, Lauren A.] Vet Affairs Puget Sound Hlth Care Syst, Div Internal Med, Seattle, WA 98108 USA. [Ioannou, George N.] Univ Washington, Div Gastroenterol, Seattle, WA 98195 USA. [Beste, Lauren A.] Univ Washington, Div Internal Med, Seattle, WA 98195 USA. RP Ioannou, GN (reprint author), Vet Affairs Puget Sound Hlth Care Syst, S 111 Gastro,1660 S Columbian Way, Seattle, WA 98108 USA. EM georgei@medicine.washington.edu FU Merit Review grant, Clinical Science Research and Development, Office of Research and Development, Veterans Affairs [I01CX000320] FX Supported by a Merit Review grant (I01CX000320), Clinical Science Research and Development, Office of Research and Development, Veterans Affairs (G.N.I.). NR 15 TC 25 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 EI 1542-7714 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD AUG PY 2014 VL 12 IS 8 BP 1371 EP 1380 DI 10.1016/j.cgh.2013.12.011 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2BG UT WOS:000341119700027 PM 24361415 ER PT J AU Bensoussan, JC Bolton, MA Pi, S Powell-Hicks, AL Postolova, A Razani, B Reyes, K IsHak, WW AF Bensoussan, Jean-Charles Bolton, Michael A. Pi, Sarah Powell-Hicks, Allycin L. Postolova, Anna Razani, Bahram Reyes, Kevin IsHak, Waguih William TI Quality of life before and after cosmetic surgery SO CNS SPECTRUMS LA English DT Review DE Aesthetic; cosmetic; plastic; quality of life; self-esteem; surgery; well-being ID REPORTED OUTCOME MEASURES; NONSURGICAL FACIAL REJUVENATION; BREAST-REDUCTION SURGERY; BODY-IMAGE; PLASTIC-SURGERY; SELF-ESTEEM; ORTHOGNATHIC SURGERY; PSYCHOSOCIAL CHANGES; BARIATRIC SURGERY; SATISFACTION AB This article reviews the literature regarding the impact of cosmetic surgery on health-related quality of life (QOL). Studies were identified through PubMed/Medline and PsycINFO searches from January 1960 to December 2011. Twenty-eight studies were included in this review, according to specific selection criteria. The procedures and tools employed in cosmetic surgery research studies were remarkably diverse, thus yielding difficulties with data analysis. However, data indicate that individuals undergoing cosmetic surgery began with lower values on aspects of QOL than control subjects, and experienced significant QOL improvement post-procedurally, an effect that appeared to plateau with time. Despite the complexity of measuring QOL in cosmetic surgery patients, most studies showed an improvement in QOL after cosmetic surgery procedures. However, this finding was clouded by measurement precision as well as heterogeneity of procedures and study populations. Future research needs to focus on refining measurement techniques, including developing cosmetic surgery-specific QOL measures. C1 [Bensoussan, Jean-Charles; Bolton, Michael A.; Pi, Sarah; Powell-Hicks, Allycin L.; Reyes, Kevin; IsHak, Waguih William] Cedars Sinai Med Ctr, Dept Psychiat & Behav Neurosci, Los Angeles, CA 90048 USA. [Bolton, Michael A.; Razani, Bahram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Pi, Sarah; IsHak, Waguih William] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Postolova, Anna] Tulane Sch Med, New Orleans, LA USA. RP IsHak, WW (reprint author), Univ Calif Los Angeles, Cedars Sinai Dept Psychiat, 8730 Alden Dr,Thalians E-132, Los Angeles, CA 90048 USA. EM Waguih.IsHak@cshs.org OI IsHak, Waguih/0000-0003-1970-4756 FU NARSAD; Pfizer FX Dr. IsHak has received research grants from NARSAD (Quality of Life in Major Depression) and Pfizer (Geodon in Major Depression) that ended on December 31, 2011. Drs. Bensoussan, Bolton, Powell-Hicks, Postolova, and Razani, Mr. Reyes, and Ms. Pi have no conflicts of interest to declare. NR 45 TC 1 Z9 1 U1 4 U2 19 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD AUG PY 2014 VL 19 IS 4 BP 282 EP 292 DI 10.1017/S1092852913000606 PG 11 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA AN9RD UT WOS:000340944500002 PM 24354998 ER PT J AU Kwak, SY Kim, S Yamakoshi, Y Simmer, JP Beniash, E Margolis, HC AF Kwak, Seo-Young Kim, Sonia Yamakoshi, Yasuo Simmer, James P. Beniash, Elia Margolis, Henry C. TI Regulation of calcium phosphate formation by native amelogenins in vitro SO CONNECTIVE TISSUE RESEARCH LA English DT Article DE Amorphous calcium phosphate; enamel matrix protein; enamel; hydroxyapatite; kinetics; mineralization ID PHOSPHORYLATION; ENAMEL; MATRIX; BOVINE AB Our previous in vitro studies have shown that recombinant full-length porcine amelogenin rP172 can transiently stabilize amorphous calcium phosphate (ACP) and uniquely guide the formation of well-aligned bundles of hydroxyapatite (HA) crystals, as seen in the secretory stage of amelogenesis. This functional capacity is dependent on the hydrophilic C-terminal domain of full-length amelogenin. However, we have also found that native phosphorylated (single S-16 site) forms of full-length (P173) and C-terminal cleaved (P148) amelogenins can stabilize ACP for >2d and prevent HA formation. The present study was carried out to test the hypothesis that, at reduced concentrations, native full-length P173 also has the capacity to guide ordered HA formation. The effect of P148 and P173 concentrations (0.2-2.0 mg/ml) on the rate of spontaneous calcium phosphate precipitation was monitored via changes in solution pH, while mineral phases formed were assessed using TEM. At higher P173 concentrations (1.0-2.0 mg/ml), limited mineral formation occurred and only ACP nanoparticles were observed during a 48 h period. However, at 0.4 mg/ml P173, a predominance of organized bundles of linear, needle-like HA crystals were observed. At 0.2 mg/ml of P173, limited quantities of less organized HA crystals were found. Although P148 similarly stabilized ACP, it did not guide ordered HA formation, like P173. Hence, the establishment of the hierarchical enamel structure during secretory stage amelogenesis may be regulated by the partial removal of full-length amelogenin via MMP20 proteolysis, while predominant amelogenin degradation products, like P148, serve to prevent uncontrolled mineral formation. C1 [Kwak, Seo-Young; Margolis, Henry C.] Forsyth Inst, Ctr Biomineralizat, Dept Appl Oral Sci, Cambridge, MA 02142 USA. [Kwak, Seo-Young; Margolis, Henry C.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Kim, Sonia] Boston Univ, Goldman Sch Dent Med, Boston, MA 02215 USA. [Yamakoshi, Yasuo] Tsurumi Univ, Sch Dent Med, Dept Biochem & Mol Biol, Yokohama, Kanagawa, Japan. [Simmer, James P.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Beniash, Elia] Univ Pittsburgh, Dept Oral Biol, Pittsburgh, PA USA. RP Margolis, HC (reprint author), Forsyth Inst, Ctr Biomineralizat, Dept Appl Oral Sci, 245 First St, Cambridge, MA 02142 USA. EM hmargolis@forsyth.org FU NIDCR [R01-DE023091, R56-DE016376] FX This work was supported by NIDCR grants (HCM) R01-DE023091 and R56-DE016376. The authors report no conflicts of interest. NR 10 TC 5 Z9 5 U1 3 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-8207 EI 1607-8438 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD AUG PY 2014 VL 55 SU 1 BP 21 EP 24 DI 10.3109/03008207.2014.923853 PG 4 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA AO3LP UT WOS:000341231000006 PM 25158174 ER PT J AU Suzuki, M Sierant, ML Antone, JV Everett, ET Whitford, GM Bartlett, JD AF Suzuki, Maiko Sierant, Megan L. Antone, Jerry V. Everett, Eric T. Whitford, Gary M. Bartlett, John D. TI Uncoupling protein-2 is an antioxidant that is up-regulated in the enamel organ of fluoride-treated rats SO CONNECTIVE TISSUE RESEARCH LA English DT Article DE Enamel; fluoride; fluorosis; oxidative stress; UCP2; vitamin E ID ENDOPLASMIC-RETICULUM STRESS; OXIDATIVE STRESS; VITAMIN-E AB Dental fluorosis is characterized by subsurface hypomineralization and retention of enamel matrix proteins. Fluoride (F-) exposure generates reactive oxygen species (ROS) that can cause endoplasmic reticulum (ER)-stress. We therefore screened oxidative stress arrays to identify genes regulated by F- exposure. Vitamin E is an antioxidant so we asked if a diet high in vitamin E would attenuate dental fluorosis. Maturation stage incisor enamel organs (EO) were harvested from F--treated rats and mice were assessed to determine if vitamin E ameliorates dental fluorosis. Uncoupling protein-2 (Ucp2) was significantly up-regulated by F- (similar to 1.5 & 2.0 fold for the 50 or 100ppm F- treatment groups, respectively). Immunohistochemical results on maturation stage rat incisors demonstrated that UCP2 protein levels increased with F- treatment. UCP2 down-regulates mitochondrial production of ROS, which decreases ATP production. Thus, in addition to reduced protein translation caused by ER-stress, a reduction in ATP production by UCP2 may contribute to the inability of ameloblasts to remove protein from the hardening enamel. Fluoride-treated mouse enamel had significantly higher quantitative fluorescence (QF) than the untreated controls. No significant QF difference was observed between control and vitamin E-enriched diets within a given F- treatment group. Therefore, a diet rich in vitamin E did not attenuate dental fluorosis. We have identified a novel oxidative stress response gene that is up-regulated in vivo by F- and activation of this gene may adversely affect ameloblast function. C1 [Suzuki, Maiko; Sierant, Megan L.; Antone, Jerry V.; Bartlett, John D.] Forsyth Inst, Dept Mineralized Tissue Biol, Cambridge, MA 02142 USA. [Suzuki, Maiko; Sierant, Megan L.; Antone, Jerry V.; Bartlett, John D.] Harvard Univ, Sch Dent Med, Cambridge, MA 02142 USA. [Everett, Eric T.] Univ N Carolina, Dept Pediat Dent, Chapel Hill, NC USA. [Everett, Eric T.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Whitford, Gary M.] Georgia Regents Univ, Coll Dent Med, Dept Oral Biol, Augusta, GA USA. RP Bartlett, JD (reprint author), Forsyth Inst, Dept Mineralized Tissue Biol, 245 First St, Cambridge, MA 02142 USA. EM jbartlett@forsyth.org FU NIH/NIDCR [R01DE018106] FX This work was supported by the NIH/NIDCR R01DE018106. The authors report no conflict of interest. The authors alone are responsible for the content and writing of this article. NR 10 TC 3 Z9 3 U1 1 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0300-8207 EI 1607-8438 J9 CONNECT TISSUE RES JI Connect. Tissue Res. PD AUG PY 2014 VL 55 SU 1 BP 25 EP 28 DI 10.3109/03008207.2014.923854 PG 4 WC Cell Biology; Orthopedics SC Cell Biology; Orthopedics GA AO3LP UT WOS:000341231000007 PM 25158175 ER PT J AU Ferguson, CJ Olson, CK Kutner, LA Warner, DE AF Ferguson, Christopher J. Olson, Cheryl K. Kutner, Lawrence A. Warner, Dorothy E. TI Violent Video Games, Catharsis Seeking, Bullying, and Delinquency: A Multivariate Analysis of Effects SO CRIME & DELINQUENCY LA English DT Article DE aggression; violence; mass media; computer games; child development ID MEDIA VIOLENCE; AGGRESSIVE-BEHAVIOR; ADOLESCENTS; CHILDREN; HOSTILITY; EXPOSURE; TIME; LIFE; BAD AB The effects of violent video game exposure on youth aggression remain an issue of significant controversy and debate. It is not yet clear whether violent video games uniquely contribute to long-term youth aggression or whether any relationship is better explained through third variables such as aggressive personality or family environment. The current study examines the influence of violent video game exposure on delinquency and bullying behavior in 1,254 seventh- and eighth-grade students. Variables such as parental involvement, trait aggression, stress, participation in extracurricular activities, and family/peer support were also considered. Results indicated that delinquent and bullying behavior were predicted by the child's trait aggression and stress level. Violent video game exposure was not found to be predictive of delinquency or bullying, nor was level of parental involvement. These results question the commonly held belief that violent video games are related to youth delinquency and bullying. C1 [Ferguson, Christopher J.] Texas A&M Int Univ, Laredo, TX 78041 USA. [Olson, Cheryl K.; Kutner, Lawrence A.] Massachusetts Gen Hosp, Ctr Mental Hlth & Media, Boston, MA 02114 USA. [Warner, Dorothy E.] Judge Baker Childrens Ctr, Boston, MA USA. RP Ferguson, CJ (reprint author), Texas A&M Int Univ, Dept Behav Appl Sci & Criminal Justice, 5201 Univ Blvd, Laredo, TX 78041 USA. EM CJFerguson1111@aol.com NR 60 TC 7 Z9 7 U1 12 U2 93 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0011-1287 EI 1552-387X J9 CRIME DELINQUENCY JI Crime Delinq. PD AUG PY 2014 VL 60 IS 5 BP 764 EP 784 DI 10.1177/0011128710362201 PG 21 WC Criminology & Penology SC Criminology & Penology GA AN6RH UT WOS:000340723300006 ER PT J AU Bayliss, G Weinrauch, LA D'Elia, JA AF Bayliss, George Weinrauch, Larry A. D'Elia, John A. TI Resistant Hypertension in Diabetes Mellitus SO CURRENT DIABETES REPORTS LA English DT Article DE Resistant hypertension; Sympathetic nervous system; Leptin; Aldosterone; Diabetes mellitus ID OBSTRUCTIVE SLEEP-APNEA; OBESITY-RELATED HYPERTENSION; SYMPATHETIC-NERVOUS-SYSTEM; HIGH BLOOD-PRESSURE; RENAL DENERVATION; UNITED-STATES; ALDOSTERONE; LEPTIN; TRIAL; SPIRONOLACTONE AB Resistant hypertension in diabetes is associated with poor cardiovascular and renal outcomes. This brief review will examine the definitions and epidemiology of resistant hypertension and consider the differences between apparent resistant hypertension and truly resistant or refractory hypertension. It will review the role of the sympathetic nervous system in resistant hypertension. It will consider the relationship between obesity and leptin resistance and sympathetic signaling; the role of obstructive sleep apnea in resistant hypertension; and the role of aldosterone in resistant hypertension. It will conclude by mentioning briefly renal nerve ablation. C1 [Bayliss, George] Rhode Isl Hosp, Div Kidney Dis & Hypertens, Providence, RI 02906 USA. [Bayliss, George] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Weinrauch, Larry A.; D'Elia, John A.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Weinrauch, Larry A.; D'Elia, John A.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Weinrauch, Larry A.; D'Elia, John A.] Harvard Univ, Sch Med, Boston, MA USA. RP Bayliss, G (reprint author), Rhode Isl Hosp, Div Kidney Dis & Hypertens, APC 9,593 Eddy St, Providence, RI 02906 USA. EM gbayliss@lifespan.org OI D'Elia, John/0000-0001-9482-581X; Weinrauch, Larry/0000-0003-1357-9528 FU Pat Covelli Foundation FX The authors thank Diane Young, research librarian, Beth Israel Deaconess Medical Center, for her expert assistance, and the Pat Covelli Foundation for its generous support. NR 62 TC 1 Z9 1 U1 1 U2 5 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2014 VL 14 IS 8 AR 516 DI 10.1007/s11892-014-0516-y PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO1OS UT WOS:000341083500009 PM 24965963 ER PT J AU Cho, H Sobrin, L AF Cho, Heeyoon Sobrin, Lucia TI Genetics of Diabetic Retinopathy SO CURRENT DIABETES REPORTS LA English DT Article DE Diabetic retinopathy; Proliferative diabetic retinopathy; Genetics; Heritability; Linkage studies; Candidate gene association studies; Genome-wide association studies ID GENOME-WIDE ASSOCIATION; MACULAR DEGENERATION; SUSCEPTIBILITY GENES; ERYTHROPOIETIN GENE; MEXICAN-AMERICANS; COMMON VARIANTS; STARR COUNTY; COMPLICATIONS; POLYMORPHISM; METAANALYSIS AB Diabetic retinopathy (DR) is a polygenic disorder. Twin studies and familial aggregation studies have documented clear familial clustering. Heritability has been estimated to be as high as 27 % for any DR and 52 % for proliferative diabetic retinopathy (PDR), an advanced form of the disease. Linkage analyses, candidate gene association studies and genome-wide association studies (GWAS) performed to date have not identified any widely reproducible risk loci for DR. Combined analysis of the data from multiple GWAS is emerging as an important next step to explain the unaccounted heritability. Key factors to future discovery of the genetic underpinnings of DR are precise DR ascertainment, a focus on the more heritable disease forms such as PDR, stringent selection of control participants with regards to duration of diabetes, and methods that allow combination of existing datasets from different ethnicities to achieve sufficient sample sizes to detect variants with modest effect sizes. C1 [Cho, Heeyoon; Sobrin, Lucia] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Cho, Heeyoon] Hanyang Univ, Coll Med, Dept Ophthalmol, Seoul 133791, South Korea. RP Sobrin, L (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St,12th floor, Boston, MA 02114 USA. EM Lucia_Sobrin@meei.harvard.edu FU NEI NIH HHS [R01 EY022302] NR 52 TC 12 Z9 13 U1 1 U2 7 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1534-4827 EI 1539-0829 J9 CURR DIABETES REP JI Curr. Diabetes Rep. PD AUG PY 2014 VL 14 IS 8 AR 515 DI 10.1007/s11892-014-0515-z PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AO1OS UT WOS:000341083500008 PM 24952107 ER PT J AU Martins, D Beca, F Schmitt, F AF Martins, D. Beca, F. Schmitt, F. TI Metastatic breast cancer: mechanisms and opportunities for cytology SO CYTOPATHOLOGY LA English DT Review DE metastasis; fine needle aspiration; cytology; immunocytochemistry; molecular analysis; breast cancer ID FINE-NEEDLE-ASPIRATION; P-CADHERIN; NEXT-GENERATION; RECEPTOR STATUS; IN-SITU; CARCINOMA; CELLS; LUNG; IMMUNOCYTOCHEMISTRY; OVEREXPRESSION AB Despite significant advances in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, metastatic disease remains the most critical condition limiting the survival of patients with breast cancer. Therefore, the development of effective treatment against late-arising metastasis has become the centre of clinical attention and is one of the current challenges in cancer research. A deeper understanding of the metastatic cascade is fundamental, and the need for repetitive tumour assessments for the evaluation of tumour evolution is a relatively new practice in routine medical care. As such, fine needle aspiration cytology (FNAC) is ideally placed to monitor biological changes in metastasis that may affect treatment and response. As FNAC is a minimally invasive method, it can be performed repeatedly with relatively little trauma, and selective ancillary tests can be applied to FNAC specimens, including for tumour whose primary nature is known. Herein, we review how the linear and parallel models explain metastatic dissemination, thus influencing therapeutic and clinical decisions, and how cytology, together with immunocytochemistry and molecular analysis, can be a tool for routine clinical practice and clinical trials aimed at metastatic disease with a special emphasis on breast cancer. C1 [Martins, D.; Beca, F.; Schmitt, F.] Univ Porto, IPATIMUP Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal. [Beca, F.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Schmitt, F.] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON M5G 2C4, Canada. [Schmitt, F.] Univ Hlth Network, Dept Pathol, Toronto, ON, Canada. RP Schmitt, F (reprint author), Univ Toronto, Univ Hlth Network, Toronto Gen Hosp, Dept Lab Med & Pathobiol,Fac Med, 200 Elizabeth St,11E-215B, Toronto, ON M5G 2C4, Canada. EM fernando.schmitt@uhn.ca OI Schmitt, Fernando/0000-0002-3711-8681; Beca, Francisco/0000-0002-4409-012X FU Portuguese National Funds through FCT - Fundacao para a Ciencia e Tecnologia [FCT: SFRH/BD/66152/2009, FCT: HMSP-ICJ/0006/2012]; FCT FX This work was partially supported by research grants to D. Martins (FCT: SFRH/BD/66152/2009) and F. Beca (FCT: HMSP-ICJ/0006/2012 within the framework of the Harvard Medical School-Portugal Program) received from Portuguese National Funds through FCT - Fundacao para a Ciencia e Tecnologia. The Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) is an Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education and is partially supported by the FCT. NR 36 TC 3 Z9 3 U1 2 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0956-5507 EI 1365-2303 J9 CYTOPATHOLOGY JI Cytopathology PD AUG PY 2014 VL 25 IS 4 BP 225 EP 230 DI 10.1111/cyt.12158 PG 6 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AN5XZ UT WOS:000340667500002 PM 24889678 ER PT J AU Ho, YH Wang, JL DeLelys, ME Murali, MR Pitman, MB Sohani, AR AF Ho, Y. H. Wang, J. L. DeLelys, M. E. Murali, M. R. Pitman, M. B. Sohani, A. R. TI Gamma heavy chain disease: cytological diagnosis of a rare lymphoid malignancy facilitated by correlation with key laboratory findings SO CYTOPATHOLOGY LA English DT Editorial Material ID LYMPHOPROLIFERATIVE DISORDERS C1 [Ho, Y. H.] Tan Tock Seng Hosp, Singapore, Singapore. [Wang, J. L.; DeLelys, M. E.; Murali, M. R.; Pitman, M. B.; Sohani, A. R.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Wang, J. L.; DeLelys, M. E.; Murali, M. R.; Pitman, M. B.; Sohani, A. R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 219, Boston, MA 02114 USA. EM arsohani@partners.org NR 10 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0956-5507 EI 1365-2303 J9 CYTOPATHOLOGY JI Cytopathology PD AUG PY 2014 VL 25 IS 4 BP 270 EP 273 DI 10.1111/cyt.12126 PG 4 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AN5XZ UT WOS:000340667500009 PM 25180407 ER PT J AU Walton, E Liu, JY Hass, J White, T Scholz, M Roessner, V Gollub, R Calhoun, VD Ehrlich, S AF Walton, Esther Liu, Jingyu Hass, Johanna White, Tonya Scholz, Markus Roessner, Veit Gollub, Randy Calhoun, Vince D. Ehrlich, Stefan TI MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls SO EPIGENETICS LA English DT Article ID DORSOLATERAL PREFRONTAL CORTEX; O-METHYLTRANSFERASE GENE; BIPOLAR DISORDER; FUNCTIONAL ACTIVATION; FMRI; METAANALYSIS; RISK; POLYMORPHISM; EXPRESSION; GENOTYPE AB Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes. C1 [Walton, Esther; Hass, Johanna; Roessner, Veit; Ehrlich, Stefan] Tech Univ Dresden, Translat Dev Neurosci Sect, Dept Child & Adolescent Psychiat, Dresden, Germany. [Liu, Jingyu; Calhoun, Vince D.] Mind Res Network, Albuquerque, NM USA. [Liu, Jingyu; Calhoun, Vince D.] Lovelace Biomed & Environm Res Inst, Albuquerque, NM USA. [White, Tonya] Erasmus Univ, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Scholz, Markus] Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany. [Scholz, Markus] Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04109 Leipzig, Germany. [Gollub, Randy; Ehrlich, Stefan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Gollub, Randy; Ehrlich, Stefan] Massachusetts Gen Hosp, HMS Martinos Ctr Biomed Imaging, MIT, MGH, Charlestown, MA USA. [Calhoun, Vince D.] Univ New Mexico, Dept Elect & Comp Engn, Albuquerque, NM 87131 USA. RP Ehrlich, S (reprint author), Tech Univ Dresden, Translat Dev Neurosci Sect, Dept Child & Adolescent Psychiat, Dresden, Germany. EM transden.lab@gmail.com OI Ehrlich, Stefan/0000-0003-2132-4445; Walton, Esther/0000-0002-0935-2200; Gollub, Randy L./0000-0002-9434-4044; Liu, Jingyu/0000-0002-1724-7523 FU National Institutes of Health [NIH/NCRR P41RR14075, K08 MH068540]; Department of Energy [DE-FG02-99ER62764]; MIND Research Network, Morphometry BIRN [1U24, RR021382A]; MIND Research Network, Function BIRN [U24RR021992-01, NIH.NCRR MO1 RR025758-01]; National Institute of General Medical Sciences; National Institute of Biomedical Imaging and Bioengineering [NIGMS P20-GM103472, NIBIB 2R01-EB000840]; National Association for Research in Schizophrenia and Affective Disorders (NARSAD award) FX This work was supported by the National Institutes of Health (NIH/NCRR P41RR14075, K08 MH068540), the Department of Energy (DE-FG02-99ER62764), the MIND Research Network, Morphometry BIRN (1U24, RR021382A), Function BIRN (U24RR021992-01, NIH.NCRR MO1 RR025758-01), the National Institute of General Medical Sciences and the National Institute of Biomedical Imaging and Bioengineering (NIGMS P20-GM103472 and NIBIB 2R01-EB000840 to V.C.), and the National Association for Research in Schizophrenia and Affective Disorders (NARSAD award to S.E.). NR 48 TC 7 Z9 8 U1 1 U2 13 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD AUG PY 2014 VL 9 IS 8 BP 1101 EP 1107 DI 10.4161/epi.29223 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AO5CV UT WOS:000341360600005 PM 24837210 ER PT J AU Harris, RA Nagy-Szakal, D Mir, SAV Frank, E Szigeti, R Kaplan, JL Bronsky, J Opekun, A Ferry, GD Winter, H Kellermayer, R AF Harris, R. Alan Nagy-Szakal, Dorottya Mir, Sabina A. V. Frank, Eibe Szigeti, Reka Kaplan, Jess L. Bronsky, Jiri Opekun, Antone Ferry, George D. Winter, Harland Kellermayer, Richard TI DNA methylation-associated colonic mucosal immune and defense responses in treatment-naive pediatric ulcerative colitis SO EPIGENETICS LA English DT Article DE Pediatric inflammatory bowel disease; ulcerative colitis; treatment-naive; epigenetics; DNA methylation; DNA expression; DNA methylome ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; GENE-EXPRESSION; PREVALENCE; ONSET; SUSCEPTIBILITY; IDENTIFICATION; EPIDEMIOLOGY; MICROARRAYS; VALIDATION AB Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naive patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naive UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naive UC separated from control. One-hundred-and-20 genes with significant expression change in UC (>2-fold, P < 0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naive UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD. C1 [Harris, R. Alan] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Nagy-Szakal, Dorottya; Mir, Sabina A. V.; Ferry, George D.; Kellermayer, Richard] Baylor Coll Med, Dept Pediat, USDA, ARS,Childrens Nutr Res Ctr,Texas Childrens Hosp, Houston, TX 77030 USA. [Frank, Eibe] Univ Waikato, Dept Comp Sci, Hamilton, New Zealand. [Szigeti, Reka] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. [Kaplan, Jess L.; Winter, Harland] MassGen Hosp Children, Dept Pediat, Boston, MA USA. [Bronsky, Jiri] Charles Univ Prague, Dept Pediat, Prague, Czech Republic. [Bronsky, Jiri] Univ Hosp Motol, Prague, Czech Republic. [Opekun, Antone] Baylor Coll Med, Dept Gastroenterol, Houston, TX 77030 USA. RP Kellermayer, R (reprint author), Baylor Coll Med, Dept Pediat, USDA, ARS,Childrens Nutr Res Ctr,Texas Childrens Hosp, Houston, TX 77030 USA. EM kellerma@bcm.edu FU Broad Medical Research Program, the Broad Foundation [IBD-0252]; Child Health Research Career Development Agency of the Baylor College of Medicine (NIH) [5K12 HD041648]; Public Health Service grant [DK56338]; Karen and Brock Wagner family; Pediatric Inflammatory Bowel Disease Foundation FX R. K. was supported in part by the Broad Medical Research Program, the Broad Foundation (IBD-0252); the Child Health Research Career Development Agency of the Baylor College of Medicine (NIH # 5K12 HD041648); a Public Health Service grant DK56338, funding the Texas Medical Center Digestive Diseases Center; and the Gutsy Kids Fund including philanthropic donation from the Karen and Brock Wagner family. H. S. W. was supported in part by a philanthropic donation from the Martin Schlaff Family. This project was also supported by the Pediatric Inflammatory Bowel Disease Foundation. NR 42 TC 13 Z9 14 U1 3 U2 9 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 EI 1559-2308 J9 EPIGENETICS-US JI Epigenetics PD AUG PY 2014 VL 9 IS 8 BP 1131 EP 1137 DI 10.4161/epi.29446 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA AO5CV UT WOS:000341360600008 PM 24937444 ER PT J AU Targum, SD Burch, DJ Asgharnejad, M Petersen, T Gomeni, R Fava, M AF Targum, Steven D. Burch, Daniel J. Asgharnejad, Mahnaz Petersen, Timothy Gomeni, Roberto Fava, Maurizio TI Use of band-pass filter analysis to evaluate outcomes in an antidepressant trial for treatment resistant patients SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Treatment resistant depression; Placebo response; Band-pass filter analysis; MAO-A; Ratings reliability ID MAJOR DEPRESSIVE DISORDER; CLINICAL-TRIALS; PLACEBO-RESPONSE; DOUBLE-BLIND; ENRICHMENT STRATEGY; IMPROVE EFFICIENCY; RATING-SCALE; SEVERITY; THERAPY; ERROR AB Band-pass filtering is a novel statistical methodology that proposes that filtering out data from trial sites generating non-plausible high or low levels of placebo response can yield a more accurate effect size and greater separation of active drug (when efficacious) from placebo. We applied band-pass filters to re-analyze data from a negative antidepressant trial (NCT00739908) evaluating CX157 (a reversible and selective monoamine oxidase inhibitor-A) versus placebo. 360 patients from 29 trial sites were randomized to either CX157 treatment (n=182) or placebo (n=178). We applied two filters of <3 or> 7 points (filter #1) or <3 and> 9 points (filter #2) mean change of the total MADRS placebo scores for each site. Trial sites that had mean placebo MADRS score changes exceeding the boundaries of these band-pass filter thresholds were considered non-informative and all of the data from these sites were excluded from the post-hoc re-analysis. The two band-pass filters reduced the sample of informative patients from 353 patients in the mITT population to 62 in filter #1 and 152 in the filter #2 group. The placebo response was reduced from 31.1% in the mITT population to 9.4% with filter #1 and 20.8% with filter #2. MMRM analysis revealed a non-statistically significant trend of p=0.13 and 0.16 for the two filters in contrast to the mITT population (p= 0.58). Our findings support the band-pass filter hypothesis and highlight issues related to site-based scoring variability and inappropriate subject selection that may contribute to trial failure. (C) 2014 Elsevier B.V. and ECNP All rights reserved. C1 [Targum, Steven D.; Petersen, Timothy] Clintara LLC, Boston, MA 02108 USA. [Burch, Daniel J.] PPD Inc, Wilmington, NC USA. [Asgharnejad, Mahnaz] UCB Biosci Inc, Raleigh, NC USA. [Gomeni, Roberto] Pharmacometrica, La Fouillade, France. [Fava, Maurizio] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Targum, SD (reprint author), Clintara LLC, Boston, MA 02108 USA. EM sdtargum@yahoo.com OI gomeni, roberto/0000-0003-3916-9578 FU CeNeRx pharmaceuticals; Krenitsky Pharmaceuticals Inc. (KPI) FX Partial support for this study and the post-hoc band-pass analysis came from CeNeRx pharmaceuticals during the clinical trial and from Krenitsky Pharmaceuticals Inc. (KPI) who currently own the rights to TriRima (R). However, the sponsor had no role in the analysis and/or interpretation of the data, the writing of this report, or the decision to submit the manuscript in its current form. NR 36 TC 3 Z9 4 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X EI 1873-7862 J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD AUG PY 2014 VL 24 IS 8 BP 1188 EP 1195 DI 10.1016/j.euroneuro.2014.06.003 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA AO0HQ UT WOS:000340990100002 PM 25012515 ER PT J AU Doherty, MF Adelmant, G Cecchetelli, AD Marto, JA Cram, EJ AF Doherty, Michael F. Adelmant, Guillaume Cecchetelli, Alyssa D. Marto, Jarrod A. Cram, Erin J. TI Proteomic Analysis Reveals CACN-1 Is a Component of the Spliceosome in Caenorhabditis elegans SO G3-GENES GENOMES GENETICS LA English DT Article DE proteomics; cell migration; C. elegans; spliceosome ID RNA-BINDING PROTEINS; DISTAL TIP CELLS; C-ELEGANS; POLYACRYLAMIDE GELS; AXON GUIDANCE; KAPPA-B; MIGRATION; CACTIN; INTERFERENCE; INTERACTS AB Cell migration is essential for embryonic development and tissue formation in all animals. cacn-1 is a conserved gene of unknown molecular function identified in a genome-wide screen for genes that regulate distal tip cell migration in the nematode worm Caenorhabditis elegans. In this study we take a proteomics approach to understand CACN-1 function. To isolate CACN-1-interacting proteins, we used an in vivo tandem-affinity purification strategy. Tandem-affinity purification-tagged CACN-1 complexes were isolated from C. elegans lysate, analyzed by mass spectrometry, and characterized bioinformatically. Results suggest significant interaction of CACN-1 with the C. elegans spliceosome. All of the identified interactors were screened for distal tip cell migration phenotypes using RNAi. Depletion of many of these factors led to distal tip cell migration defects, particularly a failure to stop migrating, a phenotype commonly seen in cacn-1 deficient animals. The results of this screen identify eight novel regulators of cell migration and suggest CACN-1 may participate in a protein network dedicated to high-fidelity gonad development. The composition of proteins comprising the CACN-1 network suggests that this critical developmental module may exert its influence through alternative splicing or other post-transcriptional gene regulation. C1 [Doherty, Michael F.; Cecchetelli, Alyssa D.; Cram, Erin J.] Northeastern Univ, Dept Biol, Boston, MA 02115 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02215 USA. [Adelmant, Guillaume; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Cram, EJ (reprint author), Northeastern Univ, Dept Biol, 360 Huntington Ave, Boston, MA 02115 USA. EM e.cram@neu.edu FU National Center for Research Resources, National Institutes of Health; Dana-Farber Strategic Research Initiative; National Institutes of Health [P01NS047572]; National Institutes of Health NIGMS [GM085077] FX C. elegans strains were provided by the Caenorhabditis Genetic Center, which is funded by the National Center for Research Resources, National Institutes of Health. We thank Ismar Kovacevic for many helpful discussions and Zachary Neuschafer and Avina Joshi for assistance with experiments. Generous financial support provided (to J.A.M.) from the Dana-Farber Strategic Research Initiative and the National Institutes of Health (P01NS047572), and by the National Institutes of Health NIGMS (GM085077) to E.J.C. NR 80 TC 4 Z9 4 U1 0 U2 7 PU GENETICS SOCIETY AMERICA PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD AUG 1 PY 2014 VL 4 IS 8 BP 1555 EP 1564 DI 10.1534/g3.114.012013 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA AO0PR UT WOS:000341013200017 PM 24948787 ER PT J AU May, FP Bromley, EG Reid, MW Baek, M Yoon, J Cohen, E Lee, A van Oijen, MGH Spiegel, BMR AF May, Folasade P. Bromley, Erica G. Reid, Mark W. Baek, Michael Yoon, Jessica Cohen, Erica Lee, Aaron van Oijen, Martijn G. H. Spiegel, Brennan M. R. TI Low uptake of colorectal cancer screening among African Americans in an integrated Veterans Affairs health care network SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID COLON-CANCER; MEDICARE BENEFICIARIES; DISPARITIES; POPULATION; PREDICTORS; PATTERNS; COVERAGE; WOMEN AB Background: African Americans have the highest incidence and mortality from colorectal cancer (CRC). Despite guidelines to initiate screening with colonoscopy at age 45 in African Americans, the CRC incidence remains high in this group. Objective: To examine the rates and predictors of CRC screening uptake as well as time to screening in a population of African Americans and non-African Americans in a health care system that minimizes variations in insurance and access. Design: Retrospective cohort study. Setting: Greater Los Angeles Veterans Affairs (VA) Healthcare System. Patients: Random sample (N = 357) of patients eligible for initial CRC screening. Main Outcome Measurements: Uptake of any screening method; uptake of colonoscopy, in particular; predictors of screening; and time to screening in African Americans and non-African Americans. Results: The overall screening rate by any method was 50%. Adjusted rates for any screening were lower among African Americans than non-African Americans (42% vs 58%; odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31-0.77). Colonoscopic screening was also lower in African Americans (11% vs 23%; adjusted OR 0.43; 95% CI, 0.24-0.77). In addition to race, homelessness, lower service connectedness, taking more prescription drugs, and not seeing a primary care provider within 2 years of screening eligibility predicted lower uptake of screening. Time to screening colonoscopy was longer in African Americans (adjusted hazard ratio 0.43; 95% CI, 0.25-0.75). Limitations: The sample may not be generalizable. Conclusions: We found marked disparities in CRC screening despite similar access to care across races. Despite current guidelines aimed at increasing CRC screening in African Americans, participation in screening remained low, and use of colonoscopy was infrequent. C1 [May, Folasade P.; Bromley, Erica G.; Baek, Michael; Yoon, Jessica; Cohen, Erica; Lee, Aaron; Spiegel, Brennan M. R.] VA Greater Los Angeles Healthcare Syst, Dept Med, Div Gastroenterol, Los Angeles, CA USA. [May, Folasade P.; van Oijen, Martijn G. H.; Spiegel, Brennan M. R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. [May, Folasade P.; Spiegel, Brennan M. R.] UCLA Fielding Sch Publ Hlth, Dept Hlth Policy & Management, Los Angeles, CA USA. [May, Folasade P.; Reid, Mark W.; Spiegel, Brennan M. R.] UCLA VA Ctr Outcomes Res & Educ CORE, Los Angeles, CA USA. RP Spiegel, BMR (reprint author), Univ Calif Los Angeles, UCLA VA Ctr Outcomes Res & Educ CORE, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. FU NIH [T32DK07180-34] FX All authors disclosed no financial relationships relevant to this publication. This research was supported by NIH training grant T32DK07180-34 to Dr May. NR 26 TC 9 Z9 9 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD AUG PY 2014 VL 80 IS 2 BP 291 EP 298 DI 10.1016/j.gie.2014.01.045 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2KX UT WOS:000341151700012 PM 24674351 ER PT J AU Yaghoobi, M AF Yaghoobi, Mohammad TI Treatment of patients with new diagnosis of achalasia: laparoscopic Heller's myotomy may be more effective than pneumatic dilation SO GASTROINTESTINAL ENDOSCOPY LA English DT Letter C1 Med Univ S Carolina, Div Gastroenterol & Hepatol, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Yaghoobi, M (reprint author), Med Univ S Carolina, Div Gastroenterol & Hepatol, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 EI 1097-6779 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD AUG PY 2014 VL 80 IS 2 BP 360 EP 360 DI 10.1016/j.gie.2014.02.029 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AO2KX UT WOS:000341151700035 PM 25034845 ER PT J AU Quackenbush, J AF Quackenbush, John TI Personal report: Richard Mural In Memoriam SO GENOMICS LA English DT Biographical-Item C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Quackenbush, J (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM johnq@jimmy.harvard.edu NR 1 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 EI 1089-8646 J9 GENOMICS JI Genomics PD AUG PY 2014 VL 104 IS 2 BP 69 EP 69 DI 10.1016/j.ygeno.2014.06.006 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA AO1GY UT WOS:000341061800001 ER PT J AU Stacy, RC Bernardo, LA Nielsen, GP AF Stacy, Rebecca C. Bernardo, Lindsay A. Nielsen, Gunnlauger Petur TI Absence of chromosomal abnormalities in herniated orbital fat SO HISTOPATHOLOGY LA English DT Article DE herniated orbital fat; lipoma; liposarcoma; orbital tumour ID PLEOMORPHIC LIPOMA; LIPOSARCOMA; KARYOTYPE; SERIES; TUMORS AB Aims: Lipomatous tumours of the orbit are rare, and can sometimes be difficult to characterize. Herniated orbital fat is thought to be a reactive process, but its presentation can mimic a lipomatous tumour such as an atypical lipomatous tumour or spindle cell/pleomorphic lipoma. Genetic studies to determine if it is indeed a reactive process rather than an adipocytic neoplasm have not been performed. Methods and results: Four samples of herniated orbital fat were reviewed clinically, histopathologically and immunohistochemically. Array comparative genomic hybridization (aCGH) was used to search for genome-wide copy number alterations within the tumours. Histological evaluation revealed that all four tumours contained collections of adipocytes sur-rounded by fibrous septae. Lochkern cells and floretlike multinucleated giant cells were present, consistent with herniated orbital fat. CD34 was positive in all tumours. Staining for MDM2 and CDK4 was negative. ACGH analysis demonstrated no copy number alterations. Conclusions: Herniated orbital fat may share some histopathological features with lipoma and atypical lipomatous tumour, but the absence of copy number gains or losses is consistent with the impression that herniated orbital fat is a reactive process. Genetic analysis may be another method to help differentiate herniated orbital fat from a lipomatous orbital tumour when the diagnosis is in question. C1 [Stacy, Rebecca C.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Stacy, Rebecca C.; Bernardo, Lindsay A.; Nielsen, Gunnlauger Petur] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Stacy, RC (reprint author), MEEI, 243 Charles St, Boston, MA 02114 USA. EM Rebecca_Stacy@meei.harvard.edu FU Massachusetts Eye and Ear Infirmary FX Dr John Iafrate is thanked for his technical assistance. Dr Joan Miller, Chair of Ophthalmology at Massachusetts Eye and Ear Infirmary, is thanked for providing departmental financial support for the aCGH testing. The Massachusetts Eye and Ear Infirmary Institutional Review Board approved this study on 13 August 2013, reference number 13-099H. NR 12 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0309-0167 EI 1365-2559 J9 HISTOPATHOLOGY JI Histopathology PD AUG PY 2014 VL 65 IS 2 BP 273 EP 277 DI 10.1111/his.12404 PG 5 WC Cell Biology; Pathology SC Cell Biology; Pathology GA AN5WK UT WOS:000340662300013 PM 24588545 ER PT J AU Elmariah, S Furlan, AJ Reisman, M Burke, D Vardi, M Wimmer, NJ Ling, SQ Chen, XH Kent, DM Massaro, J Mauri, L AF Elmariah, Sammy Furlan, Anthony J. Reisman, Mark Burke, David Vardi, Moshe Wimmer, Neil J. Ling, Shuqiong Chen, Xiaohua Kent, David M. Massaro, Joseph Mauri, Laura CA CLOSURE I Investigators TI Predictors of Recurrent Events in Patients With Cryptogenic Stroke and Patent Foramen Ovale Within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) Trial SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE patent foramen ovale; risk factor; stroke; transient ischemic attack ID LEFT CARDIAC SHUNT; PERCUTANEOUS CLOSURE; CEREBROVASCULAR EVENTS; ATRIAL-FIBRILLATION; MEDICAL-TREATMENT; RISK-FACTORS; THERAPY; PREVENTION; ANEURYSM; TIA AB OBJECTIVES This study sought to identify predictors of recurrent ischemic neurologic events within the CLOSURE I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale) trial. BACKGROUND The CLOSURE I trial found that transcatheter patent foramen ovale (PFO) closure using the STARFlex device was not superior to medical therapy in patients with cryptogenic stroke or transient ischemic attack (TIA) and PFO. METHODS The CLOSURE I trial is a multicenter, randomized trial of transcatheter PFO closure compared with medical therapy in patients who presented with cryptogenic stroke or TIA and had a PFO. We identified clinical predictors of recurrent ischemic stroke or TIA during 2 years of follow-up using Cox proportional hazards regression within the pooled intention-to-treat cohort. RESULTS In 909 patients, the incidence of recurrent events was 5.7% with 25 patients suffering a recurrent stroke and 30 a TIA. Patients who had a recurrent event had higher body mass index (30.2 +/- 6.2 vs. 28.3 +/- 5.8%; p = 0.03) and more frequently had diabetes (19.2% vs. 7.1%; p = 0.0016), hypertension (46.2% vs. 30.1%; p = 0.015), and ischemic heart disease (3.8% vs. 0.9%; p = 0.05). Diabetes (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.69 to 6.84; p = 0.0007), index TIA (HR vs. stroke: 2.13; 95% CI: 1.20 to 3.80; p = 0.01), and the detection of atrial fibrillation after study enrollment (HR: 4.85; 95% CI: 2.05 to 11.47; p = 0.0003) independently predicted recurrent ischemic neurologic events. Recurrent neurologic events were more frequent in subjects with RoPE (Risk of Paradoxical Embolism) score <= 5 than those with >5 (14.5% vs. 4.2%; p < 0.0001). CONCLUSIONS These findings suggest an alternative etiology to paradoxical embolism was frequently responsible for recurrent events within the CLOSURE I trial. (C) 2014 by the American College of Cardiology Foundation. C1 [Elmariah, Sammy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. [Elmariah, Sammy; Burke, David; Vardi, Moshe; Ling, Shuqiong; Chen, Xiaohua; Massaro, Joseph; Mauri, Laura] Harvard Clin Res Inst, Boston, MA USA. [Furlan, Anthony J.] Case Western Reserve Univ, Sch Med, Univ Hosp, Dept Neurol, Cleveland, OH USA. [Reisman, Mark] Univ Washington, Med Ctr, Div Cardiol, Seattle, WA USA. [Wimmer, Neil J.; Mauri, Laura] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA 02115 USA. [Kent, David M.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Neurol, Boston, MA 02111 USA. [Kent, David M.] Tufts Univ, Sch Med, Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies,Predict Analy, Boston, MA 02111 USA. [Massaro, Joseph] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Mauri, L (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM lmauri1@partners.org FU NMT Medical, Boston; National Institutes of Health/National Institute of Neurological Disorders and Stroke grants [R21 NS079826, R01 NS062153]; NMT Medical; Abbott Vascular; Boston Scientific; Cordis; Medtronic; Bristol-Myers Squibb; Eli Lilly; Daiichi-Sankyo; Sanofi-Aventis FX The CLOSURE I trial was supported by NMT Medical, Boston. Drs. Furlan and Reisman have received institutional research support from and have served as consultants for NMT Medical; and were principal investigators for the CLOSURE I trial. Dr. Kent has consulted for W. L. Gore Associates; and has received National Institutes of Health/National Institute of Neurological Disorders and Stroke grants (#R21 NS079826, #R01 NS062153). Dr. Massaro has received institutional research support from NMT Medical; and has served as a consultant for Harvard Clinical Research Institute and NMT Medical. Dr. Mauri has received institutional research support from Abbott Vascular, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squibb, Eli Lilly, Daiichi-Sankyo, and Sanofi-Aventis; and has served as a consultant to Biotronik, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 40 TC 11 Z9 11 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD AUG PY 2014 VL 7 IS 8 BP 913 EP 920 DI 10.1016/j.jcin.2014.01.170 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN8ZK UT WOS:000340894700020 PM 25147037 ER PT J AU McKinsey, JF Zeller, T Rocha-Singh, KJ Jaff, MR Garcia, LA AF McKinsey, James F. Zeller, Thomas Rocha-Singh, Krishna J. Jaff, Michael R. Garcia, Lawrence A. CA Definitive Le Investigators TI Lower Extremity Revascularization Using Directional Atherectomy SO JACC-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE angioplasty; atherectomy; claudication; critical limb ischemia; peripheral artery disease ID PERIPHERAL ARTERIAL-DISEASE; SITU FEMOROTIBIAL RECONSTRUCTION; SUPERFICIAL FEMORAL-ARTERY; ISCHEMIC TISSUE LESIONS; CRITICAL LEG ISCHEMIA; STAGE RENAL-FAILURE; FEMOROPOPLITEAL LESIONS; INFRAINGUINAL BYPASS; BALLOON ANGIOPLASTY; STENT IMPLANTATION AB OBJECTIVES The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. BACKGROUND To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. METHODS DEFINITIVE LE (Determination of EFfectiveness of the SilverHawk (R) PerIpheral Plaque ExcisioN System (SIlver-HawkDevice) for the Treatment of Infrainguinal VEssels / Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. RESULTS A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. CONCLUSIONS The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (C) 2014 by the American College of Cardiology Foundation. C1 [McKinsey, James F.] Univ Hosp Columbia & Cornell, New York Presbyterian Hosp, Div Vasc Surg, New York, NY USA. [Zeller, Thomas] Univ Herzzentrum Freiburg Bad Krozingen, Bad Krozingen, Germany. [Rocha-Singh, Krishna J.] St Johns Hosp, Prairie Heart Inst, Springfield, IL USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Inst Heart Vasc & Stroke Care, Boston, MA 02114 USA. [Garcia, Lawrence A.] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Sect Intervent Cardiol, Boston, MA 02111 USA. [Garcia, Lawrence A.] Tufts Univ, Sch Med, St Elizabeths Med Ctr, Sect Vasc Med, Boston, MA 02111 USA. RP McKinsey, JF (reprint author), Mt Sinai Syst Chief Complex Aort Intervent, 1000 10th Ave,Suite 5G 67, New York, NY 10019 USA. EM jmckinsey@chpnet.org FU ev3/Covidien; Bayer; Boston Scientific; Medtronic; Sanofi-Aventis; C.R. Bard; Johnson Johnson Cordis; Straub Medical; Invatec; Biotronik; Pathway Medical; W.L. Gore; IDEV; Cook; Krauth Medical; Abbott Vascular; Angioslide; Ardian; InnoRa; Veryan; Medtronic-Ardian; Medtronic-Invatec; 480 Biomedical FX From the *Division of Vascular Surgery, New York Presbyterian Hospital, University Hospital of Columbia and Cornell, New York, New York; dagger Universitats-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; dagger Prairie Heart Institute at St. John's Hospital, Springfield, Illinois; Institute for Heart, Vascular, and Stroke Care, Massachusetts General Hospital, Boston, Massachusetts; and the parallel to Sections of Interventional Cardiology and Vascular Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts. This study was funded by ev3/Covidien. Dr. McKinsey has received consulting fees/speaker honoraria from ev3/Covidien and Bayer; has received educational grants from ev3/Covidien, Bayer, Boston Scientific, and Medtronic; and is a conational principal investigator for Atheromed. Dr. Zeller has received consulting fees/honoraria from Sanofi-Aventis, C.R. Bard, Johnson & Johnson Cordis, ev3/Covidien, Boston Scientific, Straub Medical, Invatec, Biotronik, Pathway Medical, W.L. Gore, and IDEV; is on the Advisory Boards of Medtronic-Invatec, W.L. Gore, Angioslide, Medtronic-Ardian, and ev3/Covidien; and has received research grants from Cook, Krauth Medical, Pathway Medical, Abbott Vascular, Johnson & Johnson Cordis, Angioslide, Ardian, Biotronik, Invatec, InnoRa, W.L. Gore, Veryan, ev3/Covidien, Medtronic-Ardian, Medtronic-Invatec, and 480 Biomedical. Dr. Rocha-Singh is a paid consultant for ev3/Covidien and Cardiovascular Systems, Inc.; and is a board member of VIVA Physicians, a 501c3 not-for-profit education and research organization. Dr. Jaff is an advisor to Cardinal Health and a noncompensated advisor for ev3/Covidien, Abbott Vascular, Cordis Corporation, Boston Scientific and Medtronic Vascular; is an equity shareholder in PQ Bypass; and is a board member of VIVA Physicians. Dr. Garcia is a paid consultant for ev3/Covidien and iDEV/Abbott. He is a noncompensated consultant for Boston Scientific, AngioSculpt/Spectranetics, and Pathway/Volcano; and is an equity shareholder in Spirox, Primacea, TissueGen, CV Ingenuity, and Scion Cardiovascular. NR 35 TC 51 Z9 51 U1 3 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-8798 EI 1876-7605 J9 JACC-CARDIOVASC INTE JI JACC-Cardiovasc. Interv. PD AUG PY 2014 VL 7 IS 8 BP 923 EP 933 DI 10.1016/j.jcin.2014.05.006 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN8ZK UT WOS:000340894700022 PM 25147039 ER PT J AU Austad, KE Avorn, J Franklin, JM Campbell, EG Kesselheim, AS AF Austad, Kirsten E. Avorn, Jerry Franklin, Jessica M. Campbell, Eric G. Kesselheim, Aaron S. TI Association of Marketing Interactions With Medical Trainees' Knowledge About Evidence-Based Prescribing Results From a National Survey SO JAMA INTERNAL MEDICINE LA English DT Article ID OF-INTEREST; SCHOOL; PHYSICIANS; ATTITUDES; SOCIALIZATION; BEHAVIOR; EXPOSURE; POLICIES; CARE AB IMPORTANCE In recent years, numerous US medical schools and academic medical centers have enacted policies preventing pharmaceutical sales representatives from interacting directly with students. Little is known about how pharmaceutical sales representatives affect trainees' knowledge about pharmaceutical prescribing. OBJECTIVE To determine whether there is an association between medical trainees' interactions with pharmaceutical promotion and their preferences in medication use. DESIGN, SETTING, AND PARTICIPANTS We surveyed a nationally representative sample of first- and fourth-year medical students and third-year residents by randomly selecting at least 14 trainees at each level per school. EXPOSURES All trainees were asked how often they used different educational resources to learn about prescription drugs. Among fourth-year students and residents, we posed a series of multiple choice knowledge questions asking about the appropriate initial therapy for clinical scenarios involving patients with diabetes, hyperlipidemia, hypertension, and difficulty sleeping. MAIN OUTCOMES AND MEASURES Evidence-based answers followed widely used clinical guidelines, while marketed-drug answers favored brand-name drugs over generic alternatives. We used survey answers to build an industry relations index assessing each trainee's level of acceptance of pharmaceutical promotion; we used proportional odds logistic regression models to estimate the association between the index and responses to the knowledge questions. RESULTS The 1601 student (49.0% response rate) and 735 resident (42.9% response rate) respondents reported common use of unfiltered sources of drug information such as Google (74.2%-88.9%) and Wikipedia (45.2%-84.5%). We found that 48% to 90% of fourth-year students and residents accurately identified evidence-based prescribing choices. A 10-point higher industry relations index was associated with 15% lower odds of selecting an evidence-based prescribing choice (odds ratio [OR], 0.85; 95% CI, 0.79-0.92) (P <.001). There was also a significant association between the industry relations index and greater odds of choosing to prescribe brand-name drugs (OR, 1.08; 95% CI, 1.00-1.16) (P =.04). CONCLUSIONS AND RELEVANCE Among physician trainees, our survey showed an association between positive attitudes toward industry-physician interactions and less knowledge about evidence-based prescribing and greater inclination to recommend brand-name drugs. Policies intended to insulate trainees from pharmaceutical marketing may promote better educational outcomes. C1 [Austad, Kirsten E.; Avorn, Jerry; Franklin, Jessica M.; Kesselheim, Aaron S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Pharmacoepidemiol & Pharmacoecon,Dept Med, Boston, MA 02115 USA. [Austad, Kirsten E.; Kesselheim, Aaron S.] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Campbell, Eric G.] Harvard Univ, Sch Med, Boston, MA USA. RP Kesselheim, AS (reprint author), Div Pharmacoepidemiol & Pharmacoecon, Program Regulat Therapeut & Law PORTAL, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM akesselheim@partners.org FU Edmond J. Safra Center for Ethics at Harvard University; Agency for Healthcare Research Quality [K08HS18465-01]; Greenwall Faculty Scholarship in Bioethics; Robert Wood Johnson Foundation Investigator Award in Health Policy Research; AMSA FX This study was funded by a grant from the Edmond J. Safra Center for Ethics at Harvard University. Dr Kesselheim is supported by career development award K08HS18465-01 from the Agency for Healthcare Research & Quality, a Greenwall Faculty Scholarship in Bioethics, and a Robert Wood Johnson Foundation Investigator Award in Health Policy Research. Dr Austad has been a member of the American Medical Student Association (AMSA) and has received funding from AMSA to support travel and lodging to attend AMSA conferences. NR 21 TC 12 Z9 13 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1283 EP 1289 DI 10.1001/jamainternmed.2014.2202 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000018 PM 24911123 ER PT J AU Preston, MA Wilson, KM Markt, SC Ge, RB Morash, C Stampfer, MJ Loda, M Giovannucci, E Mucci, LA Olumi, AF AF Preston, Mark A. Wilson, Kathryn M. Markt, Sarah C. Ge, Rongbin Morash, Christopher Stampfer, Meir J. Loda, Massimo Giovannucci, Edward Mucci, Lorelei A. Olumi, Aria F. TI 5a-Reductase Inhibitors and Risk of High-Grade or Lethal Prostate Cancer. SO JAMA INTERNAL MEDICINE LA English DT Article ID FOLLOW-UP; 5-ALPHA-REDUCTASE INHIBITORS; PREVENTION TRIAL; FINASTERIDE; MEN; HYPERPLASIA; PROGRESSION; SURVIVAL; DUTASTERIDE; SENSITIVITY AB IMPORTANCE 5a-Reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. OBJECTIVE To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study of 38 058 men followed up for prostate cancer diagnosis and outcomes between 1996 and 2010 in the Health Professionals Follow-up Study. EXPOSURES Use of 5ARIs between 1996 and 2010. MAIN OUTCOMES AND MEASURES Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. RESULTS During 448 803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high grade (Gleason sum [GS] 8-10), 1238 were GS 7, and 1600 were low grade (GS 2-6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (hazard ratio [HR], 0.77; 95% CI, 0.65-0.91). 5ARI users had a reduced risk of GS 7 (HR, 0.67; 95% CI, 0.49-0.91) and low-grade (GS 2-6) prostate cancer (HR, 0.74; 95% CI, 0.57-0.95). 5ARI use was not associated with risk of high-grade (GS 8-10) prostate cancer (HR, 0.97; 95% CI, 0.64-1.46) or lethal disease (HR, 0.99; 95% CI, 0.58-1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use, 0.95; 95% CI, 0.92-0.99), localized (HR, 0.95; 95% CI, 0.90-1.00), and low-grade disease (HR, 0.92; 95% CI, 0.85-0.99). There was no association for lethal, high-grade, or grade 7 disease. CONCLUSIONS AND RELEVANCE While 5ARI use was not associated with developing high-grade or lethal prostate cancer, it was associated with a reduction in low-grade, GS 7, and overall prostate cancer. Because the number of patients with high-grade or lethal prostate cancer in our cohort was limited, we cannot rule out potential risk of harm with 5ARI use. C1 [Preston, Mark A.; Ge, Rongbin; Olumi, Aria F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Wilson, Kathryn M.; Markt, Sarah C.; Stampfer, Meir J.; Giovannucci, Edward; Mucci, Lorelei A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wilson, Kathryn M.; Stampfer, Meir J.; Giovannucci, Edward; Mucci, Lorelei A.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Wilson, Kathryn M.; Stampfer, Meir J.; Giovannucci, Edward; Mucci, Lorelei A.] Harvard Univ, Sch Med, Boston, MA USA. [Morash, Christopher] Univ Ottawa, Div Urol, Ottawa, ON, Canada. [Loda, Massimo] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Loda, Massimo] Broad Inst Harvard & MIT, Cambridge, MA USA. [Loda, Massimo] Kings Coll London, Div Canc Studies, London, England. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Olumi, AF (reprint author), Massachusetts Gen Hosp, Dept Urol, 55 Fruit St,Yawkey 7E, Boston, MA 02114 USA. EM Olumi.Aria@mgh.harvard.edu FU National Cancer Institute at the National Institutes of Health (NIH) [P01 CA055075, CA133891, R01-DK 091353]; NIH [R01-DK 091353, T32 CA09001, R25 CA098566]; Prostate Cancer Foundation; Urology Care Foundation; Urology Research Scholar Fund FX This work was supported by funding from the National Cancer Institute at the National Institutes of Health (NIH) (grants P01 CA055075 and CA133891); NIH training grants T32 CA09001 (Dr Wilson) and R25 CA098566 (Dr Markt); the Prostate Cancer Foundation (Dr Mucci); NIH grant R01-DK 091353 (Dr Olumi); and the Urology Care Foundation Research Scholar Program and the Robert J. Krane, MD, Urology Research Scholar Fund (Dr Preston). NR 33 TC 7 Z9 7 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1301 EP 1307 DI 10.1001/jamainternmed.2014.1600 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000022 PM 24887392 ER PT J AU Shahian, DM AF Shahian, David M. TI Preoperative beta-Blockade in Coronary Artery Bypass Grafting Surgery SO JAMA INTERNAL MEDICINE LA English DT Editorial Material ID POSTOPERATIVE ATRIAL-FIBRILLATION; METAANALYSIS; INTERVENTIONS; PREVENTION; MORTALITY C1 [Shahian, David M.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Shahian, David M.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Shahian, David M.] Harvard Univ, Sch Med, Boston, MA USA. RP Shahian, DM (reprint author), Massachusetts Gen Hosp, Dept Surg, Ctr Qual & Safety, 55 Fruit St, Boston, MA 02114 USA. EM dshahian@partners.org NR 9 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 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1328 EP 1329 DI 10.1001/jamainternmed.2014.155 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000026 PM 24934176 ER PT J AU Nelson, KM Helfrich, C Sun, HL Hebert, PL Liu, CF Dolan, E Taylor, L Wong, E Maynard, C Hernandez, SE Sanders, W Randall, I Curtis, I Schectman, G Stark, R Fihn, SD AF Nelson, Karin M. Helfrich, Christian Sun, Haili Hebert, Paul L. Liu, Chuan-Fen Dolan, Emily Taylor, Leslie Wong, Edwin Maynard, Charles Hernandez, Susan E. Sanders, William Randall, Ian Curtis, Idamay Schectman, Gordon Stark, Richard Fihn, Stephan D. TI Implementation of the Patient-Centered Medical Home in the Veterans Health Administration Associations With Patient Satisfaction, Quality of Care, Staff Burnout, and Hospital and Emergency Department Use SO JAMA INTERNAL MEDICINE LA English DT Article ID RECEIVING PRIMARY-CARE; CLINICS; TRANSFORMATION; PHYSICIANS; INVENTORY; SYSTEM AB IMPORTANCE In 2010, the Veterans Health Administration (VHA) began implementing the patient-centered medical home (PCMH) model. The Patient Aligned Care Team (PACT) initiative aims to improve health outcomes through team-based care, improved access, and care management. To track progress and evaluate outcomes at all VHA primary care clinics, we developed and validated a method to assess PCMH implementation. OBJECTIVES To create an index that measures the extent of PCMH implementation, describe variation in implementation, and examine the association between the implementation index and key outcomes. DESIGN, SETTING, AND PARTICIPANTS We conducted an observational study using data on more than 5.6 million veterans who received care at 913 VHA hospital-based and community-based primary care clinics and 5404 primary care staff from (1) VHA clinical and administrative databases, (2) a national patient survey administered to a weighted random sample of veterans who received outpatient care from June 1 to December 31, 2012, and (3) a survey of all VHA primary care staff in June 2012. Composite scores were constructed for 8 core domains of PACT: access, continuity, care coordination, comprehensiveness, self-management support, patient-centered care and communication, shared decision making, and team-based care. MAIN OUTCOMES AND MEASURES Patient satisfaction, rates of hospitalization and emergency department use, quality of care, and staff burnout. RESULTS Fifty-three items were included in the PACT Implementation Progress Index (Pi(2)). Compared with the 87 clinics in the lowest decile of the Pi(2), the 77 sites in the top decile exhibited significantly higher patient satisfaction (9.33 vs 7.53; P < .001), higher performance on 41 of 48 measures of clinical quality, lower staff burnout (Maslach Burnout Inventory emotional exhaustion subscale, 2.29 vs 2.80; P = .02), lower hospitalization rates for ambulatory care-sensitive conditions (4.42 vs 3.68 quarterly admissions for veterans 65 years or older per 1000 patients; P < .001), and lower emergency department use (188 vs 245 visits per 1000 patients; P < .001). CONCLUSIONS AND RELEVANCE The extent of PCMH implementation, as measured by the Pi2, was highly associated with important outcomes for both patients and providers. This measure will be used to track the effectiveness of implementing PACT over time and to elucidate the correlates of desired health outcomes. C1 [Nelson, Karin M.; Helfrich, Christian; Sun, Haili; Hebert, Paul L.; Liu, Chuan-Fen; Dolan, Emily; Taylor, Leslie; Maynard, Charles; Hernandez, Susan E.; Randall, Ian] VA Puget Sound Hlth Care Syst, Seattle Ctr Innovat Vet Ctr & Value Driven Care, Seattle, WA 98108 USA. [Nelson, Karin M.; Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, Gen Internal Med Serv, Seattle, WA 98108 USA. [Nelson, Karin M.; Fihn, Stephan D.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Helfrich, Christian; Sun, Haili; Hebert, Paul L.; Liu, Chuan-Fen; Wong, Edwin; Maynard, Charles; Hernandez, Susan E.; Randall, Ian] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Sanders, William; Curtis, Idamay; Fihn, Stephan D.] Vet Hlth Adm, Off Analyt & Business Intelligence, Washington, DC USA. [Schectman, Gordon] US Dept Vet Affairs, Off Patient Care Serv, Washington, DC USA. [Stark, Richard] US Dept Vet Affairs, Off Clin Operat, Washington, DC USA. RP Nelson, KM (reprint author), VA Puget Sound Hlth Care Syst, Seattle Ctr Innovat Vet Ctr & Value Driven Care, 1100 Olive Way,Ste 1400, Seattle, WA 98108 USA. EM karin.nelson@va.gov RI Maynard, Charles/N-3906-2015 OI Maynard, Charles/0000-0002-1644-7814 FU VHA Office of Patient Care Service FX This work was supported by the VHA Office of Patient Care Service. NR 43 TC 40 Z9 40 U1 11 U2 38 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1350 EP 1358 DI 10.1001/jamainternmed.2014.2488 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000031 PM 25055197 ER PT J AU Joynt, KE Jha, AK AF Joynt, Karen E. Jha, Ashish K. TI What Is a "Nonprofit" Hospital? Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Joynt, Karen E.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Joynt, Karen E.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [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. RP Jha, AK (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM ajha@hsph.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1412 EP 1412 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000049 PM 25090175 ER PT J AU Wiener, RS Slatore, CG AF Wiener, Renda Soylemez Slatore, Christopher G. TI Real-World Evidence About Potential Psychosocial Harms of Lung Cancer Screening SO JAMA INTERNAL MEDICINE LA English DT Letter ID PULMONARY NODULES C1 [Wiener, Renda Soylemez] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Wiener, Renda Soylemez] Edith Nourse Rogers Mem Vet Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA USA. [Slatore, Christopher G.] Portland VA Med Ctr, Hlth Serv Res & Dev, Portland, OR USA. [Slatore, Christopher G.] Oregon Hlth & Sci Univ, Div Pulm & Crit Care Med, Portland, OR 97201 USA. RP Wiener, RS (reprint author), Boston Univ, Sch Med, Ctr Pulm, 72 E Concord St,R-304, Boston, MA 02118 USA. EM rwiener@bu.edu OI Wiener, Renda/0000-0001-7712-2135 NR 4 TC 0 Z9 0 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6106 EI 2168-6114 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG PY 2014 VL 174 IS 8 BP 1416 EP 1416 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA AN2WP UT WOS:000340447000055 PM 25090181 ER PT J AU Rohrer, J Maturo, S Hill, C Bunting, G Ballif, C Hartnick, C AF Rohrer, Joseph Maturo, Stephen Hill, Courtney Bunting, Glenn Ballif, Cathy Hartnick, Christopher TI Pediatric Voice Analysis Comparison of 2 Computerized Analysis Systems SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article AB IMPORTANCE This research contributes to the pediatric objective voice measurement database while identifying comparable measurements between 2 available voice analysis systems. OBJECTIVE To compare selective normative pediatric acoustic variables between the Multi-Dimensional Voice Program (MDVP) and the Voice Evaluation Suite (VES) computerized voice analysis systems. Additionally, it describes the first comprehensive pediatric database analyzing fundamental frequency, jitter, shimmer, and noise to harmonic ratio using the VES. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study with planned data collection conducted at a tertiary referral otolaryngologic clinic. Participants were 335 children, aged 4 to 18 years, with normal voices. INTERVENTIONS Objective voice data were collected on the MDVP and the VES systems. MAIN OUTCOMES AND MEASURES Fundamental frequency, jitter, shimmer, and noise to harmonic ratio. RESULTS The fundamental frequencies agreed with previous pediatric normative values. There was not a statistically significant difference between MDVP and VES measurements of mean fundamental frequency (P = .23). Jitter percentage (P < .001), shimmer percentage (P < .001), and noise to harmonic ratio (P < .002) for all children were statistically different between the 2 voice evaluation systems. CONCLUSIONS AND RELEVANCE These data show that the measured fundamental frequency of normal voices in children is comparable between the MDVP and VES voice analysis systems. Jitter, shimmer, and noise to harmonic ratio values are not interchangeable between voice analysis systems. The voice analysis system should be reported when providing voice measurement outcomes in the literature. C1 [Rohrer, Joseph; Maturo, Stephen] San Antonio Mil Med Ctr, Dept Otolaryngol, San Antonio, TX 78234 USA. [Hill, Courtney; Bunting, Glenn; Ballif, Cathy] Massachusetts Eye & Ear Infirm, Voice & Speech Lab, Boston, MA 02114 USA. [Hill, Courtney; Hartnick, Christopher] Harvard Univ, Sch Med, Dept Otolaryngol & Laryngol, Boston, MA USA. [Hartnick, Christopher] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA USA. RP Maturo, S (reprint author), San Antonio Mil Med Ctr, Dept Otolaryngol, 3851 Roger Brooke Dr, San Antonio, TX 78234 USA. EM Stephen.c.maturo.mil@mail.mil FU Massachusetts Eye and Ear Infirmary FX This study was supported by Massachusetts Eye and Ear Infirmary internal funding (Dr Maturo). NR 8 TC 1 Z9 1 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD AUG PY 2014 VL 140 IS 8 BP 742 EP 745 DI 10.1001/jamaoto.2014.1162 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN9BT UT WOS:000340901500010 PM 25010950 ER PT J AU Deschler, DG AF Deschler, Daniel G. TI Extracapsular Dissection of Benign Parotid Tumors SO JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID PLEOMORPHIC ADENOMA C1 [Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Head & Neck Surg, Boston, MA 02114 USA. [Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Norman Knight Hyperbar Med Ctr, Boston, MA 02114 USA. [Deschler, Daniel G.] Massachusetts Gen Hosp, Dept Head & Neck Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Deschler, DG (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. NR 5 TC 3 Z9 3 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6181 EI 2168-619X J9 JAMA OTOLARYNGOL JI JAMA Otolaryngol-Head Neck Surg. PD AUG PY 2014 VL 140 IS 8 BP 770 EP 771 DI 10.1001/jamaoto.2014.1223 PG 2 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN9BT UT WOS:000340901500016 PM 25033390 ER PT J AU Sacks, GD Dawes, AJ Russell, MM Lin, AY Maggard-Gibbons, M Winograd, D Chung, HR Tomlinson, J Tillou, A Shew, SB Hiyama, DT Cryer, HG Brunicardi, FC Hiatt, JR Ko, C AF Sacks, Greg D. Dawes, Aaron J. Russell, Marcia M. Lin, Anne Y. Maggard-Gibbons, Melinda Winograd, Deborah Chung, Hallie R. Tomlinson, James Tillou, Areti Shew, Stephen B. Hiyama, Darryl T. Cryer, H. Gill Brunicardi, F. Charles Hiatt, Jonathan R. Ko, Clifford TI Evaluation of Hospital Readmissions in Surgical Patients Do Administrative Data Tell the Real Story? SO JAMA SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; POSTOPERATIVE ADVERSE EVENTS; DATA SETS; COMPLICATIONS; RATES AB IMPORTANCE The Centers for Medicare & Medicaid Services has developed an all-cause readmission measure that uses administrative data to measure readmission rates and financially penalize hospitals with higher-than-expected readmission rates. OBJECTIVES To examine the accuracy of administrative codes in determining the cause of readmission as determined by medical record review, to evaluate the readmission measure's ability to accurately identify a readmission as planned, and to document the frequency of readmissions for reasons clinically unrelated to the original hospital stay. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of all consecutive patients discharged from general surgery services at a tertiary care, university-affiliated teaching hospital during 8 consecutive quarters (quarter 4 [October through December] of 2009 through quarter 3 [July through September] of 2011). Clinical readmission diagnosis determined from direct medical record review was compared with the administrative diagnosis recorded in a claims database. The number of planned hospital readmissions defined by the readmission measure was compared with the number identified using clinical data. Readmissions unrelated to the original hospital stay were identified using clinical data. MAIN OUTCOMES AND MEASURES Discordance rate between administrative and clinical diagnoses for all hospital readmissions, discrepancy between planned readmissions defined by the readmission measure and identified by clinical medical record review, and fraction of hospital readmissions unrelated to the original hospital stay. RESULTS Of the 315 hospital readmissions, the readmission diagnosis listed in the administrative claims data differed from the clinical diagnosis in 97 readmissions (30.8%). The readmission measure identified 15 readmissions (4.8%) as planned, whereas clinical data identified 43 readmissions (13.7%) as planned. Unrelated readmissions comprised 70 of the 258 unplanned readmissions (27.1%). CONCLUSIONS AND RELEVANCE Administrative billing data, as used by the readmission measure, do not reliably describe the reason for readmission. The readmission measure accounts for less than half of the planned readmissions and does not account for the nearly one-third of readmissions unrelated to the original hospital stay. Implementation of this readmission measure may result in unwarranted financial penalties for hospitals. C1 [Sacks, Greg D.; Dawes, Aaron J.; Russell, Marcia M.; Lin, Anne Y.; Maggard-Gibbons, Melinda; Winograd, Deborah; Chung, Hallie R.; Tomlinson, James; Tillou, Areti; Shew, Stephen B.; Hiyama, Darryl T.; Cryer, H. Gill; Brunicardi, F. Charles; Hiatt, Jonathan R.; Ko, Clifford] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Russell, Marcia M.; Maggard-Gibbons, Melinda; Tomlinson, James; Ko, Clifford] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Sacks, GD (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 Le Conte Ave,72-215 CHS, Los Angeles, CA 90095 USA. EM gsacks@mednet.ucla.edu OI Dawes, Aaron/0000-0003-4574-6765 NR 20 TC 30 Z9 30 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6254 EI 2168-6262 J9 JAMA SURG JI JAMA Surg. PD AUG PY 2014 VL 149 IS 8 BP 759 EP 764 DI 10.1001/jamasurg.2014.18 PG 6 WC Surgery SC Surgery GA AN8DZ UT WOS:000340834300002 PM 24920156 ER PT J AU McCann, RA Armstrong, CM Skopp, NA Edwards-Stewart, A Smolenski, DJ June, JD Metzger-Abamukong, M Reger, GM AF McCann, Russell A. Armstrong, Christina M. Skopp, Nancy A. Edwards-Stewart, Amanda Smolenski, Derek J. June, Jennifer D. Metzger-Abamukong, Melinda Reger, Greg M. TI Virtual reality exposure therapy for the treatment of anxiety disorders: An evaluation of research quality SO JOURNAL OF ANXIETY DISORDERS LA English DT Review DE Randomized controlled trials; Effectiveness; Adherence ID POSTTRAUMATIC-STRESS-DISORDER; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIALS; PUBLIC SPEAKING ANXIETY; IN-VIVO EXPOSURE; CLINICAL-TRIAL; PANIC DISORDER; CONSORT STATEMENT; GRADED EXPOSURE; SPIDER PHOBIA AB Randomized controlled trials (RCTs) support the effectiveness of virtual reality exposure therapy (VRET) for anxiety disorders; however, the overall quality of the VRET RCT literature base has yet to be evaluated. This study reviewed 27 VRET RCTs and the degree of adherence to 8 RCT research design criteria derived from existing standards. Adherence to the study quality criteria was generally low as the articles met an average 2.85 criteria (SD = 1.56). None of the studies met more than six quality criteria. Study quality did not predict effect size; however, a reduction in effect size magnitude was observed for studies with larger sample sizes when comparing VRET to non-active control groups. VRET may be an effective method of treatment but caution should be exercised in interpreting the existing body of literature supporting VRET relative to existing standards of care. The need for well-designed VRET research is discussed. (C) 2014 Published by Elsevier Ltd. C1 [McCann, Russell A.; Armstrong, Christina M.; Skopp, Nancy A.; Edwards-Stewart, Amanda; Smolenski, Derek J.; June, Jennifer D.; Metzger-Abamukong, Melinda; Reger, Greg M.] Madigan Army Med Ctr, Natl Ctr Telehlth & Technol, Tacoma, WA 98431 USA. RP Reger, GM (reprint author), VA Puget Sound, 9600 Vet Dr, Tacoma, WA 98493 USA. EM Greg.reger2@gmail.com NR 58 TC 13 Z9 13 U1 9 U2 44 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 EI 1873-7897 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD AUG PY 2014 VL 28 IS 6 BP 625 EP 631 DI 10.1016/j.janxdis.2014.05.010 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AN8OW UT WOS:000340864500015 PM 25093964 ER PT J AU Canver, MC Bauer, DE Dass, A Yien, YY Chung, J Masuda, T Maeda, T Paw, BH Orkin, SH AF Canver, Matthew C. Bauer, Daniel E. Dass, Abhishek Yien, Yvette Y. Chung, Jacky Masuda, Takeshi Maeda, Takahiro Paw, Barry H. Orkin, Stuart H. TI Characterization of Genomic Deletion Efficiency Mediated by Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 Nuclease System in Mammalian Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOUSE ERYTHROLEUKEMIA-CELLS; CHROMOSOMAL DELETIONS; CRISPR-CAS9 SYSTEM; CAS9; SPECIFICITY; CRISPR/CAS; DNA; ENDONUCLEASE; MUTAGENESIS; INVERSIONS AB The clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated (Cas) 9 nuclease system has provided a powerful tool for genome engineering. Double strand breaks may trigger nonhomologous end joining repair, leading to frameshift mutations, or homology-directed repair using an extrachromosomal template. Alternatively, genomic deletions may be produced by a pair of double strand breaks. The efficiency of CRISPR/Cas9-mediated genomic deletions has not been systematically explored. Here, we present a methodology for the production of deletions in mammalian cells, ranging from 1.3 kb to greater than 1 Mb. We observed a high frequency of intended genomic deletions. Nondeleted alleles are nonetheless often edited with inversions or small insertion/deletions produced at CRISPR recognition sites. Deleted alleles also typically include small insertion/deletions at predicted deletion junctions. We retrieved cells with biallelic deletion at a frequency exceeding that of probabilistic expectation. We demonstrate an inverse relationship between deletion frequency and deletion size. This work suggests that CRISPR/Cas9 is a robust system to produce a spectrum of genomic deletions to allow investigation of genes and genetic elements. C1 [Canver, Matthew C.; Bauer, Daniel E.; Yien, Yvette Y.; Chung, Jacky; Maeda, Takahiro; Paw, Barry H.; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bauer, Daniel E.; Dass, Abhishek; Paw, Barry H.; Orkin, Stuart H.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Bauer, Daniel E.; Paw, Barry H.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Yien, Yvette Y.; Chung, Jacky; Masuda, Takeshi; Maeda, Takahiro; Paw, Barry H.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM Stuart_Orkin@dfci.harvard.edu FU National Institutes of Health [R01HL032259, P30DK049216]; NIDDK [K08DK093705]; NIAID [R01AI084905]; Canadian Institutes of Health Research fellowship; [T32HL007574]; [F32DK098866]; [R01DK070838]; [P01HL032262] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01HL032259 and P30DK049216 (Center of Excellence in Molecular Hematology to S. H. O.), Grant K08DK093705 from NIDDK (to D. E. B.), Grant R01AI084905 from NIAID (to T. M.), Grants T32HL007574 and F32DK098866 (to Y. Y. Y.), and Grants R01DK070838 and P01HL032262 (to B. H. P.).; Supported by a Canadian Institutes of Health Research fellowship. NR 35 TC 81 Z9 87 U1 7 U2 45 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 1 PY 2014 VL 289 IS 31 BP 21312 EP 21324 DI 10.1074/jbc.M114.564625 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN4LC UT WOS:000340558300012 PM 24907273 ER PT J AU Johnson, DW Bittner, EA AF Johnson, Daniel W. Bittner, Edward A. TI Con: Cardiac Anesthesiologists Should Not Be the Intensivists of the Operating Room SO JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA LA English DT Article DE intensivist; staffing model; critical care ID CRITICAL-CARE MEDICINE; PHYSICIANS; WORKFORCE; SHORTAGE C1 [Johnson, Daniel W.] Univ Nebraska Med Ctr, Dept Anesthesiol, Omaha, NE USA. [Bittner, Edward A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Bittner, EA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St WHT 437, Boston, MA 02114 USA. EM ebittner@partners.org NR 12 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-0770 EI 1532-8422 J9 J CARDIOTHOR VASC AN JI J. Cardiothorac. Vasc. Anesth. PD AUG PY 2014 VL 28 IS 4 BP 1156 EP 1158 DI 10.1053/j.jvca.2014.03.019 PG 3 WC Anesthesiology; Cardiac & Cardiovascular Systems; Respiratory System; Peripheral Vascular Disease SC Anesthesiology; Cardiovascular System & Cardiology; Respiratory System GA AN6VN UT WOS:000340736600050 PM 25107724 ER PT J AU McClatchey, AI AF McClatchey, Andrea I. TI ERM proteins at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article DE Actin cytoskeleton; Apical morphogenesis; Cell cortex; Ezrin; Moesin; Radixin ID CELL CORTEX; LUMEN MORPHOGENESIS; EPITHELIAL-CELLS; EZRIN; MOESIN; TUBULOGENESIS; EBP50; PHOSPHORYLATION; ORGANIZATION; CYTOSKELETON AB The cell cortex is a dynamic and heterogeneous structure that governs cell identity and behavior. The ERM proteins (ezrin, radixin and moesin) are major architects of the cell cortex, and they link plasma membrane phospholipids and proteins to the underlying cortical actin cytoskeleton. Recent studies in several model systems have uncovered surprisingly dynamic and complex molecular activities of the ERM proteins and have provided new mechanistic insight into how they build and maintain cortical domains. Among many well-established and essential functions of ERM proteins, this Cell Science at a Glance article and accompanying poster will focus on the role of ERMs in organizing the cell cortex during cell division and apical morphogenesis. These examples highlight an emerging appreciation that the ERM proteins both locally alter the mechanical properties of the cell cortex, and control the spatial distribution and activity of key membrane complexes, establishing the ERM proteins as a nexus for the physical and functional organization of the cell cortex and making it clear that they are much more than scaffolds. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res,Dept Pathol, Charlestown, MA 02129 USA. RP McClatchey, AI (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc Res,Dept Pathol, 149 13th St, Charlestown, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu FU National Institutes of Health; MGH Research Scholars Program; Ellison Foundation; O'Brien Trust; Children's Tumor Foundation; Advocure FX A.I.M is funded by the National Institutes of Health; MGH Research Scholars Program; Ellison Foundation; O'Brien Trust; Children's Tumor Foundation; and Advocure. Deposited in PMC for release after 12 months. NR 59 TC 20 Z9 21 U1 0 U2 14 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2014 VL 127 IS 15 BP 3199 EP 3204 DI 10.1242/jcs.098343 PG 6 WC Cell Biology SC Cell Biology GA AO2SS UT WOS:000341176800001 PM 24951115 ER PT J AU Vagin, O Tokhtaeva, E Garay, PE Souda, P Bassilian, S Whitelegge, JP Lewis, R Sachs, G Wheeler, L Aoki, R Fernandez-Salas, E AF Vagin, Olga Tokhtaeva, Elmira Garay, Patton E. Souda, Puneet Bassilian, Sara Whitelegge, Julian P. Lewis, Ramilla Sachs, George Wheeler, Larry Aoki, Roger Fernandez-Salas, Ester TI Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability SO JOURNAL OF CELL SCIENCE LA English DT Article DE Septin; Botulinum toxin A protease; Protein stability; Degradation; Ubiquitylation ID NEUROTRANSMITTER RELEASE; MAMMALIAN SEPTINS; BETA(1) SUBUNITS; NEUROTOXIN; FORCHLORFENURON; RECOGNITION; SIGNALS; COMPLEX; AP-3; LOCALIZATION AB Proteolytic cleavage of synaptosomal-associated protein 25 by the light chain of botulinum neurotoxin type A (LCA) results in a blockade of neurotransmitter release that persists for several months in motor neurons. The L428A/L429A mutation in LCA is known to significantly shorten both the proteolytic and neuroparalytic effects of the neurotoxin in mice. To elucidate the cellular mechanism for LCA longevity, we studied the effects of L428A/L429A mutation on the interactome, localization and stability of LCA expressed in cultured neuronal cells. Mass spectrometry analysis of the LCA interactome showed that the mutation prevented the interaction of LCA with septins. The wild-type LCA was concentrated in plasma-membrane-associated clusters, colocalizing with septins-2 and septin-7, which accumulated in these clusters only in the presence of LCA. The L428A/L429A mutation decreased co-clustering of LCA and septins and accelerated proteasomal and non-proteasomal degradation of LCA. Similarly, the impairment of septin oligomerization by forchlorfenuron or silencing of septin-2 prevented LCA interaction and clustering with septins and increased LCA degradation. Therefore, the dileucine-mediated LCA-septin co-clustering is crucial for the long-lasting stabilization of LCA-related proteolytic and presumably neuroparalytic activity. C1 [Vagin, Olga; Tokhtaeva, Elmira; Bassilian, Sara; Sachs, George] UCLA, Sch Med, Dept Physiol, Los Angeles, CA 91343 USA. [Vagin, Olga; Tokhtaeva, Elmira; Bassilian, Sara; Sachs, George] Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 91343 USA. [Garay, Patton E.; Lewis, Ramilla; Wheeler, Larry; Aoki, Roger; Fernandez-Salas, Ester] Allergan Pharmaceut Inc, Dept Biol Sci, Irvine, CA 92612 USA. [Souda, Puneet; Whitelegge, Julian P.] Univ Calif Los Angeles, Semel Inst, NPI, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA. RP Vagin, O (reprint author), UCLA, Sch Med, Dept Physiol, Los Angeles, CA 91343 USA. EM olgav@ucla.edu FU Allergan, Inc. FX This work was supported by a grant from Allergan, Inc. to O.V. NR 56 TC 6 Z9 6 U1 0 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2014 VL 127 IS 15 BP 3294 EP 3308 DI 10.1242/jcs.146324 PG 15 WC Cell Biology SC Cell Biology GA AO2SS UT WOS:000341176800010 PM 24928902 ER PT J AU Yilancioglu, K Weinstein, ZB Meydan, C Akhmetov, A Toprak, I Durmaz, A Iossifov, I Kazan, H Roth, FP Cokol, M AF Yilancioglu, Kaan Weinstein, Zohar B. Meydan, Cem Akhmetov, Azat Toprak, Isil Durmaz, Arda Iossifov, Ivan Kazan, Hilal Roth, Frederick P. Cokol, Murat TI Target-Independent Prediction of Drug Synergies Using Only Drug Lipophilicity SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID BIOLOGICAL-ACTIVITY; PARTITION-COEFFICIENTS; MODELS; MOLECULES; NETWORKS; SYSTEMS; PASS AB Physicochemical properties of compounds have been instrumental in selecting lead compounds with increased drug-likeness. However, the relationship between physicochemical properties of constituent drugs and the tendency to exhibit drug interaction has not been systematically studied. We assembled physicochemical descriptors for a set of antifungal compounds ("drugs") previously examined for interaction. Analyzing the relationship between molecular weight, lipophilicity, H-bond donor, and H-bond acceptor values for drugs and their propensity to show pairwise antifungal drug synergy, we found that combinations of two lipophilic drugs had a greater tendency to show drug synergy. We developed a more refined decision tree model that successfully predicted drug synergy in stringent cross-validation tests based on only lipophilicity of drugs. Our predictions achieved a precision of 63% and allowed successful prediction for 58% of synergistic drug pairs, suggesting that this phenomenon can extend our understanding for a substantial fraction of synergistic drug interactions. We also generated and analyzed a large-scale synergistic human toxicity network, in which we observed that combinations of lipophilic compounds show a tendency for increased toxicity. Thus, lipophilicity, a simple and easily determined molecular descriptor, is a powerful predictor of drug synergy. It is well established that lipophilic compounds (i) are promiscuous, having many targets in the cell, and (ii) often penetrate into the cell via the cellular membrane by passive diffusion. We discuss the positive relationship between drug lipophilicity and drug synergy in the context of potential drug synergy mechanisms. C1 [Yilancioglu, Kaan; Meydan, Cem; Akhmetov, Azat; Durmaz, Arda; Cokol, Murat] Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. [Toprak, Isil] Sabanci Univ, Fac Engn & Nat Sci, Comp Sci & Engn Program, TR-34956 Istanbul, Turkey. [Cokol, Murat] Sabanci Univ, Nanotechnol Res & Applicat Ctr, TR-34956 Istanbul, Turkey. [Yilancioglu, Kaan] Uskudar Univ, Biomed Equipment Technol Program, TR-34662 Istanbul, Turkey. [Weinstein, Zohar B.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Meydan, Cem] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10065 USA. [Akhmetov, Azat] Univ Texas Austin, Inst Cellular & Mol Biol, Austin, TX 78712 USA. [Iossifov, Ivan] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kazan, Hilal] Antalya Int Univ, Dept Comp Engn, Fac Engn, TR-07190 Antalya, Turkey. [Roth, Frederick P.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada. [Roth, Frederick P.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada. [Roth, Frederick P.] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada. [Roth, Frederick P.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. RP Cokol, M (reprint author), Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, TR-34956 Istanbul, Turkey. EM cokol@sabanciuniv.edu RI Roth, Frederick/H-6308-2011; OI Roth, Frederick/0000-0002-6628-649X FU NIH [HG001715, HG004233]; Krembil Foundation; Avon Foundation; Canadian Institute for Advanced Research; Canada Excellence Research Chairs Program; Turkish Academy of Sciences GEBIP Programme FX F.P.R. was supported by NIH grants (HG001715 and HG004233), by the Krembil Foundation, the Avon Foundation, a Canadian Institute for Advanced Research Fellowship, and the Canada Excellence Research Chairs Program. M.C. was supported by the Turkish Academy of Sciences GEBIP Programme. NR 34 TC 4 Z9 4 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 EI 1549-960X J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD AUG PY 2014 VL 54 IS 8 BP 2286 EP 2293 DI 10.1021/ci500276x PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA AN8NW UT WOS:000340861900011 PM 25026390 ER PT J AU Akgoz, A Rahman, R You, H Qu, JR Hamdan, A Seethamraju, RT Wen, PY Young, GS AF Akgoz, Ayca Rahman, Rifaquat You, Hui Qu, Jinrong Hamdan, Alhafidz Seethamraju, Ravi T. Wen, Patrick Y. Young, Geoffrey S. TI Spin-echo echo-planar perfusion prior to chemoradiation is a strong independent predictor of progression-free and overall survival in newly diagnosed glioblastoma SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Cerebral blood volume; Perfusion MRI; Prognostic factors ID CEREBRAL BLOOD-VOLUME; CONTRAST-ENHANCED MR; HIGH-GRADE GLIOMAS; PROGNOSTIC-FACTORS; GRADIENT-ECHO; TUMOR GRADE; BRAIN; MAPS; PSEUDOPROGRESSION; NEUROONCOLOGY AB Spin-echo echo planar (EP) perfusion weighted imaging (SE-PWI) has been demonstrated to be more selective than gradient-echo EP PWI for blood volume in microvessels the size of glioma neocapillaries, but it has not been comprehensively studied in human clinical use. We assessed whether SE-PWI before and after initiating chemoradiation can stratify patients with respect to progression free survival (PFS) and overall survival (OS). Sixty-eight patients with newly diagnosed glioblastoma (mean age 58.3, 36 males) were included in analysis. SE EP cerebral blood volumes (SE-CBVs) in enhancing and nonenhancing tumor, normalized to contralateral normal appearing white matter (SE-nCBV), were assessed at baseline and after initial chemoradiation. SE-nCBV parameters predictive of PFS and OS were identified in univariate and multivariate Cox proportional hazards models. Multivariate analysis demonstrated that baseline tumor mean SE-nCBV was predictive of PFS (p = 0.038) and OS (p = 0.004). Within the patient sample, baseline tumor mean SE-nCBV < 2.0 predicted longer patient PFS (median 47.0 weeks, p < 0.001) and OS (median 98.6 weeks, p = 0.003) compared with baseline mean SE-nCBV > 2.0 (median PFS 25.3, median OS 56.0 weeks). Exploratory multi-group stratification demonstrated that very high (> 4.0) tumor SE-nCBV was associated with worse patient OS than intermediate high (> 2.0, < 4.0) SE-nCBV (p = 0.025). Baseline mean SE-nCBV can stratify patients for PFS and OS prior to initiation of chemoradiation, which may help select patients who require closer surveillance. Our exploratory analysis indicates a magnitude-dependent relationship between baseline SE-nCBV and OS. C1 [Akgoz, Ayca; You, Hui; Qu, Jinrong; Young, Geoffrey S.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Rahman, Rifaquat; You, Hui; Qu, Jinrong; Hamdan, Alhafidz; Wen, Patrick Y.; Young, Geoffrey S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [You, Hui] Beijing Union Med Coll Hosp, Dept Radiol, Beijing 100730, Peoples R China. [Qu, Jinrong] Zhengzhou Univ, Henan Canc Hosp, Affiliated Canc Hosp, Dept Radiol, Zhengzhou 450008, Peoples R China. [Seethamraju, Ravi T.] Siemens Healthcare, MR Res & Dev, Boston, MA USA. [Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Wen, Patrick Y.; Young, Geoffrey S.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. RP Young, GS (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM gsyoung@partners.org FU National Key Project of Science and Technology Supporting Programs of China [2007BAI05B08]; National Natural Science Foundation of China [30770617, 30730035]; International Cooperation Project of Henan Science and Technology Supporting Programs of China [114300510016]; Henan Health Science and Technology Innovation Talent Project [201004057]; Siemens Medical Solutions(R) FX Dr. Qu acknowledges salary support from the National Key Project of Science and Technology Supporting Programs of China (No. 2007BAI05B08), the National Natural Science Foundation of China (No. 30770617, 30730035), the International Cooperation Project of Henan Science and Technology Supporting Programs of China (No. 114300510016), and Special funding from the Henan Health Science and Technology Innovation Talent Project (No. 201004057). The Authors acknowledge in support from Siemens Medical Solutions (R) in the form of salary support for Dr. Seethamraju and provision of MRI image processing and analysis hardware and software. NR 28 TC 2 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2014 VL 119 IS 1 BP 111 EP 119 DI 10.1007/s11060-014-1454-x PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AN4EI UT WOS:000340540000013 PM 24792644 ER PT J AU Rahman, R Hamdan, A Zweifler, R Jiang, H Norden, AD Reardon, DA Mukundan, S Wen, PY Huang, RY AF Rahman, Rifaquat Hamdan, Alhafidz Zweifler, Rebecca Jiang, Han Norden, Andrew D. Reardon, David A. Mukundan, Srinivasan Wen, Patrick Y. Huang, Raymond Y. TI Histogram analysis of apparent diffusion coefficient within enhancing and nonenhancing tumor volumes in recurrent glioblastoma patients treated with bevacizumab SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Glioblastoma; Bevacizumab; Apparent diffusion coefficient; Survival analysis ID IMAGING BIOMARKER; MALIGNANT GLIOMAS; SURVIVAL; PROGRESSION; CRITERIA; GRADE; MAPS; GBM AB While patients with recurrent glioblastoma receiving anti-angiogenic therapy demonstrate significant response rates, the benefit on patient survival is less clear. We assessed whether histogram analysis of diffusion weighted MRI can stratify for progression-free and overall survival. Baseline and 3-6 week post-treatment MRI exams of 91 patients with recurrent glioblastoma treated with bevacizumab were retrospectively evaluated. Histograms of apparent diffusion coefficient (ADC) within the volume of contrast enhancing and nonenhancing T2/FLAIR lesions were analyzed using curve-fit analysis. Overall survival (OS) and progression-free survival (PFS) were assessed using ADC parameters in a Cox proportional hazards model adjusted for clinical variables. Baseline ADC(L)/ADC(M) within nonenhancing T2/FLAIR volume (> or a parts per thousand currency sign0.64) can stratify OS (HR = 2.24, p = 0.002) and PFS (HR = 1.90, p = 0.005). %ADC(H) within enhancing T1+C volume (> or a parts per thousand currency sign25 %) can also stratify OS (HR = 0.59, p = 0.034) and PFS (HR = 0.56, p = 0.01). Stratification of patient survival can be improved by merging these two ADC parameters into a single combined ADC factor (HR = 0.17, p < 0.0001). The median OS ratio of patient groups stratified by this combined factor was 2.03, larger than median OS ratio when stratifying by either %ADC(H) within T1+C volume alone (1.3) or ADC(L)/ADC(M) within T2/FLAIR alone (1.86). ADC histogram analysis within both enhancing and nonenhancing components of tumor can be used to stratify for PFS and OS in patients with recurrent glioblastoma. C1 [Rahman, Rifaquat] Harvard Univ, Sch Med, Boston, MA USA. [Hamdan, Alhafidz; Zweifler, Rebecca; Jiang, Han; Norden, Andrew D.; Reardon, David A.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Mukundan, Srinivasan; Huang, Raymond Y.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Huang, RY (reprint author), Brigham & Womens Hosp, Dept Radiol, 75 Francis St, Boston, MA 02115 USA. EM ryhuang@partners.org OI Huang, Raymond/0000-0001-7661-797X NR 24 TC 8 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD AUG PY 2014 VL 119 IS 1 BP 149 EP 158 DI 10.1007/s11060-014-1464-8 PG 10 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA AN4EI UT WOS:000340540000018 PM 24805151 ER PT J AU Pierre, JF Barlow-Anacker, AJ Erickson, CS Heneghan, AF Leverson, GE Dowd, SE Epstein, ML Kudsk, KA Gosain, A AF Pierre, Joseph F. Barlow-Anacker, Amanda J. Erickson, Christopher S. Heneghan, Aaron F. Leverson, Glen E. Dowd, Scot E. Epstein, Miles L. Kudsk, Kenneth A. Gosain, Ankush TI Intestinal dysbiosis and bacterial enteroinvasion in a murine model of Hirschsprung's disease SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Hirschsprung's disease; Hirschsprung's-associated enterocolitis; Microbiome; Secretory phospholipase A2; Dysbiosis; Mucosal immunity ID AMPLICON PYROSEQUENCING BTEFAP; INFLAMMATORY-BOWEL-DISEASE; ALPHA-DEFENSIN EXPRESSION; ENTERIC NERVOUS-SYSTEM; ILEAL CROHNS-DISEASE; KINASE RECEPTOR RET; NECROTIZING ENTEROCOLITIS; PHOSPHOLIPASE A(2); ESCHERICHIA-COLI; NEURAL CREST AB Background/purpose: Hirschsprung's disease (HSCR), characterized by the absence of ganglia in the distal colon, results in functional obstruction. Despite surgical resection of the aganglionic segment, around 40% of patients suffer recurrent life threatening Hirschsprung's-associated enterocolitis (HAEC). The aim of this study was to investigate whether gut microbiota and intestinal immunity changes contribute to the HAEC risk in an HSCR model. Methods: Mice with neural crest conditional deletion of Endothelin receptor B (EdnrB) and their littermate controls were used (EdnrB-null and EdnrB-het). Bacterial DNA was prepared from cecal contents of P16-18 and P21-24 animals and pyrosequencing employed for microbiome analysis. Ileal tissue was isolated and secretory phospholipase A(2) (sPLA(2)) expression and activity determined. Enteroinvasion of Escherichia coli into ileal explants was measured using an ex vivo organ culture system. Results: EdnrB-het and EdnrB-nulls displayed similar flora, sPLA(2) expression and activity at P16-18. However, by P21-24, EdnrB-hets demonstrated increased Lactobacillus and decreased Bacteroides and Clostridium, while EdnrB-nulls exhibited reciprocal changes. EdnrB-nulls also showed reduced sPLA(2) expression and luminal activity at this stage. Functionally, EdnrB-nulls were more susceptible to enteroinvasion with E. coli ex vivo and released less sPLA(2) than EdnrB-hets. Conclusions: Initially, EdnrB-het and EdnrB-nulls contain similar cecal flora but then undergo reciprocal changes. EdnrB-nulls display dysbiosis, demonstrate impaired mucosal defense, decreased luminal sPLA(2) and increased enteroinvasion of E. coli just prior to robust colonic inflammation and death. These findings suggest a role for the intestinal microbiome in the development of HAEC. (C) 2014 Elsevier Inc. All rights reserved. C1 [Pierre, Joseph F.; Barlow-Anacker, Amanda J.; Erickson, Christopher S.; Heneghan, Aaron F.; Leverson, Glen E.; Kudsk, Kenneth A.; Gosain, Ankush] Univ Wisconsin, Dept Surg, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Epstein, Miles L.; Gosain, Ankush] Univ Wisconsin, Dept Neurosci, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Dowd, Scot E.] Res & Testing Lab, Lubbock, TX USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Gosain, A (reprint author), Univ Wisconsin, Dept Surg, Clin Sci Ctr H4 750, 600 Highland Ave, Madison, WI 53792 USA. EM gosain@surgery.wisc.edu FU National Institutes of Health [NIDDK RO1DK081634]; Veteran's Affairs Office of Research and Development (Biomedical Laboratory Research & Development Award) [I01BX001672]; Central Surgical Association Foundation Turcotte Award; American Pediatric Surgery Association Foundation Award FX This work was supported by the National Institutes of Health (NIDDK RO1DK081634) to MLE, the Veteran's Affairs Office of Research and Development (Biomedical Laboratory Research & Development Award I01BX001672) to KAK, the Central Surgical Association Foundation Turcotte Award to AG, and the American Pediatric Surgery Association Foundation Award to AG. The contents of this article do not represent the views of the Veterans Affairs or the United States Government (KAK). NR 60 TC 11 Z9 13 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 EI 1531-5037 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD AUG PY 2014 VL 49 IS 8 BP 1242 EP 1251 DI 10.1016/j.jpedsurg.2014.01.060 PG 10 WC Pediatrics; Surgery SC Pediatrics; Surgery GA AN0EM UT WOS:000340256200011 PM 25092084 ER PT J AU Alvey, NJ Pedley, A Rosenquist, KJ Massaro, JM O'Donnell, CJ Hoffmann, U Fox, CS AF Alvey, Nicholas J. Pedley, Alison Rosenquist, Klara J. Massaro, Joseph M. O'Donnell, Christopher J. Hoffmann, Udo Fox, Caroline S. TI Association of Fat Density With Subclinical Atherosclerosis SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE atherosclerosis; epidemiology; fat density; obesity ID CORONARY-ARTERY CALCIFICATION; ADIPOSE-TISSUE; INSULIN-RESISTANCE; RISK-FACTORS; VISCERAL ADIPOSITY; JAPANESE-AMERICANS; ABDOMINAL OBESITY; LIPID-METABOLISM; YOUNG-ADULTS; CELL-SIZE AB Background-Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis. Methods and Results-Participants were drawn from the Multi-Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable-adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age-/sex-specific cutoffs). Per 5-unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC. Conclusions-Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis. C1 [Alvey, Nicholas J.; Rosenquist, Klara J.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Alvey, Nicholas J.; Pedley, Alison; Rosenquist, Klara J.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rosenquist, Klara J.; Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Rosenquist, Klara J.; Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Rosenquist, Klara J.; Fox, Caroline S.] Ctr Populat Studies, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res Cardiovasc Epidemiol & Human G, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NHLBI's FHS [N01-HC-25195]; NHLBI Division of Intramural Research FX This research was, in part, supported by the NHLBI's FHS (Contract No. N01-HC-25195). Dr Fox is supported by the NHLBI Division of Intramural Research. NR 54 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000788 DI 10.1161/JAHA.114.000788 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600012 ER PT J AU Lip, GYH Al-Khatib, SM Cosio, FG Banerjee, A Savelieva, I Ruskin, J Blendea, D Nattel, S De Bono, J Conroy, JM Hess, PL Guasch, E Halperin, JL Kirchhof, P Cosio, MDG Camm, AJ AF Lip, Gregory Y. H. Al-Khatib, Sana M. Cosio, Francisco G. Banerjee, Amitava Savelieva, Irina Ruskin, Jeremy Blendea, Dan Nattel, Stanley De Bono, Joseph Conroy, Jennifer M. Hess, Paul L. Guasch, Eduard Halperin, Jonathan L. Kirchhof, Paulus Cosio, M. Dolores G. Camm, A. John TI Contemporary Management of Atrial Fibrillation: What Can Clinical Registries Tell Us About Stroke Prevention and Current Therapeutic Approaches? SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Review DE Antiarrhythmic drugs; anticoagulant; atrial fibrillation; catheter ablation; registry; stroke ID RISK STRATIFICATION SCHEMES; RANDOMIZED CONTROLLED-TRIAL; INCUBATOR THINK-TANK; EURO HEART SURVEY; BASE-LINE DATA; CATHETER ABLATION; ANTITHROMBOTIC THERAPY; ORAL ANTICOAGULATION; PREDICTING STROKE; NATIONWIDE COHORT C1 [Lip, Gregory Y. H.; Banerjee, Amitava] Univ Birmingham, Ctr Cardiovasc Sci, City Hosp, Birmingham, W Midlands, England. [Al-Khatib, Sana M.; Hess, Paul L.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Cosio, Francisco G.] Hosp Univ Getafe, Dept Cardiol, Madrid, Spain. [Savelieva, Irina; Camm, A. John] St Georges Univ London, Div Clin Sci, London SW17 0RE, England. [Savelieva, Irina; Camm, A. John] Univ London Imperial Coll Sci Technol & Med, London, England. [Ruskin, Jeremy; Blendea, Dan] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Nattel, Stanley; Guasch, Eduard] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [De Bono, Joseph] Univ Hosp Birmingham NHS Trust, Birmingham, W Midlands, England. [Conroy, Jennifer M.; Halperin, Jonathan L.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Kirchhof, Paulus] Univ Birmingham, Ctr Cardiovasc Sci, Birmingham, W Midlands, England. [Kirchhof, Paulus] Sandwell & West Birmingham NHS Trust, Birmingham, W Midlands, England. [Kirchhof, Paulus] Hosp Univ Munster, Dept Cardiol & Angiol, Munster, Germany. [Kirchhof, Paulus] German Atrial Fibrillat Competence NETwork AFNET, Munster, Germany. [Cosio, M. Dolores G.] Cardiol Hosp Santa Creu & St Pau, Heart Failure & Cardiac Transplant Unit, Barcelona, Spain. RP Camm, AJ (reprint author), St Georges Univ London, Cranmer Terrace, London SW17 0RE, England. EM jcamm@sgul.ac.uk RI Banerjee, Amitava/D-4381-2014; OI Banerjee, Amitava/0000-0001-8741-3411; Guasch, Eduard/0000-0003-4238-5319; Kirchhof, Paulus/0000-0002-1881-0197 FU Sanofi FX Lip, Al Khatib, Cosio, Ruskin, Nattel, Halperin, Kirchhof, and Camm attended a meeting in London to discuss the content for this article, for which they received financial compensation for their time (apart from Al Khatib) and expenses, from an unrestricted educational grant by Sanofi. No reimbursement was received for drafting or reviewing the article. Sanofi had no input into the meeting agenda or discussions nor into the contents of the manuscript. Logistical and editorial support was provided by HealthCare21 Communications Ltd. (Macclesfield, UK) and was supported by Sanofi. NR 86 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e001179 DI 10.1161/JAHA.114.001179 PG 15 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600066 ER PT J AU Mishra, RK Beatty, AL Jaganath, R Regan, M Wu, AHB Whooley, MA AF Mishra, Rakesh K. Beatty, Alexis L. Jaganath, Rajesh Regan, Mathilda Wu, Alan H. B. Whooley, Mary A. TI B-type Natriuretic Peptides for the Prediction of Cardiovascular Events in Patients With Stable Coronary Heart Disease: The Heart and Soul Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adverse cardiovascular outcomes; BNP; NT-proBNP; risk assessment; stable coronary heart disease ID TERMINAL PRO-BNP; ARTERY-DISEASE; PROGNOSTIC VALUE; NT-PROBNP; BIOMARKERS; FAILURE; MORTALITY; PREVENTION; SECRETION; TRIAL AB Background-Brain-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are known predictors of cardiovascular outcomes in patients with coronary heart disease; however, the relative prognostic value of these 2 biomarkers for secondary events remains unclear. Methods and Results-In 983 participants with stable coronary heart disease, we evaluated the association of BNP and NT-proBNP with time to hospitalization for heart failure, nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and combined major adverse cardiovascular events (MACE). During an average follow-up of 6.5 +/- 3.3 years, both BNP and NT-proBNP were associated with increased risk of MACE in a multivariable-adjusted model (hazard ratio per standard deviation of log BNP: 1.58; 95% Cl: 1.32 to 1.89; hazard ratio per standard deviation of log NT-proBNP: 1.84; 95% Cl: 1.52 to 2.24). When added to traditional risk factors, NT-proBNP predicted MACE better than BNP (C statistic: 0.76 versus 0.72, P<0.001). Similarly, the addition of NT-proBNP resulted in a greater net reclassification improvement for predicting MACE than the addition of BNP (65% for NT-proBNP, 56% for BNP). Conclusions-Both BNP and NT-proBNP were significant predictors of MACE in stable coronary heart disease; however, NT-proBNP was superior to BNP for net risk reclassification for MACE. C1 [Mishra, Rakesh K.; Beatty, Alexis L.; Jaganath, Rajesh; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Wu, Alan H. B.] Univ Calif San Francisco, Dept Pathol & Lab Med, San Francisco, CA 94121 USA. [Mishra, Rakesh K.; Regan, Mathilda; Whooley, Mary A.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Mishra, RK (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. EM rakesh.mishra@ucsf.edu FU Department of Veterans Affairs (Washington, DC); National Heart, Lung, and Blood Institute [R01 HL079235]; American Federation for Aging Research; Robert Wood Johnson Foundation; Nancy Kirwan Heart Research Fund, San Francisco, California; Ischemia Research and Education Foundation; Roche Diagnostics Corporation; Alere Inc. FX The Heart and Soul Study was funded by the Department of Veterans Affairs (Washington, DC); the National Heart, Lung, and Blood Institute (grant R01 HL079235); the American Federation for Aging Research (Paul Beeson Scholars Program); the Robert Wood Johnson Foundation (Faculty Scholars Program); the Nancy Kirwan Heart Research Fund, San Francisco, California; and the Ischemia Research and Education Foundation. The NT-proBNP assays were funded by Roche Diagnostics Corporation. The BNP assays were funded by Alere Inc. NR 32 TC 8 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000907 DI 10.1161/JAHA.114.000907 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600024 ER PT J AU Ofman, P Petrone, AB Peralta, A Hoffmeister, P Albert, CM Djousse, L Gaziano, JM Rahilly-Tierney, CR AF Ofman, Peter Petrone, Andrew B. Peralta, Adelqui Hoffmeister, Peter Albert, Christine M. Djousse, Luc Gaziano, J. Michael Rahilly-Tierney, Catherine R. TI Aspirin Use and Risk of Atrial Fibrillation in the Physicians' Health Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE aspirin; atrial fibrillation; epidemiology; risk factors ID LIFE-STYLE FACTORS; EUROPEAN-SOCIETY; ASSOCIATION; INFLAMMATION; MANAGEMENT AB Background-Inflammatory processes have been associated with an increased risk of atrial fibrillation (AF), potentially allowing for preventive therapy by anti-inflammatory agents such as aspirin. However, the effect of chronic aspirin on the incidence of AF has not been evaluated in a prospective cohort followed for an extended period. Methods and Results-This study was comprised of a prospective cohort of 23 480 male participants of the Physicians' Health Study. Aspirin intake and covariates were estimated using self-reported questionnaires. Incident AF was ascertained through yearly follow-up questionnaires. Cox's regression, with adjustment for multiple covariates, was used to estimate relative risk of AF. Average age at baseline was 65.1 +/- 8.9 years. During a mean follow-up of 10.0 years, 2820 cases of AF were reported. Age-standardized incidence rates were 12.6, 11.1, 12.7, 11.3, 15.8, and 13.8/1000 person-years for people reporting baseline aspirin intake of 0, <14 days per year, 14 to 30 days per year, 30 to 120 days per year, 121 to 180 days per year, and >180 days per year, respectively. Multivariable adjusted hazard ratios (95% confidence interval) for incident AF were 1.00 (reference), 0.88 (0.76 to 1.02), 0.93 (0.76 to 1.14), 0.96 (0.80 to 1.14), 1.07 (0.80 to 1.14), and 1.04 (0.94 to 1.15) across consecutive categories of aspirin intake. Analysis of the data using time-varying Cox's regression model to update aspirin intake over time showed similar results. Conclusions-In a large cohort of males followed for a long period, we did not find any association between aspirin use and incident C1 [Ofman, Peter; Peralta, Adelqui; Hoffmeister, Peter; Gaziano, J. Michael] VA Boston Healthcare Syst, Div Cardiol, Boston, MA USA. [Ofman, Peter; Peralta, Adelqui; Hoffmeister, Peter; Gaziano, J. Michael] Harvard Univ, Sch Med, Boston, MA USA. [Ofman, Peter; Gaziano, J. Michael] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ofman, Peter; Petrone, Andrew B.; Djousse, Luc; Gaziano, J. Michael; Rahilly-Tierney, Catherine R.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Albert, Christine M.; Gaziano, J. Michael] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA USA. [Ofman, Peter; Djousse, Luc; Gaziano, J. Michael; Rahilly-Tierney, Catherine R.] Boston Vet Affairs Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA. [Djousse, Luc; Gaziano, J. Michael] Boston Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. RP Ofman, P (reprint author), VA Boston Healthcare Syst, Dept Cardiol, 1400 VFW Pkwy, West Roxbury, MA 02132 USA. EM Peter.Ofman@VA.gov RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU National Cancer Institute [CA-34944, CA-40360, CA-097193]; National Heart, Lung and Blood Institute (Bethesda, MD) [HL-26490, HL-34595] FX The Physicians' Health Study is supported by grants CA-34944, CA-40360, and CA-097193 from the National Cancer Institute and grants HL-26490 and HL-34595 from the National Heart, Lung and Blood Institute (Bethesda, MD). NR 13 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD AUG PY 2014 VL 3 IS 4 AR e000763 DI 10.1161/JAHA.113.000763 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AO4HD UT WOS:000341296600009 ER PT J AU Alosco, ML Gunstad, J Xu, X Clark, US Labbe, DR Riskin-Jones, HH Terrero, G Schwarz, NF Walsh, EG Poppas, A Cohen, RA Sweet, LH AF Alosco, Michael L. Gunstad, John Xu, Xiaomeng Clark, Uraina S. Labbe, Donald R. Riskin-Jones, Hannah H. Terrero, Gretel Schwarz, Nicolette F. Walsh, Edward G. Poppas, Athena Cohen, Ronald A. Sweet, Lawrence H. TI The impact of hypertension on cerebral perfusion and cortical thickness in older adults SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE Arterial spin labeling; Blood pressure; brain structure; cerebral blood flow ID SURFACE-BASED ANALYSIS; BLOOD-PRESSURE LEVELS; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; ANTIHYPERTENSIVE THERAPY; CEREBROVASCULAR-DISEASE; LONGITUDINAL CHANGES; BRAIN MORPHOLOGY; APOLIPOPROTEIN-E; FLOW-VELOCITY AB Hypertension may increase risk for dementia possibly because of its association with decreased cortical thickness. Disturbed cerebral autoregulation is one plausible mechanism by which hypertension impacts the cerebral structure, but the associations among hypertension, brain perfusion, and cortical thickness are poorly understood. The current sample consisted of 58 older adults with varying levels of vascular disease. Diagnostic history of hypertension and antihypertensive medication status was ascertained through self-report, and when available, confirmed by medical record review. All participants underwent arterial spin labeling and T1-weighted magnetic resonance imaging to quantify total and regional cortical perfusion and thickness. Analysis of covariance adjusting for medical variables showed that participants with hypertension exhibited reduced temporal and occipital brain perfusion and total and regional cortical thickness relative to those without hypertension. The effects of hypertension on total brain perfusion remained unchanged even after adjustment for age, although no such pattern emerged for cortical thickness. Decreased total brain perfusion predicted reduced thickness of the total brain and of the frontal, temporal, and parietal lobe cortices. Antihypertensive treatment was not associated with total cerebral perfusion or cortical thickness. This study provides initial evidence for the adverse effects of a diagnostic history of hypertension on brain hypoperfusion and reduced cortical thickness. Longitudinal studies are needed to investigate the role of hypertension and its interaction with other contributing factors (eg, age) in the manifestation of cerebral hypoperfusion and reduced cortical thickness. (C) 2014 American Society of Hypertension. All rights reserved. C1 [Alosco, Michael L.; Gunstad, John] Kent State Univ, Dept Psychol, Kent, OH 44242 USA. [Xu, Xiaomeng] Idaho State Univ, Dept Psychol, Pocatello, ID 83209 USA. [Clark, Uraina S.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA. [Labbe, Donald R.] Brown Univ, Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Riskin-Jones, Hannah H.] VA Greater Los Angeles Healthcare Syst, Brain Behav & Aging Res Ctr, Los Angeles, CA USA. [Terrero, Gretel] Brown Univ, Alpert Med Sch, Providence, RI 02912 USA. [Schwarz, Nicolette F.; Sweet, Lawrence H.] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Walsh, Edward G.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Walsh, Edward G.] Brown Univ, Dept Diagnost Imaging, Providence, RI 02912 USA. [Poppas, Athena] Brown Univ, Dept Med, Alpert Med Sch, Providence, RI 02912 USA. [Cohen, Ronald A.] Univ Florida, Inst Aging, Clin Translat Res Program, Cognit Aging & Memory Program, Gainesville, FL USA. RP Alosco, ML (reprint author), Kent State Univ, Dept Psychol, Kent, OH 44242 USA. EM Malosco@kent.edu OI Clark, Uraina/0000-0002-2683-6696 FU National Institutes of Health Grant [R01HL084178] FX Support for this work was provided by National Institutes of Health Grant R01HL084178. NR 69 TC 11 Z9 11 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 EI 1878-7436 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD AUG PY 2014 VL 8 IS 8 BP 561 EP 570 DI 10.1016/j.jash.2014.04.002 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA AO3JT UT WOS:000341226200006 PM 25151318 ER PT J AU Wolf, EJ Mitchell, KS Logue, MW Baldwin, CT Reardon, AF Aiello, A Galea, S Koenen, KC Uddin, M Wildman, D Miller, MW AF Wolf, Erika J. Mitchell, Karen S. Logue, Mark W. Baldwin, Clinton T. Reardon, Annemarie F. Aiello, Alison Galea, Sandro Koenen, Karestan C. Uddin, Monica Wildman, Derek Miller, Mark W. TI The Dopamine D-3 Receptor Gene and Posttraumatic Stress Disorder SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID MULTILOCUS GENOTYPE DATA; NICOTINE DEPENDENCE; NUCLEUS-ACCUMBENS; MAJOR DEPRESSION; SEX-DIFFERENCES; SCHIZOPHRENIA; D3; ASSOCIATION; DRD3; POPULATION AB The dopamine D-3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). The aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed White, non-Hispanic U.S. veterans and their trauma-exposed intimate partners (N = 491); 60.3% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants living in Detroit, Michigan; 23.6% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, 4 single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (OR range= 0.59 to 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (OR = 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors could potentially explain this association. C1 [Wolf, Erika J.; Mitchell, Karen S.; Reardon, Annemarie F.; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Wolf, Erika J.; Mitchell, Karen S.; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Logue, Mark W.; Baldwin, Clinton T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Logue, Mark W.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Baldwin, Clinton T.] Boston Univ, Sch Med, Ctr Human Genet, Boston, MA 02118 USA. [Aiello, Alison] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Galea, Sandro; Koenen, Karestan C.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Uddin, Monica; Wildman, Derek] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Uddin, Monica] Wayne State Univ, Sch Med, Dept Psychiat & Behav Neurosci, Detroit, MI USA. RP Miller, MW (reprint author), 150 South Huntington Ave 116B-2, Boston, MA 02130 USA. EM Mark.Miller5@va.gov RI Miller, Mark/G-7322-2011; Koenen, Karestan/K-5402-2014 OI Miller, Mark/0000-0001-6393-8563; Wolf, Erika/0000-0003-2666-2435; Koenen, Karestan/0000-0003-3293-4281 FU BLRD VA [I01 BX002150]; CSRD VA [I01 CX000431]; Intramural VA [CDA-2-067-10S]; NIDA NIH HHS [DA 022720-S1, DA022720, R01 DA022720]; NIMH NIH HHS [1K01MH093750-01A1, K01 MH076100, K01 MH093750, MH 088283, R01 MH079806, RC1 MH088283] NR 68 TC 3 Z9 3 U1 8 U2 20 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 EI 1573-6598 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2014 VL 27 IS 4 BP 379 EP 387 DI 10.1002/jts.21937 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA AO2ZQ UT WOS:000341198000001 PM 25158632 ER PT J AU White, JM Reisner, SL Dunham, E Mimiaga, MJ AF White, Jaclyn M. Reisner, Sari L. Dunham, Emilia Mimiaga, Matthew J. TI Race-Based Sexual Preferences in a Sample of Online Profiles of Urban Men Seeking Sex with Men SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE MSM; Internet; Race/ethnicity; HIV; Sexual risk ID ISLANDER GAY MEN; HIV RISK; INTERNET; PARTNERS; PREVENTION; HEALTH; DISCRIMINATION; SELECTION; IDENTIFY; ADS AB Race-based sexual preferences in the online profiles of men who have sex with men (MSM) may be relevant for understanding the sexual health of this population, including racial/ethnic disparities in HIV infection. In October 2011, a content analysis was conducted of the profiles of Boston-area members of a racially diverse website for MSM. The present analysis formatively examined the use of demographic and partner selection criteria by race/ethnicity appearing in the profiles of men who indicated race-based partner preferences (n = 89). Latino men were the most frequently preferred race (54 %), followed by White (52 %), Black (48 %), and Asian (12 %) men. In separate multivariable models adjusted for age and HIV status disclosure, wanting low-risk foreplay was associated with a preference for White men (aOR) = 4.27; 95 % CI = 1.70-10.75; p = 0.002), while wanting group sex was associated with a preference for Black (OR = 2.28; 95 % CI = 1.08-4.81; p = 0.03) and Latino men (OR = 2.56; 95 % CI = 1.25-5.23; p = 0.01). Future studies are needed to replicate findings in larger online samples. Mixed-methods research should explore how racial and behavioral preferences impact the sexual mixing patterns and health of MSM online in urban areas. C1 [White, Jaclyn M.; Reisner, Sari L.; Dunham, Emilia; Mimiaga, Matthew J.] Fenway Hlth, Fenway Inst, Boston, MA 02215 USA. [Reisner, Sari L.; Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP White, JM (reprint author), Fenway Hlth, Fenway Inst, 1340 Boylston St 8th Floor, Boston, MA 02215 USA. EM jwhite@fenwayhealth.org FU NIMH NIH HHS [P30 MH062294, T32 MH020031] NR 30 TC 6 Z9 6 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 EI 1468-2869 J9 J URBAN HEALTH JI J. Urban Health PD AUG PY 2014 VL 91 IS 4 BP 768 EP 775 DI 10.1007/s11524-013-9853-4 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA AN6AH UT WOS:000340674900013 PM 24496568 ER PT J AU Tipps, ME Raybuck, JD Buck, KJ Lattal, KM AF Tipps, Megan E. Raybuck, Jonathan D. Buck, Kari J. Lattal, K. Matthew TI Delay and trace fear conditioning in C57BL/6 and DBA/2 mice: issues of measurement and performance SO LEARNING & MEMORY LA English DT Article ID INBRED MOUSE STRAINS; PROTEIN-KINASE-C; HIPPOCAMPUS-DEPENDENT MEMORY; F-1 HYBRIDS IMPLICATIONS; TRAIT LOCUS ANALYSIS; CONTEXTUAL FEAR; PREPULSE INHIBITION; GENETIC-DIFFERENCES; DORSAL HIPPOCAMPUS; SINGLE-GENE AB Strain comparison studies have been critical to the identification of novel genetic and molecular mechanisms in learning and memory. However, even within a single learning paradigm, the behavioral data for the same strain can vary greatly, making it difficult to form meaningful conclusions at both the behavioral and cellular level. In fear conditioning, there is a high level of variability across reports, especially regarding responses to the conditioned stimulus ( CS). Here, we compare C57BL/6 and DBA/2 mice using delay fear conditioning, trace fear conditioning, and a nonassociative condition. Our data highlight both the significant strain differences apparent in these fear conditioning paradigms and the significant differences in conditioning type within each strain. We then compare our data to an extensive literature review of delay and trace fear conditioning in these two strains. Finally, we apply a number of commonly used baseline normalization approaches to compare how they alter the reported differences. Our findings highlight three major sources of variability in the fear conditioning literature: CS duration, number of CS presentations, and data normalization to baseline measures. C1 [Tipps, Megan E.; Raybuck, Jonathan D.; Buck, Kari J.; Lattal, K. Matthew] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Buck, Kari J.] Portland VA Med Ctr, Portland Alcohol Res Ctr, Portland, OR 97239 USA. RP Tipps, ME (reprint author), Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. EM metipps@gmail.com FU National Institutes of Health [1F32 AA022011, F32DA031537, R01 DA005228, P60 AA10760, R01 AA011114, R24 AA020245, DA02592, T32 DA07262, T32 AA07468]; US Department of the Army/DOD-TATRC [W81XWH-12-2-0048]; Portland VA Medical Center FX This work was funded by National Institutes of Health 1F32 AA022011 (to M.E.T.); National Institutes of Health F32DA031537 (to J.D.R.); National Institutes of Health R01 DA005228, P60 AA10760, R01 AA011114, and R24 AA020245 (to K.J.B.); National Institutes of Health DA02592 and US Department of the Army/DOD-TATRC:W81XWH-12-2-0048 (to K.M.L.); and National Institutes of Health T32 DA07262 and T32 AA07468 and the Portland VA Medical Center. NR 76 TC 4 Z9 4 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1072-0502 EI 1549-5485 J9 LEARN MEMORY JI Learn. Mem. PD AUG PY 2014 VL 21 IS 8 BP 380 EP 393 DI 10.1101/lm.035261.114 PG 14 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA AO4IO UT WOS:000341300900003 PM 25031364 ER PT J AU Rochau, U Sroczynski, G Wolf, D Schmidt, S Conrads-Frank, A Jahn, B Saverno, K Brixner, D Radich, J Gastl, G Siebert, U AF Rochau, Ursula Sroczynski, Gaby Wolf, Dominik Schmidt, Stefan Conrads-Frank, Annette Jahn, Beate Saverno, Kim Brixner, Diana Radich, Jerald Gastl, Guenther Siebert, Uwe TI Medical decision analysis for first-line therapy of chronic myeloid leukemia SO LEUKEMIA & LYMPHOMA LA English DT Article DE Chronic myeloid leukemia; decision-analytic model; tyrosine kinase inhibitors; decision analysis; quality-adjusted life years AB Several tyrosine kinase inhibitors (TKIs) are approved for the treatment of chronic myeloid leukemia (CML). Our goal was to develop a clinical decision-analytic model for evaluation of the long-term effectiveness of different therapy regimens. We developed a Markov cohort model with a lifelong time horizon for first-line treatment with imatinib, dasatinib or nilotinib. Seven strategies including combinations of TKIs, chemotherapy and stem cell transplant were evaluated. The model was parameterized using published trial data, the Austrian CML registry and practice patterns estimated by experts. Health outcomes evaluated were life-years (LYs) and quality-adjusted LYs (QALYs). Based on our decision analysis, dasatinib following nilotinib failure was the most effective treatment in terms of LYs (19.8 LYs) and QALYs (16.1 QALYs). Sensitivity analyses showed that the ranking of strategies was mostly influenced by the duration of first- and second-line therapies. Our results may support decision-making regarding the sequential application of TKIs. C1 [Rochau, Ursula; Sroczynski, Gaby; Conrads-Frank, Annette; Jahn, Beate; Saverno, Kim; Brixner, Diana; Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth & Hlth Technol Assessment, Inst Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. [Rochau, Ursula; Sroczynski, Gaby; Jahn, Beate; Brixner, Diana; Siebert, Uwe] ONCOTYROL Ctr Personalized Canc Med, Div Publ Hlth Decis Modeling Hlth Technol Assessm, Innsbruck, Austria. [Wolf, Dominik; Schmidt, Stefan; Gastl, Guenther] Med Univ Innsbruck, A-6020 Innsbruck, Austria. [Wolf, Dominik] Univ Bonn, Bonn, Germany. [Saverno, Kim; Brixner, Diana] Univ Utah, Dept Pharmacotherapy, Salt Lake City, UT USA. [Brixner, Diana] Univ Utah, Program Personalized Hlth Care, Salt Lake City, UT USA. [Radich, Jerald] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment,Cardiovasc Res Program, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. RP Rochau, U (reprint author), ONCOTYROL Ctr Personalized Canc Med, Area Hlth Technol Assessment & Bioinformat 4, Innrain 66a, A-6020 Innsbruck, Austria. EM ursula.rochau@oncotyrol.at FU COMET Center ONCOTYROL - Austrian Federal Ministries BMVIT/BMWFJ (via FFG); Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT) FX This work was supported by the COMET Center ONCOTYROL, which is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT). NR 8 TC 2 Z9 2 U1 0 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1042-8194 EI 1029-2403 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD AUG PY 2014 VL 55 IS 8 BP 1758 EP 1767 DI 10.3109/10428194.2013.858149 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA AM9TO UT WOS:000340224100012 PM 24160847 ER PT J AU Nativ, NI Yarmush, G So, A Barminko, J Maguire, TJ Schloss, R Berthiaume, F Yarmush, ML AF Nativ, Nir I. Yarmush, Gabriel So, Ashley Barminko, Jeffery Maguire, Timothy J. Schloss, Rene Berthiaume, Francois Yarmush, Martin L. TI Elevated Sensitivity of Macrosteatotic Hepatocytes to Hypoxia/Reoxygenation Stress is Reversed by a Novel Defatting Protocol SO LIVER TRANSPLANTATION LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; ACTIVATED RECEPTOR-ALPHA; STEATOTIC RAT LIVERS; FATTY LIVER; L-CARNITINE; HEPATIC STEATOSIS; COLD PRESERVATION; TRANSPLANTATION; PERFUSION; MODEL AB Macrosteatotic livers exhibit elevated intrahepatic triglyceride (TG) levels in the form of large lipid droplets (LDs), reduced adenosine triphosphate (ATP) levels, and elevated reactive oxygen species (ROS) levels, and this contributes to their elevated sensitivity to ischemia/reperfusion injury during transplantation. Reducing macrosteatosis in living donors through dieting has been shown to improve transplant outcomes. Accomplishing the same feat for deceased donor grafts would require ex vivo exposure to potent defatting agents. Here we used a rat hepatocyte culture system exhibiting a macrosteatotic LD morphology, elevated TG levels, and an elevated sensitivity to hypoxia/reoxygenation (H/R) to test for such agents and ameliorate H/R sensitivity. Macrosteatotic hepatocyte preconditioning for 48 hours with a defatting cocktail that was previously developed to promote TG catabolism reduced the number of macrosteatotic LDs and intracellular TG levels by 82% and 27%, respectively, but it did not ameliorate sensitivity to H/R. Supplementation of this cocktail with L-carnitine, together with hyperoxic exposure, yielded a similar reduction in the number of macrosteatotic LDs and a 57% reduction in intrahepatic TG storage, likely by increasing the supply of acetyl coenzyme A to mitochondria, as indicated by a 70% increase in ketone body secretion. Furthermore, this treatment reduced ROS levels by 32%, increased ATP levels by 27% (to levels near those of lean controls), and completely abolished H/R sensitivity as indicated by approximately 85% viability after H/R and the reduction of cytosolic lactate dehydrogenase release to levels seen in lean controls. Cultures maintained for 48 hours after H/R were approximately 83% viable and exhibited superior urea secretion and bile canalicular transport in comparison with untreated macrosteatotic cultures. In conclusion, these findings show that the elevated sensitivity of macrosteatotic hepatocytes to H/R can be overcome by defatting agents, and they suggest a possible route for the recovery of discarded macrosteatotic grafts. (C) 2014 AASLD. C1 [Nativ, Nir I.; Yarmush, Gabriel; So, Ashley; Barminko, Jeffery; Maguire, Timothy J.; Schloss, Rene; Berthiaume, Francois; Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Yarmush, Martin L.] Massachusetts Gen Hosp, Surg Serv, Ctr Engn Med, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM fberthia@rci.rutgers.edu; yarmush@rci.rutgers.edu FU National Institutes of Health [R01DK059766]; National Institutes of Health FX This work was partially supported by the National Institutes of Health (grant R01DK059766). Nir I. Nativ and Gabriel Yarmush were supported by a National Institutes of Health-funded Biotechnology Training Fellowship. NR 41 TC 8 Z9 8 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1527-6465 EI 1527-6473 J9 LIVER TRANSPLANT JI Liver Transplant. PD AUG PY 2014 VL 20 IS 8 BP 1000 EP 1011 DI 10.1002/lt.23905 PG 12 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA AO2YZ UT WOS:000341196200018 PM 24802973 ER PT J AU Mishra, P Li, RJ Mak, RH Rottmann, J Bryant, JH Williams, CL Berbeco, RI Lewis, JH AF Mishra, Pankaj Li, Ruijiang Mak, Raymond H. Rottmann, Joerg Bryant, Jonathan H. Williams, Christopher L. Berbeco, Ross I. Lewis, John H. TI An initial study on the estimation of time-varying volumetric treatment images and 3D tumor localization from single MV cine EPID images SO MEDICAL PHYSICS LA English DT Article DE MV imaging; lung motion model; cine EPID images; 4DCT; treatment verification ID DOSE-RESPONSE; MOTION MODEL; XCAT PHANTOM; LUNG-TUMORS; RADIOTHERAPY; IMPLEMENTATION; TRACKING AB Purpose: In this work the authors develop and investigate the feasibility of a method to estimate time-varying volumetric images from individual MV cine electronic portal image device (EPID) images. Methods: The authors adopt a two-step approach to time-varying volumetric image estimation from a single cine EPID image. In the first step, a patient-specific motion model is constructed from 4DCT. In the second step, parameters in the motion model are tuned according to the information in the EPID image. The patient-specific motion model is based on a compact representation of lung motion represented in displacement vector fields (DVFs). DVFs are calculated through deformable image registration (DIR) of a reference 4DCT phase image (typically peak-exhale) to a set of 4DCT images corresponding to different phases of a breathing cycle. The salient characteristics in the DVFs are captured in a compact representation through principal component analysis (PCA). PCA decouples the spatial and temporal components of the DVFs. Spatial information is represented in eigenvectors and the temporal information is represented by eigen-coefficients. To generate a new volumetric image, the eigen-coefficients are updated via cost function optimization based on digitally reconstructed radiographs and projection images. The updated eigen-coefficients are then multiplied with the eigenvectors to obtain updated DVFs that, in turn, give the volumetric image corresponding to the cine EPID image. Results: The algorithm was tested on (1) Eight digital eXtended CArdiac-Torso phantom datasets based on different irregular patient breathing patterns and (2) patient cine EPID images acquired during SBRT treatments. The root-mean-squared tumor localization error is (0.73 +/- 0.63 mm) for the XCAT data and (0.90 +/- 0.65 mm) for the patient data. Conclusions: The authors introduced a novel method of estimating volumetric time-varying images from single cine EPID images and a PCA-based lung motion model. This is the first method to estimate volumetric time-varying images from single MV eine EPID images, and has the potential to provide volumetric information with no additional imaging dose to the patient. (C) 2014 American Association of Physicists in Medicine. C1 [Mishra, Pankaj; Mak, Raymond H.; Rottmann, Joerg; Bryant, Jonathan H.; Williams, Christopher L.; Berbeco, Ross I.; Lewis, John H.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mishra, Pankaj; Mak, Raymond H.; Rottmann, Joerg; Bryant, Jonathan H.; Williams, Christopher L.; Berbeco, Ross I.; Lewis, John H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Li, Ruijiang] Stanford Univ, Dept Radiat Oncol, Sch Med, Stanford, CA 94305 USA. RP Mishra, P (reprint author), Varian Med Syst Inc, 3120 Hansen Way, Palo Alto, CA 94304 USA. EM pankaj.mishra@varian.com FU NCI NIH HHS [1K99CA166186, K99 CA166186] NR 21 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD AUG PY 2014 VL 41 IS 8 BP 171 EP 178 AR 081713 DI 10.1118/1.4889779 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AO1JJ UT WOS:000341068100015 PM 25086523 ER PT J AU Rasmussen, CA Tam, J Steiglitz, BM Bauer, RL Peters, NR Wang, Y Anderson, RR Allen-Hoffmann, BL AF Rasmussen, Cathy Ann Tam, Joshua Steiglitz, Barry M. Bauer, Rebecca L. Peters, Noel R. Wang, Ying Anderson, R. Rox Allen-Hoffmann, B. Lynn TI Chimeric Autologous/Allogeneic Constructs for Skin Regeneration SO MILITARY MEDICINE LA English DT Article ID OPERATION-IRAQI-FREEDOM; FRACTIONAL PHOTOTHERMOLYSIS; TISSUE; KERATINOCYTES; SUBSTITUTES; OPPORTUNITIES; PATTERNS; WOUNDS; PHASE AB The ideal treatment for severe cutaneous injuries would eliminate the need for autografts and promote fully functional, aesthetically pleasing autologous skin regeneration. NIKS progenitor cell-based skin tissues have been developed to promote healing by providing barrier function and delivering wound healing factors. Independently, a device has recently been created to "copy" skin by harvesting full-thickness microscopic tissue columns (MTCs) in lieu of autografts traditionally harvested as sheets. We evaluated the feasibility of combining these two technologies by embedding MTCs in NIKS-based skin tissues to generate chimeric autologous/allogeneic constructs. Chimeric constructs have the potential to provide immediate wound coverage, eliminate painful donor site wounds, and promote restoration of a pigmented skin tissue possessing hair follicles, sweat glands, and sebaceous glands. After MTC insertion, chimeric constructs and Controls were reintroduced into air-interface culture and maintained in vitro for several weeks. Tissue viability, proliferative capacity, and morphology were evaluated after long-term culture. Our results confirmed successful MTC insertion and integration, and demonstrated the feasibility of generating chimeric autologous/allogeneic constructs that preserved the viability, proliferative capacity, and structure of autologous pigmented skin. These feasibility studies established the proof-of-principle necessary to further develop chimeric autologous/allogeneic constructs for the treatment of complex skin defects. C1 [Rasmussen, Cathy Ann; Steiglitz, Barry M.; Bauer, Rebecca L.; Peters, Noel R.; Allen-Hoffmann, B. Lynn] Stratatech Corp, Madison, WI 53719 USA. [Tam, Joshua; Wang, Ying; Anderson, R. Rox] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Rasmussen, CA (reprint author), Stratatech Corp, 505 S Rosa Rd,Suite 169, Madison, WI 53719 USA. FU U.S. Army Medical Research and Materiel Command [W81XWH-12-C-0063] FX The authors thank Christina Thomas-Virnig for comments and suggestions on the manuscript. We also thank Sandy Schlosser and Laura Cominetti for the processing and handling of histologic samples. This work was supported by the U.S. Army Medical Research and Materiel Command under Contract No. W81XWH-12-C-0063. NR 24 TC 0 Z9 0 U1 0 U2 2 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 AUG PY 2014 VL 179 IS 8 SU S SI SI BP 71 EP 78 DI 10.7205/MILMED-D-13-00480 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UP UT WOS:000340806800014 PM 25102552 ER PT J AU Huttenhain, R Choi, M Chang, CY Dinulescu, D Vitek, O Nimeus-Malmstrom, E Aebersold, R AF Huettenhain, Ruth Choi, Meena Chang, Ching-Yun Dinulescu, Daniela Vitek, Olga Nimeus-Malmstrom, Emma Aebersold, Ruedi TI Validating Plasma-based Biomarkers for Ovarian Cancer Using Targeted Proteomics SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Huettenhain, Ruth] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Choi, Meena; Chang, Ching-Yun; Vitek, Olga] Purdue Univ, W Lafayette, IN 47907 USA. [Dinulescu, Daniela] Dana Farber Harvard Canc Inst, Boston, MA USA. [Nimeus-Malmstrom, Emma] Lund Univ, S-22100 Lund, Sweden. [Aebersold, Ruedi] Swiss Fed Inst Technol, Zurich, Switzerland. NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2014 VL 13 IS 8 SU 1 MA C.13 BP S50 EP S50 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AN6QH UT WOS:000340720100077 ER PT J AU Lam, S Hung, V Martell, JD Udeshi, ND Mootha, VK Carr, SA Ting, AY AF Lam, Stephanie Hung, Victoria Martell, Jeffrey D. Udeshi, Namrata D. Mootha, Vamsi K. Carr, Steven A. Ting, Alice Y. TI Proteomic Mapping of Living Cells with An Evolved Peroxidase Reporter, and Application to Mitochondrial and Endoplasmic Reticulum Proteomes SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Lam, Stephanie; Hung, Victoria; Martell, Jeffrey D.; Ting, Alice Y.] MIT, Cambridge, MA 02139 USA. [Udeshi, Namrata D.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Mootha, Vamsi K.] Massachussets Gen Hosp, Howard Hughes Med Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 EI 1535-9484 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2014 VL 13 IS 8 SU 1 MA C.7 BP S47 EP S47 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA AN6QH UT WOS:000340720100071 ER PT J AU Kraja, AT Chasman, DI North, KE Reiner, AP Yanek, LR Kilpelainen, TO Smith, JA Dehghan, A Dupuis, J Johnson, AD Feitosa, MF Tekola-Ayele, F Chu, AY Nolte, IM Dastani, Z Morris, A Pendergrass, SA Sun, YV Ritchie, MD Vaez, A Lin, HH Ligthart, S Marullo, L Rohde, R Shao, Y Ziegler, MA Im, HK Schnabel, RB Jorgensen, T Jorgensen, ME Hansen, T Pedersen, O Stolk, RP Snieder, H Hofman, A Uitterlinden, AG Franco, OH Ikram, MA Richards, JB Rotimi, C Wilson, JG Lange, L Ganesh, SK Nalls, M Rasmussen-Torvik, LJ Pankow, JS Coresh, J Tang, W Kao, WHL Boerwinkle, E Morrison, AC Ridker, PM Becker, DM Rotter, JI Kardia, SLR Loos, RJF Larson, MG Hsu, YH Province, MA Tracy, R Voight, BF Vaidya, D O'Donnell, CJ Benjamin, EJ Alizadeh, BZ Prokopenko, I Meigs, JB Borecki, IB AF Kraja, Aldi T. Chasman, Daniel I. North, Kari E. Reiner, Alexander P. Yanek, Lisa R. Kilpelainen, Tuomas O. Smith, Jennifer A. Dehghan, Abbas Dupuis, Josee Johnson, Andrew D. Feitosa, Mary F. Tekola-Ayele, Fasil Chu, Audrey Y. Nolte, Ilja M. Dastani, Zari Morris, Andrew Pendergrass, Sarah A. Sun, Yan V. Ritchie, Marylyn D. Vaez, Ahmad Lin, Honghuang Ligthart, Symen Marullo, Letizia Rohde, Rebecca Shao, Yarning Ziegler, Mark A. Im, Hae Kyung Schnabel, Renate B. Jorgensen, Torben Jorgensen, Marit E. Hansen, Torben Pedersen, Oluf Stolk, Ronald P. Snieder, Harold Hofman, Albert Uitterlinden, Andre G. Franco, Oscar H. Ikram, M. Arfan Richards, J. Brent Rotimi, Charles Wilson, James G. Lange, Leslie Ganesh, Santhi K. Nalls, Mike Rasmussen-Torvik, Laura J. Pankow, James S. Coresh, Josef Tang, Weihong Kao, W. H. Linda Boerwinkle, Eric Morrison, Alanna C. Ridker, Paul M. Becker, Diane M. Rotter, Jerome I. Kardia, Sharon L. R. Loos, Ruth J. F. Larson, Martin G. Hsu, Yi-Hsiang Province, Michael A. Tracy, Russell Voight, Benjamin F. Vaidya, Dhananjay O'Donnell, Christopher J. Benjamin, Emelia J. Alizadeh, Behrooz Z. Prokopenko, Inga Meigs, James B. Borecki, Ingrid B. CA Cross Consortia Pleiotropy CHARGE Genetic Invest Anthropomet GLGC MAGIC GBPG ADIPOGen Consortium WGHS HUFS TI Pleiotropic genes for metabolic syndrome and inflammation SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Metabolic syndrome; Inflammatory markers; Pleiotropic associations; Meta-analysis; Regulome ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-ARTERY-DISEASE; DIABETES SUSCEPTIBILITY LOCI; C-REACTIVE PROTEIN; NF-KAPPA-B; INSULIN-RESISTANCE; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; CIRCULATING ADIPONECTIN AB Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation. (C) 2014 Elsevier Inc. All rights reserved. C1 [Kraja, Aldi T.; Feitosa, Mary F.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. [Kraja, Aldi T.; Feitosa, Mary F.; Province, Michael A.; Borecki, Ingrid B.] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA. [Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [North, Kari E.; Rohde, Rebecca; Shao, Yarning] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [North, Kari E.; Rohde, Rebecca; Shao, Yarning] Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Yanek, Lisa R.; Becker, Diane M.; Vaidya, Dhananjay] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD USA. [Kilpelainen, Tuomas O.; Hansen, Torben; Pedersen, Oluf] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark. [Smith, Jennifer A.; Kardia, Sharon L. R.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Dehghan, Abbas; Ligthart, Symen; Hofman, Albert; Franco, Oscar H.; Ikram, M. Arfan] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Tekola-Ayele, Fasil; Rotimi, Charles] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Dupuis, Josee; Larson, Martin G.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Framingham, MA USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Tekola-Ayele, Fasil; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Nolte, Ilja M.; Vaez, Ahmad; Stolk, Ronald P.; Snieder, Harold; Alizadeh, Behrooz Z.] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Dastani, Zari; Richards, J. Brent] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Morris, Andrew; Marullo, Letizia] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England. [Pendergrass, Sarah A.] Penn State Univ, Eberly Coll Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Pendergrass, Sarah A.] Penn State Univ, Eberly Coll Sci, Huck Inst Life Sci, University Pk, PA 16802 USA. [Sun, Yan V.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Sun, Yan V.] Emory Univ, Sch Med, Dept Biomed Informat, Atlanta, GA 30322 USA. [Ritchie, Marylyn D.] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. [Lin, Honghuang] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA. [Marullo, Letizia] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy. [Ziegler, Mark A.] Washington Univ, Sch Med, MSIBS Program, Div Biostat, St Louis, MO USA. [Im, Hae Kyung] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Schnabel, Renate B.] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany. [Jorgensen, Torben] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark. [Jorgensen, Torben] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark. [Jorgensen, Marit E.] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Richards, J. Brent] McGill Univ, Dept Med Human Genet Epidemiol & Biostat, Montreal, PQ H3A 2T5, Canada. [Richards, J. Brent] Kings Coll London, Dept Twin Res, London, England. [Wilson, James G.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Lange, Leslie] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA. [Ganesh, Santhi K.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nalls, Mike] Natl Inst Aging, Neurogenet Lab, Mol Genet Sect, NIH, Bethesda, MD USA. [Rasmussen-Torvik, Laura J.] Northwestern Univ, Feinberg Sch Med, Chicago, IL USA. [Boerwinkle, Eric; Morrison, Alanna C.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Coresh, Josef] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA. [Kao, W. H. Linda] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Boerwinkle, Eric; Morrison, Alanna C.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Rotter, Jerome I.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA. [Loos, Ruth J. F.] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Charles Bronfrnan Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA USA. [Hsu, Yi-Hsiang] Harvard Univ, Sch Publ Hlth, Hebrew Senior Life Inst Aging Res, Harvard Med Sch & Mol & Integrat Physiol Sci, Boston, MA 02115 USA. [Tracy, Russell] Univ Vermont, Coll Med, Burlington, VT 05401 USA. [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Voight, Benjamin F.] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol & Prevent Med Sect, Boston, MA 02118 USA. [Prokopenko, Inga] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London W12 0NN, England. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chasman, Daniel I.; Chu, Audrey Y.; Ridker, Paul M.; Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. RP Kraja, AT (reprint author), Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA. EM aldi@wustl.edu; dchasman@research.bwh.harvard.edu; kari_north@unc.edu; apreiner@u.washington.edu; lryanek@jhmi.edu; tuomas.kilpelainen@sund.ku.dk; smjenn@umich.edu; a.dehghan@erasmusmc.nl; dupuis@bu.edu; johnsonad2@nhIbi.nih.gov; mfeitosa@wustl.edu; fasiLayele2@nih.gov; aychu@parmers.org; i.m.nolte@umcg.nl; zari.dastani@mail.mcgill.ca; andrew.morris@well.ox.ac.uk; sap29@psu.edu; yan.v.sun@emory.edu; marylyn.ritchie@psu.edu; a.vaez@umcg.nl; hhlin@bu.edu; sligthart@erasmusmc.nl; lety@well.ox.ac.uk; rohde@email.unc.edu; yaming_shao@unc.edu; MZiegler23@WUSTL.EDU; haky@uchicago.edu; schnabelr@gmx.de; tojo@glo.regionh.dk; maej@steno.dk; torben.hansen@sund.ku.dk; oluf@sund.ku.dk; r.p.stolk@umcg.nl; h.snieder@umcg.nl; a.hofman@erasmusmc.nl; a.g.uitterlinden@erasmusmc.nl; ofranco@erasmusmc.nl; m.a.ikram@erasmusmc.nl; brent.richards@mcgill.ca; rotimic@mail.nih.gov; jgwilson2@umc.edu; leslie_lange@med.unc.edu; sganesh@med.umich.edu; nallsm@mail.nih.gov; ljrtorvik@northwestem.edu; panko001@umn.edu; coresh@jhu.edu; tang0097@umn.edu; wkao@jhsph.edu; Eric.Boerwinkle@uth.tmc.edu; Alanna.CMorrison@uth.tmc.edu; pridker@partners.org; DBecker@6078aol.com; jrotter@labiomed.org; skardia@umich.edu; ruth.loos@mssm.edu; mlarson@bu.edu; YiHsiangHsu@hsl.harvard.edu; mprovince@wustl.edu; russell.tracy@med.uvm.edu; bvoight@upenn.edu; dvaidyal@jhmi.edu; odonnellc@nhIbinih.gov; emelia@bu.edu; b.z.alizadeh@umcg.nl; Lprokopenko@imperiaLac.uk; jmeigs@partners.org; iborecki@wustl.edu RI Prokopenko, Inga/H-3241-2014; Johnson, Andrew/G-6520-2013; Feitosa, Mary/K-8044-2012; OI Dehghan, Abbas/0000-0001-6403-016X; Tekola-Ayele, Fasil/0000-0003-4194-9370; Ikram, Mohammad Arfan/0000-0003-0372-8585; Lin, Honghuang/0000-0003-3043-3942; Benjamin, Emelia/0000-0003-4076-2336; Jorgensen, Torben/0000-0001-9453-2830; Vaidya, Dhananjay/0000-0002-7164-1601; Smith, Jennifer/0000-0002-3575-5468; Pankow, James/0000-0001-7076-483X; Prokopenko, Inga/0000-0003-1624-7457; Feitosa, Mary/0000-0002-0933-2410; Ziad Alizadeh, Behrooz/0000-0002-1415-8007 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100 012C, HL043851, HL080467]; 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]; National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI [U01 HL72518]; NIH/National Institute of Nursing Research [NR0224103]; NIH/National Center for Research Resources [M01-RR000052]; National Heart, Lung and Blood Institute of the National Institutes of Health [HL054464, HL054457, HL054481, HL081331, HL087660]; NIDDK [1R01DK8925601]; National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine; National Institute for Diabetes and Digestive and Kidney Diseases [RO1 DK078616, K24 DK080140, 1RO1 HL64753, RO1 HL076784, 1RO1 G028321, 1RO1HL092577]; Danish Medical Research Council; Danish Centre for Health Technology Assessment; Novo Nordisk; Copenhagen County; Danish Heart Foundation; Danish Pharmaceutical Association; Augustinus Foundation; Ib Henriksen Foundation; Becket Foundation; Lundbeck Foundation; Novo Nordisk Foundation; Danish Ministry of Science, Technology and Innovation; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation; Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Netherlands Heart Foundation; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Organisation of Scientific Research NWO Investments [175.010, 2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; NWO [916.12.154]; EUR Fellowship; National Cancer Institute [CA047988]; Donald W. Reynolds Foundation; U01 HL108630; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201100046C, HHSN26 8201100001C, HHSN268201100002C, HHSN268201100003C, HHSN26 8201100004C, HHSN271201100004C]; Intramural Research Program of the NIH, National Institute on Aging [Z01-AG000932-06]; [R01DK075681]; [HL58625-01A1]; [HL59684]; [HL071025-01A1] FX The authors express their gratitude to large meta-GWAS Consortia and studies for contributing results in the XC-Pleiotropy. They are recognized as contributing studies in the coauthorship. In addition we acknowledge the followings studies for contributing correlation analyses:; ARIC:; The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100 012C). This work is also funded in part by R01DK075681 (K.E.N.).; The authors thank the staff and participants of the ARIC study for their important contributions.; CARDIA:; Coronary Artery Risk in Young Adults was 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).; GeneSTAR:; GeneSTAR was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) consortium as well as grants HL58625-01A1, HL59684, and HL071025-01A1, and a grant from the NIH/National Institute of Nursing Research (NR0224103). Additional support was provided by a grant from the NIH/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center.; GENOA:; Support for the Genetic Epidemiology Network of Arteriopathy was provided by the National Heart, Lung and Blood Institute of the National Institutes of Health (HL054464, HL054457, HL054481, HL081331, and HL087660). We would also like to thank the families that participated in the GENOA study.; FamHS:; This work was supported in part by NIDDK grant 1R01DK8925601 (I.B.B.).; FHS:; This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by National Institute for Diabetes and Digestive and Kidney Diseases RO1 DK078616 and K24 DK080140 (J.B.M.), and 1RO1 HL64753, RO1 HL076784, 1RO1 AG028321, 1RO1HL092577 (E.J.B.).; INTER99:; The Inter99 Study was initiated by Torben Jorgensen, Knut Borch-Johnsen, Hans Ibsen and Troels F. Thomsen. The steering committee comprises Torben Jorgensen, Knut Borch-Johnsen and Charlotta Pisinger. The phenotyping was financially supported by grants from the Danish Medical Research Council, The Danish Centre for Health Technology Assessment, Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish Pharmaceutical Association, The Augustinus Foundation, The Ib Henriksen Foundation, and the Becket Foundation. The genetic research was supported by grants from the Lundbeck Foundation (www.lucamp.org) and the Novo Nordisk Foundation (metabol.ku.dk). This work is carried out as a part of the research program of the UNIK: Food, Fitness & Pharma for Health and Disease (see www.foodfitnesspharma.ku.dk). The UNIK project is supported by the Danish Ministry of Science, Technology and Innovation.; LifeLines:; The LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centers delivering data to LifeLines, and all the study participants.; RS:; The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam.; Support for genotyping was provided by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010. 2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. This work is supported also by NWO grant (veni, 916.12.154) and the EUR Fellowship (A.D.).; WGHS:; The WGHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA047988 from the National Cancer Institute, and the Donald W. Reynolds Foundation, with collaborative scientific support and funding for genotyping provided by Amgen. This research was partially supported by U01 HL108630.; WHI:; The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN26 8201100001C, HHSN268201100002C, HHSN268201100003C, HHSN26 8201100004C, and HHSN271201100004C. A listing of WHI investigators can be found at https://cleo.whi.org/researchers/Documents% 20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf; Other:; This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, Z01-AG000932-06, (M.N.). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster (http://biowultnih.gov) at the National Institutes of Health, Bethesda, MD (M.N.).; Guarantor's statement: Drs. Aldi T. Kraja and Ingrid B. Borecki are the guarantors of this work and, as such, had full access to all results produced for this study and take responsibility for the integrity of the results and of the accuracy of the analyses. Drs. Daniel I. Chasman, Kari E. North, Alexander P. Reiner, Lisa R. Yanek, Tuomas O. Kilpelainen, Jennifer A. Smith, Abbas Dehghan, Martin G. Larson, and Behrooz Z. Alizadeh are the guarantors of the individual studies, as such, had full access to all results produced by their corresponding study and take responsibility for the integrity of the results and of the accuracy of their results' analyses. NR 134 TC 32 Z9 32 U1 2 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2014 VL 112 IS 4 BP 317 EP 338 DI 10.1016/j.ymgme.2014.04.007 PG 22 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA AN1OU UT WOS:000340354000009 PM 24981077 ER PT J AU Goldman, SM Kamel, F Ross, GW Jewell, SA Marras, C Hoppin, JA Umbach, DM Bhudhikanok, GS Meng, C Korell, M Comyns, K Hauser, RA Jankovic, J Factor, SA Bressman, S Lyons, KE Sandler, DP Langston, JW Tanner, CM AF Goldman, Samuel M. Kamel, Freya Ross, G. Webster Jewell, Sarah A. Marras, Connie Hoppin, Jane A. Umbach, David M. Bhudhikanok, Grace S. Meng, Cheryl Korell, Monica Comyns, Kathleen Hauser, Robert A. Jankovic, Joseph Factor, Stewart A. Bressman, Susan Lyons, Kelly E. Sandler, Dale P. Langston, J. William Tanner, Caroline M. TI Peptidoglycan Recognition Protein Genes and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; peptidoglycan; PGLYRP; microbiome; gut ID ALPHA-SYNUCLEIN; IMMUNE-RESPONSES; GUT MICROBIOTA; ASSOCIATION; INFLAMMATION; PATHOLOGY; SYSTEM; BRAIN; NEUROINFLAMMATION; NEURODEGENERATION AB Increased gut permeability, inflammation, and colonic alpha-synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case-control studies were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5' untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95% CI 0.4-0.9], CC OR 0.15 [95% CI 0.04-0.6]; log-additive P-trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD. (C) 2014 International Parkinson and Movement Disorder Society C1 [Goldman, Samuel M.; Tanner, Caroline M.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Goldman, Samuel M.; Tanner, Caroline M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goldman, Samuel M.; Bhudhikanok, Grace S.; Meng, Cheryl; Korell, Monica; Comyns, Kathleen; Langston, J. William] Parkinsons Inst, Sunnyvale, CA USA. [Kamel, Freya; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Jewell, Sarah A.] German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany. [Marras, Connie] Univ Toronto, Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Hoppin, Jane A.] N Carolina State Univ, Raleigh, NC 27695 USA. [Umbach, David M.] NIEHS, Biostat Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Hauser, Robert A.] Univ S Florida, Tampa, FL USA. [Jankovic, Joseph] Baylor Coll Med, Houston, TX 77030 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Atlanta, GA USA. [Bressman, Susan] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Lyons, Kelly E.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Goldman, SM (reprint author), San Francisco VA Med Ctr, 4150 Clement St,PADRECC 127P, San Francisco, CA 94121 USA. EM samuel.goldman@ucsf.edu OI Jewell, Sarah/0000-0002-9877-2599; Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU NIH; National Institute of Environmental Health Sciences; NIEHS [Z01-ES044007, Z01-ES049030, R01-ES10803, U54 ES012077]; NCI [Z01-CP010119]; Michael J. Fox Foundation; Parkinson's Unity Walk FX This study was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, NIEHS (grants Z01-ES044007 and Z01-ES049030), NCI (grant Z01-CP010119), NIEHS grants R01-ES10803 and U54 ES012077, the Michael J. Fox Foundation, Parkinson's Unity Walk, and James and Sharron Clark. SEARCH was supported by an unrestricted grant from a group of current and former manufacturers of welding consumables awarded to The Parkinson's Institute. NR 59 TC 8 Z9 9 U1 6 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2014 VL 29 IS 9 BP 1171 EP 1180 DI 10.1002/mds.25895 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AN4BJ UT WOS:000340532300015 PM 24838182 ER PT J AU Patel, K Foretz, M Marion, A Campbell, DG Gourlay, R Boudaba, N Tournier, E Titchenell, P Peggie, M Deak, M Wan, M Kaestner, KH Goransson, O Viollet, B Gray, NS Birnbaum, MJ Sutherland, C Sakamoto, K AF Patel, Kashyap Foretz, Marc Marion, Allison Campbell, David G. Gourlay, Robert Boudaba, Nadia Tournier, Emilie Titchenell, Paul Peggie, Mark Deak, Maria Wan, Min Kaestner, Klaus H. Goransson, Olga Viollet, Benoit Gray, Nathanael S. Birnbaum, Morris J. Sutherland, Calum Sakamoto, Kei TI The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver SO NATURE COMMUNICATIONS LA English DT Article ID ACTIVATED PROTEIN-KINASE; HEPATIC GLUCOSE-PRODUCTION; CREB COACTIVATOR TORC2; AMP; METFORMIN; LKB1; PHOSPHORYLATION; HOMEOSTASIS; MECHANISM; FAMILY AB LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver. C1 [Patel, Kashyap; Campbell, David G.; Gourlay, Robert; Peggie, Mark; Deak, Maria; Sakamoto, Kei] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Foretz, Marc; Marion, Allison; Boudaba, Nadia; Tournier, Emilie; Viollet, Benoit] INSERM, Inst Cochin, U1016, F-75014 Paris, France. [Foretz, Marc; Marion, Allison; Boudaba, Nadia; Tournier, Emilie; Viollet, Benoit] CNRS, UMR 8104, F-75014 Paris, France. [Foretz, Marc; Marion, Allison; Boudaba, Nadia; Tournier, Emilie; Viollet, Benoit] Univ Paris 05, F-75006 Paris, France. [Titchenell, Paul; Wan, Min; Kaestner, Klaus H.; Birnbaum, Morris J.] Univ Penn, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Goransson, Olga] Lund Univ, Dept Expt Med Sci, BMC C11, S-22184 Lund, Sweden. [Gray, Nathanael S.] Boston Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Sutherland, Calum] Univ Dundee, Sch Med, Ninewells Hosp, Dundee DD1 9SY, Scotland. RP Foretz, M (reprint author), INSERM, Inst Cochin, U1016, F-75014 Paris, France. EM marc.foretz@inserm.fr; Kei.Sakamoto@rd.nestle.com RI Campbell, David/K-1874-2015; OI Campbell, David/0000-0003-2278-2149; Patel, Kashyap/0000-0002-9240-8104; Birnbaum, Morris/0000-0001-9972-8680; Sutherland, Calum/0000-0003-4398-7434 FU British MRC; Region Ile-de-France (CORDDIM); Societe Francophone du Diabete (SFD); Division of Signal Transduction Therapy Unit; AstraZeneca; Boehringer-Ingelheim; GlaxoSmithKline; Merck KgaA; Janssen Pharmaceutica; Pfizer; Wellcome Trust [093991/Z/10/Z]; NIHR [RO1DK56886] FX We thank Ronald DePinho (the Harvard University) for kindly providing LKB1lox/lox mice, Daniel Metzger (the IGBMC, France) for the Albumin-Cre-ERT2 mice and Hiroshi Takemori (the National Institute of Biomedical Innovation, Osaka, Japan) for SIK1 pSer577 antibody. We thank Philip Cohen and Kris Clark for advice and Gail Fraser and Elaine Forsyth for genotyping. We also thank the technical support of the Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit (PPU) DNA Sequencing Service, the MRC-PPU tissue culture team (coordinated by Kirsten McLeod), the Division of Signal Transduction Therapy (DSTT) antibody and protein purification teams (coordinated by Hilary McLauchlan and James Hastie). We would like to acknowledge the assistance of the PRIDE Team at the EBI for their help in enabling public deposition of the mass spectrometry data. This work was supported by the British MRC, the Region Ile-de-France (CORDDIM), Societe Francophone du Diabete (SFD) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer). K. P. is supported by the Wellcome Trust PhD Programme for Clinicians (093991/Z/10/Z) and A. M. is a recipient of a post-doctoral fellowship from the Region Ile-de-France (CORDDIM). This work is supported by the NIH Grant RO1DK56886 to M.J.B. NR 40 TC 28 Z9 28 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2014 VL 5 AR 4535 DI 10.1038/ncomms5535 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1AO UT WOS:000341044300001 PM 25088745 ER PT J AU Ritorto, MS Ewan, R Perez-Oliva, AB Knebel, A Buhrlage, SJ Wightman, M Kelly, SM Wood, NT Virdee, S Gray, NS Morrice, NA Alessi, DR Trost, M AF Ritorto, Maria Stella Ewan, Richard Perez-Oliva, Ana B. Knebel, Axel Buhrlage, Sara J. Wightman, Melanie Kelly, Sharon M. Wood, Nicola T. Virdee, Satpal Gray, Nathanael S. Morrice, Nicholas A. Alessi, Dario R. Trost, Matthias TI Screening of DUB activity and specificity by MALDI-TOF mass spectrometry SO NATURE COMMUNICATIONS LA English DT Article ID ATYPICAL UBIQUITIN CHAINS; SMALL-MOLECULE INHIBITOR; CELL LYMPHOMA-CELLS; DEUBIQUITINATING ENZYMES; ENZYMATIC-ACTIVITIES; IN-VIVO; PROTEIN; PROTEASES; PROBES; ISOPEPTIDASE AB Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analysing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAB/MPN/Mov34 metalloenzyme DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs. C1 [Ritorto, Maria Stella; Ewan, Richard; Perez-Oliva, Ana B.; Knebel, Axel; Wightman, Melanie; Wood, Nicola T.; Virdee, Satpal; Alessi, Dario R.; Trost, Matthias] Univ Dundee, MRC, Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. [Buhrlage, Sara J.; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Buhrlage, Sara J.; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kelly, Sharon M.] Univ Glasgow, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark, Scotland. [Morrice, Nicholas A.] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. RP Trost, M (reprint author), Univ Dundee, MRC, Prot Phosphorylat & Ubiquitylat Unit, Dundee DD1 5EH, Scotland. EM m.trost@dundee.ac.uk RI Trost, Matthias/A-9999-2009; OI Trost, Matthias/0000-0002-5732-700X; Alessi, Dario/0000-0002-2140-9185; Wood, Nicola/0000-0002-3347-6625; Ritorto, Maria Stella/0000-0001-9861-6863 FU Medical Research Council UK; Division of Signal Transduction Therapy (DSTT) (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck KGaA and Pfizer); MRC Protein Phosphorylation and Ubiquitylation Unit FX This work was funded by the Medical Research Council UK and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (DSTT) (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janssen Pharmaceutica, Merck KGaA and Pfizer). We thank the DNA cloning, Protein Production, DNA sequencing and Mass Spectrometry teams of the MRC Protein Phosphorylation and Ubiquitylation Unit for their support, Yogesh Kulathu for expression of vOTU and suggestions and Natalia Shpiro for the synthesis of compounds. We also thank Bruker Daltonics and particularly Anja Resemann and Rainer Paape, as well as Rod Watson and Julia Smith for providing NR 63 TC 47 Z9 47 U1 3 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2014 VL 5 AR 4763 DI 10.1038/ncomms5763 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1PA UT WOS:000341084300002 PM 25159004 ER PT J AU Wang, HS Burnett, T Kono, S Haiman, CA Iwasaki, M Wilkens, LR Loo, LWM Van den Berg, D Kolonel, LN Henderson, BE Keku, TO Sandler, RS Signorello, LB Blot, WJ Newcomb, PA Pande, M Amos, CI West, DW Bezieau, S Berndt, SI Zanke, BW Hsu, L Lindor, NM Haile, RW Hopper, JL Jenkins, MA Gallinger, S Casey, G Stenzel, SL Schumacher, FR Peters, U Gruber, SB Tsugane, S Stram, DO Le Marchand, L AF Wang, Hansong Burnett, Terrilea Kono, Suminori Haiman, Christopher A. Iwasaki, Motoki Wilkens, Lynne R. Loo, Lenora W. M. Van den Berg, David Kolonel, Laurence N. Henderson, Brian E. Keku, Temitope O. Sandler, Robert S. Signorello, Lisa B. Blot, William J. Newcomb, Polly A. Pande, Mala Amos, Christopher I. West, Dee W. Bezieau, Stephane Berndt, Sonja I. Zanke, Brent W. Hsu, Li Lindor, Noralane M. Haile, Robert W. Hopper, John L. Jenkins, Mark A. Gallinger, Steven Casey, Graham Stenzel, Stephanie L. Schumacher, Fredrick R. Peters, Ulrike Gruber, Stephen B. Tsugane, Shoichiro Stram, Daniel O. Le Marchand, Loic CA Genetics Epidemiology Colorectal C Colon Canc Family Registry CCFR Colorectal Transdisciplinary Study TI Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A SO NATURE COMMUNICATIONS LA English DT Article ID PANCREATIC-CANCER; PROSTATE-CANCER; METAANALYSIS; RISK; 8Q24 AB The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 x 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P = 1.4 x 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations. C1 [Wang, Hansong; Burnett, Terrilea; Wilkens, Lynne R.; Loo, Lenora W. M.; Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Kono, Suminori] Kyushu Univ, Grad Sch Med Sci, Dept Prevent Med, Fukuoka 8128581, Japan. [Haiman, Christopher A.; Van den Berg, David; Henderson, Brian E.; Casey, Graham; Stenzel, Stephanie L.; Schumacher, Fredrick R.; Gruber, Stephen B.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Haiman, Christopher A.; Van den Berg, David; Henderson, Brian E.; Casey, Graham; Stenzel, Stephanie L.; Schumacher, Fredrick R.; Gruber, Stephen B.; Stram, Daniel O.] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. [Iwasaki, Motoki; Tsugane, Shoichiro] Natl Canc Ctr, Res Ctr Canc Prevent & Screening, Tokyo 1040045, Japan. [Keku, Temitope O.; Sandler, Robert S.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC 27599 USA. [Signorello, Lisa B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Signorello, Lisa B.] Harvard Univ, Sch Med, Channing Div Network Med, Boston, MA 02115 USA. [Signorello, Lisa B.] Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Div Epidemiol, Nashville, TN 37235 USA. [Blot, William J.] Int Epidemiol Inst, Rockville, MD 20850 USA. [Newcomb, Polly A.; Hsu, Li; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98124 USA. [Pande, Mala] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Res, Houston, TX 77030 USA. [Amos, Christopher I.] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Lebanon, NH 03755 USA. [West, Dee W.] Canc Prevent Inst Calif, Fremont, CA 94538 USA. [Bezieau, Stephane] CHU Nantes, Serv Genet Med, F-44093 Nantes, France. [Berndt, Sonja I.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Zanke, Brent W.] Univ Ottawa, Fac Med, Div Hematol, Ottawa, ON K1J 8M5, Canada. [Zanke, Brent W.] Ottawa Hosp Res Inst, Clin Epidemiol Program, Ottawa, ON K1J 8M5, Canada. [Lindor, Noralane M.] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ 85054 USA. [Haile, Robert W.] Stanford Canc Inst, Stanford, CA 94305 USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia. [Gallinger, Steven] Canc Care Ontario, Toronto, ON M5G 2L3, Canada. RP Le Marchand, L (reprint author), Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. EM loic@cc.hawaii.edu RI Gallinger, Steven/E-4575-2013; Tsugane, Shocichiro/A-2424-2015; Hoffmeister, Michael/B-5745-2012; KURY, Sebastien/G-5971-2015; Bezieau, stephane/G-5621-2015; Jenkins, Mark/P-7803-2015; U-ID, Kyushu/C-5291-2016; Brenner, Hermann/B-4627-2017 OI Hoffmeister, Michael/0000-0002-8307-3197; KURY, Sebastien/0000-0001-5497-0465; Bezieau, stephane/0000-0003-0095-1319; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572 FU US National Institutes of Health (NIH) [1R01-CA126895, 1R01-CA126895-S1, 1R01-CA104132, 2U24-CA074806]; NIH [R01-CA132839, RC2-CA148085, R01-CA1326792, U01-HG004726, R37 CA54281, P01 CA033619, R01 CA63464, R01CA092447]; Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award [W81XWH-08-1-0383]; National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC); MD Anderson University Cancer Fund; MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment; Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston, NCI Cancer Center Support Grant [CA16672]; NCI [K07CA160753, R01 CA81488, P30 CA014089]; National Cancer Center Research and Development Fund; Ministry of Health, Labor and Welfare of Japan; Ministry of Education, Culture, Sports, Science and Technology, Japan; National Cancer Institute as part of the GAME-ON consortium [U19 CA148107]; National Human Genome Research Institute at the NIH [T32 HG000040]; National Institute of Environmental Health Sciences at the NIH [T32 ES013678]; National Cancer Institute, NIH under RFA [CA-95-011]; National Cancer Institute [P30 CA014089, U01CA122839]; Australasian Colorectal Cancer Family Registry [U01 CA097735]; Seattle Colorectal Cancer Family Registry [U01 CA074794]; Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; NHS by the NIH [R01 CA137178, P01 CA 087969, P50 CA 127003]; PHS by the NIH [R01 CA042182]; GL2 grant from the Ontario Research Fund; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH; NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200]; NIH GEI [U01 HG 004438]; NIH. [U01 CA137088, R01 CA059045, R01 CA60987]; The NIH [U01 CA074783, P50 CA 127003, R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, U01 HG004446, R01 CA076366, CA 087969, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]; [U01 CA 093326]; [P50 CA 106991]; [R01 CA 66635] FX We thank Dr Daniel Mirel, who supervised the genotyping of samples while working at the Broad Institute, Boston, MA, and Xin Sheng, Loreall Pooler, Dr Gary K. Chen and Alex H. Stram at the University of Southern California (USC), and Lucy Shen and Mike Loomis at the University of Hawai'i Cancer Center for their technical assistance. The colorectal cancer GWAS among Japanese and African Americans was funded through US National Institutes of Health (NIH) grants 1R01-CA126895, 1R01-CA126895-S1, 1R01-CA104132 and 2U24-CA074806. Genotyping of the additional MEC controls was funded through NIH grants R01-CA132839, RC2-CA148085, R01-CA1326792 and U01-HG004726, as well as a Department of Defense Breast Cancer Research Program, Era of Hope Scholar Award to CAH (W81XWH-08-1-0383). MEC was funded through NIH grants R37 CA54281, P01 CA033619, and R01 CA63464. The SCCS was funded by NIH grant R01CA092447. Data on SCCS cancer cases used in this publication were provided by the Alabama Statewide Cancer Registry; Kentucky Cancer Registry, Lexington, KY; Tennessee Department of Health, Office of Cancer Surveillance; Florida Cancer Data System; North Carolina Central Cancer Registry, North Carolina Division of Public Health; Georgia Comprehensive Cancer Registry; Louisiana Tumor Registry; Mississippi Cancer Registry; South Carolina Central Cancer Registry; Virginia Department of Health, Virginia Cancer Registry; Arkansas Department of Health, Cancer Registry, 4815 W. Markham, Little Rock, AR 72205. The Arkansas Central Cancer Registry is fully funded by a grant from National Program of Cancer Registries, Centers for Disease Control and Prevention (CDC). Data on SCCS cancer cases from Mississippi were collected by the Mississippi Cancer Registry, which participates in the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry. The UNC studies were supported by grants U01 CA 093326, P50 CA 106991 and R01 CA 66635. The MD Anderson data collection was supported in part by the MD Anderson University Cancer Fund, the MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, the Center for Clinical and Translational Sciences of the University of Texas Health Science Center at Houston, NCI Cancer Center Support Grant (CA16672) and NCI grant (K07CA160753). JPHC was supported by the National Cancer Center Research and Development Fund (since 2011) and a Grant-in-Aid for Cancer Research (from 1989 to 2010) from the Ministry of Health, Labor and Welfare of Japan. The Fukuoka Colorectal Cancer Study was funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan. The CORECT Study is supported by the National Cancer Institute as part of the GAME-ON consortium (U19 CA148107) with additional support from NCI grants (R01 CA81488, P30 CA014089), the National Human Genome Research Institute at the NIH (T32 HG000040) and the National Institute of Environmental Health Sciences at the NIH (T32 ES013678). CCFR (http://www.coloncfr.; org/) is supported by the National Cancer Institute, NIH under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and PIs of the Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC], Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794) and the University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). The Colon CFR GWAS work was supported by a National Cancer Institute grant (U01CA122839 and P30 CA014089), Australasian Colorectal Cancer Family Registry (U01 CA097735), Seattle Colorectal Cancer Family Registry (U01 CA074794) and Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute, NIH or any of the collaborating centres in the CCFRs, nor does it mention trade names, commercial products or organizations imply endorsement by the US Government or the CCFR. GECCO was funded by NIH grants U01 CA137088 and R01 CA059045. ASTERISK was supported by a Hospital Clinical Research Program (PHRC) and by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). CR2&3 was funded by NIH grant R01 CA60987. DACHS was funded by the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1) and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS was funded by the NIH (R01 CA48998 to M. L. S.). HPFS is supported by the NIH (P01 CA 055075, UM1 CA167552, R01 137178, and P50 CA 127003), NHS by the NIH (R01 CA137178, P01 CA 087969 and P50 CA 127003) and PHS by the NIH (R01 CA042182). OFCCR was supported by the NIH through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see the CCFR section above. As a subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. Thomas J. Hudson and Brent W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO (http://dcp.cancer.gov/plco) was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS22, CGEMS pancreatic cancer scan (PanScan)23,24 and the Lung Cancer and Smoking study25. The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2.; Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446 and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH was funded by the NIH grant R01 CA076366 to P. A. Newcomb. NHS was supported by NIH grants CA 087969, R01 137178, and P50 CA 127003. VITAL was funded by NIH grant K05 CA154337. The WHI program is funded by the National Heart, Lung, and Blood Institute, and NIH through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. The ASTERISK study are very grateful to Dr Bruno Buecher, without whom this project would not have existed and also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. The DACHS study thank all participants and cooperating clinicians, and Ute Handte-Daub, Renate Hettler-Jensen, Utz Benscheid, Muhabbet Celik and Ursula Eilber at DACHS for excellent technical assistance. GECCO would like to thank all those at the Coordinating Center for helping to bring together the data and people that made this project possible. HPFS, NHS and PHS would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS, and PHS under the supervision of Dr Immaculata Devivo and Dr David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS, and Haiyan Zhang who assisted in programming for the PHS. We would like to thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. In addition, this study was approved by the Connecticut Department of Public Health (DPH) Human Investigations Committee. Certain data used in this publication were obtained from the DPH. The authors assume full responsibility for analyses and interpretation of these data. The PLCO thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the PLCO Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs Bill Kopp, Wen Shao, and staff, SAIC-Frederick, and most importantly the study participants for their contributions to making this study possible. The PMH study would like to thank the study participants and staff of the Hormones and Colon Cancer study. The WHI study thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: https://cleo.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20 Investigator%20Short%20List.pdf. NR 26 TC 22 Z9 22 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2014 VL 5 AR 4613 DI 10.1038/ncomms5613 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1FE UT WOS:000341057000004 PM 25105248 ER PT J AU West, JA Cook, A Alver, BH Stadtfeld, M Deaton, AM Hochedlinger, K Park, PJ Tolstorukov, MY Kingston, RE AF West, Jason A. Cook, April Alver, Burak H. Stadtfeld, Matthias Deaton, Aimee M. Hochedlinger, Konrad Park, Peter J. Tolstorukov, Michael Y. Kingston, Robert E. TI Nucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming SO NATURE COMMUNICATIONS LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; CHROMATIN-STRUCTURE; SUPER-ENHANCERS; HUMAN GENOME; TRANSCRIPTION; PLURIPOTENCY; COMPLEX; GENES; DNA AB Chromatin structure determines DNA accessibility. We compare nucleosome occupancy in mouse and human embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs) and differentiated cell types using MNase-seq. To address variability inherent in this technique, we developed a bioinformatic approach to identify regions of difference (RoD) in nucleosome occupancy between pluripotent and somatic cells. Surprisingly, most chromatin remains unchanged; a majority of rearrangements appear to affect a single nucleosome. RoDs are enriched at genes and regulatory elements, including enhancers associated with pluripotency and differentiation. RoDs co-localize with binding sites of key developmental regulators, including the reprogramming factors Klf4, Oct4/Sox2 and c-Myc. Nucleosomal landscapes in ESC enhancers are extensively altered, exhibiting lower nucleosome occupancy in pluripotent cells than in somatic cells. Most changes are reset during reprogramming. We conclude that changes in nucleosome occupancy are a hallmark of cell differentiation and reprogramming and likely identify regulatory regions essential for these processes. C1 [West, Jason A.; Cook, April; Deaton, Aimee M.; Tolstorukov, Michael Y.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [West, Jason A.; Cook, April; Deaton, Aimee M.; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Alver, Burak H.; Park, Peter J.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. [Stadtfeld, Matthias] NYU, Sch Med, Helen L & Martin S Kimmel Ctr Biol & Med, Skirball Inst Biomol Med,Dept Cell Biol, New York, NY 10016 USA. [Hochedlinger, Konrad] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Park, PJ (reprint author), Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02115 USA. EM peter_park@hms.harvard.edu; tolstorukov@molbio.mgh.harvard.edu; kingston@molbio.mgh.harvard.edu RI West, Jason/I-4445-2014; OI West, Jason/0000-0002-7252-8651; Stadtfeld, Matthias/0000-0002-5852-9906 FU National Institute of General Medical Sciences, NIH [F32GM093491, R01GM043901, R37GM048405, R01GM082798]; National Institute of Child Health and Human Development, NIH [R01GM082798] FX We thank S. Bowman and M. Simon for optimizing sequencing library preparation, Z. Wang, C. Woo, J. Dennis, and the Kingston and Park labs for helpful discussions, G.Q. Daley for human cell lines, and the MGH Molecular Biology NextGen Sequencing Core. J.A.W., R.E.K., and P.J.P. were supported by the National Institute of General Medical Sciences, NIH (F32GM093491 to J.A.W.; R01GM043901 and R37GM048405 to R.E.K.; R01GM082798 to P.J.P.). K.H. was supported by the grant R01HD058013 from the National Institute of Child Health and Human Development, NIH. NR 65 TC 24 Z9 24 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD AUG PY 2014 VL 5 AR 4719 DI 10.1038/ncomms5719 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA AO1NL UT WOS:000341079700002 PM 25158628 ER PT J AU Grilli, MD Verfaellie, M AF Grilli, Matthew D. Verfaellie, Mieke TI Personal semantic memory: Insights from neuropsychological research on amnesia SO NEUROPSYCHOLOGIA LA English DT Review DE Personal semantic memory; Amnesia; Self; Autobiographical memory ID FOCAL RETROGRADE-AMNESIA; TEMPORAL-LOBE DAMAGE; AUTOBIOGRAPHICAL MEMORY; EPISODIC MEMORY; CONCEPTUAL KNOWLEDGE; IMPAIRED INDIVIDUALS; NEUROLOGICAL DAMAGE; HIPPOCAMPAL DAMAGE; RECOGNITION MEMORY; ALZHEIMERS-DISEASE AB This paper provides insight into the cognitive and neural mechanisms of personal semantic memory, knowledge that is specific and unique to individuals, by reviewing neuropsychological research on stable amnesia secondary to medial temporal lobe damage. The results reveal that personal semantic memory does not depend on a unitary set of cognitive and neural mechanisms. Findings show that autobiographical fact knowledge reflects an experience-near type of personal semantic memory that relies on the medial temporal lobe for retrieval, albeit less so than personal episodic memory. Additional evidence demonstrates that new autobiographical fact learning likely relies on the medial temporal lobe, but the extent to which remains unclear. Other findings show that retrieval of personal traits/roles and new learning of personal traits/roles and thoughts/beliefs are independent of the medial temporal lobe and thus may represent highly conceptual types of personal semantic memory that are stored in the neocortex. Published by Elsevier Ltd. C1 VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Med, Memory Disorders Res Ctr, Boston, MA 02118 USA. RP Grilli, MD (reprint author), VA Boston Healthcare Syst, Mental Hlth Serv Line 116B, 150 South Huntington Ave, Boston, MA 02130 USA. EM matthew.grilli@va.gov OI Verfaellie, Mieke/0000-0001-5535-4584 FU Clinical Science Research and Development Service, Department of Veterans Affairs [IO1 CX000925] FX Grant sponsor: Clinical Science Research and Development Service, Department of Veterans Affairs IO1 CX000925. We thank M. Kopelman for providing the means and standard deviations from the healthy control group published in Kopelman (1989). We thank Daniela Palombo and Craig McFarland for their comments on an earlier version of this paper and Cindy Woolverton for help with accessing articles. NR 86 TC 9 Z9 9 U1 4 U2 19 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD AUG PY 2014 VL 61 BP 56 EP 64 DI 10.1016/j.neuropsychologia.2014.06.012 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AO0DX UT WOS:000340980400006 PM 24949553 ER PT J AU Verfaellie, M Bousquet, K Keane, MM AF Verfaellie, Mieke Bousquet, Kathryn Keane, Margaret M. TI Medial temporal and neocortical contributions to remote memory for semantic narratives: Evidence from amnesia SO NEUROPSYCHOLOGIA LA English DT Article DE Semantic memory; Narratives; Remote memory; Amnesia; Medial temporal lobes; Consolidation ID RETROGRADE-AMNESIA; PREFRONTAL CORTEX; EPISODIC MEMORY; RETRIEVAL; LOBE; CONSOLIDATION; DAMAGE; RECOGNITION; KNOWLEDGE; NEUROSCIENCE AB Studies of remote memory for semantic facts and concepts suggest that hippocampal lesions lead to a temporally graded impairment that extends no more than ten years prior to the onset of amnesia. Such findings have led to the notion that once consolidated, semantic memories are represented neocortically and are no longer dependent on the hippocampus. Here, we examined the fate of well-established semantic narratives following medial temporal lobe (MTL) lesions. Seven amnesic patients, five with lesions restricted to the MTL and two with lesions extending into lateral temporal cortex (MTL+), were asked to recount fairy tales and bible stories that they rated as familiar. Narratives were scored for number and type of details, number of main thematic elements, and order in which the main thematic elements were recounted. In comparison to controls, patients with MTL lesions produced fewer details, but the number and order of main thematic elements generated was intact. By contrast, patients with MTL+ lesions showed a pervasive impairment, affecting not only the generation of details, but also the generation and ordering of main steps. These findings challenge the notion that, once consolidated, semantic memories are no longer dependent on the hippocampus for retrieval. Possible hippocampal contributions to the retrieval of detailed semantic narratives are discussed. Published by Elsevier Ltd. C1 [Verfaellie, Mieke; Bousquet, Kathryn; Keane, Margaret M.] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02130 USA. [Verfaellie, Mieke; Bousquet, Kathryn; Keane, Margaret M.] Boston Univ, Sch Med, Boston, MA 02130 USA. [Keane, Margaret M.] Wellesley Coll, Dept Psychol, Wellesley, MA 02481 USA. RP Verfaellie, M (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr, 150 S Huntington Ave, Boston, MA 02130 USA. EM verf@bu.edu FU NIMH [R01MH093431]; Clinical Science Research and Development Service, Department of Veterans Affairs FX This research was supported by NIMH Grant no. R01MH093431 and the Clinical Science Research and Development Service, Department of Veterans Affairs. The authors thank Dr. Daniela Palombo for help with lesion analysis and Aubrey Wank for help with data analysis and manuscript preparation. NR 48 TC 8 Z9 8 U1 2 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD AUG PY 2014 VL 61 BP 105 EP 112 DI 10.1016/j.neuropsychologia.2014.06.018 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA AO0DX UT WOS:000340980400011 PM 24953960 ER PT J AU Reed, SD Mitchell, CM Joffe, H Cohen, L Shifren, JL Newton, KM Freeman, EW Larson, JC Manson, JE LaCroix, AZ Guthrie, KA AF Reed, Susan D. Mitchell, Caroline M. Joffe, Hadine Cohen, Lee Shifren, Jan L. Newton, Katherine M. Freeman, Ellen W. Larson, Joseph C. Manson, JoAnn E. LaCroix, Andrea Z. Guthrie, Katherine A. TI Sexual Function in Women on Estradiol or Venlafaxine for Hot Flushes A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the North-American-Menopause-Society CY OCT 09-12, 2013 CL Dallas, TX SP N Amer Menopause Soc ID QUALITY-OF-LIFE; MENOPAUSAL VASOMOTOR SYMPTOMS; TRANSDERMAL ESTROGEN THERAPY; DOUBLE-BLIND; ANTIDEPRESSANT EFFICACY; POSTMENOPAUSAL WOMEN; BREAST-CANCER; INDEX FSFI; FLASHES; TOLERABILITY AB OBJECTIVE: To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes. METHODS: In an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between 0.5 mg oral estradiol per day or 75 mg venlafaxine per day (both compared with a placebo). Measures included composite and six domain scores from the Female Sexual Function Index and sexually related personal distress. RESULTS: Participants were aged 54.6 years (standard deviation [SD] 3.8) years, 59% white, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean Female Sexual Function Index change from baseline to week 8 was 1.4 (95% confidence interval [CI] 20.4 to 3.2) for estradiol, 1.1 (95% CI 20.5 to 2.7) for venlafaxine, and 20.3 (95% CI 21.6 to 1.0) for placebo. Composite Female Sexual Function Index and sexually related distress change from baseline did not differ between estradiol and placebo (P=.38, P=.30) or venlafaxine and placebo (P=.79, P=.48). Among sexually active women, Female Sexual Function Index domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0-0.6) for estradiol, 20.6 (95% CI -1.2 to 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2-1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction. CONCLUSION: Overall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8 weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although a subtle increase in desire (estradiol) and decreases in orgasm and pain (venlafaxine) may exist. C1 Univ Washington, Dept Obstet & Gynecol, Sch Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Sch Med, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Grp Hlth Res Inst, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Data Coordinating Ctr, Seattle, WA 98104 USA. Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Penn, Dept Obstet & Gynecol, Perelman Sch Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Reed, SD (reprint author), Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. EM reeds@u.washington.edu FU NIA NIH HHS [U01AG032669, U01AG032700, U01 AG032656, U01 AG032659, U01AG032699, U01 AG032669, U01AG032682, U01 AG032700, U01 AG032682, U01 AG032699] NR 44 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2014 VL 124 IS 2 BP 233 EP 241 DI 10.1097/AOG.0000000000000386 PN 1 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4NT UT WOS:000341317600006 PM 25004335 ER PT J AU Pham-Thomas, N Pereira, N Powell, AM Croft, DJ Guilfoil, DS Montgomery, OC AF Pham-Thomas, Nancy Pereira, Nigel Powell, Anna M. Croft, Damien J. Guilfoil, Daniel S. Montgomery, Owen C. TI Outcomes of Effective Transmission of Electronic Prenatal Records From the Office to the Hospital SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MEDICAL-RECORD; HEALTH RECORDS; NETWORK AB OBJECTIVE: To investigate the outcomes associated with improved transmission of prenatal test results between the outpatient and inpatient obstetric setting after implementation of an electronic prenatal record system. METHODS: Admission paper charts of patients admitted to our labor and delivery unit were reviewed before and after implementation of an electronic prenatal record system. The availability of maternal hepatitis B and human immunodeficiency virus (HIV) serology on admission, the occurrence of repeat hepatitis B surface antigen and rapid HIV blood testing, and the occurrence of hepatitis B immunoglobulin administration to the newborns of mothers without available hepatitis B serology was recorded. Fisher's exact tests were performed to determine differences in availability of prenatal test results, the occurrence of repeat blood testing, and the occurrence of immunoglobulin administration before and after implementation. RESULTS: A total of 460 admission charts were reviewed, 229 preimplementation and 231 postimplementation. Of the preimplementation charts, 78.2% contained maternal hepatitis B and HIV serology results, whereas all postimplementation charts contained such results (P,. 001). Although repeat hepatitis B surface antigen testing was performed in 3.1% of patients preimplementation, no patients required repeat testing postimplementation (P=.007). Similarly, rapid HIV blood testing was performed in 3.5% of patients preimplementation, but no patients required repeat testing postimplementation (P=.003). Increased availability of testing results prevented unnecessary administration of hepatitis B immunoglobulin postimplementation. CONCLUSION: Implementation of an electronic perinatal record system was associated with improved transmission of prenatal test results between the outpatient and inpatient obstetric setting and a decreased rate of unnecessary maternal testing and newborn interventions. C1 Palo Alto Med Fdn, Dublin Ctr, Dept Obstet, Dublin, CA USA. Palo Alto Med Fdn, Dublin Ctr, Dept Gynecol, Dublin, CA USA. Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Pereira, N (reprint author), Dept Obstet & Gynecol, 245 N 15th St,MS 495,16th Floor,New Coll Bldg, Philadelphia, PA 19102 USA. EM Nigel.Pereira@drexelmed.edu NR 11 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2014 VL 124 IS 2 BP 317 EP 322 DI 10.1097/AOG.0000000000000349 PN 1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AO4NT UT WOS:000341317600016 PM 25004337 ER PT J AU Chang, JY Kestin, LL Barriger, RB Chetty, IJ Ginsburg, ME Kumar, S Loo, BW Movsas, B Rimner, A Rosenzweig, KE Stinchcombe, TE Videtic, GMM Willers, H AF Chang, Joe Yujiao Kestin, Larry L. Barriger, R. Bryan Chetty, Indrin J. Ginsburg, Mark E. Kumar, Sanath Loo, Billy W., Jr. Movsas, Benjamin Rimner, Andreas Rosenzweig, Kenneth E. Stinchcombe, Thomas E. Videtic, Gregory M. M. Willers, Henning TI ACR Appropriateness Criteria (R) Nonsurgical Treatment for Locally Advanced Non-Small-Cell Lung Cancer: Good Performance Status/Definitive Intent SO ONCOLOGY-NEW YORK LA English DT Review ID THERAPY-ONCOLOGY-GROUP; PHASE-III TRIAL; ELECTIVE NODAL IRRADIATION; LEUKEMIA-GROUP-B; MODULATED RADIATION-THERAPY; GROWTH-FACTOR-RECEPTOR; CONCURRENT CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; RANDOMIZED-TRIAL; I/II TRIAL AB Concurrent chemotherapy/radiotherapy has been considered the standard treatment for patients with a good performance status and inoperable stage III non-small-cell lung cancer (NSCLC). Three-dimensional chemoradiation therapy and intensity-modulated radiation therapy have been reported to reduce toxicity and allow a dose escalation to 70 Gy and beyond. However, the Radiation Therapy Oncology Group 0617 trial recently showed that dose escalation, from 60 Gy to 74 Gy with concurrent chemotherapy in stage III NSCLC was associated with higher toxicity and worse survival. A "one size fits all" treatment approach may need to be changed and adapted to each patient's particular disease and unique biologic/anatomic features, as well as the most appropriate radiotherapy modalities for that patient. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment. C1 [Chang, Joe Yujiao] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kestin, Larry L.] 21st Century Oncol Michigan Healthcare Profess, Farmington Hills, MI USA. [Barriger, R. Bryan] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Chetty, Indrin J.; Movsas, Benjamin] Henry Ford Hlth Syst, Detroit, MI USA. [Ginsburg, Mark E.] Columbia Univ, Soc Thorac Surg, New York, NY USA. [Kumar, Sanath] Henry Ford Hosp, Detroit, MI 48202 USA. [Loo, Billy W., Jr.] Stanford Univ, Stanford, CA 94305 USA. [Loo, Billy W., Jr.] Stanford Canc Inst, Stanford, CA 94305 USA. [Rimner, Andreas] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Rosenzweig, Kenneth E.] Mt Sinai Sch Med, New York, NY USA. [Stinchcombe, Thomas E.] Univ North Carolina Hlth Care Syst, Amer Soc Clin Oncol, Chapel Hill, NC USA. [Videtic, Gregory M. M.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Willers, Henning] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Chang, JY (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Radiat Oncol, 1515 Holcombe Blvd,Ste 97, Houston, TX 77030 USA. EM jychang@mdanderson.org FU D3 Oncology Solutions; Co-Chair of both the Lung Cancer Pathways and Esophageal Pathways committees of Via Oncology FX Benjamin Movsas, MD, FACR, reports research support to Henry Ford Health System Radiation Oncology Department from Varian, Inc, Philips, Inc, and Resonant, Inc. R. Bryan Barriger, MD, reports receiving a stipend from D3 Oncology Solutions for his work as Co-Chair of both the Lung Cancer Pathways and Esophageal Pathways committees of Via Oncology. NR 74 TC 13 Z9 14 U1 0 U2 2 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2014 VL 28 IS 8 BP 706 EP + PG 13 WC Oncology SC Oncology GA AN8PL UT WOS:000340866000009 PM 25140629 ER PT J AU Rodriguez-Violante, M Gonzalez-Latapi, P Cervantes-Arriaga, A Camacho-Ordonez, A Weintraub, D AF Rodriguez-Violante, Mayela Gonzalez-Latapi, Paulina Cervantes-Arriaga, Amin Camacho-Ordonez, Azyadeh Weintraub, Daniel TI Impulse control and related disorders in Mexican Parkinson's disease patients SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Impulse control disorder; Parkinson's disease; Mexico; QUIP-RS ID COMPULSIVE DISORDERS; DOPAMINE AGONIST; RATING-SCALE; PREVALENCE; BEHAVIORS; QUESTIONNAIRE; VALIDATION; SYMPTOMS; DRUGS AB Background: Impulse control disorders (ICDs) are a relatively recent addition to the behavioral spectrum of PD-related non-motor symptoms. Social and economic factors may play a role on the ICD phenotype of PD patients. Objective: The aim of this study is to determine the prevalence and characterize the clinical profile of ICDs in a sample of low-income, low-education PD patients with no social security benefits from a Latin American country. Methods: We included 300 consecutive PD patients and 150 control subjects. The presence of ICD and related disorders was assessed using a structured interview. After the interview and neurological evaluation were concluded, all subjects completed the Questionnaire for Impulsive-compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS). Results: Regarding ICDs and related disorders (hobbyism-punding), 25.6% (n = 77) of patients in the PD group and 16.6% (n = 25) in the control group fulfilled criteria for at least one ICD or related disorder (p = 0.032). There was a statistically significant difference in the QUIP-RS mean score between PD and control subjects (5.6 +/- 9.7 and 2.7 +/- 4.21, p = 0.001). The most common ICD was compulsive eating for both PD (8.6%) and control (2.6%) groups. Conclusions: The results of this study confirm that for this population, symptoms of an ICD are significantly more frequent in PD subjects than in control subjects. Nevertheless, socioeconomic differences may contribute to a lower overall frequency and distinct pattern of ICDs in PD patients compared with what has been reported in other countries. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Rodriguez-Violante, Mayela; Gonzalez-Latapi, Paulina; Cervantes-Arriaga, Amin; Camacho-Ordonez, Azyadeh] Natl Inst Neurol & Neurosurg, Clin Lab Neurodegenerat Dis, Mexico City 14269, DF, Mexico. [Rodriguez-Violante, Mayela] Natl Inst Neurol & Neurosurg, Movement Disorders Clin, Mexico City 14269, DF, Mexico. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. RP Rodriguez-Violante, M (reprint author), Natl Inst Neurol & Neurosurg, Clin Lab Neurodegenerat Dis, Insurgentes 3877, Mexico City 14269, DF, Mexico. EM mrodriguez@innn.edu.mx RI Rodriguez-Violante, Mayela/G-7056-2015; OI Rodriguez-Violante, Mayela/0000-0002-6041-9941; Cervantes-Arriaga, Amin/0000-0002-3935-9278 NR 28 TC 9 Z9 9 U1 1 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 EI 1873-5126 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD AUG PY 2014 VL 20 IS 8 BP 907 EP 910 DI 10.1016/j.parkreldis.2014.05.014 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA AO0DF UT WOS:000340978600021 PM 24935236 ER PT J AU Ullrich, CK Wolfe, J AF Ullrich, Christina K. Wolfe, Joanne TI Caring for Children Living with Life-Threatening Illness: A Growing Relationship Between Pediatric Hospital Medicine and Pediatric Palliative Care Preface SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 [Ullrich, Christina K.] Dept Psychosocial Oncol & Palliat Care, Dept Pediat Hematology Oncol, Div Pediat Palliat Care, Dana Farber Canc Inst, Boston, MA 02215 USA. [Wolfe, Joanne] Dept Psychosocial Oncol & Palliat Care, Div Pediat Palliat Care, Dana Farber Canc Inst, Boston, MA 02215 USA. RP Ullrich, CK (reprint author), Dept Psychosocial Oncol & Palliat Care, Dept Pediat Hematology Oncol, Div Pediat Palliat Care, Dana Farber Canc Inst, 450 Brookline Ave Dana 1102, Boston, MA 02215 USA. EM Christina_Ullrich@dfci.harvard.edu; Joanne_Wolfe@dfci.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 EI 1557-8240 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD AUG PY 2014 VL 61 IS 4 BP XXI EP XXIII DI 10.1016/j.pc1.2014.05.004 PG 3 WC Pediatrics SC Pediatrics GA AN6DX UT WOS:000340686200010 PM 25084730 ER PT J AU Bogetz, JF Ullrich, CK Berry, JG AF Bogetz, Jon F. Ullrich, Christina K. Berry, Jay G. TI Pediatric Hospital Care for Children with Life-threatening Illness and the Role of Palliative Care SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Pediatric; Child; Palliative care; Chronic disease; Life-threatening illness; Hospitalization; Hospital care; Health care reform ID MEDICALLY COMPLEX CHILDREN; LENGTH-OF-STAY; HEALTH-CARE; CEREBRAL-PALSY; WASHINGTON-STATE; RESOURCE USE; CANCER; COMMUNICATION; READMISSION; PREFERENCES AB Under increasing pressure to contain costs, hospitals are challenged to provide high-quality care to an increasingly complex group of children with life-threatening illness (LTI) that often worsen overtime. Pediatric palliative care is an essential component of optimal hospital care delivery for these children and their families. This article describes (1) the current landscape of pediatric hospital care for children with LTI, (2) the connection between palliative care and hospital care for such children, and (3) the relationship between health care reform and palliative care for children with LTI. C1 [Bogetz, Jon F.] Stanford Univ, Lucile Packard Childrens Hosp, Sch Med, Dept Pediat,Div Gen Pediat, Palo Alto, CA 94304 USA. [Ullrich, Christina K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ullrich, Christina K.] Harvard Univ, Sch Med, Boston Childrens Hosp, Boston, MA 02215 USA. [Berry, Jay G.] Harvard Univ, Boston Childrens Hosp, Sch Med, Dept Pediat,Div Gen Pediat, Boston, MA 02215 USA. RP Bogetz, JF (reprint author), Stanford Univ, Lucile Packard Childrens Hosp, Sch Med, Dept Pediat,Div Gen Pediat, 770 Welch Rd,Suite 100, Palo Alto, CA 94304 USA. EM jbogetz@stanford.edu NR 86 TC 6 Z9 6 U1 9 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 EI 1557-8240 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD AUG PY 2014 VL 61 IS 4 BP 719 EP 733 DI 10.1016/j.pcl.2014.05.002 PG 15 WC Pediatrics SC Pediatrics GA AN6DX UT WOS:000340686200011 PM 25084720 ER PT J AU Ogelby, M Goldstein, RD AF Ogelby, Monica Goldstein, Richard D. TI Interdisciplinary Care Using Your Team SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Interdisciplinary; Pediatric palliative care; Children and youth with special health care needs; Medical home; Continuity of care ID PEDIATRIC PALLIATIVE CARE; INTENSIVE-CARE; MULTIDISCIPLINARY TEAM; PATIENT OUTCOMES; NATIONAL-SURVEY; HOSPICE CARE; LUNG-CANCER; HOME-CARE; CHILDREN; COLLABORATION AB The interdisciplinary approach is a cornerstone of a well-functioning pediatric palliative care team. These teams are most often available as an inpatient consultation service, are composed of professionals representing multiple disciplines, and are used during the illness course of a child with life-threatening and chronic complex conditions, especially during challenging health care decision-making near end of life. This article reviews the current structure of the palliative care team, explores opportunities for inclusion of other vital team members, and proactively identifies the challenges that may occur when involving more providers in a child's and family's care. C1 [Ogelby, Monica] Dept Vermont Hlth Access, Pediat Palliat Care Program, Williston, VT 05495 USA. [Goldstein, Richard D.] Boston Childrens Hosp, Harvard Med Sch, Dana Farber Canc Inst, Pediat Adv Care Team, Boston, MA 02215 USA. RP Goldstein, RD (reprint author), Boston Childrens Hosp, Harvard Med Sch, Dana Farber Canc Inst, Pediat Adv Care Team, 450 Brookline Ave, Boston, MA 02215 USA. EM Richard_Goldstein@dfci.harvard.edu NR 48 TC 5 Z9 5 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 EI 1557-8240 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD AUG PY 2014 VL 61 IS 4 BP 823 EP 834 DI 10.1016/j.pcl.2014.04.009 PG 12 WC Pediatrics SC Pediatrics GA AN6DX UT WOS:000340686200017 PM 25084726 ER PT J AU McCormack, SE McCarthy, MA Harrington, SG Farilla, L Hrovat, MI Systrom, DM Thomas, BJ Torriani, M McInnis, K Grinspoon, SK Fleischman, A AF McCormack, S. E. McCarthy, M. A. Harrington, S. G. Farilla, L. Hrovat, M. I. Systrom, D. M. Thomas, B. J. Torriani, M. McInnis, K. Grinspoon, S. K. Fleischman, A. TI Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents SO PEDIATRIC OBESITY LA English DT Article DE IMCL; mitochondrial function; paediatric obesity ID HOMEOSTASIS MODEL ASSESSMENT; RANDOMIZED CONTROLLED-TRIAL; FASTING PLASMA-GLUCOSE; PHYSICAL-ACTIVITY; BODY-COMPOSITION; OVERWEIGHT; SENSITIVITY; WEIGHT; RISK; FAT AB Background: Obesity is associated with poor fitness and adverse metabolic consequences in children. Objective: To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. Design and subjects: Randomized controlled trial, 21 obese (body mass index >= 95% percentile) subjects, ages 10 to 17 years. Methods: Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). Measurements: Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. Results: Subjects were 13.0 +/- 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). Conclusions: Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity. C1 [McCormack, S. E.; McCarthy, M. A.; Harrington, S. G.; Farilla, L.; Grinspoon, S. K.; Fleischman, A.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [McCormack, S. E.; McCarthy, M. A.; Harrington, S. G.; Farilla, L.; Grinspoon, S. K.; Fleischman, A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [McCormack, S. E.; McCarthy, M. A.; Harrington, S. G.; Farilla, L.; Thomas, B. J.; Torriani, M.; Grinspoon, S. K.; Fleischman, A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [McCormack, S. E.; Fleischman, A.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [McCormack, S. E.] Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA. [Hrovat, M. I.] Mirtech Inc, Brockton, MA USA. [Systrom, D. M.] Brigham & Womens Hosp, Div Pulm, Boston, MA 02115 USA. [Thomas, B. J.; Torriani, M.] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Radiol, Boston, MA 02114 USA. [McInnis, K.] Merrimack Coll, N Andover, MA 01845 USA. RP Fleischman, A (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON 207, Boston, MA 02114 USA. EM afleischman@partners.org FU National Institutes of Health grants [K23 DK 080658, F32 DK 093206]; Genentech Clinical Scholars Award from the Lawson Wilkins Endocrinology Society; Career Development Award from Children's Hospital Boston; Pediatric Endocrine Society Research Fellowship; Endocrine Fellows Foundation Development Research Grant; [1 UL1 RR025758-03]; [M01-RR-01066] FX This work was supported in part by National Institutes of Health grants [K23 DK 080658 (AF) and F32 DK 093206 (SM)]. In addition, the study was supported by a Genentech Clinical Scholars Award from the Lawson Wilkins Endocrinology Society (AF), a gift from the Henry T. Zarrow Foundation (AF), the Career Development Award from Children's Hospital Boston (AF), Pediatric Endocrine Society Research Fellowship (SEM) and Endocrine Fellows Foundation Development Research Grant (SEM). The project described was supported by Grants 1 UL1 RR025758-03 and M01-RR-01066 to the Harvard Clinical Translational Science Center. (The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.) NR 33 TC 10 Z9 10 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-6310 EI 2047-6302 J9 PEDIATR OBES JI Pediatr. Obes. PD AUG PY 2014 VL 9 IS 4 BP 281 EP 291 DI 10.1111/j.2047-6310.2013.00180.x PG 11 WC Pediatrics SC Pediatrics GA AN5ZX UT WOS:000340673800005 PM 23801526 ER PT J AU Hu, XM Liou, AKF Leak, RK Xu, MY An, CR Suenaga, J Shi, YJ Gao, YQ Zheng, P Chen, J AF Hu, Xiaoming Liou, Anthony K. F. Leak, Rehana K. Xu, Mingyue An, Chengrui Suenaga, Jun Shi, Yejie Gao, Yanqin Zheng, Ping Chen, Jun TI Neurobiology of microglial action in CNS injuries: Receptor-mediated signaling mechanisms and functional roles SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Microglia; Receptor; Central nervous system injuries ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; FC-GAMMA-RECEPTOR; FOCAL CEREBRAL-ISCHEMIA; CENTRAL-NERVOUS-SYSTEM; ADVANCED GLYCATION ENDPRODUCTS; TOLL-LIKE RECEPTORS; NF-KAPPA-B; AMYLOID-BETA-PEPTIDE; MAST-CELL ACTIVATION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AB Microglia are the first line of immune defense against central nervous system (CNS) injuries and disorders. These highly plastic cells play dualistic roles in neuronal injury and recovery and are known for their ability to assume diverse phenotypes. A broad range of surface receptors are expressed on microglia and mediate microglial 'On' or 'Off' responses to signals from other host cells as well as invading microorganisms. The integrated actions of these receptors result in tightly regulated biological functions, including cell mobility, phagocytosis, the induction of acquired immunity, and trophic factor/inflammatory mediator release. Over the last few years, significant advances have been made toward deciphering the signaling mechanisms related to these receptors and their specific cellular functions. In this review, we describe the current state of knowledge of the surface receptors involved in microglial activation, with an emphasis on their engagement of distinct functional programs and their roles in CNS injuries. It will become evident from this review that microglial homeostasis is carefully maintained by multiple counterbalanced strategies, including, but not limited to, 'On' and 'Off' receptor signaling. Specific regulation of theses microglial receptors may be a promising therapeutic strategy against CNS injuries. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Hu, Xiaoming; Liou, Anthony K. F.; Suenaga, Jun; Shi, Yejie; Chen, Jun] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15213 USA. [Hu, Xiaoming; Xu, Mingyue; An, Chengrui; Gao, Yanqin; Zheng, Ping; Chen, Jun] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200433, Peoples R China. [Hu, Xiaoming; Xu, Mingyue; An, Chengrui; Gao, Yanqin; Zheng, Ping; Chen, Jun] Fudan Univ, Inst Brain Sci, Shanghai 200433, Peoples R China. [Hu, Xiaoming; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA 15240 USA. [Leak, Rehana K.] Duquesne Univ, Div Pharmaceut Sci, Pittsburgh, PA 15282 USA. RP Hu, XM (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. EM hux2@upmc.edu; chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016; OI Gao, Yanqin/0000-0002-4915-9819; Leak, Rehana/0000-0003-2817-7417; Shi, Yejie/0000-0001-7502-9201 FU American Heart Association [13SDG14570025]; Ethyl Vincent pilot grant in multiple sclerosis from Department of Neurology, University of Pittsburgh; Commonwealth Universal Research Enhancement (C.U.R.E.) Award from the Department of Health; Michael J. Fox Foundation Innovation Award; Chinese Natural Science Foundation grants [81171149, 81371306]; National Institutes of Health Grants [NS45048, NS62157, NS59806, NS36736]; Chinese Natural Science Foundation [81228008]; VA Merit Review FX Dr. Xiaoming Hu is supported by the American Heart Association (13SDG14570025) and the Ethyl Vincent pilot grant in multiple sclerosis from Department of Neurology, University of Pittsburgh. Dr. Rehana K. Leak is supported by a Commonwealth Universal Research Enhancement (C.U.R.E.) Award from the Department of Health and a Michael J. Fox Foundation Innovation Award. Dr. Yanqin Gao is supported by the Chinese Natural Science Foundation grants (81171149 and 81371306). Dr. Jun Chen is supported by the National Institutes of Health Grants (NS45048, NS62157, NS59806, and NS36736), Chinese Natural Science Foundation grants (81228008) and a VA Merit Review. NR 353 TC 27 Z9 28 U1 3 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD AUG-SEP PY 2014 VL 119 BP 60 EP 84 DI 10.1016/j.pneurobio.2014.06.002 PG 25 WC Neurosciences SC Neurosciences & Neurology GA AO0GI UT WOS:000340986700004 PM 24923657 ER PT J AU Iverson, KM Huang, K Wells, SY Wright, JD Gerber, MR Wiltsey-Stirman, S AF Iverson, Katherine M. Huang, Kristin Wells, Stephanie Y. Wright, Jason D. Gerber, Megan R. Wiltsey-Stirman, Shannon TI Women Veterans' Preferences for Intimate Partner Violence Screening and Response Procedures Within the Veterans Health Administration SO RESEARCH IN NURSING & HEALTH LA English DT Article DE female veterans; Department of Veterans Affairs; domestic violence; screening; counseling; qualitative research ID POSTTRAUMATIC-STRESS-DISORDER; DOMESTIC VIOLENCE; MEDICAL-CARE; SYMPTOMS; VICTIMIZATION; INTERVENTIONS; EXPERIENCES; PROVIDERS; KNOWLEDGE; VICTIMS AB Intimate partner violence (IPV) is a significant health issue faced by women veterans, but little is known about their preferences for IPV-related care. Five focus groups were conducted with 24 women Veterans Health Administration (VHA) patients with and without a lifetime history of IPV to understand their attitudes and preferences regarding IPV screening and responses within VHA. Women veterans wanted disclosure options, follow-up support, transparency in documentation, and VHA and community resources. They supported routine screening for IPV and articulated preferences for procedural aspects of screening. Women suggested that these procedures could be provided most effectively when delivered with sensitivity and connectedness. Findings can inform the development of IPV screening and response programs within VHA and other healthcare settings. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. C1 [Iverson, Katherine M.; Wiltsey-Stirman, Shannon] Boston Univ, Sch Med, Natl Ctr Posttraumat Stress Disorder, VA Boston Healthcare Syst,Dept Psychiat, Boston, MA 02130 USA. [Huang, Kristin] Suffolk Univ, Dept Psychol, VA Boston Healthcare Syst, Boston, MA 02114 USA. [Wells, Stephanie Y.; Wright, Jason D.] VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Boston, MA USA. [Gerber, Megan R.] Boston Univ, Sch Med, Dept Med, VA Boston Healthcare Syst, Boston, MA 02130 USA. RP Iverson, KM (reprint author), Boston Univ, Sch Med, Natl Ctr Posttraumat Stress Disorder, VA Boston Healthcare Syst,Dept Psychiat, 150 South Huntington Ave,116B-3, Boston, MA 02130 USA. EM katherine.iverson@va.gov OI Gerber, Megan/0000-0002-8444-5554; Wiltsey Stirman, Shannon/0000-0001-9917-5078 NR 46 TC 6 Z9 6 U1 4 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-6891 EI 1098-240X J9 RES NURS HEALTH JI Res. Nurs. Health PD AUG PY 2014 VL 37 IS 4 BP 302 EP 311 DI 10.1002/nur.21602 PG 10 WC Nursing SC Nursing GA AN5XL UT WOS:000340665400006 PM 24990824 ER PT J AU Costa, DK Barg, FK Asch, DA Kahn, JM AF Costa, Deena Kelly Barg, Frances K. Asch, David A. Kahn, Jeremy M. TI Facilitators of an Interprofessional Approach to Care in Medical and Mixed Medical/Surgical ICUs: A Multicenter Qualitative Study SO RESEARCH IN NURSING & HEALTH LA English DT Article DE critical care; collaboration; communication; hospital/institutional environment; interprofessional care; health care delivery ID INTENSIVE-CARE; HEALTH-CARE; MECHANICAL VENTILATION; UNIT; COLLABORATION; MULTIDISCIPLINARY; MORTALITY; TEAMWORK; OUTCOMES; ASSOCIATION AB The purpose of this study was to describe clinicians' perceptions of interprofessional collaboration in the intensive care unit and identify factors associated with interprofessional collaboration. We performed 64 semi-structured interviews in seven hospitals with ICU nurses, physicians, respiratory therapists, nurse managers, clinical pharmacists, and dieticians. ICU clinicians perceived two distinct types of facilitators to interprofessional collaboration in critical care: cultural and structural. In the critical care setting, cultural and structural facilitators worked independently as well as in concert to create effective interprofessional collaboration. Initiatives aimed at creating and facilitating interprofessional collaboration should focus attention on cultural and structural facilitators to improve patient care and team effectiveness. (C) 2014 Wiley Periodicals, Inc. C1 [Costa, Deena Kelly] Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15221 USA. [Barg, Frances K.] Univ Penn, Dept Family Med & Community Hlth, Perelman Sch Med, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Perelman Sch Med, Ctr Hlth Equ Res & Promot, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Wharton Sch, Ctr Hlth Equ Res & Promot, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Asch, David A.] Univ Penn, Ctr Hlth Care Innovat, Ctr Hlth Equ Res & Promot, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Kahn, Jeremy M.] Univ Pittsburgh, Dept Crit Care Med, Grad Sch Publ Hlth, Pittsburgh, PA 15221 USA. RP Costa, DK (reprint author), Univ Pittsburgh, Dept Crit Care Med, Scaife Hall Room 607 3550 Terrace Sreet, Pittsburgh, PA 15221 USA. EM kellydm2@upmc.edu FU National Institutes of Health [K23HL082650, T32HL007820] FX This work was supported by a career development award (K23HL082650) and an institutional training grant (T32HL007820) from the National Institutes of Health. We would like to acknowledge Eve Weiss at the University of Pennsylvania for thoughtful input and feedback on the manuscript. NR 45 TC 5 Z9 5 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-6891 EI 1098-240X J9 RES NURS HEALTH JI Res. Nurs. Health PD AUG PY 2014 VL 37 IS 4 BP 326 EP 335 DI 10.1002/nur.21607 PG 10 WC Nursing SC Nursing GA AN5XL UT WOS:000340665400008 PM 24995554 ER PT J AU Mehta, NN Miyasaki, SH Hirsch, J Fidler, RL AF Mehta, Niyati N. Miyasaki, Shelley H. Hirsch, Jan Fidler, Richard L. TI Easy-to-Implement Oral Cavity Modification to Expand Simulation-based Training in Airway Management SO SIMULATION IN HEALTHCARE-JOURNAL OF THE SOCIETY FOR SIMULATION IN HEALTHCARE LA English DT Article DE Emergency airway management; Dental trauma ID DENTAL INJURIES; INTUBATION AB Introduction: Injuries to the oral cavity and teeth can occur during routine intubation and general anesthesia but often occur in emergency situations when the priority of securing the airway supersedes preanesthetic evaluation. This study demonstrates the feasibility of modifying the oral cavity to increase the dental fidelity during emergency airway management. Methods: A Laerdal Manikin was used to manipulate the preexisting Polyester (hard) and the Vinyl (flexible) dentition sets that are interchangeable among the Laerdal family of manikins. Items easily available in a dental laboratory such as dental acrylic and dental impression material were used to create modifications. Results: Laerdal dentition sets were altered to simulate common dental (tooth-related) trauma encountered during intubation such as a fracture, luxation, or avulsion injuries. Anatomic variations such as carious (decayed) teeth, loose teeth, and class II malocclusion (overbite) were also fabricated. Tooth luxation was engineered to occur with pressure by a laryngoscope, and bleeding teeth were also created to demonstrate excessive pressure applied during direct laryngoscopy. It is feasible to improve the realism of the Laerdal family of manikins with simple modifications. Conclusions: This project proves the concept of feasibly fabricating anatomic variations to increase the fidelity of existing simulation manikins. Other anatomic variations present challenges to airway management, and future research will aim at creating additional modifications. In addition, future research will seek to quantify the improvement in airway management skills by anesthesia and emergency medicine providers by training on manikins with variable oral cavity anatomy. C1 [Mehta, Niyati N.; Miyasaki, Shelley H.; Hirsch, Jan; Fidler, Richard L.] Univ Calif San Francisco, San Francisco VA Med Ctr, Dept Clin Simulat Program, San Francisco, CA 94143 USA. RP Mehta, NN (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM niyati.n.mehta@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-2332 EI 1559-713X J9 SIMUL HEALTHC JI Simul. Healthc. PD AUG PY 2014 VL 9 IS 4 BP 260 EP 263 DI 10.1097/SIH.0000000000000028 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AN7XG UT WOS:000340813700007 PM 24787560 ER PT J AU Allen, RP Picchietti, DL Garcia-Borreguero, D Ondo, WG Walters, AS Winkelman, JW Zucconi, M Ferri, R Trenkwalder, C Lee, HB AF Allen, Richard P. Picchietti, Daniel L. Garcia-Borreguero, Diego Ondo, William G. Walters, Arthur S. Winkelman, John W. Zucconi, Marco Ferri, Raffaele Trenkwalder, Claudia Lee, Hochang B. CA Int Restless Legs Syndrome Study TI Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance SO SLEEP MEDICINE LA English DT Article DE Neurologic disorder; Movement disorder; Sleep disorder; Diagnosis; Consensus; Restless legs syndrome; Willis-Ekbom disease ID QUALITY-OF-LIFE; PERIODIC LIMB MOVEMENTS; SLEEP BEHAVIOR DISORDER; PRIMARY-CARE POPULATION; IRON-DEFICIENCY ANEMIA; SYNDROME RLS; CIRCADIAN-RHYTHM; BRAIN IRON; SENSORY SYMPTOMS; TIME STRUCTURE AB Background: In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. Methods: The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. Results: Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. Conclusions: The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research. (C) 2014 The Authors. Published by Elsevier B.V. C1 [Allen, Richard P.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Picchietti, Daniel L.] Univ Illinois, Sch Med, Urbana, IL 61801 USA. [Picchietti, Daniel L.] Carle Fdn Hosp, Urbana, IL 61801 USA. [Garcia-Borreguero, Diego] Sleep Res Inst, Madrid, Spain. [Ondo, William G.] Univ Texas Med Sch Houston, Houston, TX USA. [Walters, Arthur S.] Vanderbilt Univ, Sch Med, Dept Neurol, Nashville, TN 37212 USA. [Winkelman, John W.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Winkelman, John W.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Zucconi, Marco] Univ Vita Salute San Raffaele, Inst Sci, Dept Neurosci, Sleep Disorders Ctr, Milan, Italy. [Zucconi, Marco] Univ Vita Salute San Raffaele, Univ Osped San Raffaele, Milan, Italy. [Ferri, Raffaele] Oasi Inst IRCCS, Dept Neurol IC, Sleep Res Ctr, Troina, Italy. [Trenkwalder, Claudia] Paracelsus Elena Hosp, Kassel, Germany. [Trenkwalder, Claudia] Univ Gottingen, Dept Clin Neurophysiol, D-37073 Gottingen, Germany. [Lee, Hochang B.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Picchietti, DL (reprint author), Univ Illinois, Sch Med, 602 W Univ Ave, Urbana, IL 61801 USA. EM dpicchie@illinois.edu OI Ferri, Raffaele/0000-0001-6937-3065 NR 181 TC 132 Z9 134 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 EI 1878-5506 J9 SLEEP MED JI Sleep Med. PD AUG PY 2014 VL 15 IS 8 BP 860 EP 873 DI 10.1016/j.sleep.2014.03.025 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA AO3HK UT WOS:000341220100006 PM 25023924 ER PT J AU Sheridan, RL AF Sheridan, Robert L. TI Preface Management of Burns SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Boston Shriners Hosp Children, Div Burns,Dept Surg,Med Sch,Boston Shriners Hosp, Boston, MA 02114 USA. RP Sheridan, RL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Boston Shriners Hosp Children, Div Burns,Dept Surg,Med Sch,Boston Shriners Hosp, 51 Blossom St, Boston, MA 02114 USA. EM rsheridan@mgh.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2014 VL 94 IS 4 BP XV EP XVI DI 10.1016/j.suc.2014.06.001 PG 2 WC Surgery SC Surgery GA AO2CN UT WOS:000341123200002 PM 25085099 ER PT J AU Fagan, SP Bilodeau, ML Goverman, J AF Fagan, Shawn P. Bilodeau, Mary-Liz Goverman, Jeremy TI Burn Intensive Care SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Burns; Intensive care; Postburn hypermetabolism; Colloid ID ACUTE-RENAL-FAILURE; ACUTE KIDNEY INJURY; RESPIRATORY-DISTRESS-SYNDROME; CRITICALLY-ILL PATIENTS; INTERNATIONAL CONSENSUS CONFERENCE; RANDOMIZED CONTROLLED-TRIAL; THERMAL-INJURY; ACUTE HYPERGLYCEMIA; GLUCOSE-METABOLISM; PEDIATRIC-PATIENTS AB As a result of continuous development in the treatment of burns, the LD50 (the burn size lethal to 50% of the population) for thermal injuries has risen from 42% total body surface area (TBSA) during the 1940s and 1950s to more than 90% TBSA for young thermally injured patients. This vast improvement in survival is due to simultaneous developments in critical care, advancements in resuscitation, control of infection through early excision, and pharmacologic support of the hypermetabolic response to burns. This article reviews these recent advances and how they influence modern intensive care of burns. C1 [Fagan, Shawn P.; Bilodeau, Mary-Liz; Goverman, Jeremy] Massachusetts Gen Hosp, Sumner Redstone Burn Ctr, Boston, MA 02114 USA. RP Goverman, J (reprint author), Massachusetts Gen Hosp, Sumner Redstone Burn Ctr, 55 Fruit St, Boston, MA 02114 USA. EM jgoverman@partners.org NR 104 TC 4 Z9 4 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2014 VL 94 IS 4 BP 765 EP + DI 10.1016/j.suc.2014.05.004 PG 17 WC Surgery SC Surgery GA AO2CN UT WOS:000341123200006 PM 25085087 ER PT J AU Tredget, EE Levi, B Donelan, MB AF Tredget, Edward E. Levi, Benjamin Donelan, Matthias B. TI Biology and Principles of Scar Management and Burn Reconstruction SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Burn reconstruction; Laser; Heterotopic ossification; Fibrocytes; Scar ID POSTBURN HYPERTROPHIC SCAR; RANDOMIZED CONTROLLED-TRIAL; PRESSURE GARMENT THERAPY; GROWTH-FACTOR-BETA; PULSED-DYE-LASER; DERMAL FIBROBLASTS CONTRIBUTE; PERIPHERAL-BLOOD FIBROCYTES; TISSUE-ENGINEERED SKIN; HETEROTOPIC OSSIFICATION; STERNOTOMY SCARS AB Hypertrophic scarring is extremely common and is the source of most morbidity related to burns. The biology of hypertrophic healing is complex and poorly understood. Multiple host and injury factors contribute, but protracted healing of partial thickness injury is a common theme. Hypertrophic scarring and heterotopic ossification may share some basic causes involving marrow-derived cells. Several traditional clinical interventions exist to modify hypertrophic scar. All have limited efficacy. Laser interventions for scar modification show promise, but as yet do not provide a definitive solution. Their efficacy is only seen when used as part of a multimodality scar management program. C1 [Tredget, Edward E.] Univ Edmonton, Edmonton, AB, Canada. [Levi, Benjamin; Donelan, Matthias B.] Shriners Hosp Children, Boston, MA USA. [Levi, Benjamin; Donelan, Matthias B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tredget, EE (reprint author), Univ Alberta, 2D2-28 WMC,8440-112 St, Edmonton, AB T6G 2B7, Canada. EM etredget@ualberta.ca FU Firefighters' Burn Trust Fund of the University of Alberta Hospital; Canadian Institutes of Health Research; Alberta Heritage Trust Fund for Medical Research; Plastic Surgery Foundation National Endowment Award; [1K08GM109105-01] FX This work was supported by the Firefighters' Burn Trust Fund of the University of Alberta Hospital, the Canadian Institutes of Health Research, and the Alberta Heritage Trust Fund for Medical Research. Dr Levi was funded by 1K08GM109105-01 and Plastic Surgery Foundation National Endowment Award. NR 90 TC 14 Z9 16 U1 2 U2 16 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2014 VL 94 IS 4 BP 793 EP + DI 10.1016/j.suc.2014.05.005 PG 24 WC Surgery SC Surgery GA AO2CN UT WOS:000341123200008 PM 25085089 ER PT J AU Anderson, TA Fuzaylov, G AF Anderson, T. Anthony Fuzaylov, Gennadiy TI Perioperative Anesthesia Management of the Burn Patient SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Burn patients; Anesthetic management; Phamacokinetics; Burn resuscitation ID PEDIATRIC-PATIENTS; INHALATION INJURY; DRESSING CHANGES; CHILDREN; PAIN; DEXMEDETOMIDINE; KETAMINE; CARE; RESUSCITATION; COMBINATIONS AB Burn patients provide numerous challenges to the anesthesiologist. It is important to understand the multiple physiologic disruptions that follow a burn injury as well as the alterations in pharmacokinetics and pharmacodynamics of commonly used anesthetics. Thought must be given to surgery during initial fluid resuscitation and the airway challenges many of these patients present. Finally, the central role of pain management through all phases of care is a constant concern. C1 [Anderson, T. Anthony; Fuzaylov, Gennadiy] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Anderson, TA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444, Boston, MA 02114 USA. EM tanderson9@partners.org NR 34 TC 0 Z9 0 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2014 VL 94 IS 4 BP 851 EP + DI 10.1016/j.suc.2014.05.008 PG 12 WC Surgery SC Surgery GA AO2CN UT WOS:000341123200011 PM 25085092 ER PT J AU Stoddard, FJ Ryan, CM Schneider, JC AF Stoddard, Frederick J., Jr. Ryan, Colleen M. Schneider, Jeffrey C. TI Physical and Psychiatric Recovery from Burns SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Rehabilitation; Resilience; Recovery; Body image; Posttraumatic stress disorder; Depression; Hypertrophic scar; Burn reconstruction ID SPINAL-CORD-INJURY; HETEROTOPIC BONE-FORMATION; ELECTRICAL BURNS; HEALED BURNS; DOUBLE-BLIND; HIP-REPLACEMENT; GROWTH-HORMONE; FOLLOW-UP; CHILDREN; OSSIFICATION AB Burn injuries pose complex biopsychosocial challenges to recovery and improved comprehensive care. The physical and emotional sequelae of burns differ, depending on burn severity, individual resilience, and stage of development when they occur. Most burn survivors are resilient and recover, whereas some are more vulnerable and have complicated outcomes. Physical rehabilitation is affected by orthopedic, neurologic, and metabolic complications and disabilities. Psychiatric recovery is affected by pain, mental disorders, substance abuse, and burn stigmatization. Individual resilience, social supports, and educational or occupational achievements affect outcomes. C1 [Stoddard, Frederick J., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Ryan, Colleen M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Schneider, Jeffrey C.] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Trauma Burn & Orthoped Program, Boston, MA 02114 USA. RP Schneider, JC (reprint author), Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Trauma Burn & Orthoped Program, Boston, MA 02114 USA. EM jcschneider@partners.org NR 103 TC 7 Z9 7 U1 1 U2 18 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 EI 1558-3171 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2014 VL 94 IS 4 BP 863 EP + DI 10.1016/j.suc.2014.05.007 PG 17 WC Surgery SC Surgery GA AO2CN UT WOS:000341123200012 PM 25085093 ER PT J AU De Waele, JJ Rello, J Anzueto, A Moreno, R Lipman, J Sakr, Y Pickkers, P Leone, M Ferguson, A Oud, L Vincent, JL AF De Waele, Jan J. Rello, Jordi Anzueto, Antonio Moreno, Rui Lipman, Jeffrey Sakr, Yasser Pickkers, Peter Leone, Marc Ferguson, Andrew Oud, Lavi Vincent, Jean-Louis CA EPIC II Investigators TI Infections and Use of Antibiotics in Patients Admitted for Severe Acute Pancreatitis: Data from the EPIC II Study SO SURGICAL INFECTIONS LA English DT Article ID ACUTE NECROTIZING PANCREATITIS; DOUBLE-BLIND; FUNGAL-INFECTION; PREVALENCE; MANAGEMENT; TRIAL AB Background: Infectious complications are frequent in severe acute pancreatitis (SAP) but multinational epidemiologic data are lacking. The aim of the study was to analyze the characteristics of the infectious complications and antimicrobial use in this setting. Methods: One-day point prevalence study of infection in critically ill patients (Extended Prevalence of Infection in the ICU-II study), performed in 1,265 ICUs in 75 countries. Results: Of the 13,796 patients in the study, 159 were admitted with SAP. One-hundred sixteen (73%) had infections: 31% intra-abdominal, 16% extra-abdominal, and 26% both. Gram-negative bacteria were more prevalent than gram-positive organisms, anaerobes, or fungi. Therapeutically, penicillins and other beta-lactams were used most frequently. Prophylactic antibiotics were administered to 24% of the patients with SAP. Conclusions: Infections are frequent in patients admitted with SAP; most are intra-abdominal infections. Microbiology is diverse with gram-negative micro-organisms most frequently isolated. Most patients admitted to the ICU for SAP receive antibiotics at some point. C1 [De Waele, Jan J.] Ghent Med Sch & Univ Hosp, Dept Crit Care Med, Ghent, Belgium. [Rello, Jordi] Univ Autonoma Barcelona, Hosp Vall dHebron, Crit Care Dept, CIBERES, E-08193 Barcelona, Spain. [Anzueto, Antonio] Univ Texas Hlth Sci, Dept Pulm Crit Care, San Antonio, TX USA. [Anzueto, Antonio] Univ Texas Hlth Sci, Dept Internal Med, San Antonio, TX USA. [Anzueto, Antonio] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Moreno, Rui] Hosp Sao Jose, Ctr Hosp Lisboa Cent, UCINC, Lisbon, Portugal. [Lipman, Jeffrey] Univ Queensland, Sch Med, Discipline Anesthesiol & Crit Care, Herston, Qld, Australia. [Lipman, Jeffrey] Royal Brisbane & Womens Hosp, Dept Intens Care Med, Herston, Qld, Australia. [Sakr, Yasser] Univ Jena, Dept Anesthesiol & Intens Care, Jena, Germany. [Pickkers, Peter] Radboud Univ Nijmegen, Med Ctr, Dept Intens Care, NL-6525 ED Nijmegen, Netherlands. [Leone, Marc] Aix Marseille Univ, Hop Nord, AP HM,Dept Intens Care & Anesthesiol, Unite Rech Malad Infect & Transmissibles URMITE, Marseilles, France. [Ferguson, Andrew] Craigavon Area Hosp, Dept Intens Care Med, Portadown, North Ireland. [Oud, Lavi] Texas Tech Univ HSC, Div Pulm & Crit Care Med, Odessa, TX USA. [Vincent, Jean-Louis] Univ Libre Brussels, Erasme Hosp, Dept Intens Care, Brussels, Belgium. RP De Waele, JJ (reprint author), Ghent Univ Hosp, Dept Crit Care Med, De Pintelaan 185, B-9000 Ghent, Belgium. EM jan.dewaele@UGent.be RI Pickkers, R.P./H-8080-2014; Sakr, Yasser/D-9802-2013; Leone, Marc/P-4835-2016; OI Leone, Marc/0000-0002-3097-758X; Rello, Jordi/0000-0003-0676-6210 NR 21 TC 4 Z9 4 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-2964 EI 1557-8674 J9 SURG INFECT JI Surg. Infect. PD AUG PY 2014 VL 15 IS 4 BP 394 EP 398 DI 10.1089/sur.2012.228 PG 5 WC Infectious Diseases; Surgery SC Infectious Diseases; Surgery GA AO0PY UT WOS:000341014100007 PM 24819027 ER PT J AU Non, AL Rewak, M Kawachi, I Gilman, SE Loucks, EB Appleton, AA Roman, JC Buka, SL Kubzansky, LD AF Non, Amy L. Rewak, Marissa Kawachi, Ichiro Gilman, Stephen E. Loucks, Eric B. Appleton, Allison A. Roman, Jorge C. Buka, Stephen L. Kubzansky, Laura D. TI Childhood Social Disadvantage, Cardiometabolic Risk, and Chronic Disease in Adulthood SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE biological markers; cardiometabolic risk; cohort studies; psychosocial factors; social disadvantage; social environment; socioeconomic status ID C-REACTIVE PROTEIN; CUMULATIVE BIOLOGICAL RISK; CORONARY-HEART-DISEASE; LIFE-COURSE; SOCIOECONOMIC CIRCUMSTANCES; CARDIOVASCULAR-DISEASE; ALLOSTATIC LOAD; BIRTH COHORT; HEALTH; ADVERSITY AB Adverse social environments in early life are hypothesized to become biologically embedded during the first few years of life, with potentially far-reaching implications for health across the life course. Using prospective data from a subset of a US birth cohort, the Collaborative Perinatal Project, started in 1959-1966 (n = 566), we examined associations of social disadvantage assessed in childhood with cardiometabolic function and chronic disease status more than 40 years later (in 2005-2007). Social disadvantage was measured with an index that combined information on adverse socioeconomic and family stability factors experienced between birth and age 7 years. Cardiometabolic risk (CMR) was assessed by combining information from 8 CMR biomarkers; an index of chronic disease status was derived by assessing 8 chronic diseases. Poisson models were used to investigate associations between social disadvantage and CMR or chronic disease scores while adjusting for childhood covariates and potential pathway variables. A high level of social disadvantage was significantly associated with both higher CMR (incident rate ratio = 1.69, 95% confidence interval: 1.19, 2.39) and with a higher number of chronic diseases (incident rate ratio = 1.39, 95% confidence interval: 1.00, 1.92) in minimally adjusted models. Associations with CMR persisted even after accounting for childhood and adult covariates. C1 [Non, Amy L.] Vanderbilt Univ, Dept Anthropol, Nashville, TN 37235 USA. [Rewak, Marissa; Kawachi, Ichiro; Gilman, Stephen E.; Kubzansky, Laura D.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, 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.; Buka, Stephen L.] Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA. [Appleton, Allison A.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol & Biostat, Rensselaer, NY USA. [Roman, Jorge C.] Vanderbilt Univ, Dept Math, Nashville, TN 37235 USA. RP Non, AL (reprint author), Vanderbilt Univ, VU Stn B 356050, 2301 Vanderbilt Pl, Nashville, TN 37235 USA. EM amy.non@vanderbilt.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU National Institutes of Health Transdisciplinary Tobacco Use Research Center of the National Cancer Institute [P50 CA98029, CA084719]; National Institute on Drug Abuse; National Institute of Aging [AG023397]; Robert Wood Johnson Health and Society Scholars Program FX This work was supported by the National Institutes of Health Transdisciplinary Tobacco Use Research Center (awards P50 CA98029 and CA084719) of the National Cancer Institute; the National Institute on Drug Abuse; the National Institute of Aging (grant AG023397); and the Robert Wood Johnson Health and Society Scholars Program (to A.L.N.). NR 44 TC 15 Z9 15 U1 3 U2 22 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2014 VL 180 IS 3 BP 263 EP 271 DI 10.1093/aje/kwu127 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AN2RK UT WOS:000340432800006 PM 24970845 ER PT J AU Subak, LL Goode, PS Brubaker, L Kusek, JW Schembri, M Lukacz, ES Kraus, SR Chai, TC Norton, P Tennstedt, SL AF Subak, Leslee L. Goode, Patricia S. Brubaker, Linda Kusek, John W. Schembri, Michael Lukacz, Emily S. Kraus, Stephen R. Chai, Toby C. Norton, Peggy Tennstedt, Sharon L. CA Urinary Incontinence Treatment Net TI Urinary incontinence management costs are reduced following Burch or sling surgery for stress incontinence SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE costs; cost analysis; urinary incontinence; urinary incontinence costs ID QUALITY-OF-LIFE; WOMEN; TRIAL AB OBJECTIVE: The objective of the study was to estimate the effect of Burch and fascial sling surgery on out-of-pocket urinary incontinence (UI) management costs at 24 months postoperatively and identify predictors of change in cost among women enrolled in a randomized trial comparing these procedures. STUDY DESIGN: Resources used for UI management (supplies, laundry, dry cleaning) were self-reported by 491 women at baseline and 24 months after surgery, and total out-of-pocket costs for UI management (in 2012 US dollars) were estimated. Data from the 2 surgical groups were combined to examine the change in cost for UI management over 24 months. Univariate and bivariate changes in cost were analyzed using the Wilcoxon signed rank test. Predictors of change in cost were examined using multivariate mixed models. RESULTS: At baseline mean (+/- SD) age of participants was 53 +/- 10 years, and the frequency of weekly UI episodes was 23 +/- 21. Weekly UI episodes decreased by 86% at 24 months (P < .001). The mean weekly cost was $16.60 +/- $27.00 (median $9.39) at baseline and $4.57 +/- $15.00 (median $0.10) at 24 months (P < .001), a decrease of 72%. In multivariate analyses, cost decreased by $3.38 +/- $0.77 per week for each decrease of 1 UI episode per day (P < .001) and was strongly associated with greater improvement in Urogenital Distress Inventory and Incontinence Impact Questionnaire scores (P < .001) and decreased 24-hour pad weight (P < .02). CONCLUSION: Following Burch or fascial sling surgery, the UI management cost at 24 months decreased by 72% ($625 per woman per year) and was strongly associated with decreasing UI frequency. Reduced out-of-pocket expenses may be a benefit of these established urinary incontinence procedures. C1 [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94115 USA. [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94115 USA. [Subak, Leslee L.; Schembri, Michael] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94115 USA. [Subak, Leslee L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Lukacz, Emily S.] Univ Calif San Diego, Sch Med, Dept Reprod Med, San Diego, CA 92103 USA. [Goode, Patricia S.] Birmingham Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. [Goode, Patricia S.] Univ Alabama Birmingham, Birmingham, AL USA. [Brubaker, Linda] Loyola Univ, Chicago Sch Med, Dept Obstet & Gynecol, Chicago, IL 60611 USA. [Brubaker, Linda] Loyola Univ, Chicago Sch Med, Dept Urol, Chicago, IL 60611 USA. [Kusek, John W.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Chai, Toby C.] Univ Maryland, Sch Med, Dept Urol, Baltimore, MD 21201 USA. [Kraus, Stephen R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Norton, Peggy] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Tennstedt, Sharon L.] New England Res Inst, Watertown, MA 02172 USA. RP Subak, LL (reprint author), Univ Calif San Francisco, Mt Zion Womens Hlth Clin Res Ctr, 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM subakl@obgyn.ucsf.edu OI Wadie, Bassem/0000-0002-6977-6849 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, U01 DK60401]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research in Women's Health, National Institutes of Health FX This study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (U01 DK58225, U01 DK58229, U01 DK58234, U01 DK58231, U01 DK60379, U01 DK60380, U01 DK60393, U01 DK60395, U01 DK60397, and U01 DK60401) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Office of Research in Women's Health, National Institutes of Health. NR 21 TC 3 Z9 3 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 EI 1097-6868 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2014 VL 211 IS 2 AR 171.e1 DI 10.1016/j.ajog.2014.03.012 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN0FM UT WOS:000340259300025 PM 24631433 ER PT J AU Buie, JNJ Oates, JC AF Buie, Joy N. Jones Oates, Jim C. TI Role of Interferon Alpha in Endothelial Dysfunction: Insights Into Endothelial Nitric Oxide Synthase-Related Mechanisms SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Review DE Autoimmune disease; SLE: Systemic Lupus Erythematosus; Endothelial dysfunction; Type I interferons; Endothelial nitric oxide synthase; Lupus ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CHRONIC HEPATITIS-C; ENOS-KNOCKOUT MICE; DEPENDENT PROTEIN-KINASE; NF-KAPPA-B; PROGENITOR CELLS; GROWTH-FACTOR; INSULIN-RESISTANCE; PROMOTER ACTIVITY; AP-1 ACTIVITY AB Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the production of autoantibodies against nuclear antigens such as double-stranded DNA. Lupus predominantly affects women (ratio, 9:1). Moreover, premenopausal women with SLE are 50 times more likely to have a myocardial infarction. Although specific risk factors for advanced cardiovascular complications have not been identified in this patient population, endothelial dysfunction is highly prevalent. Recent studies show that the type I interferon signature gene expression coincides with impaired brachial artery flow-mediated dilation and diminished endothelial progenitor cell circulation, both markers of impaired endothelial function. Although many factors promote the development of vascular endothelial dysfunction, all pathways converge on the diminished activity of endothelial nitric oxide synthase (eNOS) and loss of nitric oxide (NO) bioavailability. Studies examining the effects of type I interferons on eNOS and NO in SLE are missing. This literature review examines the current literature regarding the role of type I interferons in cardiovascular disease and its known effects on regulators of eNOS and NO bioavailability that are important for proper endothelial cell function. C1 [Buie, Joy N. Jones; Oates, Jim C.] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Buie, Joy N. Jones; Oates, Jim C.] Med Univ S Carolina, Ralph H Johnson VAMC, Med Res Serv, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Buie, JNJ (reprint author), Med Univ S Carolina, Div Rheumatol & Immunol, Dept Microbiol & Immunol, 96 Jonathan Lucas St,Clin Sci Bldg Suite 816, Charleston, SC 29425 USA. EM jonejn@musc.edu FU Ralph H. Johnson VA Medical Center [5I01CX00021804]; National Institute of Arthritis and Musculoskeletal and Skin Diseases Veterans Affairs Research Enhancement Awards Program [5RO1AR04547613]; Initiative for Maximizing Student Diversity (IMSD); National Institute of General Medical Sciences National Arthritis Foundation [5R25GM07264308] FX Supported by Ralph H. Johnson VA Medical Center (5I01CX00021804), National Institute of Arthritis and Musculoskeletal and Skin Diseases Veterans Affairs Research Enhancement Awards Program (5RO1AR04547613), Initiative for Maximizing Student Diversity (IMSD), National Institute of General Medical Sciences National Arthritis Foundation (5R25GM07264308). NR 90 TC 5 Z9 5 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 EI 1538-2990 J9 AM J MED SCI JI Am. J. Med. Sci. PD AUG PY 2014 VL 348 IS 2 BP 168 EP 175 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA AN4LK UT WOS:000340559100015 ER PT J AU Chen, XL Redline, S Shields, AE Williams, DR Williams, MA AF Chen, Xiaoli Redline, Susan Shields, Alexandra E. Williams, David R. Williams, Michelle A. TI Associations of allostatic load with sleep apnea, insomnia, short sleep duration, and other sleep disturbances: findings from the National Health and Nutrition Examination Survey 2005 to 2008 SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Adult; Allostatic load; Insomnia; National survey; Short sleep duration; Sleep apnea; Sleep disorder; Sleep disturbance ID BIOLOGICAL RISK PROFILES; MEXICAN-AMERICAN WOMEN; US ADULTS; UNITED-STATES; NHANES-III; OBESITY; DISPARITIES; SAMPLE; ACCULTURATION; PREVALENCE AB Purpose: To examine whether allostatic load (AL), a measure of cumulative physiologic dysregulation across biological systems, was associated with sleep apnea, insomnia, and other sleep disturbances. Methods: Data from the National Health and Nutrition Examination Survey 2005-2008 were used. AL was measured using nine biomarkers representing cardiovascular, inflammatory, and metabolic system functioning. A total of 3330 US adults aged 18 years and older were included in this study. Results: The prevalence of high AL (AL score >= 3) was the highest among African Americans (26.3%), followed by Hispanic Americans (20.3%), whites (17.7%), and other racial/ethnic group (13.8%). After adjustment for sociodemographic and lifestyle factors, high AL was significantly associated with sleep apnea (odds ratio [OR], 1.92; 95% confidence interval [Cl], 1.40-2.63), snoring (OR, 2.20; 95% Cl, 1.79-2.69), snorting/stop breathing (OR, 2.16; 95% Cl, 1.46-3.21), prolonged sleep latency (OR, 1.42; 95% Cl, 1.08-1.88), short sleep duration (<6 hours) (OR, 1.35; 95% Cl, 1.00-1.82), and diagnosed sleep disorder (OR, 2.26; 95% Cl, 1.66-3.08). There was no clear evidence that observed associations varied by sociodemographic characteristics. Conclusions: This study suggests significant associations of high AL with sleep apnea, sleep apnea symptoms, insomnia component, short sleep duration, and diagnosed sleep disorder among US adults. (C) 2014 Elsevier Inc. All rights reserved. C1 [Chen, Xiaoli; Williams, Michelle A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Redline, Susan] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Redline, Susan] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Shields, Alexandra E.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Shields, Alexandra E.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Williams, David R.] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02115 USA. RP Chen, XL (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave,Kresge 500, Boston, MA 02115 USA. EM xchen@hsph.harvard.edu FU National Institutes of Health (NIH); National Institute on Minority Health and Health Disparities (NIMHD) [T37-MD001449]; NIH/National Center for Research Resources/National Center for Advancing Translational Sciences [8UL1TR000170] FX This study was supported by National Institutes of Health (NIH) and National Institute on Minority Health and Health Disparities (NIMHD) grants (T37-MD001449) and NIH/National Center for Research Resources/National Center for Advancing Translational Sciences (8UL1TR000170). The authors thank Dr. Bizu Gelaye for his technical assistance. NR 43 TC 10 Z9 10 U1 4 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 EI 1873-2585 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2014 VL 24 IS 8 BP 612 EP 619 DI 10.1016/j.annepidem.2014.05.014 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM9PZ UT WOS:000340214800009 PM 24985316 ER PT J AU Choueiri, TK Pal, SK McDermott, DF Morrissey, S Ferguson, KC Holland, J Kaelin, WG Dutcher, JP AF Choueiri, T. K. Pal, S. K. McDermott, D. F. Morrissey, S. Ferguson, K. C. Holland, J. Kaelin, W. G. Dutcher, J. P. TI A phase I study of cabozantinib (XL184) in patients with renal cell cancer SO ANNALS OF ONCOLOGY LA English DT Article DE clinical trial; c-Met; VEGFR-2; receptor tyrosine kinase; renal cancer ID RESISTANT PROSTATE-CANCER; MEDULLARY-THYROID CANCER; C-MET; CARCINOMA; METASTASIS; SORAFENIB; SUNITINIB; TRIAL; GROWTH; TUMORS AB Background: Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). Patients and methods: This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. Results: The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. Conclusion: Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. C1 [Choueiri, T. K.; McDermott, D. F.; Morrissey, S.; Kaelin, W. G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Choueiri, T. K.; McDermott, D. F.; Morrissey, S.; Kaelin, W. G.] Harvard Univ, Sch Med, Kidney Canc Program, Boston, MA 02215 USA. [Pal, S. K.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [McDermott, D. F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Ferguson, K. C.; Holland, J.] Exelixis Inc, Clin Dev, San Francisco, CA USA. [Dutcher, J. P.] Columbia Univ, St Lukes Roosevelt Hosp Ctr, New York, NY USA. RP Choueiri, TK (reprint author), Brigham & Womens Hosp, Kidney Canc Ctr, Dana Farber Canc Inst, 450 Brookline Ave,Mailstop Dana 1230, Boston, MA 02215 USA. EM Toni_Choueiri@dfci.harvard.edu FU Exelixis, Inc.; Trust family fund for Kidney Cancer Research; Loker Pinard fund for Kidney Cancer Research; Michael Brigham fund for Kidney Cancer Research; DF/HCC SPORE in Kidney Cancer FX This clinical trial was supported by Exelixis, Inc. Additional funding was provided by the Trust family, Loker Pinard, and Michael Brigham funds for Kidney Cancer Research (TKC) and the DF/HCC SPORE in Kidney Cancer (TKC, DFM). NR 30 TC 42 Z9 44 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2014 VL 25 IS 8 BP 1603 EP 1608 DI 10.1093/annonc/mdu184 PG 7 WC Oncology SC Oncology GA AM8DU UT WOS:000340101600024 PM 24827131 ER PT J AU Balmana, J Tung, NM Isakoff, SJ Grana, B Ryan, PD Saura, C Lowe, ES Frewer, P Winer, E Baselga, J Garber, JE AF Balmana, J. Tung, N. M. Isakoff, S. J. Grana, B. Ryan, P. D. Saura, C. Lowe, E. S. Frewer, P. Winer, E. Baselga, J. Garber, J. E. TI Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors SO ANNALS OF ONCOLOGY LA English DT Article DE olaparib; cisplatin; BRCA1; BRCA2; breast cancer ID POLY(ADP-RIBOSE) POLYMERASE; OPEN-LABEL; CANCER; INHIBITORS; AZD2281; THERAPY; GEMCITABINE; REPAIR; CELLS AB Background: To establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors. Patients and methods: Patients aged >= 18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50-200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1-5 or 1-10) in combination with cisplatin (60-75 mg/m(2) intravenously) on day 1 of each cycle. Results: Dose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m(2) with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m(2) with olaparib 100 mg bid days 1-10 or 50 mg bid days 1-5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m(2), respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade >= 3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively. Conclusions: Olaparib in combination with cisplatin 75 mg/m(2) was not considered tolerable; intermittent olaparib (50 mg bid, days 1-5) with cisplatin 60 mg/m(2) improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation. C1 [Balmana, J.; Grana, B.; Saura, C.] Univ Hosp Vall dHebron, VHIO, Barcelona, Spain. [Balmana, J.; Grana, B.; Saura, C.] VHIO, Barcelona, Spain. [Tung, N. M.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Isakoff, S. J.; Ryan, P. D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lowe, E. S.] AstraZeneca, Wilmington, NC USA. [Frewer, P.] AstraZeneca, Macclesfield, Cheshire, England. [Winer, E.; Garber, J. E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Baselga, J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Balmana, J (reprint author), Univ Hosp Vall dHebron, VHIO, Paseo Vall dHebron 119-129, Barcelona, Spain. EM jbalmana@vhio.net RI Grana, Begona/M-2542-2014; OI Saura, Cristina/0000-0001-8296-5065 FU AstraZeneca [D0810C00021] FX This study was sponsored by AstraZeneca (D0810C00021). NR 24 TC 26 Z9 28 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 EI 1569-8041 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2014 VL 25 IS 8 BP 1656 EP 1663 DI 10.1093/annonc/mdu187 PG 9 WC Oncology SC Oncology GA AM8DU UT WOS:000340101600032 PM 24827126 ER PT J AU Allen, KD Golightly, YM Callahan, LF Helmick, CG Ibrahim, SA Kwoh, CK Renner, JB Jordan, JM AF Allen, Kelli D. Golightly, Yvonne M. Callahan, Leigh F. Helmick, Charles G. Ibrahim, Said A. Kwoh, C. Kent Renner, Jordan B. Jordan, Joanne M. TI Race and Sex Differences in Willingness to Undergo Total Joint Replacement: The Johnston County Osteoarthritis Project SO ARTHRITIS CARE & RESEARCH LA English DT Article ID TOTAL KNEE REPLACEMENT; TOTAL HIP-ARTHROPLASTY; PATIENT EXPECTATIONS; AFRICAN-AMERICANS; SOCIAL SUPPORT; UNITED-STATES; SURGERY; OUTCOMES; DISPARITIES; PREFERENCES AB Objective. Using data from the community-based Johnston County Osteoarthritis Project, we examined race and sex variations in willingness to undergo, and perceptions regarding, total joint replacement (TJR). Methods. Analyses were conducted for the total sample who participated in a followup measurement period from 2006-2010 (n = 1,522) and a subsample with symptomatic hip and/or knee osteoarthritis (sOA; n = 445). Participants indicated how willing they would be to have TJR (hip or knee) if their doctor recommended it; responses were categorized as "definitely" or "probably" willing versus "unsure," "probably not," or "definitely not" willing, or "don't know." Participants answered 7 questions regarding perceptions of TJR outcomes. Multivariable logistic regression models of willingness included participant characteristics (including socioeconomic status) and TJR perception variables that were associated with willingness at the P < 0.1 level in bivariate analyses. Results. African Americans had lower odds of willingness to undergo TJR than whites in the total sample (adjusted odds ratio [OR] 0.47 [95% confidence interval (95% CI) 0.31-0.72]) and the sOA subsample (adjusted OR 0.42 [95% CI 0.25-0.69]). There were no sex differences in willingness. African Americans expected poorer TJR outcomes than whites, but sex differences were minimal; perceptions of TJR outcomes were not significantly associated with willingness. Conclusion. In this community sample, race differences in TJR willingness and perceptions were substantial, but sex differences were small. Perceptions of TJR did not appear to affect willingness or explain race differences in willingness. C1 [Allen, Kelli D.] Durham VA Med Ctr, Durham, NC 27705 USA. [Allen, Kelli D.] Duke Univ, Med Ctr, Durham, NC USA. [Golightly, Yvonne M.; Callahan, Leigh F.; Renner, Jordan B.; Jordan, Joanne M.] Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC USA. [Helmick, Charles G.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Ibrahim, Said A.] Vet Affairs Med Ctr, Philadelphia, PA USA. [Ibrahim, Said A.] Perelman Univ Penn, Sch Med, Philadelphia, PA USA. [Kwoh, C. Kent] Univ Arizona, Tucson, AZ USA. RP Allen, KD (reprint author), Durham VA Med Ctr, Hlth Serv Res & Dev Serv 152, 508 Fulton St, Durham, NC 27705 USA. EM kelli.allen@duke.edu FU CDC/Association of Schools of Public Health [S1734, S3486]; National Institute of Arthritis and Musculoskeletal and Skin Diseases Multipurpose Arthritis and Musculoskeletal Disease Center [5-P60-AR30701]; National Institute of Arthritis and Musculoskeletal and Skin Diseases Multidisciplinary Clinical Research Center [5-P60-AR49465-03]; Arthritis Foundation Postdoctoral Fellowship Award; K24 Award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases [1-K24-AR-055259-01]; Sci Metrika, LLC.; Pfizer FX Supported in part by the CDC/Association of Schools of Public Health (cooperative agreements S1734 and S3486), the National Institute of Arthritis and Musculoskeletal and Skin Diseases Multipurpose Arthritis and Musculoskeletal Disease Center (grant 5-P60-AR30701), the National Institute of Arthritis and Musculoskeletal and Skin Diseases Multidisciplinary Clinical Research Center (grant 5-P60-AR49465-03), and an Arthritis Foundation Postdoctoral Fellowship Award to Dr. Golightly. Dr. Ibrahim's work was supported by a K24 Award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant 1-K24-AR-055259-01).; Dr. Callahan has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Sci Metrika, LLC. Dr. Kwoh has received consultancy fees, speaking fees, and/or honoraria (less than $10,000) from Pfizer. NR 39 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD AUG PY 2014 VL 66 IS 8 BP 1193 EP 1202 DI 10.1002/acr.22295 PG 10 WC Rheumatology SC Rheumatology GA AN1PR UT WOS:000340356600008 PM 24470235 ER PT J AU Sponholtz, TR Zhang, XC Fontes, JDT Meigs, JB Cupples, LA Kiel, DP Hannan, MT McLean, RR AF Sponholtz, Todd R. Zhang, Xiaochun Fontes, Joao D. T. Meigs, James B. Cupples, L. Adrienne Kiel, Douglas P. Hannan, Marian T. McLean, Robert R. TI Association Between Inflammatory Biomarkers and Bone Mineral Density in a Community-Based Cohort of Men and Women SO ARTHRITIS CARE & RESEARCH LA English DT Article ID C-REACTIVE PROTEIN; HORMONE-REPLACEMENT THERAPY; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; SERUM INTERLEUKIN-6; FRACTURE RISK; OSTEOPOROTIC FRACTURES; SOLUBLE INTERLEUKIN-6; RHEUMATOID-ARTHRITIS; HEALTHY-INDIVIDUALS AB Objective. Based upon evidence in animal and in vitro studies, we tested the hypothesis that higher serum concentrations of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) and the inflammatory marker C-reactive protein (CRP) would be inversely associated with bone mineral density (BMD) in a community-based cohort of men and women, with the strongest associations among postmenopausal women not receiving menopause hormonal therapy (MHT). Methods. We ascertained fasting serum concentrations of IL-6, TNF alpha, and CRP and measured BMD at the femoral neck, trochanter, total femur, and spine (L2-L4) using dual x-ray absorptiometry in 2,915 members of the Framingham Offspring Study (1996-2001). We used multivariable linear regression to estimate the difference (beta) in BMD at each bone site associated with a 1-unit increase in log-transformed serum concentrations of IL-6, TNF alpha, and CRP separately for men (n = 1,293), premenopausal women (n = 231), postmenopausal women receiving MHT (n = 498), and postmenopausal women not receiving MHT (n = 893). Results. Inflammatory biomarkers were not associated with BMD in men. Among premenopausal women, there were statistically significant, modest inverse associations between IL-6 and trochanter BMD (beta = 0.030, P < 0.01) and between CRP and femoral neck (beta = 0.015, P = 0.05) and trochanter BMD (beta = -0.014, P = 0.04). TNF alpha was positively associated with spine BMD (beta = 0.043, P = 0.01). In postmenopausal women receiving MHT, CRP was positively associated with femoral neck BMD (beta = 0.011, P = 0.04). There were no associations among postmenopausal women not receiving MHT. Conclusion. The lack of consistency in our results suggests that elevated circulating concentrations of inflammatory biomarkers may not be a risk factor for low BMD. C1 [Sponholtz, Todd R.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Zhang, Xiaochun] Hebrew SeniorLife, Boston, MA 02131 USA. [Fontes, Joao D. T.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Fontes, Joao D. T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Kiel, Douglas P.; Hannan, Marian T.; McLean, Robert R.] Harvard Univ, Sch Med, Hebrew SeniorLife, Boston, MA USA. [Kiel, Douglas P.; Hannan, Marian T.; McLean, Robert R.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP McLean, RR (reprint author), Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM rmclean@hsl.harvard.edu OI Hannan, Marian/0000-0002-9586-6928; Kiel, Douglas/0000-0001-8474-0310 FU Rheumatology Research Foundation of the American College of Rheumatology; Beth Israel Deaconess Medical Center/Harvard NIH T32 Translational Research in Aging Training Program; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Aging [R01-AR/AG-041398, R01-AG-028321]; National Heart, Lung, and Blood Institute [R01-HL-064753, R01-HL-076784]; National Institute of Diabetes and Digestive and Kidney Diseases [K24-DK-080140]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Merck; Amgen; Lilly; Novartis FX Supported by a Health Professional New Investigator Award from the Rheumatology Research Foundation of the American College of Rheumatology, the Beth Israel Deaconess Medical Center/Harvard NIH T32 Translational Research in Aging Training Program, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging (grants R01-AR/AG-041398 and R01-AG-028321), the National Heart, Lung, and Blood Institute (grants R01-HL-064753 and R01-HL-076784), the National Institute of Diabetes and Digestive and Kidney Diseases (grant K24-DK-080140), and the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195).; Dr. Kiel has received consultancy fees, speaking fees, and/or honoraria (less than $10,000 each) from Merck, Amgen, Lilly, and Novartis; was an author/editor on books published by Springer and UpToDate with Wolters Kluwer, for which he received royalties; and has served as a paid consultant with investment analysts on behalf of Guidepoint for osteoporosis market developments. Dr. Hannan has received honoraria (more than $10,000) for her role as Editor of Arthritis Care & Research. NR 57 TC 2 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD AUG PY 2014 VL 66 IS 8 BP 1233 EP 1240 DI 10.1002/acr.22270 PG 8 WC Rheumatology SC Rheumatology GA AN1PR UT WOS:000340356600013 PM 24375982 ER PT J AU George, M Pullman-Mooar, S Hussain, F Schumacher, HR AF George, Michael Pullman-Mooar, Sally Hussain, Fauzia Schumacher, H. Ralph TI Evaluating Appropriate Use of Prophylactic Colchicine for Gout Flare Prevention SO ARTHRITIS CARE & RESEARCH LA English DT Article ID SERUM URATE; ARTHRITIS; THERAPY; HYPERURICEMIA; ALLOPURINOL; FEBUXOSTAT; MANAGEMENT; PLACEBO; ATTACKS; TRIAL AB Objective. American College of Rheumatology and European League Against Rheumatism guidelines recommend colchicine to prevent gout flares in patients initiating and increasing uric acid-lowering therapy until serum uric acid is maintained at <= 6 mg/dl. We aimed to evaluate how well colchicine prescribing practices adhere to these guidelines and to examine factors associated with improved prescribing. Methods. Electronic medical records were reviewed for 126 patients with active colchicine prescriptions for prophylaxis of gout flares. Colchicine prescribing was defined as inappropriate if 1) no concurrent urate-lowering therapy was prescribed, 2) uric acid was not at goal and urate-lowering therapy had not been increased in the past 3 months, or 3) uric acid goals were met for >1 year and flares had resolved in the absence of tophi. Results. Colchicine use was considered inappropriate in 93 patients (73.8%). Thirty-four were prescribed no urate-lowering therapy, 50 were above the uric acid goal without urate-lowering therapy increase in the prior 3 months, and 9 were at the uric acid goal for >1 year without flares or tophi. Patients appropriately prescribed colchicine were younger and were more likely to have been seen by a rheumatologist. Allopurinol dose and allergy, uric acid level, and renal function were similar in the 2 groups. Conclusion. We found a high prevalence of what we considered inappropriate prophylactic colchicine use, driven largely by failure to prescribe concurrent urate-lowering therapies or adequately increase these medications. Rheumatology consultation was associated with improved colchicine prescribing. C1 [George, Michael] Hosp Univ Penn, Philadelphia, PA 19104 USA. [Pullman-Mooar, Sally; Schumacher, H. Ralph] VA Med Ctr, Philadelphia, PA USA. [Pullman-Mooar, Sally; Schumacher, H. Ralph] Univ Penn, Philadelphia, PA 19104 USA. [Hussain, Fauzia] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP George, M (reprint author), Univ Penn, Div Rheumatol, 8th Floor,Penn Tower,3400 Spruce St, Philadelphia, PA 19104 USA. EM michael.george@uphs.upenn.edu FU American College of Rheumatology Ephraim P. Engelman Endowed Resident Research Preceptorship Award; Ardea; Metabolex; Novartis; Pfizer; Regeneron; Takeda FX Supported by the American College of Rheumatology Ephraim P. Engelman Endowed Resident Research Preceptorship Award.; Dr. Schumacher has received consulting fees (less than $10,000 each) from Ardea, Metabolex, Novartis, Pfizer, Regeneron, and Takeda. NR 16 TC 3 Z9 3 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X EI 2151-4658 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD AUG PY 2014 VL 66 IS 8 BP 1258 EP 1262 DI 10.1002/acr.22275 PG 5 WC Rheumatology SC Rheumatology GA AN1PR UT WOS:000340356600017 PM 24376081 ER PT J AU Romano, D Matallanas, D Frederick, DT Flaherty, KT Kolch, W AF Romano, David Matallanas, David Frederick, Dennie T. Flaherty, Keith T. Kolch, Walter TI One Hippo and many masters: differential regulation of the Hippo pathway in cancer SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE cancer; cross-talk; drug resistance; Hippo/mammalian sterile 20 (MST) pathway; phosphoinositide 3-kinase (PI3K)/Akt pathway; phosphorylation; protein-protein interaction; RAS-association domain family 1 isoform A (RASSF1A); RAS/mitogen-activated protein kinase (MAPK) pathway ID TUMOR-SUPPRESSOR; K-RAS; WILD-TYPE; PROGNOSTIC-SIGNIFICANCE; SIGNALING PATHWAY; INDUCED APOPTOSIS; MST2 PATHWAY; KINASE MST2; ACTIVATION; THERAPY AB The Hippo/MST2 (mammalian sterile 20-like kinase 2) pathway is a signalling cascade evolutionarily conserved in its structure. Originally described in Drosophila melanogaster as a regulator of organ size, this pathway has greater functions in mammals. Disturbance of mammalian MST2 pathway is associated with tumorigenesis by affecting apoptosis, cell cycle and polarity. In addition, this pathway has been shown to cross-talk with mitogenic pathways at multiple levels. In the present mini-review, we discuss our contribution highlighting the regulation of MST2 signalling by frequently observed oncogenic perturbations affecting mitogenic pathways. In particular, we review the role of RAS isoforms and PI3K (phosphoinositide 3-kinase)/Akt in the regulation of MST2 activity by phosphorylation. We also put the emphasis on RAF-induced control of MST2 signalling by protein-protein interactions. Finally, we recapitulate some of the direct mechanisms, such as ubiquitin-dependent degradation or gene silencing by promoter hypermethylation, involved in MST2 pathway component down-regulation in cancers. C1 [Romano, David; Matallanas, David; Kolch, Walter] Univ Coll Dublin, Syst Biol Ireland, Dublin 4, Ireland. [Frederick, Dennie T.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Div Med Oncol, Boston, MA 02114 USA. [Kolch, Walter] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. [Kolch, Walter] Univ Coll Dublin, Sch Med & Med Sci, Dublin 4, Ireland. RP Romano, D (reprint author), Univ Coll Dublin, Syst Biol Ireland, Dublin 4, Ireland. EM david.romano@ucd.ie; walter.kolch@ucd.ie OI Matallanas, David/0000-0002-2360-3141; Kolch, Walter/0000-0001-5777-5016 FU Science Foundation Ireland [06/CE/B1129] FX This work was supported by Science Foundation Ireland [grant number 06/CE/B1129]. NR 57 TC 4 Z9 5 U1 3 U2 7 PU PORTLAND PRESS LTD PI LONDON PA CHARLES DARWIN HOUSE, 12 ROGER STREET, LONDON WC1N 2JU, ENGLAND SN 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2014 VL 42 BP 816 EP 821 DI 10.1042/BST20140030 PN 4 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA AN1FX UT WOS:000340329200016 PM 25109963 ER PT J AU Bellmunt, J Leow, JJ Martin-Doyle, W AF Bellmunt, Joaquim Leow, Jeffrey J. Martin-Doyle, William TI Unveiling the surgical risk associated with neoadjuvant chemotherapy in bladder cancer SO BJU INTERNATIONAL LA English DT Editorial Material ID CYSTECTOMY C1 [Bellmunt, Joaquim] Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, Boston, MA 02215 USA. [Bellmunt, Joaquim] Univ Hosp Del Mar IMIM, Barcelona, Spain. [Leow, Jeffrey J.] Brigham & Womens Hosp, Div Neurol, Boston, MA 02115 USA. [Leow, Jeffrey J.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Martin-Doyle, William] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Bellmunt, J (reprint author), Dana Farber Brigham & Womens Canc Ctr, Bladder Canc Ctr, Boston, MA 02215 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD AUG PY 2014 VL 114 IS 2 BP 163 EP 164 DI 10.1111/bju.12661 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AN1PE UT WOS:000340355000005 PM 25070136 ER PT J AU Sammon, JD Trinh, QD Menon, M AF Sammon, Jesse D. Quoc-Dien Trinh Menon, Mani TI Use of advanced treatment technologies among men at low risk of dying from prostate cancer SO BJU INTERNATIONAL LA English DT Editorial Material ID OUTCOMES; SAMPLE C1 [Sammon, Jesse D.] Henry Ford Hlth Syst, Ctr Outcomes Res Analyt & Evaluat, Vattikuti Urol Inst, Detroit, MI 48202 USA. Harvard Univ, Sch Med, Div Urol Surg, Boston, MA USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Surg & Publ Hlth,Brigham & Womens Hosp, Boston, MA 02115 USA. RP Sammon, JD (reprint author), Henry Ford Hlth Syst, Ctr Outcomes Res Analyt & Evaluat, Vattikuti Urol Inst, K-9,2799 W Grand Blvd, Detroit, MI 48202 USA. EM jsammon79@gmail.com NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD AUG PY 2014 VL 114 IS 2 BP 166 EP 167 DI 10.1111/bju.12547 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA AN1PE UT WOS:000340355000007 PM 24180347 ER PT J AU Chan, CY Papakostas, TD Vavvas, D AF Chan, Chee Yee Papakostas, Thanos D. Vavvas, Demetrios TI Evaluation of choroidal thickness among patients with oculocutaneous albinism SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Letter ID OPTICAL COHERENCE TOMOGRAPHY; VOLUME C1 [Chan, Chee Yee] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02134 USA. [Papakostas, Thanos D.; Vavvas, Demetrios] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Retina Serv, Boston, MA 02134 USA. RP Chan, CY (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 7 Islington St, Boston, MA 02134 USA. EM drchenziyi100@gmail.com OI Vavvas, Demetrios/0000-0002-8622-6478 NR 5 TC 1 Z9 1 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD AUG PY 2014 VL 98 IS 8 DI 10.1136/bjophthalmol-2014-305395 PG 1 WC Ophthalmology SC Ophthalmology GA AN3OG UT WOS:000340497200031 PM 24814965 ER PT J AU Pusztaszeri, MP Sadow, PM Faquin, WC AF Pusztaszeri, Marc P. Sadow, Peter M. Faquin, William C. TI CD117: A Novel Ancillary Marker for Papillary Thyroid Carcinoma in Fine-Needle Aspiration Biopsies SO CANCER CYTOPATHOLOGY LA English DT Article DE thyroid; papillary carcinoma; cytopathology; fine-needle aspiration; CD117; c-KIT; immunohistochemistry; immunocytochemistry ID C-KIT PROTOONCOGENE; DIAGNOSTIC-ACCURACY; SCIENCE CONFERENCE; MOLECULAR MARKERS; BETHESDA SYSTEM; FNA SAMPLES; EXPRESSION; INDETERMINATE; NODULES; CANCER AB BACKGROUND: c-KIT/CD117 down-regulation has been described in papillary thyroid carcinoma (PTC). In this study, the authors investigated CD117 as an ancillary immunocytochemical test for PTC in fine-needle aspiration biopsy (FNAB). METHODS: The expression of CD117 was assessed in cytologic samples of histologically confirmed classic PTC (n=35) and in a control group of benign thyroid nodules (BTNs) (n=30) using immunocytochemistry. The corresponding PTCs and BTNs from surgical resection specimens also were evaluated immunohistochemically for CD117. The expression of CD117 was assessed semiquantitatively using a scoring system from 0 to 5 that combined the proportion and the intensity of staining. RESULTS: The difference in immunoreactivity for CD117 between PTC and BTNs was highly significant both in FNAB samples and in the corresponding histology samples (P<.0001). On cytology, most PTCs (74%; n=26) lacked immunoreactivity for CD117, and 9 samples (26%) had faint reactivity in <2% of tumor cells (score, 0). In contrast, all BTNs (100%; n=30) were positive for CD117, and at least 50% of the cells (score, 2-4) were positive in 79% (n=24) of BTNs. Results with corresponding histology were similar to the cytology results; most PTCs (89%; n=31) lacked immunoreactivity for CD117, and 4 samples (11%) had faint reactivity in <2% of tumor cells. In contrast, all BTNs (n=30) were variably positive for CD117 (score, 2-4). Normal follicular epithelium also was positive for CD117 (score, 2-4). CONCLUSIONS: CD117 is expressed in both normal follicular epithelium and in BTNs. In contrast, expression of CD117 is absent or weak in PTC. These results suggest that CD117 may be useful as an ancillary marker for PTC. Cancer (Cancer Cytopathol) 2014; 122: 596-603. (C) 2014 American Cancer Society. C1 [Pusztaszeri, Marc P.] Univ Hosp Geneva, Dept Pathol, Geneva, Switzerland. [Sadow, Peter M.; Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sadow, Peter M.; Faquin, William C.] Harvard Univ, Sch Med, Boston, MA USA. RP Pusztaszeri, MP (reprint author), Hop Cantonal Univ Geneva, Serv Pathol Clin, 1 Rue Michel Servet, CH-1211 Geneva 14, Switzerland. EM marc.pusztaszeri@hcuge.ch FU Department of Pathology, Massachusetts General Hospital; Nuovo-Soldati Foundation FX This study was supported by a Mini-Vickery Award grant from Department of Pathology, Massachusetts General Hospital. Dr. Pusztaszeri was supported by a visiting fellowship to the Massachusetts General Hospital from the Nuovo-Soldati Foundation. NR 48 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1934-662X EI 1934-6638 J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG PY 2014 VL 122 IS 8 BP 596 EP 603 DI 10.1002/cncy.21437 PG 8 WC Oncology; Pathology SC Oncology; Pathology GA AN4BI UT WOS:000340532200006 PM 24920192 ER PT J AU Gruberg, L Jeremias, A Rundback, JH Anderson, HV Spertus, JA Kennedy, KF Rosenfield, KA AF Gruberg, Luis Jeremias, Allen Rundback, John H. Anderson, H. Vernon Spertus, John A. Kennedy, Kevin F. Rosenfield, Kenneth A. TI Impact of Glomerular Filtration Rate on Clinical Outcomes After Carotid Artery Revascularization in 11,832 Patients From the CARE Registry (R) SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE chronic renal insufficiency; cerebrovascular disease; peripheral vascular disease ID CHRONIC KIDNEY-DISEASE; MILD RENAL-INSUFFICIENCY; CARDIOVASCULAR-DISEASE; SYMPTOMATIC PATIENTS; RANDOMIZED-TRIAL; SURGERY-TRIAL; ENDARTERECTOMY; STENOSIS; RISK; MORTALITY AB Objective: The aim of this study was to assess the association of kidney function with carotid artery revascularization outcomes in a large contemporary database. Background: Chronic kidney disease (CKD) is associated with increased mortality and adverse cardiovascular events after coronary intervention. There are limited data evaluating the association between CKD and adverse events among patients undergoing carotid artery revascularization procedures. Methods: The Carotid Artery Revascularization and Endarterectomy (CARE) Registr (R) is a voluntary registry of 168 hospitals. Using data from the CARE Registry (R), we examined registry patients undergoing carotid artery revascularization by either carotid endarterectomy (CEA) or carotid artery stenting (CAS) from May 2005 through March 2010. Patients were divided into four groups according to their glomerular filtration rate (GFR), as estimated by the Modification of Diet in Renal Disease Study Group equation using preprocedural serum creatinine levels. Results: The analysis included 11,832 patients who underwent carotid revascularization (6,899 CAS and 4,933 CEA). Patients with lower GFR were older, more frequently female, had more comorbidities, including hypertension, dyslipidemia, peripheral arterial disease, diabetes mellitus, chronic lung disease, ischemic heart disease, heart failure, and reduced left ventricular function, and were more likely to undergo CAS than CEA. In the overall population, CKD was associated with higher unadjusted in-hospital and 30-day rates of the combined endpoint of death, stroke, and myocardial infarction and the individual endpoint of stroke. After adjustment for baseline and preprocedural characteristics, CKD was not an independent predictor of adverse events in either CAS or CEA. Conclusions: Patients with CKD have a greater number of comorbidities and worse unadjusted in-hospital and 30-day outcomes; CKD was not, however, an independent predictor of in-hospital and 30-day outcomes after carotid artery revascularization. (C) 2013 Wiley Periodicals, Inc. C1 [Gruberg, Luis; Jeremias, Allen] SUNY Stony Brook, Med Ctr, Dept Med, Div Cardiovasc Dis, Stony Brook, NY 11794 USA. [Rundback, John H.] Holy Name Hosp, Teaneck, NJ USA. [Anderson, H. Vernon] Univ Texas Hlth Sci Ctr Houston, Div Cardiol, Houston, TX 77030 USA. [Spertus, John A.; Kennedy, Kevin F.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Spertus, John A.; Kennedy, Kevin F.] Univ Missouri, Kansas City, MO 64110 USA. [Rosenfield, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Gruberg, L (reprint author), SUNY Stony Brook, Hlth Sci Ctr, Dept Med, Div Cardiovasc Dis, T16-080, Stony Brook, NY 11794 USA. EM luis.gruberg@stonybrook.edu NR 27 TC 3 Z9 3 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 EI 1522-726X J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD AUG 1 PY 2014 VL 84 IS 2 BP 246 EP 254 DI 10.1002/ccd.25101 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN4JP UT WOS:000340554200014 PM 23813603 ER PT J AU Czarny, MJ Nathan, AS Yeh, RW Mauri, L AF Czarny, Matthew J. Nathan, Ashwin S. Yeh, Robert W. Mauri, Laura TI Adherence to Dual Antiplatelet Therapy After Coronary Stenting: A Systematic Review SO CLINICAL CARDIOLOGY LA English DT Review ID DRUG-ELUTING STENT; DAILY CLINICAL-PRACTICE; REAL-WORLD PRACTICE; PREMATURE DISCONTINUATION; FOLLOW-UP; BLEEDING COMPLICATIONS; SURVEILLANCE REGISTRY; CYPHER REGISTRY; CARDIAC EVENTS; RISK-FACTORS AB Background: Adherence to dual antiplatelet therapy (DAPT) is critical after coronary stenting. Although adherence rates are frequently assessed in clinical trials, adherence rates in the unselected population recommended for treatment but beyond clinical trials are largely unknown. Therefore, we performed a systematic review of published observational studies to describe rates of DAPT adherence, trends in DAPT use over time, and patient-level factors associated with nonadherence. Hypothesis: DAPT adherence declines with increasing time after drug-eluting stent implantation. Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature, Embase, and Web of Knowledge were searched through November 20, 2012 for studies including patients receiving 1 or more drug-eluting stents and reporting the use of aspirin and/or thienopyridines, or assessing factors associated with nonadherence to DAPT after bare metal or drug-eluting stent placement. Results: We included 34 studies in the description of DAPT adherence and 11 studies in the description of factors associated with nonadherence. Adherence to DAPT and thienopyridines was high at 1 month but declined by 12 months. Aspirin adherence was at least 90% throughout. Factors associated with nonadherence included bleeding, lower education level, immigrant status, and lack of education regarding DAPT. Conclusions: DAPT adherence is suboptimal at 12 months, and interventions to increase adherence should focus on reducing bleeding risk and improving communication between patients and physicians. C1 [Czarny, Matthew J.] Johns Hopkins Univ Hosp, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. [Nathan, Ashwin S.; Mauri, Laura] Brigham & Womens Hosp, Dept Med, Div Cardiol, Boston, MA 02115 USA. [Nathan, Ashwin S.; Mauri, Laura] Harvard Univ, Sch Med, Boston, MA USA. [Yeh, Robert W.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Mauri, L (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM lmauri1@partners.org FU Abbott; Boston Scientific; Cordis; Medtronic; Eli Lilly; Daiichi-Sankyo; Bristol-Myers Squibb; Sanofi-Aventis; St. Jude Medical; Biotronik; National Heart, Lung, and Blood Institute [1K23HL118138] FX Dr. Mauri reports grants to the institution from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi-Sankyo, Bristol-Myers Squibb, and Sanofi-Aventis, and consulting for St. Jude Medical and Biotronik. Dr. Yeh is supported by a Career Development Award (1K23HL118138) from the National Heart, Lung, and Blood Institute. None of the remaining authors have any other actual or potential conflicts of interest to report. NR 49 TC 4 Z9 4 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD AUG PY 2014 VL 37 IS 8 BP 505 EP 513 DI 10.1002/clc.22289 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AN3ZW UT WOS:000340528400009 PM 24797884 ER PT J AU Winkler, SJ Cagliero, E Witte, E Bierer, BE AF Winkler, Sabune J. Cagliero, Enrico Witte, Elizabeth Bierer, Barbara E. TI A Distributed Model: Redefining a Robust Research Subject Advocacy Program at the Harvard Clinical and Translational Science Center SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE research subject advocacy; clinical and translational science centers; clinical research AB The Harvard Clinical and Translational Science Center ("Harvard Catalyst") Research Subject Advocacy (RSA) Program has reengineered subject advocacy, distributing the delivery of advocacy functions through a multi-institutional, central platform rather than vesting these roles and responsibilities in a single individual functioning as a subject advocate. The program is process-oriented and output-driven, drawing on the strengths of participating institutions to engage local stakeholders both in the protection of research subjects and in advocacy for subjects' rights. The program engages stakeholder communities in the collaborative development and distributed delivery of accessible and applicable educational programming and resources. The Harvard Catalyst RSA Program identifies, develops, and supports the sharing and distribution of expertise, education, and resources for the benefit of all institutions, with a particular focus on the frontline: research subjects, researchers, research coordinators, and research nurses. C1 [Winkler, Sabune J.; Witte, Elizabeth] Harvard Univ, Sch Med, Boston, MA 02138 USA. [Cagliero, Enrico] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Bierer, Barbara E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Cagliero, E (reprint author), Harvard Univ, Sch Med, Boston, MA 02138 USA. EM ecagliero@partners.org FU Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Research Resources) [8UL1TR000170-05, 8KL2TR000168-05]; Harvard University; Harvard Catalyst [1UL1 TR001102-01]; Harvard Catalyst \ The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Awards) [8UL1TR000170-05, 8KL2TR000168-05] FX We thank Rhonda Kost whose leadership was instrumental in encouraging us to write this manuscript. The initial iteration of this manuscript profited from her kind and clarifying suggestions. This work was conducted with support from Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Awards 8UL1TR000170-05 and 8KL2TR000168-05, and financial contributions from Harvard University and its affiliated academic healthcare centers. In 2013, Harvard Catalyst was awarded a new 5-year Clinical and Translational Science Award (1UL1 TR001102-01), with additional funding from Harvard University and its affiliated academic healthcare centers. NR 5 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 EI 1752-8062 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD AUG PY 2014 VL 7 IS 4 BP 329 EP 335 DI 10.1111/cts.12160 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN4HM UT WOS:000340548300015 PM 24841488 ER PT J AU Tremaine, AM Friedmann, DP Goldman, MP AF Tremaine, Anne Marie Friedmann, Daniel P. Goldman, Mitchel P. TI Foam Sclerotherapy for Reticular Veins of the Dorsal Hands: A Retrospective Review SO DERMATOLOGIC SURGERY LA English DT Review ID PAGET-SCHROETTER-SYNDROME; VARICOSE AB BACKGROUND Despite being the gold standard for lower extremity reticular vein treatment, few studies have yet evaluated foam sclerotherapy for hand veins. OBJECTIVE This retrospective study evaluates the safety and efficacy of foam sclerotherapy for reticular veins of the dorsal hands. METHODS A telephone-based questionnaire was used for patient self-assessment of overall improvement, satisfaction, prevalence of adverse events, and willingness for repeat treatment after foam sclerotherapy with sodium tetradecyl sulfate (STS). All patients had been treated with foam STS of 0.25% to 1.0% concentration using room air. RESULTS Twenty-one of 45 patients were successfully contacted, with a total of 54 treatment sessions performed on 38 hands. Overall, patients reported scores of 2.55 +/- 0.56 for overall improvement (0 = none, 1 = mild, 2 = moderate, and 3 = complete resolution) and 1.79 +/- 0.41 for satisfaction with results (0 = not satisfied at all, 1 = mildly satisfied, and 2 = very satisfied), with few significant treatment-related adverse events. Most patients stated they would undergo another treatment if needed. CONCLUSION This single-center experience found that foam sclerotherapy with STS is a safe and effective treatment for reticular veins of the dorsal hands with excellent long-term patient satisfaction. C1 [Tremaine, Anne Marie] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tremaine, Anne Marie] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Friedmann, Daniel P.; Goldman, Mitchel P.] Goldman Butterwick Fitzpatrick Groff & Fabi Cosme, San Diego, CA USA. RP Tremaine, AM (reprint author), 50 Staniford St,Suite 250, Boston, MA 02114 USA. EM amt1998@gmail.com NR 20 TC 1 Z9 1 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1076-0512 EI 1524-4725 J9 DERMATOL SURG JI Dermatol. Surg. PD AUG PY 2014 VL 40 IS 8 BP 892 EP 898 DI 10.1097/DSS.0000000000000076 PG 7 WC Dermatology; Surgery SC Dermatology; Surgery GA AN1YH UT WOS:000340379400010 PM 25022711 ER PT J AU Halter, JB Musi, N Horne, FM Crandall, JP Goldberg, A Harkless, L Hazzard, WR Huang, ES Kirkman, MS Plutzky, J Schmader, KE Zieman, S High, KP AF Halter, Jeffrey B. Musi, Nicolas Horne, Frances McFarland Crandall, Jill P. Goldberg, Andrew Harkless, Lawrence Hazzard, William R. Huang, Elbert S. Kirkman, M. Sue Plutzky, Jorge Schmader, Kenneth E. Zieman, Susan High, Kevin P. TI Diabetes and Cardiovascular Disease in Older Adults: Current Status and Future Directions SO DIABETES LA English DT Article ID 10-YEAR FOLLOW-UP; A-BETA OLIGOMERS; WEIGHT-LOSS; INSULIN-RESISTANCE; RISK-FACTORS; SEVERE HYPOGLYCEMIA; ALZHEIMER-DISEASE; KIDNEY-DISEASE; HEART-FAILURE; UNITED-STATES AB The prevalence of diabetes increases with age, driven in part by an absolute increase in incidence among adults aged 65 years and older. Individuals with diabetes are at higher risk for cardiovascular disease, and age strongly predicts cardiovascular complications. Inflammation and oxidative stress appear to play some role in the mechanisms underlying aging, diabetes, cardiovascular disease, and other complications of diabetes. However, the mechanisms underlying the age-associated increase in risk for diabetes and diabetes-related cardiovascular disease remain poorly understood. Moreover, because of the heterogeneity of the older population, a lack of understanding of the biology of aging, and inadequate study of the effects of treatments on traditional complications and geriatric conditions associated with diabetes, no consensus exists on the optimal interventions for older diabetic adults. The Association of Specialty Professors, along with the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the American Diabetes Association, held a workshop, summarized in this Perspective, to discuss current knowledge regarding diabetes and cardiovascular disease in older adults, identify gaps, and propose questions to guide future research. C1 [Halter, Jeffrey B.] Univ Michigan, Sch Med, Dept Internal Med, Div Geriatr & Palliat Med, Ann Arbor, MI 48109 USA. [Musi, Nicolas] Univ Texas Hlth Sci Ctr San Antonio, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Musi, Nicolas] South Texas Vet Hlth Care Syst, San Antonio, TX USA. [Horne, Frances McFarland] Assoc Specialty Prof, Alexandria, VA USA. [Crandall, Jill P.] Albert Einstein Coll Med, Div Endocrinol, Dept Med, Bronx, NY 10467 USA. [Goldberg, Andrew] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Goldberg, Andrew] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Harkless, Lawrence] Western Univ Hlth Sci, Pomona, CA USA. [Hazzard, William R.] Univ Washington, Dept Med, Puget Sound VA Hlth Care Syst, Seattle, WA USA. [Huang, Elbert S.] Univ Chicago, Dept Med, Div Gen Internal Med, Chicago, IL 60637 USA. [Kirkman, M. Sue] Univ N Carolina, Dept Med, Div Endocrinol & Metab, Chapel Hill, NC USA. [Plutzky, Jorge] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Schmader, Kenneth E.] Duke Univ, Sch Med, Geriatr Res Educ & Clin Ctr, Durham, NC USA. [Schmader, Kenneth E.] Durham VA Med Ctr, Durham, NC USA. [Zieman, Susan] NIA, Bethesda, MD 20892 USA. [High, Kevin P.] Wake Forest Sch Med, Dept Internal Med, Infect Dis Sect, Winston Salem, NC USA. RP Halter, JB (reprint author), Univ Michigan, Sch Med, Dept Internal Med, Div Geriatr & Palliat Med, Ann Arbor, MI 48109 USA. EM jhalter@umich.edu; musi@uthscsa.edu FU National Institute on Aging [1-U13-AG-040938 01]; John A. Hartford Foundation; National Institutes of Health's National Institute on Aging; Alliance for Academic Internal Medicine; American Diabetes Association FX Funding. This workshop was supported by generous grants to Association of Specialty Professors from the National Institute on Aging (1-U13-AG-040938 01) and the John A. Hartford Foundation (J.B.H., K.E.S., K.P.H.). J.B.H. reports grants from the John A. Hartford Foundation, National Institutes of Health's National Institute on Aging, and Alliance for Academic Internal Medicine during the conduct of the project, and from the American Diabetes Association outside the submitted work. F.M.H. reports grants from the John A. Hartford Foundation during the conduct of the project. NR 54 TC 27 Z9 27 U1 2 U2 12 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2014 VL 63 IS 8 BP 2578 EP 2589 DI 10.2337/db14-0020 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0GK UT WOS:000340262100004 PM 25060886 ER PT J AU Pawlyk, AC Giacomini, KM McKeon, C Shuldiner, AR Florez, JC AF Pawlyk, Aaron C. Giacomini, Kathleen M. McKeon, Catherine Shuldiner, Alan R. Florez, Jose C. TI Metformin Pharmacogenomics: Current Status and Future Directions SO DIABETES LA English DT Article ID DIABETES PREVENTION PROGRAM; POLYCYSTIC-OVARY-SYNDROME; LIFE-STYLE INTERVENTION; CATION TRANSPORTER 1; GENETIC-VARIATION; IMPLEMENTATION CONSORTIUM; RESEARCH NETWORK; GLYCEMIC CONTROL; WEIGHT-LOSS; TYPE-2 AB The incidence of type 2 diabetes (T2D) and its costs to the health care system continue to rise. Despite the availability of at least 10 drug classes for the treatment of T2D, metformin remains the most widely used first-line pharmacotherapy for its treatment; however, marked interindividual variability in response and few clinical or biomarker predictors of response reduce its optimal use. As clinical care moves toward precision medicine, a variety of broad discovery-based "omics" approaches will be required. Technical innovation, decreasing sequencing cost, and routine sample storage and processing has made pharmacogenomics the most widely applied discovery-based approach to date. This opens up the opportunity to understand the genetics underlying the interindividual variation in metformin responses in order for clinicians to prescribe specific treatments to given individuals for better efficacy and safety: metformin for those predicted to respond and alternative therapies for those predicted to be nonresponders or who are at increased risk for adverse side effects. Furthermore, understanding of the genetic determinants of metformin response may lead to the identification of novel targets and development of more effective agents for diabetes treatment. The goals of this workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases were to review the state of research on metformin pharmacogenomics, discuss the scientific and clinical hurdles to furthering our knowledge of the variability in patient responses to metformin, and consider how to effectively use this increased understanding to improve patient outcomes. C1 [Pawlyk, Aaron C.; McKeon, Catherine] NIDDK, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. [Giacomini, Kathleen M.] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA. [Giacomini, Kathleen M.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Diabet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org FU NIDDK FX Funding. The workshop was sponsored by NIDDK. NR 58 TC 31 Z9 32 U1 1 U2 14 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD AUG PY 2014 VL 63 IS 8 BP 2590 EP 2599 DI 10.2337/db13-1367 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN0GK UT WOS:000340262100005 PM 25060887 ER PT J AU Lopez, L Golden, SH AF Lopez, Lenny Golden, Sherita Hill TI A New Era in Understanding Diabetes Disparities Among US Latinos-All Are Not Equal SO DIABETES CARE LA English DT Editorial Material ID NON-HISPANIC WHITES; UNITED-STATES; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ACCULTURATION; HEALTH; MORTALITY; ASSOCIATION; PREVALENCE; IMMIGRANTS C1 [Lopez, Lenny] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dispar Solut Ctr, Boston, MA 02114 USA. [Lopez, Lenny] Massachusetts Gen Hosp, Dept Gen Med, Boston, MA 02114 USA. [Lopez, Lenny] Brigham & Womens Hosp, Boston, MA 02115 USA. [Golden, Sherita Hill] Johns Hopkins Univ, Sch Med, Div Endocrinol Diabet & Metab, Baltimore, MD USA. [Golden, Sherita Hill] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Golden, Sherita Hill] Johns Hopkins Ctr Eliminate Cardiovasc Hlth Dispa, Baltimore, MD USA. RP Lopez, L (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. EM llopez1@partners.org FU NHLBI NIH HHS [P50 HL105187, P50-HL-0105187]; NIDDK NIH HHS [1K23-DK-09828001, K23 DK098280, P30 DK079637] NR 24 TC 5 Z9 5 U1 2 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2081 EP 2083 DI 10.2337/dc14-0923 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800018 PM 25061137 ER PT J AU Hernandez, SL Gong, JH Chen, LM Wu, IH Sun, JK Keenan, HA King, GL AF Hernandez, Sonia L. Gong, Jennifer H. Chen, Liming Wu, I-Hsien Sun, Jennifer K. Keenan, Hillary A. King, George L. TI Characterization of Circulating and Endothelial Progenitor Cells in Patients With Extreme-Duration Type 1 Diabetes SO DIABETES CARE LA English DT Article ID POSTNATAL NEOVASCULARIZATION; VASCULAR COMPLICATIONS; 50-YEAR MEDALIST; ATHEROSCLEROSIS; CONTRIBUTE; MELLITUS; NUMBER; PATHOGENESIS; RETINOPATHY; PRECURSORS AB OBJECTIVE We characterized and correlated endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in the Joslin Medalist Study in patients with type 1 diabetes for 50 years or longer. RESEARCH DESIGN AND METHODS EPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared. RESULTS Medalists' EPC and CPC levels equaled those of their nondiabetic age-matched controls, were 10% higher than those in younger type 1 diabetic patients, and were 20% higher than those in age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than in those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than in those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than those from nondiabetic controls. CONCLUSIONS Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues. C1 [Hernandez, Sonia L.; Gong, Jennifer H.; Chen, Liming; Wu, I-Hsien; Sun, Jennifer K.; Keenan, Hillary A.; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. [Gong, Jennifer H.; Chen, Liming; Keenan, Hillary A.] Harvard Univ, Sch Med, Dept Internal Med, Boston, MA USA. [Chen, Liming] Tianjin Med Univ, Tianjin, Peoples R China. [Sun, Jennifer K.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02115 USA. [Sun, Jennifer K.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP King, GL (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. EM george.king@joslin.harvard.edu FU National Institutes of Health [5P30 DK36836]; American Diabetes Association [7-10-MERK-04] FX This research was funded by National Institutes of Health grant 5P30 DK36836 and American Diabetes Association grant 7-10-MERK-04. NR 36 TC 11 Z9 11 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2193 EP 2201 DI 10.2337/dc13-2547 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800032 PM 24780357 ER PT J AU Long, JA Wang, A Medvedeva, EL Eisen, SV Gordon, AJ Kreyenbuhl, J Marcus, SC AF Long, Judith A. Wang, Andrew Medvedeva, Elina L. Eisen, Susan V. Gordon, Adam J. Kreyenbuhl, Julie Marcus, Steven C. TI Glucose Control and Medication Adherence Among Veterans With Diabetes and Serious Mental Illness: Does Collocation of Primary Care and Mental Health Care Matter? SO DIABETES CARE LA English DT Article ID NEUROPSYCHOLOGICAL STATUS; REPEATABLE BATTERY; SCREENING-TEST; SCHIZOPHRENIA; DISORDERS; VALIDITY; RELIABILITY; PREVALENCE; MORTALITY; MELLITUS AB OBJECTIVE Persons with serious mental illness (SMI) may benefit from collocation of medical and mental health healthcare professionals and services in attending to their chronic comorbid medical conditions. We evaluated and compared glucose control and diabetes medication adherence among patients with SMI who received collocated care to those not receiving collocated care (which we call usual care). RESEARCH DESIGN AND METHODS We performed a cross-sectional, observational cohort study of 363 veteran patients with type 2 diabetes and SMI who received care from one of three Veterans Affairs medical facilities: two sites that provided both collocated and usual care and one site that provided only usual care. Through a survey, laboratory tests, and medical records, we assessed patient characteristics, glucose control as measured by a current HbA(1c), and adherence to diabetes medication as measured by the medication possession ration (MPR) and self-report. RESULTS In the sample, the mean HbA(1c) was 7.4% (57 mmol/mol), the mean MPR was 80%, and 51% reported perfect adherence to their diabetes medications. In both unadjusted and adjusted analyses, there were no differences in glucose control and medication adherence by collocation of care. Patients seen in collocated care tended to have better HbA(1c) levels (beta = 20.149; P = 0.393) and MPR values (beta = 0.34; P = 0.132) and worse self-reported adherence (odds ratio 0.71; P = 0.143), but these were not statistically significant. CONCLUSIONS In a population of veterans with comorbid diabetes and SMI, patients on average had good glucose control and medication adherence regardless of where they received primary care. C1 [Long, Judith A.; Wang, Andrew; Medvedeva, Elina L.; Marcus, Steven C.] Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. [Long, Judith A.] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA. [Eisen, Susan V.] Edith Nourse Rogers Mem Vet Adm Hosp, Ctr Healthcare Org & Implementat Res, Bedford, MA 01730 USA. [Eisen, Susan V.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA. [Gordon, Adam J.] VA Pittsburgh Healthcare Syst, Mental Illness Res Educ & Clin Ctr, Pittsburgh, PA USA. [Gordon, Adam J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kreyenbuhl, Julie] VA Capitol Hlth Care Network, Mental Illness Res Educ & Clin Ctr, Baltimore, MD USA. [Kreyenbuhl, Julie] Univ Maryland, Sch Med, Dept Psychiat, Div Res Serv, Baltimore, MD 21201 USA. [Marcus, Steven C.] Univ Penn, Penn Sch Social Policy & Practice, Philadelphia, PA 19104 USA. RP Long, JA (reprint author), Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. EM jalong@mail.med.upenn.edu FU VA Health Services Research Development [IIR-07-124-3] FX This work was supported by VA Health Services Research & Development IIR-07-124-3. NR 30 TC 6 Z9 6 U1 1 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD AUG PY 2014 VL 37 IS 8 BP 2261 EP 2267 DI 10.2337/dc13-0051 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN3MI UT WOS:000340491800041 PM 24879839 ER PT J AU Katz, ML Mehta, S Nansel, T Quinn, H Lipsky, LM Laffel, LMB AF Katz, Michelle L. Mehta, Sanjeev Nansel, Tonja Quinn, Heidi Lipsky, Leah M. Laffel, Lori M. B. TI Associations of Nutrient Intake with Glycemic Control in Youth with Type 1 Diabetes: Differences by Insulin Regimen SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID GLUCOSE CONTROL; DIETARY-INTAKE; ADOLESCENTS; CHILDREN; FAT; FIBER; COMPLICATIONS; MANAGEMENT; EAT AB Background: Type 1 diabetes management has evolved from meal plans towards flexible eating with carbohydrate counting. With this shift, youth with type 1 diabetes may consume excess fat and insufficient fiber, which may impact glycemic control. Few studies consider whether insulin regimen influences associations between dietary intake and hemoglobin A1c. Patients and Methods: In this cross-sectional study, 252 youth (52% male; age, 13.2 +/- 2.8 years; body mass index z-score [z-BMI], 0.7 +/- 0.8) with type 1 diabetes completed 3-day food records. Dietary intake was compared with published guidelines. Logistic regression predicted the odds of suboptimal glycemic control (an A1c level of >= 8.5%) related to fat and protein intake or fiber intake according to insulin regimen (pump vs. injection) adjusting for age, sex, diabetes duration, z-BMI, insulin dose, glucose monitoring frequency, and total energy intake (TEI). Results: Youth had a mean TEI of 40.9 +/- 15.4 kcal/kg/day and excess fat and insufficient fiber intake compared against published guidelines. Pump-treated youth consuming the highest quartile of fat intake (as percentage TEI) had 3.6 (95% confidence interval, 1.3-9.7) times the odds of a suboptimal A1c than those in the lowest quartile. No such association was found in injection-treated youth. In the total sample, youth with the lowest quartile of fiber intake had 3.6 (95% confidence interval, 1.4-9.0) times the odds of a suboptimal A1c, but this association did not differ by insulin regimen. There was no association between protein intake and A1c. Conclusions: Higher fat intake in pump-treated youth and lower fiber intake in all youth were associated with an A1c level of >= 8.5%. Improving dietary quality may help improve A1c. C1 [Katz, Michelle L.; Mehta, Sanjeev; Quinn, Heidi; Laffel, Lori M. B.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Genet & Epidemiol Sect, Boston, MA 02215 USA. [Nansel, Tonja; Lipsky, Leah M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Hlth Behav Branch, Div Intramural Populat Hlth Res, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Genet & Epidemiol Sect, One Joslin Pl, Boston, MA 02215 USA. EM lori.laffel@joslin.harvard.edu OI Nansel, Tonja/0000-0002-8298-7595 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200703434C]; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health grants T32 [5T32DK007260-35, 1K12DK094721-01, P30DK036836]; Katherine Adler Astrove Youth Education Fund; Maria Griffin Drury Fund; Eleanor Chesterman Beatson Care Ambassador Fund FX We thank all the families for their participation in this investigation. We also thank the research staff for their efforts. This research was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract number HHSN267200703434C) and by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health grants T32 #5T32DK007260-35, 1K12DK094721-01, and grant P30DK036836 to the Joslin Diabetes and Endocrinology Research Center. Additional support came from the Katherine Adler Astrove Youth Education Fund, the Maria Griffin Drury Fund, and the Eleanor Chesterman Beatson Care Ambassador Fund. NR 24 TC 4 Z9 4 U1 1 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 EI 1557-8593 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD AUG PY 2014 VL 16 IS 8 BP 512 EP 518 DI 10.1089/dia.2013.0389 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA AN4EL UT WOS:000340540300005 PM 24766666 ER PT J AU Ewer, MS Suter, TM Lenihan, DJ Niculescu, L Breazna, A Demetri, GD Motzer, RJ AF Ewer, Michael S. Suter, Thomas M. Lenihan, Daniel J. Niculescu, Liviu Breazna, Aurora Demetri, George D. Motzer, Robert J. TI Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: A comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Sunitinib; Cardiotoxicity; Cancer treatment-related hypertension; Reversibility of cardiotoxic events ID RENAL-CELL CARCINOMA; TYROSINE KINASE INHIBITOR; CARDIOTOXICITY; HYPERTENSION; MANAGEMENT; FAILURE; ALPHA AB Purpose: To define cardiovascular (CV) risk and reversibility of cardiac events in patients who received sunitinib versus comparator treatment (interferon-alfa or placebo). Patients and methods: We performed a retrospective adjudication of comprehensive CV adverse events (AEs) from two phase 3 trials. Components of the comprehensive CV AE end-point comprised hypertension, symptomatic and asymptomatic left ventricular ejection fraction decreases (SD-LVEF; AD-LVEF) and extent of reversibility, heart-failure symptoms, thromboembolic events, dysrhythmia and CV death. Three cardiologists and one oncologist, blinded to treatment allocation, adjudicated suspected CV AEs in the pooled trial database (N = 1090). Results: Incidence rates (IR) for sunitinib versus Interferon-alfa (IFN-alpha)/placebo were hypertension: 6.9 versus 2.6 (hazard ratio (HR), 3.1; 95% confidence interval (CI), 2.4-1.0); SD-LVEF: 0.4 versus 0.2 (HR, 2.5; 95% CI, 1.0-6.2); AD-LVEF: 1.1 versus 0.8 (HR, 2.1; 95% CI, 1.3-3.4); and composite CV AE end-point: 10.1 versus 4.8 (HR, 2.5; 95% CI, 2.0-3.1), however reversibility, not previously quantified, was found to be clinically meaningful. Conclusions: Hypertension and SD-LVEF/AD-LVEF were significantly higher with sunitinib versus IFN-alpha/placebo. Among patients who experienced a cardiac event, symptomatic and asymptomatic instances of decreased cardiac dysfunction were adjudicated as reversible in 47 of 83 (56%) and 17 of 30 (57%), respectively. Among sunitinib-treated patients, many were able to resume sunitinib dosing following resolution of events, a finding that is important for clinical care. In comparator groups, symptomatic and asymptomatic instances were adjudicated as reversible in 4 of 6 (66.7%) and 11 of 21(52%), respectively. Thromboembolic, dysrhythmic and/or CV deaths were not significantly higher in sunitinib-treated patients. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Ewer, Michael S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Suter, Thomas M.] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Lenihan, Daniel J.] Vanderbilt Heart & Vasc Inst, Nashville, TN USA. [Niculescu, Liviu; Breazna, Aurora] Pfizer Oncol, New York, NY USA. [Demetri, George D.] Harvard Univ, Sarcoma Ctr, Dana Farber Canc Inst, Ludwig Ctr, Boston, MA 02115 USA. [Demetri, George D.] Harvard Univ, Sch Med, Boston, MA USA. [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Ewer, MS (reprint author), Univ Texas MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM mewer@mdanderson.org FU Pfizer, Inc. FX This study was sponsored by Pfizer, Inc. Medical writing support was provided by Wendy Sacks at ACUMED (R) (New York, NY, USA). NR 23 TC 17 Z9 19 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2014 VL 50 IS 12 BP 2162 EP 2170 DI 10.1016/j.ejca.2014.05.013 PG 9 WC Oncology SC Oncology GA AN1GE UT WOS:000340329900019 PM 24930624 ER PT J AU Morrison, JF Neufeld, EJ Grace, RF AF Morrison, Jacqueline F. Neufeld, Ellis J. Grace, Rachael F. TI The use of erythropoietin-stimulating agents versus supportive care in newborns with hereditary spherocytosis: a single centre's experience SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE paediatric; hereditary spherocytosis; erythropoietin ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; HEMOLYTIC-DISEASE; THERAPY; ANEMIA AB Hereditary Spherocytosis (HS) is a common haemolytic anaemia in which 75% of cases are autosomal dominant. As most newborns with HS have a family history of disease, haematologists often see these infants before their physiologic haemoglobin nadir, which is exaggerated in comparison with healthy infants. The objective of this study was to evaluate the frequency of implementation and cost of erythropoietin-stimulating agents (EPO) versus transfusion in infants with HS at a single paediatric programme. In the last decade, only 15% of infants with HS at our centre have been treated with EPO, which costs twice that of a single transfusion and EPO treated infants did not always avoid transfusion. Infrequent prescription of EPO therapy to infants with HS at our centre may be related to the incomplete data supporting its use. C1 [Morrison, Jacqueline F.; Neufeld, Ellis J.; Grace, Rachael F.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Neufeld, Ellis J.; Grace, Rachael F.] Harvard Univ, Sch Med, Boston, MA USA. [Neufeld, Ellis J.; Grace, Rachael F.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Grace, RF (reprint author), Boston Childrens Hosp, 300 Longwood Ave,Fegan 7, Boston, MA 02115 USA. EM Rachael.Grace@childrens.harvard.edu OI Grace, Fergal/0000-0002-3144-5999 FU Scholars in Clinical Science programme of Harvard Catalyst \ The Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University and its affiliated academic health care centres; NIH [K24 HL004184]; National Hemophilia Foundation FX This work was conducted with support from the Scholars in Clinical Science programme of Harvard Catalyst (RFG) vertical bar The Harvard Clinical and Translational Science Center (Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centres) (RFG). Other grant support includes: NIH Grant K24 HL004184 (EJN); National Hemophilia Foundation (RFG). NR 13 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0902-4441 EI 1600-0609 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD AUG PY 2014 VL 93 IS 2 BP 161 EP 164 DI 10.1111/ejh.12321 PG 4 WC Hematology SC Hematology GA AN4UN UT WOS:000340584100011 PM 24660843 ER PT J AU Carroll, K Dovey, M Liu, S Frechette, G Esain, V Goessling, W North, T AF Carroll, Kelli Dovey, Michael Liu, Sarah Frechette, Gregory Esain, Virginie Goessling, Wolfram North, Trista TI ESTROGEN ENHANCES HSPC PRODUCTION DURING DEVELOPMENT AND REGENERATION SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Carroll, Kelli; Dovey, Michael; Liu, Sarah; Frechette, Gregory; Esain, Virginie; North, Trista] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Goessling, Wolfram] Harvard Univ, Sch Med, BWH, Boston, MA 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 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1022 BP S28 EP S28 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300087 ER PT J AU Deshpande, A Deshpande, A Sinha, A Chen, LY Chang, J Chen, D Koche, R Krivtsov, A Luo, MK Bradner, J Bernt, K Armstrong, S AF Deshpande, Aniruddha Deshpande, Anagha Sinha, Amit Chen, Liying Chang, Jenny Chen, David Koche, Richard Krivtsov, Andrei Luo, Minkui Bradner, James Bernt, Kathrin Armstrong, Scott TI REGULATION OF HOX GENE EXPRESSION BY AF10-MEDIATED CONVERSION OF H3K79ME1 TO H3K79ME2 SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Deshpande, Aniruddha; Deshpande, Anagha; Sinha, Amit; Chang, Jenny; Chen, David; Koche, Richard; Krivtsov, Andrei; Luo, Minkui; Armstrong, Scott] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Chen, Liying; Bradner, James] Dana Farber Canc Ctr, Boston, MA USA. [Bernt, Kathrin] Univ Colorado, Denver, CO 80202 USA. NR 0 TC 0 Z9 0 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1031 BP S30 EP S30 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300095 ER PT J AU Epperly, M Shinde, A Rhieu, BH Berhane, H Guinan, E Parmar, K Wang, H Franicola, D Zhang, XC Dixon, T Greenberger, J AF Epperly, Michael Shinde, Ashwin Rhieu, Byung Han Berhane, Hebist Guinan, Eva Parmar, Kalindi Wang, Hong Franicola, Darcy Zhang, Xichen Dixon, Tracy Greenberger, Joel TI INTRAORAL MITOCHONDRIAL-TARGETED GS NITROXIDE JP4-039 AMELIORATES RADIATION-INDUCED MUCOSITIS AND GENE TRANSCRIPT BIOMARKERS IN HEAD AND NECK TUMOR-BEARING FANCONI ANEMIA (FA) (FANCD2-/-) MICE SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Epperly, Michael; Shinde, Ashwin; Rhieu, Byung Han; Berhane, Hebist; Wang, Hong; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Greenberger, Joel] Univ Pittsburgh, Pittsburgh, PA USA. [Guinan, Eva; Parmar, Kalindi] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1038 BP S32 EP S32 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300103 ER PT J AU Mercier, F Shi, JT Sykes, D Kfoury, Y Scadden, D AF Mercier, Francois Shi, Jiantao Sykes, David Kfoury, Youmna Scadden, David TI DECLINED PRESENTATION TRACKING CLONAL COMPETITION AND EVOLUTION AT THE FUNCTIONAL LEVEL IN MURINE EXPERIMENTAL MODELS OF ACUTE MYELOID LEUKEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Mercier, Francois; Sykes, David; Kfoury, Youmna; Scadden, David] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Shi, Jiantao] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1111 BP S50 EP S50 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300176 ER PT J AU Shafiee, S Lee, J Papa, M Helgeland, L Gjertsen, BT Kittang, AO Parekkadan, B McCormack, E AF Shafiee, Sahba Lee, Jungwoo Papa, Mihaela Helgeland, Lars Gjertsen, Bjorn Tore Kittang, Astrid Olsnes Parekkadan, Biju McCormack, Emmet TI NOVEL PRE-CLINICAL MODELS OF MYELODYSPLASTIC SYNDROME (MDS) SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Shafiee, Sahba; Gjertsen, Bjorn Tore; Kittang, Astrid Olsnes; McCormack, Emmet] Univ Bergen, Dept Clin Sci, Bergen, Hordaland, Norway. [Helgeland, Lars] Haukeland Hosp, Dept Pathol, N-5021 Bergen, Hordaland, Norway. [Parekkadan, Biju] Harvard Stem Cell Inst, Boston, MA USA. [Papa, Mihaela] KinN Therapeut AS, Bergen, Hordaland, Norway. [Lee, Jungwoo] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Mc Cormack, Emmet/D-2922-2012; Gjertsen, Bjorn T/O-1542-2015 OI Mc Cormack, Emmet/0000-0002-7621-4625; Gjertsen, Bjorn T/0000-0001-9358-9704 NR 0 TC 0 Z9 0 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1146 BP S59 EP S59 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300211 ER PT J AU Sykes, D Kfoury, Y Blanco, A Scadden, D AF Sykes, David Kfoury, Youmna Blanco, Andres Scadden, David TI PHENOTYPIC SCREENING IDENTIFIES PROSTACYCLIN AGONISTS AS DIFFERENTIATION AGENTS IN THE TREATMENT OF ACUTE MYELOID LEUKEMIA SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract CT 43rd Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) CY AUG 21-24, 2014 CL Montreal, CANADA SP Int Soc Expt Hematol C1 [Sykes, David; Kfoury, Youmna; Scadden, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Scadden, David] Harvard Stem Cell Inst, Boston, MA USA. [Blanco, Andres] Childrens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X EI 1873-2399 J9 EXP HEMATOL JI Exp. Hematol. PD AUG PY 2014 VL 42 IS 8 SU 1 MA P1008 BP S25 EP S25 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA AN1LF UT WOS:000340344300074 ER PT J AU Golay, HG Barbie, DA AF Golay, Hadrien G. Barbie, David A. TI Targeting cytokine networks in KRAS-driven tumorigenesis SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Editorial Material DE cytokines; JAK; KRAS; targeted therapy; TBK1/IKKepsilon ID LUNG ADENOCARCINOMA; ACTIVATION; CANCER; INHIBITOR; TBK1; IL-6 AB KRAS is one of the most commonly mutated oncogenes in human tumors, and is typically associated with aggressive disease. Despite intensive study and years of effort, KRAS has remained refractory to targeted inhibition. Given the challenge of inhibiting KRAS directly, current approaches to KRAS targeted therapy have involved the disruption of downstream signaling pathways. However, combinations of drugs that target RAF/MEK and PI3K/AKT signaling have failed to live up to expectations in the clinic. Here we summarize the evidence that the cytokine signaling circuitry of KRAS-driven tumors represents an equally tractable drug target. Indeed, the incorporation of novel therapeutics that disrupts these cytokine signaling networks may hold the key to overcoming this seemingly impenetrable treatment barrier. C1 [Golay, Hadrien G.; Barbie, David A.] Dana Farber Canc Inst, Dept Med Oncol & Canc Biol, Boston, MA 02215 USA. [Golay, Hadrien G.] Swiss Fed Inst Technol Lausanne EPFL, Sch Life Sci, CH-1015 Lausanne, Switzerland. [Barbie, David A.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. RP Barbie, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol & Canc Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM dbarbie@partners.org FU NCI NIH HHS [K08 CA138918] NR 20 TC 2 Z9 2 U1 0 U2 5 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 EI 1744-8328 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD AUG PY 2014 VL 14 IS 8 BP 869 EP 871 DI 10.1586/14737140.2014.928596 PG 3 WC Oncology SC Oncology GA AN3JY UT WOS:000340484900002 PM 24928447 ER PT J AU Dominitz, JA Robertson, DJ AF Dominitz, Jason A. Robertson, Douglas J. TI Tailoring Colonoscopic Screening to Individual Risk SO GASTROENTEROLOGY LA English DT Editorial Material ID SOCIETY-TASK-FORCE; COLORECTAL-CANCER; AMERICAN-COLLEGE; ADVANCED NEOPLASIA; GREATER-THAN-9 MM; SURVEILLANCE; POLYPS; SEX; COLONOGRAPHY; PREVALENCE C1 [Dominitz, Jason A.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, White River Junct VA Med Ctr, Gastroenterol Sect, White River Jct, VT USA. RP Dominitz, JA (reprint author), Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, 1660 S Columbian Way 111 Gastro, Seattle, WA 98108 USA. EM jason.dominitz@va.gov OI Dominitz, Jason/0000-0002-8070-7086 NR 24 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2014 VL 147 IS 2 BP 264 EP 266 DI 10.1053/j.gastro.2014.06.018 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2WX UT WOS:000340447800008 PM 24976032 ER PT J AU Derks, S Bass, AJ AF Derks, Sarah Bass, Adam J. TI Mutational Signatures in Helicobacter pylori-induced Gastric Cancer: Lessons From New Sequencing Technologies SO GASTROENTEROLOGY LA English DT Editorial Material ID CYTIDINE DEAMINASE; GENOME; DNA; HYPERMUTATION; PHENOTYPE; APOBEC3; LESIONS C1 [Derks, Sarah; Bass, Adam J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Bass, Adam J.] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA USA. RP Bass, AJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM adam_bass@dfci.harvard.edu NR 19 TC 5 Z9 5 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2014 VL 147 IS 2 BP 267 EP 269 DI 10.1053/j.gastro.2014.06.019 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2WX UT WOS:000340447800009 PM 24973679 ER PT J AU Luo, YX Wong, CJ Kaz, AM Dzieciatkowski, S Carter, KT Morris, SM Wang, JP Willis, JE Makar, KW Ulrich, CM Lutterbaugh, JD Shrubsole, MJ Zheng, W Markowitz, SD Grady, WM AF Luo, Yanxin Wong, Chao-Jen Kaz, Andrew M. Dzieciatkowski, Slavomir Carter, Kelly T. Morris, Shelli M. Wang, Jianping Willis, Joseph E. Makar, Karen W. Ulrich, Cornelia M. Lutterbaugh, James D. Shrubsole, Martha J. Zheng, Wei Markowitz, Sanford D. Grady, William M. TI Differences in DNA Methylation Signatures Reveal Multiple Pathways of Progression From Adenoma to Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Epigenetic Modifications; Colon Cancer; Progression; Gene Regulation ID CPG ISLAND METHYLATION; HUMAN COLON; MICROSATELLITE INSTABILITY; SERRATED PATHWAY; BRAF MUTATION; PHENOTYPE; HYPERMETHYLATION; PATHOGENESIS; LESIONS; POLYPS AB BACKGROUND & AIMS: Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. METHODS: We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. RESULTS: We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. CONCLUSIONS: Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process. C1 [Luo, Yanxin; Wang, Jianping] Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou 510655, Guangdong, Peoples R China. [Luo, Yanxin; Wong, Chao-Jen; Kaz, Andrew M.; Dzieciatkowski, Slavomir; Carter, Kelly T.; Morris, Shelli M.; Grady, William M.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Kaz, Andrew M.] VA Puget Sound Hlth Care Syst, Res & Dev Serv, Seattle, WA USA. [Kaz, Andrew M.; Grady, William M.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Willis, Joseph E.] Case Comprehens Canc Ctr, Case Med Ctr, Dept Pathol, Cleveland, OH USA. [Willis, Joseph E.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Makar, Karen W.; Ulrich, Cornelia M.] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. [Ulrich, Cornelia M.] Heidelberg Univ, Natl Ctr Tumor Dis NCT, Heidelberg, Germany. [Ulrich, Cornelia M.] Heidelberg Univ, German Canc Res Ctr DKFZ, Heidelberg, Germany. [Lutterbaugh, James D.; Markowitz, Sanford D.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Lutterbaugh, James D.; Markowitz, Sanford D.] Case Western Reserve Univ, Ireland Canc Ctr, Sch Med, Cleveland, OH 44106 USA. [Lutterbaugh, James D.; Markowitz, Sanford D.] Case Med Ctr, Cleveland, OH USA. [Shrubsole, Martha J.; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Epidemiol Ctr,Div Epidemiol, Nashville, TN 37212 USA. RP Luo, YX (reprint author), Sun Yat Sen Univ, Affiliated Hosp 6, Dept Colorectal Surg, Guangzhou 510655, Guangdong, Peoples R China. EM luoyx25@mail.sysu.edu.cn; wgrady@fhcrc.org RI Shrubsole, Martha/K-5052-2015 OI Shrubsole, Martha/0000-0002-5591-7575 FU National Cancer Institute of the National Institutes of Health [RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, P01CA077852, P50CA95103, R01CA121060, P30CA68485, K07CA122451]; Burroughs Wellcome Fund; Program of Introducing Talents of Discipline to Universities of China [B12003]; International Science & Technology Cooperation Program of China [2011DFA32570]; National Natural Science Foundation of China [81201920]; [5P50CA150964] FX This research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number RO1CA115513, P30CA15704, UO1CA152756, U54CA143862, and P01CA077852 (WMG), P50CA95103 (ZW), R01CA121060, P30CA68485, K07CA122451 (MJS). The content is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health. Support for these studies was also provided by a Burroughs Wellcome Fund Translational Research Award for Clinician Scientist (WMG), Program of Introducing Talents of Discipline to Universities of China (B12003, JW) and International Science & Technology Cooperation Program of China (2011DFA32570, JW), National Natural Science Foundation of China (81201920, YL); and 5P50CA150964 (SDM). NR 52 TC 36 Z9 36 U1 1 U2 18 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2014 VL 147 IS 2 BP 418 EP + DI 10.1053/j.gastro.2014.04.039 PG 20 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2WX UT WOS:000340447800030 PM 24793120 ER PT J AU Giardiello, FM Allen, JI Axilbund, JE Boland, CR Burke, CA Burt, RW Church, JM Dominitz, JA Johnson, DA Kaltenbach, T Levin, TR Lieberman, DA Robertson, DJ Syngal, S Rex, DK AF Giardiello, Francis M. Allen, John I. Axilbund, Jennifer E. Boland, C. Richard Burke, Carol A. Burt, Randall W. Church, James M. Dominitz, Jason A. Johnson, David A. Kaltenbach, Tonya Levin, Theodore R. Lieberman, David A. Robertson, Douglas J. Syngal, Sapna Rex, Douglas K. TI Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer SO GASTROENTEROLOGY LA English DT Article DE Lynch Syndrome; Colorectal Cancer; Genetic Testing ID NONPOLYPOSIS COLON-CANCER; MISMATCH-REPAIR GENES; REVISED BETHESDA GUIDELINES; COST-EFFECTIVENESS ANALYSIS; MSH2 MUTATION CARRIERS; MUIR-TORRE-SYNDROME; TUMOR MICROSATELLITE INSTABILITY; TESTING STRATEGIES; ENDOMETRIAL CANCER; GERMLINE MUTATIONS AB The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided. C1 [Giardiello, Francis M.; Axilbund, Jennifer E.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Allen, John I.] Yale Univ, Sch Med, New Haven, CT USA. [Boland, C. Richard] Baylor Univ, Med Ctr, Dallas, TX USA. [Burke, Carol A.; Church, James M.] Cleveland Clin, Cleveland, OH 44106 USA. [Burt, Randall W.] Univ Utah, Salt Lake City, UT USA. [Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Dominitz, Jason A.] Univ Washington, Seattle, WA 98195 USA. [Johnson, David A.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Kaltenbach, Tonya] Stanford Univ, Palo Alto, CA 94304 USA. [Levin, Theodore R.] Kaiser Permanente Med Ctr, Walnut Creek, CA USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Robertson, Douglas J.] White River Junction VA Med Ctr, White River Jct, VT USA. [Robertson, Douglas J.] Geisel Sch Med Dartmouth, White River Jct, VT USA. [Syngal, Sapna] Brigham & Womens Hosp, Boston, MA 02115 USA. [Syngal, Sapna] Dana Farber Canc Inst, Boston, MA 02115 USA. [Syngal, Sapna] Harvard Univ, Sch Med, Boston, MA USA. [Rex, Douglas K.] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. RP Giardiello, FM (reprint author), 1830 East Monument St,Rm 431, Baltimore, MD 21205 USA. EM fgiardi@jhmi.edu OI Dominitz, Jason/0000-0002-8070-7086 FU Olympus American Inc.; Olympus America FX These authors disclose the following: C. Richard Boland and Randall W. Burt are consultants for Myriad Genetic. Jason A. Dominitz received resources in support of this work from the VA Puget Sound Health Care System, Seattle, Washington. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. David A. Johnson is a clinical investigator for EXACT Sciences, a consultant for Epigenomics, and on the advisory board for Given Imaging. Tonya Kaltenbach is a research grant recipient and consultant for Olympus American Inc. David A. Lieberman is on the advisory board for Given Imaging and Exact Sciences. Douglas J. Robertson is on the advisory board of Given Imaging. Sapna Syngal is an unpaid advisor/collaborator with Myriad genetics and a consultant for Archimedes, Inc. Douglas K. Rex is a consultant for Olympus America, Braintree Laboratories, Ferring Pharmaceuticals, Epigenomics, EXACT Sciences, Given Imaging, received research support from Olympus America; and is on the speaker's bureau for Olympus America and Boston Scientific. The remaining authors disclose no conflicts. NR 162 TC 61 Z9 61 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2014 VL 147 IS 2 BP 502 EP 526 DI 10.1053/j.gastro.2014.04.001 PG 25 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2WX UT WOS:000340447800038 PM 25043945 ER PT J AU Torabi, M Gupta, R Walsh, CJ AF Torabi, Meysam Gupta, Rajiv Walsh, Conor James TI Compact Robotically Steerable Image-Guided Instrument for Multi-Adjacent-Point (MAP) Targeting SO IEEE TRANSACTIONS ON ROBOTICS LA English DT Article DE Computer-assisted surgery; image-guided therapy; prostate intervention; steerable needles; surgical planning ID ASSISTED PROSTATE BRACHYTHERAPY; CONCENTRIC TUBE ROBOTS; CONTINUUM ROBOTS; NEEDLE INSERTION; GUIDANCE; DESIGN; BIOPSY; SYSTEM; MOTION; INTERVENTIONS AB Accurately targeting multi-adjacent points (MAPs) during image-guided percutaneous procedures is challenging due to needle deflection and misalignment. The associated errors can result in inadequate treatment of cancer in the case of prostate brachytherapy, or inaccurate diagnosis during biopsy, while repeated insertions increase procedure time, radiation dose, and complications. To address these challenges, we present an image-guided robotic system capable of MAP targeting of irregularly shaped volumes after a single insertion of a percutaneous instrument. The design of the compact CT-compatible drive mechanism is based on a nested screw and screw-spline combination that actuates a straight outer cannula and a curved inner stylet that can be repeatedly straightened when retracted inside the cannula. The stylet translation and cannula rotation/translation enable a 3-D workspace to be reached with the stylet's tip. A closed-form inverse kinematics and image-to-robot registration are implemented in an image-guided system including a point-and-click user interface. The complete system is successfully evaluated with a phantom under a Siemens Definition Flash CT scanner. We demonstrate that the system is capable of MAP targeting for a 2-D shape of the letter "H" and a 3-D helical pattern with an average targeting error of 2.41 mm. These results highlight the benefit and efficacy of the proposed robotic system in seed placement during image-guided brachytherapy. C1 [Torabi, Meysam] Harvard Univ, Sch Engn & Appl Sci, Boston, MA 02115 USA. [Torabi, Meysam] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Gupta, Rajiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Walsh, Conor James] Harvard Univ, Sch Engn & Appl Sci, Wyss Inst Biologically Inspired Engn, Cambridge, MA 02138 USA. [Walsh, Conor James] Harvard Univ, Harvard Biodesign Lab, Cambridge, MA 02138 USA. RP Torabi, M (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM torabi@bwh.harvard.edu; rgupta1@partners.org; walsh@seas.harvard.edu FU Wyss Institute for Biologically Inspired Engineering at Harvard University; Deshpande Center for Technological Innovation at Massachusetts Institute of Technology; Department of Radiology at Massachusetts General Hospital FX This work was supported by the Wyss Institute for Biologically Inspired Engineering at Harvard University, the Deshpande Center for Technological Innovation at Massachusetts Institute of Technology, and the Department of Radiology at Massachusetts General Hospital. NR 76 TC 4 Z9 4 U1 0 U2 13 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1552-3098 EI 1941-0468 J9 IEEE T ROBOT JI IEEE Trans. Robot. PD AUG PY 2014 VL 30 IS 4 BP 802 EP 815 DI 10.1109/TRO.2014.2304773 PG 14 WC Robotics SC Robotics GA AN2YK UT WOS:000340451800003 ER PT J AU Cheng, AG Oxford, EC Sauk, J Nguyen, DD Yajnik, V Friedman, S Ananthakrishnan, AN AF Cheng, Alice G. Oxford, Emily C. Sauk, Jenny Nguyen, Deanna D. Yajnik, Vijay Friedman, Sonia Ananthakrishnan, Ashwin N. TI Impact of Mode of Delivery on Outcomes in Patients with Perianal Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE perianal fistula; Crohn's disease; pregnancy; C-section ID INFLAMMATORY-BOWEL-DISEASE; NATURAL-HISTORY; PREGNANCY; COMPLICATIONS; THERAPY; COHORT; WOMEN AB Background: Crohn's disease (CD) often affects women during the reproductive years. Although several studies have examined the impact of pregnancy on luminal disease, limited literature exists in those with perianal CD. Decision regarding mode of delivery is a unique challenge in such patients due to concerns regarding the effect of pelvic floor trauma during delivery on preexisting perianal involvement. Methods: We performed a retrospective chart review of patients with CD with established perianal disease undergoing either vaginal delivery or caesarean section (C-section) at our institutions. We examined the occurrence of symptomatic perianal disease flares within 5 years after delivery in such women compared with nonpregnant CD controls. We also compared the occurrence of such flares between the 2 modes of delivery in women with established perianal CD. Results: We identified 61 pregnant patients with CD with established perianal disease (11 vaginal delivery, 50 through C-section) and 61 nonpregnant CD controls with perianal disease. One-third of the C-sections were primarily for obstetric indications. Six of the vaginal deliveries were complicated. Approximately, 36% of cases had a symptomatic perianal flare within 1 year after delivery. This was similar across both modes of delivery (P = 0.53) and similar to nonpregnant patients with CD. There was no difference in the rates of perianal surgical intervention or luminal disease flares in our population based on mode of delivery or between pregnant patients with CD and nonpregnant CD controls. Conclusions: We observed no difference in risk of symptomatic perianal flares in patients with established perianal CD delivering vaginally or through C-section. C1 [Cheng, Alice G.; Sauk, Jenny; Nguyen, Deanna D.; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Oxford, Emily C.; Sauk, Jenny; Nguyen, Deanna D.; Yajnik, Vijay; Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Sauk, Jenny; Nguyen, Deanna D.; Yajnik, Vijay; Friedman, Sonia; Ananthakrishnan, Ashwin N.] Harvard Univ, Sch Med, Boston, MA USA. [Friedman, Sonia] Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, Gastrointestinal Unit, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU National Institutes of Health (NIH) [P30 DK043351, K23 DK097142] FX Supported by the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A. N. Ananthakrishnan is supported in part by a grant from the NIH (K23 DK097142). NR 23 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD AUG PY 2014 VL 20 IS 8 BP 1391 EP 1398 DI 10.1097/MIB.0000000000000093 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2OK UT WOS:000340425000014 PM 24918322 ER PT J AU Redmann, M Dodson, M Boyer-Guittaut, M Darley-Usmar, V Zhang, JH AF Redmann, Matthew Dodson, Matthew Boyer-Guittaut, Michael Darley-Usmar, Victor Zhang, Jianhua TI Mitophagy mechanisms and role in human diseases SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Mitochondria; Parkinson's disease; Cancer; Mitophagy; Heart disease ID MITOCHONDRIAL QUALITY-CONTROL; OXIDATIVE STRESS; PARKINSONS-DISEASE; HEPATOCELLULAR-CARCINOMA; BREAST-CANCER; PINK1/PARKIN-MEDIATED MITOPHAGY; ADRENOCORTICAL TUMORS; DAMAGED MITOCHONDRIA; ATTENUATES MITOPHAGY; SELECTIVE AUTOPHAGY AB Mitophagy is a process of mitochondrial turnover through lysosomal mediated autophagy activities. This review will highlight recent studies that have identified mediators of mitophagy in response to starvation, loss of mitochondrial membrane potential or perturbation of mitochondrial integrity. Furthermore, we will review evidence of mitophagy dysfunction in various human diseases and discuss the potential for therapeutic interventions that target mitophagy processes. (C) 2014 Elsevier Ltd. All rights reserved. C1 [Redmann, Matthew; Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua] Univ Alabama Birmingham, Ctr Free Radical Biol, Birmingham, AL 35294 USA. [Redmann, Matthew; Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Zhang, Jianhua] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL 35294 USA. [Boyer-Guittaut, Michael] Univ Franche Comte, Biochim Lab, EA3922, SFR IBCT FED4234, F-25030 Besancon, France. RP Zhang, JH (reprint author), Univ Alabama Birmingham, Dept Pathol, BMRII 534,901 19th St S, Birmingham, AL 35294 USA. EM zhanja@uab.edu OI Zhang, Jianhua/0000-0002-2128-9574 FU NIH [R01-NS064090]; VA FX This work was supported by NIH R01-NS064090 and a VA merit award (to JZ). NR 113 TC 31 Z9 32 U1 3 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 EI 1878-5875 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2014 VL 53 BP 127 EP 133 DI 10.1016/j.biocel.2014.05.010 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA AN1KE UT WOS:000340340400016 PM 24842106 ER PT J AU Donohue, MC Sperling, RA Salmon, DP Rentz, DM Raman, R Thomas, RG Weiner, M Aisen, PS AF Donohue, Michael C. Sperling, Reisa A. Salmon, David P. Rentz, Dorene M. Raman, Rema Thomas, Ronald G. Weiner, Michael Aisen, Paul S. TI The Preclinical Alzheimer Cognitive Composite Measuring Amyloid-Related Decline SO JAMA NEUROLOGY LA English DT Article ID MINI-MENTAL STATE; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; CLINICAL-TRIALS; OLDEST-OLD; DISEASE; RECOMMENDATIONS; IMPAIRMENT; PREDICTION AB IMPORTANCE As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. OBJECTIVE To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). DESIGN, SETTING, AND PARTICIPANTS With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. MAIN OUTCOMES AND MEASURES For the 2 studies that collected data on A beta levels (ADNI and AIBL), we estimate decline in a preclinical AD "A beta-positive" placebo group and compare them with an "A beta-negative" group. For the study that did not include data on A beta levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-epsilon 4 and by clinical progression. RESULTS In ADNI, A beta-positive participants showed more decline than did A beta-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P = .02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P = .01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P = .002). In the ADCS-PI study, APOE-epsilon 4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P = .01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P = .001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P < .001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% a level, we project 80% power to detect effects in the range of Delta = 0.467 to 0.733 on the ADCS-PACC. CONCLUSIONS AND RELEVANCE Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials. C1 [Donohue, Michael C.; Raman, Rema] Univ Calif San Diego, Dept Family & Prevent Med, Div Biostat & Bioinformat, La Jolla, CA 92093 USA. [Donohue, Michael C.; Salmon, David P.; Raman, Rema; Thomas, Ronald G.; Aisen, Paul S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Sperling, Reisa A.; Rentz, Dorene M.] Harvard Univ, Brigham & Womens Hosp, Ctr Alzheimer Res & Treatment, Dept Neurol, Boston, MA USA. [Sperling, Reisa A.; Rentz, Dorene M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA USA. [Weiner, Michael] Ctr Imaging Neurodegenerat Dis, Dept Vet Affairs Med Ctr, San Francisco, CA USA. [Weiner, Michael] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP Donohue, MC (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, Div Biostat & Bioinformat, 9500 Gilman Dr,MC 0949, La Jolla, CA 92093 USA. EM mdonohue@ucsd.edu OI Donohue, Michael/0000-0001-6026-2238 FU National Institute on Aging - National Institutes of Health [U01-AG10483]; National Institutes of Health [1KL2RR031978]; Abbott; AC Immune; Alzheimer's Association; Alzheimer's Diseases Research Center; University of California, San Diego; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences; Araclon; AstraZeneca; Avid Radiopharmaceuticals; Bayer HealthCare; BioClinica; Biogen Idec; Bristol-Myers Squibb; Eisai; Elan; Eli Lilly; F. Hoffmann-La Roche; Genentech; GE Healthcare; Innogenetics NV; IXICO; Janssen Alzheimer Immunotherapy Research and Development, LLC; Johnson & Johnson Pharmaceutical Research and Development LLC; Kenes, International; Medpace; Merck; Meso Scale Diagnostics, LLC; National Brain Research Center, India; New York Academy of Sciences; Novartis; Pfizer; sanofi-aventis; Servier; Smartfish AS; Synarc; Takeda; University of Californa, Los Angeles FX Dr Donohue was supported by National Institute on Aging grant U01-AG10483 (principal investigator) funded by the National Institutes of Health. Dr Donohue was funded by grant 1KL2RR031978 from the National Institutes of Health and was supported by the generous contributions from Abbott; AC Immune; the Alzheimer's Association; the Alzheimer's Diseases Research Center; the University of California, San Diego; the Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences; Araclon; AstraZeneca; Avid Radiopharmaceuticals; Bayer HealthCare; BioClinica; Biogen Idec; Bristol-Myers Squibb; Eisai; Elan; Eli Lilly; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics NV; IXICO; Janssen Alzheimer Immunotherapy Research and Development, LLC; Johnson & Johnson Pharmaceutical Research and Development LLC; Kenes, International; Medpace; Merck; Meso Scale Diagnostics, LLC; National Brain Research Center, India, for Johns Hopkins Medicine; New York Academy of Sciences; Novartis; Pfizer; sanofi-aventis; Servier; Smartfish AS; Synarc; Takeda; and the University of Californa, Los Angeles. NR 51 TC 64 Z9 64 U1 4 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD AUG PY 2014 VL 71 IS 8 BP 961 EP 970 DI 10.1001/jamaneurol.2014.803 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA AN3IW UT WOS:000340481800005 PM 24886908 ER PT J AU Margolis, JM Chu, BC Wang, ZXJ Copher, R Cavazos, JE AF Margolis, Jay M. Chu, Bong-Chul Wang, Zhixiao J. Copher, Ronda Cavazos, Jose E. TI Effectiveness of Antiepileptic Drug Combination Therapy for Partial-Onset Seizures Based on Mechanisms of Action SO JAMA NEUROLOGY LA English DT Article ID TONIC CLONIC SEIZURES; CARBAMAZEPINE; EPILEPSY; ADULTS AB IMPORTANCE To our knowledge, the current study is the first to describe antiepileptic drug (AED) combination therapy patterns according to their mechanism of action (MOA) in a real-world setting and to evaluate the differences in outcomes comparing different-MOA combination therapy with same-MOA combination therapy for patients with partial-onset seizure. OBJECTIVE To compare treatment persistence and health care use with AED combinations categorized by MOA in patients with partial-onset seizures. DESIGN, SETTING, AND PARTICIPANTS Using the Truven Health MarketScan Commercial Claims Database containing 96 million covered lives from July 1, 2004, through March 31, 2011, adults with concomitant use of 2 different AEDs and a recent partial-onset seizure diagnosis were selected. Antiepileptic drugs were categorized by MOA: sodium channel blockers (SC), gamma-aminobutyric acid analogs (G), synaptic vesicle protein 2A binding (SV2), and multiple mechanisms (M). Patients were assigned a combination category based on their concomitant AED use. MAIN OUTCOMES AND MEASURES Treatment persistence was measured from the start of AED combination therapy until the end of the combination. Health care resource use was measured during the combination treatment duration. Multivariate analyses evaluated AED discontinuation risk and health care use according to MOA combinations. RESULTS Distribution of 8615 selected patients by combination was 3.3% for G+G, 7.5% for G+SV2, 8.6% for G+M, 13.9% for SC+SC, 19.0% for G+SC, 21.5% for SC+M, and 26.3% for SC+SV2. The same-MOA (G+G and SC+SC) combinations had the shortest persistence (mean [SD], 344 [345] days and 513 [530] days, respectively) and greater hazard of discontinuation compared with different-MOA combinations. Patients with different-MOA G combinations had a significantly lower risk for inpatient admission (odds ratio, 0.716; 95% CI, 0.539-0.952; P = .02) compared with G+G combinations. Patients with different-MOA SC combinations had significantly lower risks for emergency department visits (odds ratio, 0.853; 95% CI, 0.742-0.980; P = .03) compared with SC+SC combinations. CONCLUSIONS AND RELEVANCE The findings suggest that AED combinations with different MOAs have greater effectiveness as measured by treatment persistence and lower risks for hospitalization and emergency department visits. Further research is needed to more fully understand the role of the MOA in achieving optimal outcomes. C1 [Margolis, Jay M.] Truven Hlth Analyt, Bethesda, MD USA. [Chu, Bong-Chul] Truven Hlth Analyt, Santa Barbara, CA USA. [Wang, Zhixiao J.] Eisai Inc, Woodcliff Lake, NJ USA. [Copher, Ronda] Eisai Inc, Minneapolis, MN USA. [Cavazos, Jose E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Cavazos, Jose E.] South Texas Vet Hlth Care Syst, San Antonio Epilepsy Ctr Excellence, San Antonio, TX USA. RP Margolis, JM (reprint author), Truven Hlth Analyt, 332 Bryn Mawr Ave, Bala Cynwyd, PA 19004 USA. EM jay.margolis@truvenhealth.com RI Cavazos, Jose/J-4122-2016; OI Cavazos, Jose/0000-0001-5777-2608 FU Eisai Inc, Woodcliff Lake, New Jersey FX This research was sponsored by Eisai Inc, Woodcliff Lake, New Jersey. NR 15 TC 21 Z9 21 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 2168-6149 EI 2168-6157 J9 JAMA NEUROL JI JAMA Neurol. PD AUG PY 2014 VL 71 IS 8 BP 985 EP 993 DI 10.1001/jamaneurol.2014.808 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA AN3IW UT WOS:000340481800008 PM 24911669 ER PT J AU Fowler, SA Ananthakrishnan, AN Gardet, A Stevens, CR Korzenik, JR Sands, BE Daly, MJ Xavier, RJ Yajnik, V AF Fowler, Sharyle A. Ananthakrishnan, Ashwin N. Gardet, Agnes Stevens, Christine R. Korzenik, Joshua R. Sands, Bruce E. Daly, Mark J. Xavier, Ramnik J. Yajnik, Vijay TI SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease SO JOURNAL OF CROHNS & COLITIS LA English DT Article DE Crohn's disease; Surgery for IBD; Genotype/clinical phenotype; NOD2; SMAD3 ID INFLAMMATORY-BOWEL-DISEASE; NOD2/CARD15 GENE; NOD2 GENE; MUTATIONS; GENOTYPE; BETA; SUSCEPTIBILITY; ASSOCIATION; POPULATION; PREVALENCE AB Background and aims: More than 80% of Crohn's disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. Methods: CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. Results: 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p = 0.022) and penetrating behavior (HR 3.97, p = 0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p = 0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p = 0.001). NOD2 was not associated with increased risk of surgical recurrence. Conclusion: Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence. (c) 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. C1 [Fowler, Sharyle A.; Ananthakrishnan, Ashwin N.; Gardet, Agnes; Korzenik, Joshua R.; Xavier, Ramnik J.; Yajnik, Vijay] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Gardet, Agnes; Daly, Mark J.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Sands, Bruce E.] Mt Sinai Sch Med, Div Gastroenterol, New York, NY USA. [Stevens, Christine R.] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Yajnik, V (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St, Boston, MA 02114 USA. EM VYAJNIK@PARTNERS.ORG OI Sands, Bruce/0000-0001-5762-5042 FU National Institute of Diabetes and Digestive and Kidney Diseases [P30DK043351] FX Funding support: The project described was supported by Grant Number P30DK043351 from the National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health. NR 42 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1873-9946 EI 1876-4479 J9 J CROHNS COLITIS JI J. Crohns Colitis PD AUG 1 PY 2014 VL 8 IS 8 BP 845 EP 851 DI 10.1016/j.crohns.2014.01.003 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN1HL UT WOS:000340333200017 PM 24461721 ER PT J AU Lee, IA Low, D Kamba, A Llado, V Mizoguchi, E AF Lee, In-Ah Low, Daren Kamba, Alan Llado, Victoria Mizoguchi, Emiko TI Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells SO JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Chitinase inhibitor; Inflammatory bowel disease; AKT; Host-microbial interactions ID INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; COFFEE ENEMAS; PARKINSON-DISEASE; RISK; LOCI; NUMBER; DRUG AB The initial trigger of inflammatory bowel disease (IBD) can be partly attributed towards the interaction and invasion of intestinal epithelial cells (IECs) and submucosal compartments. Identifying safe and economical methods to block these interactions may help prevent the onset of early colitis. Chitinase 3-like 1 (CHI3L1) is an inducible host protein that facilitates bacterial attachment and invasion on/into IECs. Therefore, we test the hypothesis of inhibiting CHI3L1 using the pan-chitinase inhibitor caffeine to reduce the likelihood of early colitis onset. IEC lines were treated with caffeine (2.5 or 5 mM) and analyzed for CHI3L1 expression and the impact on bacterial invasion. In vivo, mice were treated with 2.5 mM caffeine and induced with 3.5 % dextran sulfate sodium (DSS)-mediated colitis and subsequently analyzed colitis development. In vitro, caffeine treatment in IEC lines down-regulated CHI3L1 mRNA expression, which resulted in the reduction of bacterial invasion in a caffeine dose-dependent manner. In vivo, mice treated with caffeine displayed a delayed response towards DSS-induced colitis, characterized by lower body weight loss, clinical and histological scores. Bacterial translocation into other organs and pro-inflammatory cytokines production were also reduced in the caffeine-treated mice with DSS-induced colitis. Caffeine treatment also resulted in the loss of CHI3L1-associated AKT signaling pathway activation both in vitro and in vivo. Development of acute colitis is reduced upon caffeine treatment. The mechanism involves the down-regulation of CHI3L1 expression and its associated bacterial interaction effect. Therefore, caffeine is proposed as a safe and economical candidate for successful IBD management. C1 [Lee, In-Ah; Low, Daren; Kamba, Alan; Llado, Victoria; Mizoguchi, Emiko] Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Boston, MA 02114 USA. [Lee, In-Ah; Low, Daren; Kamba, Alan; Llado, Victoria; Mizoguchi, Emiko] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mizoguchi, Emiko] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU National Institute of Health [DK 80070, DK74454, DK64289, DK43351, DK-068181, DK-033506, AI093588]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation; National Research Foundation of Korea (Seoul, South Korea); A*STAR Graduate Academy (Singapore) FX This work has been supported by the National Institute of Health (DK 80070, DK74454, DK64289 and DK43351, DK-068181, DK-033506, AI093588), and grants from the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation to EM. IAL was supported by the National Research Foundation of Korea (Seoul, South Korea) and DL has been awarded the international fellowship grant supported by A*STAR Graduate Academy (Singapore). NR 28 TC 7 Z9 7 U1 2 U2 11 PU SPRINGER JAPAN KK PI TOKYO PA CHIYODA FIRST BLDG EAST, 3-8-1 NISHI-KANDA, CHIYODA-KU, TOKYO, 101-0065, JAPAN SN 0944-1174 EI 1435-5922 J9 J GASTROENTEROL JI J. Gastroenterol. PD AUG PY 2014 VL 49 IS 8 BP 1206 EP 1216 DI 10.1007/s00535-013-0865-3 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AN2LH UT WOS:000340416200002 PM 23925589 ER PT J AU Eberlin, KR Babushkina, A Neira, JR Mudgal, CS AF Eberlin, Kyle R. Babushkina, Anna Neira, Juliana Rojas Mudgal, Chaitanya S. TI Outcomes of Closed Reduction and Periarticular Pinning of Base and Shaft Fractures of the Proximal Phalanx SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Base; percutaneous pinning; proximal phalanx; shaft ID K-WIRE FIXATION; INTERNAL-FIXATION; PLATE FIXATION; HAND FRACTURES; PIN FIXATION; COMPLICATIONS; DISLOCATIONS; METACARPAL; SCREW; WRIST AB Purpose To review the results of periarticular pinning of extra-articular fractures of the proximal phalanx base and shaft. Methods A retrospective review was performed of the senior author's practice (C.S.M.) from 2006 to 2012. The inclusion criteria were patients older than 18 years of age who underwent periarticular pinning of base or shaft fractures of the proximal phalanx. Age, sex, fracture location, fracture pattern, and time to surgery were recorded. Outcome measures were range of motion, time to healing, and complication rate. Results A total of 43 patients with 50 fractures were identified. There were 19 men and 24 women with 16 shaft and 34 base fractures. Five fractures were open. The little finger was involved in 62%, the ring finger in 30%, and the index and middle fingers in 4% each. Most fractures were transverse or oblique, and just over half had comminution and/or impaction. Average follow-up was 17 weeks, and average time to clinical union was 35 days. Nine patients (18%) were lost to follow-up. Twenty-six fingers had excellent results (63%), lacking less than 10 degrees of total motion. Seven patients (17%) had good results, lacking less than 20 degrees of motion; 7 patients had fair results (17%); and 1 patient had a poor result. Three patients (7%) developed stiffness requiring tenolysis. There were 2 pin-site infections, 1 of which resulted in a loss of reduction. Results for shaft and base fractures were not significantly different. Conclusions Percutaneous periarticular pinning is an acceptable option for unstable base and shaft fractures of the proximal phalanx. Most fractures healed within 4 weeks. The majority of patients had excellent or good results. Copyright (C) 2014 by the American Society for Surgery of the Hand. All rights reserved. C1 Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Hand Surg Serv, Boston, MA 02114 USA. RP Mudgal, CS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Suite 2100, Boston, MA 02114 USA. EM cmudgal@partners.org NR 24 TC 7 Z9 7 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD AUG PY 2014 VL 39 IS 8 BP 1524 EP 1528 DI 10.1016/j.jhsa.2014.05.008 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AN3TE UT WOS:000340510800010 PM 24996674 ER PT J AU Janssen, SJ Teunis, T ter Meulen, DP Hageman, MGJS Ring, D AF Janssen, Stein J. Teunis, Teun ter Meulen, Dirk P. Hageman, Michiel G. J. S. Ring, David TI Estimation of Base of Middle Phalanx Size Using Anatomical Landmarks SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Anatomical landmarks; articular surface size; fracture; middle phalanx; proximal interphalangeal joint ID INTERPHALANGEAL JOINT; HAND AB Purpose To determine whether there is a measurable and reproducible relationship between the articular surface size of the middle phalanx base and the size of the middle phalanx head and proximal phalanx length of the same finger. Methods Size of the articular surface of the middle phalanx base, size of the middle phalanx head, and proximal phalanx length were measured in 84 lateral radiographs by 3 observers. Results The ratio of articular surface size of the middle phalanx base to the proximal phalanx length of the same finger was 0.17. The ratio of articular surface size of the middle phalanx base to the size of the middle phalanx head of the same finger was 1.34. The intraclass correlation (ICC) among 3 raters was 0.99 for proximal phalanx length and 0.88 for size of the middle phalanx head. Conclusions Knowledge of this relationship and ratios allow for accurate estimation of the percentage of articular surface involvement in a fracture of the middle phalanx base. The ICC was highest for measuring proximal phalanx length, making it the most reliable measurement for estimation of the articular surface size. Copyright (C) 2014 by the American Society for Surgery of the Hand. All rights reserved. C1 [Janssen, Stein J.; Teunis, Teun; ter Meulen, Dirk P.; Hageman, Michiel G. J. S.; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Hand & Upper Extrem Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@mgh.harvard.edu OI Ring, David/0000-0002-6506-4879 FU Dutch from Marti-Keunig Eckhart Stichting; Anna Foundation; Spinoza Foundation; Dutch from the Anna Foundation FX M.G.J.S.H. supported by Dutch research grants from Marti-Keunig Eckhart Stichting, Anna Foundation, and Spinoza Foundation. D.P.t.M. is supported by a Dutch research grant from the Anna Foundation. NR 11 TC 2 Z9 2 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD AUG PY 2014 VL 39 IS 8 BP 1544 EP 1548 DI 10.1016/j.jhsa.2014.05.019 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AN3TE UT WOS:000340510800014 PM 24996675 ER PT J AU Barber, LA Hageman, MGJS King, JD Bekkers, S Bot, AG Ring, D AF Barber, Lauren A. Hageman, Michiel G. J. S. King, John D. Bekkers, Stijn Bot, Arjan G. Ring, David TI The Influence of Patients' Participation in Research on Their Satisfaction SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Clinical research; hand surgery; patient satisfaction; questionnaires ID QUALITY-ASSURANCE STANDARDS; HEALTH ANXIETY INVENTORY; MEDICAL-CARE; CHRONIC DISEASE; METAANALYSIS; MODEL; PAIN; AGE AB Purpose To determine if there was a difference between patients participating in research and those who did not regarding their satisfaction with the medical encounter and their physician. Methods We prospectively randomized 128 patients to either complete 20 minutes of questionnaires (participate in research) or not. After the visit, all patients rated their satisfaction with their visit and satisfaction with the doctor on an 11-point ordinal satisfaction scales, with 0 being not at all satisfied and 10 being completely satisfied. Average satisfaction scores were analyzed in relation to demographics, questionnaires, and involvement in research. Results There were no significant differences between patients that did and did not participate in research for satisfaction with the medical encounter or satisfaction with the treating physician. Satisfaction was not associated with marital status, work status, or diagnosis. There was a significant correlation between greater satisfaction and both less education and lower self-efficacy. There was no significant correlation between patient satisfaction and magnitude of disability, pain intensity, or health anxiety. Conclusions This study demonstrated that patients' participation in research can coexist with patient satisfaction. (C) 2014 American Society for Surgery of the Hand All rights reserved. C1 [Barber, Lauren A.; Hageman, Michiel G. J. S.; King, John D.; Bekkers, Stijn; Bot, Arjan G.; Ring, David] Massachusetts Gen Hosp, Orthopaed Hand Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Orthopaed Hand Serv, Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Bekkers, Stijn/0000-0002-8330-9243 FU Dutch from Marti-Keunig Eckhart Stichting; Dutch from Anna Foundation [br2012/06] FX M.G.J.S.H. is supported by Dutch research grants from Marti-Keunig Eckhart Stichting and Anna Foundation (identification number br2012/06) NR 18 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 EI 1531-6564 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD AUG PY 2014 VL 39 IS 8 BP 1591 EP 1594 DI 10.1016/j.jhsa.2014.04.032 PG 4 WC Orthopedics; Surgery SC Orthopedics; Surgery GA AN3TE UT WOS:000340510800023 PM 24881898 ER PT J AU Ojikutu, B Nnaji, C Sithole-Berk, J Bogart, LM Gona, P AF Ojikutu, Bisola Nnaji, Chioma Sithole-Berk, Juliet Bogart, Laura M. Gona, Philimon TI Barriers to HIV Testing in Black Immigrants to the US SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE HIV; HIV testing; Black immigrants; health care access ID AFRICAN-AMERICAN MEN; HEALTH-CARE EXPERIENCES; UNITED-STATES; LATINO IMMIGRANTS; UNDOCUMENTED IMMIGRANTS; CONSPIRACY BELIEFS; INFECTED PERSONS; HIGH-RISK; ACCESS; CANCER AB Background. Late HIV testing is common among immigrants from sub Saharan Africa and the Caribbean. Since 2010, HIV testing is no longer a required component of immigrant screening examinations or mandatory for immigrants seeking long term residence in the US. Thus, barriers to HIV testing must be addressed. Methods. Five hundred and fifty-five (555) immigrants completed a barriers-to-HIV testing scale. Univariate and multivariate linear regression were performed to examine predictors of barriers. Results. In multivariate analysis, primary language other than English (beta=2.9, p=.04), lower education (beta=5.8, p=.03), low income [= below $20K/year] (beta=4.6, p=.01), no regular provider (beta=5.2, p=.002) and recent immigration (beta=5.7, p=.0008) were independently associated with greater barriers. Barriers due to health care access, privacy, fatalism, and anticipated stigma were greater for recent versus longer term immigrants. Discussion. Immigrants from sub-Saharan Africa and the Caribbean face significant barriers to HIV testing. Interventions to improve access and timely entry into care are needed. C1 [Ojikutu, Bisola] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ojikutu, Bisola; Bogart, Laura M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Ojikutu, Bisola] Johns Snow Res & Training Inst, Boston, MA USA. [Nnaji, Chioma; Sithole-Berk, Juliet] Multicultural AIDS Coalit, Jamaica Plain, MA USA. [Bogart, Laura M.] Boston Childrens Hosp, Boston, MA USA. [Gona, Philimon] Univ Massachusetts, Boston, MA 02125 USA. RP Ojikutu, B (reprint author), Massachusetts Gen Hosp, Cox 5,55 Fruit St, Boston, MA 02114 USA. EM bojikutu@partners.org FU NIAID NIH HHS [P30 AI060354]; NIMH NIH HHS [K23 MH107316] NR 68 TC 7 Z9 7 U1 4 U2 9 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2014 VL 25 IS 3 BP 1052 EP 1066 PG 15 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AN0XC UT WOS:000340306300009 PM 25130224 ER PT J AU Chang, TE Weiss, AP Marques, L Baer, L Vogeli, C Trinh, NHT Clain, AJ Blais, MA Fava, M Yeung, AS AF Chang, Trina E. Weiss, Anthony P. Marques, Luana Baer, Lee Vogeli, Christine Trinh, Nhi-Ha T. Clain, Alisabet J. Blais, Mark A. Fava, Maurizio Yeung, Albert S. TI Race/Ethnicity and Other Social Determinants of Psychological Well-being and Functioning in Mental Health Clinics SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE Mental health; minority health; health status disparities; social determinants of health ID NATIONAL COMORBIDITY SURVEY; DEPRESSION TREATMENT; UNITED-STATES; ETHNIC-DIFFERENCES; ASIAN-AMERICANS; OUTCOME MEASURE; LATINOS; CARE; DISPARITIES; SERVICES AB Significant racial and ethnic differences exist in the receipt of psychiatric care and help-seeking. We examined the relationship between race/ethnicity and psychological well-being and functioning in psychiatric outpatients. We analyzed intake data for 8,697 adult patients in psychiatry clinics in New England between 2008 and 2010. Patients rated psychological wellbeing using the Schwartz Outcome Scale (SOS-10); clinicians rated the Global Assessment of Functioning (GAF). In an analysis of variance with covariates, race/ethnicity exhibited a small but statistically significant association with GAF (F(4,8481)=17.902, p<.001) and SOS-10 scores (F(4,8165)=7.271, p<.001). However, after adjustment for physical health and socioeconomic variables, these differences became insignificant or were reversed. Our findings suggest that the relationship between race/ethnicity and mental health may be confounded by other socioeconomic or health differences and may be small compared with the effect of those variables. Future studies on race and psychological well-being should take social determinants of health into consideration. C1 [Chang, Trina E.; Weiss, Anthony P.; Marques, Luana; Baer, Lee; Trinh, Nhi-Ha T.; Clain, Alisabet J.; Blais, Mark A.; Fava, Maurizio; Yeung, Albert S.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Vogeli, Christine] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Chang, TE (reprint author), Depress Clin & Res Program, 1 Bowdoin Sq 6th Floor, Boston, MA 02114 USA. FU NCRR NIH HHS [UL1 RR 025758, UL1 RR025758]; NIMH NIH HHS [MH- 19126] NR 25 TC 2 Z9 2 U1 2 U2 5 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 EI 1548-6869 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2014 VL 25 IS 3 BP 1418 EP 1431 PG 14 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA AN0XC UT WOS:000340306300034 PM 25130249 ER PT J AU Makam, AN Auerbach, AD Steinman, MA AF Makam, Anil N. Auerbach, Andrew D. Steinman, Michael A. TI Blood culture use in the emergency department in patients hospitalized with respiratory symptoms due to a nonpneumonia illness SO JOURNAL OF HOSPITAL MEDICINE LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; HOLD-UP; MANAGEMENT; SCRUTINY; NHAMCS; RULE AB BACKGROUND Guidelines and performance measures recommend obtaining blood cultures in selected patients hospitalized with community-acquired pneumonia (CAP). Due to inherent diagnostic uncertainty, there may be spillover effects of these recommendations on other conditions that resemble pneumonia. METHODS Using data from the 2002 to 2010 National Hospital Ambulatory Medical Care Survey, a nationally representative sample of emergency department (ED) visits in the United States, we analyzed trends in obtaining cultures in patients hospitalized with respiratory symptoms due to a nonpneumonia illness using linear regression. RESULTS The most common primary admission diagnoses for these visits included heart failure (16%), chronic obstructive pulmonary disease (13%), and chest pain (12%). The proportion of cultures collected in the ED during these visits increased from 10% (95% confidence interval [CI]: 7%-14%) in 2002 to 20% (95% CI: 16%-26%) in 2010 (P<0.001 for the trend). This represented a parallel increase compared to patients hospitalized with CAP (P=0.12 for the difference in trends). CONCLUSIONS The increase in collecting cultures in the ED in patients hospitalized with respiratory symptoms due to a nonpneumonia illness suggests an important potential unintended consequence of blood culture recommendations for CAP. More attention to the judicious use of blood cultures to reduce harm and costs is needed. Journal of Hospital Medicine 2014;9:521-524. (c) 2014 Society of Hospital Medicine C1 [Makam, Anil N.] Univ Texas SW Med Ctr Dallas, Div Gen Internal Med, Dallas, TX 75390 USA. [Auerbach, Andrew D.] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94143 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Steinman, Michael A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Makam, AN (reprint author), 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM anil.makam@utsouthwestern.edu OI Makam, Anil/0000-0001-7072-9946 FU NRSA [T32HP19025-07-00] FX Dr. Makam's work on this project was completed while he was a Primary Care Research Fellow at the University of California San Francisco, funded by an NRSA training grant (T32HP19025-07-00). The authors report no conflicts of interest. NR 17 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 EI 1553-5606 J9 J HOSP MED JI J. Hosp. Med. PD AUG PY 2014 VL 9 IS 8 BP 521 EP 524 DI 10.1002/jhm.2205 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA AN3YM UT WOS:000340524800007 PM 24753399 ER PT J AU Chmelik, M Povazan, M Jiru, F Kukurova, IJ Dezortova, M Krssak, M Bogner, W Hajek, M Trattnig, S Valkovic, L AF Chmelik, Marek Povazan, Michal Jiru, Filip Kukurova, Ivica Just Dezortova, Monika Krssak, Martin Bogner, Wolfgang Hajek, Milan Trattnig, Siegfried Valkovic, Ladislav TI Flip-Angle Mapping of P-31 Coils by Steady-State MR Spectroscopic Imaging SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE B-1 mapping; MRSI; steady-state; P-31; 7 Tesla; flip-angle ID IN-VIVO; RADIOFREQUENCY FIELD; 7 T; HUMAN BRAIN; LIVER; QUANTIFICATION; SHIFT AB Purpose: Phosphorus (P-31) MR spectroscopic imaging (MRSI) is primarily applied with sensitive, surface radio-frequency (RF) coils that provide inhomogeneous excitation RF field (B-1(+)) and rough localization due to their B-1(+) and sensitivity (B-1(+)) profiles. A careful and time-consuming pulse adjustment and an accurate knowledge of flip angle (FA) are mandatory for quantification corrections. Materials and Methods: In this study, a simple, fast, and universal P-31 B-1(+) mapping method is proposed, which requires fast steady-state MRSI (typically one sixth of normal measurement time) in addition to the typical MRSI acquired within the examination protocol. The FA maps are calculated from the ratio of the signal intensities acquired by these two measurements and were used to correct for the influence of B-1(+) on the metabolite maps. Results: In vitro tests were performed on two scanners (3 and 7 Tesla) using a surface and a volume coil. The calculated FA maps were in good agreement with adjusted nominal FAs and the theoretical calculation using the Biot-Savart law. The method was successfully tested in vivo in the calf muscle and the brain of healthy volunteers (n = 4). The corrected metabolite maps show higher homogeneity compared with their noncorrected versions. Conclusion: The calculated FA maps helped with B-1(+) inhomogeneity corrections of acquired in vivo data, and should also be useful with optimization and testing of pulse performances, or with the construction quality tests of new dual-channel H-1/P-31 coils. C1 [Chmelik, Marek; Povazan, Michal; Kukurova, Ivica Just; Krssak, Martin; Bogner, Wolfgang; Trattnig, Siegfried; Valkovic, Ladislav] Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, MR Ctr Excellence, A-1090 Vienna, Austria. [Jiru, Filip; Dezortova, Monika; Hajek, Milan] Inst Clin & Expt Med, Dept Diagnost & Intervent Radiol, MR Unit, Prague, Czech Republic. [Kukurova, Ivica Just] Slovak Univ Technol Bratislava, Fac Chem & Food Technol, Dept NMR & MS, Bratislava, Slovakia. [Krssak, Martin] Med Univ Vienna, Dept Internal Med 3, A-1090 Vienna, Austria. [Bogner, Wolfgang] Harvard Univ, Sch Med, Dept Radiol,Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02115 USA. [Valkovic, Ladislav] Slovak Acad Sci, Inst Measurement Sci, Dept Imaging Methods, Bratislava, Slovakia. RP Trattnig, S (reprint author), Med Univ Vienna, Dept Biomed Imaging & Image Guided Therapy, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM siegfried.trattnig@meduniwien.ac.at OI Povazan, Michal/0000-0002-5498-5162; Valkovic, Ladislav/0000-0003-2567-3642; Bogner, Wolfgang/0000-0002-0130-3463 FU Vienna Spots of Excellence des Wiener Wissenschafts-und Technologie-Fonds (WWTF) - Vienna Advanced Imaging Center (VIACLIC); OeNB Jubilaeumsfond [13629, 15455]; Aktion AUT-CZE [61p4]; Slovak Grant Agency VEGA [2/0090/11] FX Contract grant sponsor: Vienna Spots of Excellence des Wiener Wissenschafts-und Technologie-Fonds (WWTF) - Vienna Advanced Imaging Center (VIACLIC); Contract grant sponsor: OeNB Jubilaeumsfond; Contract grant numbers: 13629, 15455; Contract grant sponsor: Aktion AUT-CZE; Contract grant number: 61p4; Contract grant sponsor: Slovak Grant Agency VEGA; Contract grant number: 2/0090/11. NR 26 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-1807 EI 1522-2586 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD AUG PY 2014 VL 40 IS 2 BP 391 EP 397 DI 10.1002/jmri.24401 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AN4DJ UT WOS:000340537500019 PM 24925600 ER PT J AU Kellner, V Menkes-Caspi, N Beker, S Stern, EA AF Kellner, V Menkes-Caspi, N. Beker, S. Stern, E. A. TI Amyloid-beta alters ongoing neuronal activity and excitability in frontal cortex SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Meeting Abstract CT 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting CY DEC 14-17, 2013 CL Eilat, ISRAEL SP Israel Soc Neuroscience C1 [Kellner, V; Menkes-Caspi, N.; Beker, S.; Stern, E. A.] Bar Ilan Univ, Gonda Interdisciplinary Brain Res Ctr, Ramat Gan, Israel. [Stern, E. A.] Massachusetts Gen Hosp, Dept Neurol, MIND, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2014 VL 53 SU 1 BP S68 EP S68 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA AN3GN UT WOS:000340474000176 ER PT J AU Bailey, FA Williams, BR Goode, PS Woodby, LL Granstaff, US Echt, KV Redden, DT Kvale, E Burgio, KL AF Bailey, F. Amos Williams, Beverly R. Goode, Patricia S. Woodby, Lesa L. Granstaff, U. Shanette Echt, Katharina V. Redden, David T. Kvale, Elizabeth Burgio, Kathryn L. TI Impact of a Hospice Emergency Kit for Veterans and Their Caregivers: A Prospective Cohort Study SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID MANAGING MEDICATIONS; CARE; HOME; SUPPORT AB Background: Although hospice emergency kits (HEKs) are provided by many home hospice agencies, little is known about their use, side effects, and perceived impact. Objective: To evaluate HEK medication utilization, side effects, and impact as perceived by home hospice patients and their caregivers. Methods: We conducted a prospective longitudinal cohort study. Participants included 43 veterans and their family/caregivers referred to community home hospices with a Veterans Affairs (VA)-provided HEK. Measurements included patient/family reports based on weekly telephone interviews, electronic medical record (EMR) review, and after-death caregiver interviews. Results: The HEK was used by 27 of 43 patients/caregivers (62.8%). In 11 cases, they reported using the kit on more than one occasion. The most commonly used medications were morphine concentrate (30.2% of patients), lorazepam (20.9%), and levofloxacin (16.3%). In 15 cases (34.9%), the family thought the HEK may have helped the patient stay at home. Nineteen of the 43 patients made at least one visit to the emergency department (ED) and 22 were hospitalized. Most admissions through the ED were due to uncontrolled pain and/or gastrointestinal problems, such as nausea or bowel obstruction. In after-death interviews, opinions of the HEK were uniformly positive. Respondents described the HEK's usefulness and felt supported and empowered by its presence in the home. Minor side effects were reported in four cases. Conclusions: Findings provide promising evidence that HEKs are a feasible and well-tolerated method for achieving timely relief of emergent symptoms in home hospice patients and possibly avoiding unwanted ED visits and hospitalizations. C1 [Bailey, F. Amos; Williams, Beverly R.; Goode, Patricia S.; Woodby, Lesa L.; Granstaff, U. Shanette; Echt, Katharina V.; Redden, David T.; Kvale, Elizabeth; Burgio, Kathryn L.] Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, Birmingham, AL USA. [Bailey, F. Amos; Williams, Beverly R.; Goode, Patricia S.; Woodby, Lesa L.; Granstaff, U. Shanette; Echt, Katharina V.; Redden, David T.; Kvale, Elizabeth; Burgio, Kathryn L.] Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Dept Vet Affairs, Atlanta, GA USA. [Bailey, F. Amos; Williams, Beverly R.; Goode, Patricia S.; Woodby, Lesa L.; Granstaff, U. Shanette; Redden, David T.; Kvale, Elizabeth; Burgio, Kathryn L.] Univ Alabama Birmingham, Birmingham, AL USA. [Echt, Katharina V.] Emory Univ, Atlanta, GA 30322 USA. RP Burgio, KL (reprint author), Birmingham VA Med Ctr, Geriatr Res Educ & Clin Ctr, 11G 700 South 19th St, Birmingham, AL 35233 USA. EM kburgio@uabmc.edu FU Birmingham/Atlanta Geriatric Research, Education, and Clinical Center (GRECC); Research Enhancement Award Program (REAP), Department of Veterans Affairs FX This research was supported by the Birmingham/Atlanta Geriatric Research, Education, and Clinical Center (GRECC) and Research Enhancement Award Program (REAP), Department of Veterans Affairs. NR 19 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2014 VL 17 IS 8 BP 931 EP 938 DI 10.1089/jpm.2013.0395 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AN4BP UT WOS:000340532900013 PM 24927070 ER PT J AU Rosenberg, AR Dussel, V Orellana, L Kang, T Geyer, JR Feudtner, C Wolfe, J AF Rosenberg, Abby R. Dussel, Veronica Orellana, Liliana Kang, Tammy Geyer, J. Russel Feudtner, Chris Wolfe, Joanne TI What's Missing in Missing Data? Omissions in Survey Responses among Parents of Children with Advanced Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID OF-LIFE CARE; PROGNOSIS; IMPACT; EXPERIENCES; PREFERENCES; THERAPY AB Background: Missing data is a common phenomenon with survey-based research; patterns of missing data may elucidate why participants decline to answer certain questions. Objective: To describe patterns of missing data in the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) study, and highlight challenges in asking sensitive research questions. Design: Cross-sectional, survey-based study embedded within a randomized controlled trial. Setting: Three large children's hospitals: Dana-Farber/Boston Children's Cancer and Blood Disorders Center (DF/BCCDC); Children's Hospital of Philadelphia (CHOP); and Seattle Children's Hospital (SCH). Measurements: At the time of their child's enrollment, parents completed the Survey about Caring for Children with Cancer (SCCC), including demographics, perceptions of prognosis, treatment goals, quality of life, and psychological distress. Results: Eighty-six of 104 parents completed surveys (83% response). The proportion of missing data varied by question type. While 14 parents (16%) left demographic fields blank, over half (n = 48; 56%) declined to answer at least one question about their child's prognosis, especially life expectancy. The presence of missing data was unrelated to the child's diagnosis, time from progression, time to death, or parent distress (p > 0.3 for each). Written explanations in survey margins suggested that addressing a child's life expectancy is particularly challenging for parents. Conclusions and Relevance: Parents of children with cancer commonly refrain from answering questions about their child's prognosis, however, they may be more likely to address general cure likelihood than explicit life expectancy. Understanding acceptability of sensitive questions in survey-based research will foster higher quality palliative care research. C1 [Rosenberg, Abby R.; Geyer, J. Russel] Seattle Childrens Hosp, Seattle, WA USA. [Rosenberg, Abby R.; Geyer, J. Russel] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Rosenberg, Abby R.; Geyer, J. Russel] Univ Washington, Seattle, WA 98195 USA. [Rosenberg, Abby R.] Treuman Katz Ctr Pediat Bioeth, Seattle, WA USA. [Dussel, Veronica; Wolfe, Joanne] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02215 USA. [Wolfe, Joanne] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02215 USA. [Dussel, Veronica] Inst Clin Effectiveness & Hlth Policy, Buenos Aires, DF, Argentina. [Orellana, Liliana] Natl Canc Inst, Buenos Aires, DF, Argentina. [Kang, Tammy; Feudtner, Chris] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Wolfe, Joanne] Boston Childrens Hosp, Boston, MA USA. RP Wolfe, J (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, 450 Brookline Ave, Boston, MA 02215 USA. EM joanne_wolfe@dfci.harvard.edu RI Orellana, Liliana/I-5249-2013; Orellana, Liliana/S-3302-2016 OI Orellana, Liliana/0000-0003-3736-4337; Orellana, Liliana/0000-0003-3736-4337 FU NIH/NCI [1K07 CA096746-01]; Charles H. Hood Foundation Child Health Research Award; American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families; St. Baldrick's Research Fellowship FX We want to thank the families for their willingness to participate in the study; and Sara Aldridge, Lindsay Teittinen, Janis Scanlon, Karen Carroll, and Karina Bloom for their work on enrollment and data collection. This project was part of the PediQUEST study (Evaluation of Pediatric Quality of Life and Evaluation of Symptoms Technology in Children with Cancer) and funded by NIH/NCI 1K07 CA096746-01, a Charles H. Hood Foundation Child Health Research Award and an American Cancer Society Pilot and Exploratory Project Award in Palliative Care of Cancer Patients and Their Families. A. R. R. is supported by a St. Baldrick's Research Fellowship. NR 18 TC 0 Z9 0 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 EI 1557-7740 J9 J PALLIAT MED JI J. Palliat. Med. PD AUG PY 2014 VL 17 IS 8 BP 953 EP 956 DI 10.1089/jpm.2013.0663 PG 4 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AN4BP UT WOS:000340532900017 PM 24865204 ER PT J AU Stey, AM Ko, CY Hall, BL Louie, R Lawson, EH Gibbons, MM Zingmond, DS Russell, MM AF Stey, Anne M. Ko, Clifford Y. Hall, Bruce Lee Louie, Rachel Lawson, Elise H. Gibbons, Melinda M. Zingmond, David S. Russell, Marcia M. TI Are Procedures Codes in Claims Data a Reliable Indicator of Intraoperative Splenic Injury Compared with Clinical Registry Data? SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID OF-VETERANS-AFFAIRS; QUALITY IMPROVEMENT PROGRAM; SURGEONS NATIONAL DATABASES; BYPASS GRAFT-SURGERY; ADMINISTRATIVE DATA; SURGICAL QUALITY; ACS-NSQIP; COMPLICATION RATES; DECADES EXPERIENCE; ADVERSE EVENTS AB BACKGROUND: Identifying iatrogenic injuries using existing data sources is important for improved transparency in the occurrence of intraoperative events. There is evidence that procedure codes are reliably recorded in claims data. The objective of this study was to assess whether concurrent splenic procedure codes in patients undergoing colectomy procedures are reliably coded in claims data as compared with clinical registry data. STUDY DESIGN: Patients who underwent colectomy procedures in the absence of neoplastic diagnosis codes were identified from American College of Surgeons (ACS) NSQIP data linked with Medicare inpatient claims data file (2005 to 2008). A kappa statistic was used to assess coding concordance between ACS NSQIP and Medicare inpatient claims, with ACS NSQIP serving as the reference standard. RESULTS: A total of 11,367 colectomy patients were identified from 212 hospitals. There were 114 patients (1%) who had a concurrent splenic procedure code recorded in either ACS NSQIP or Medicare inpatient claims. There were 7 patients who had a splenic injury diagnosis code recorded in either data source. Agreement of splenic procedure codes between the data sources was substantial (kappa statistic 0.72; 95% CI, 0.64-0.79). Medicare inpatient claims identified 81% of the splenic procedure codes recorded in ACS NSQIP, and 99% of the patients without a splenic procedure code. CONCLUSIONS: It is feasible to use Medicare claims data to identify splenic injuries occurring during colectomy procedures, as claims data have moderate sensitivity and excellent specificity for capturing concurrent splenic procedure codes compared with ACS NSQIP. (C) 2014 by the American College of Surgeons C1 [Stey, Anne M.] Mt Sinai Med Ctr, Icahn Sch Med, New York, NY 10029 USA. [Stey, Anne M.; Ko, Clifford Y.; Louie, Rachel; Lawson, Elise H.; Gibbons, Melinda M.; Zingmond, David S.; Russell, Marcia M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ko, Clifford Y.; Russell, Marcia M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Ko, Clifford Y.; Hall, Bruce Lee] Amer Coll Surg, Chicago, IL USA. [Hall, Bruce Lee] Washington Univ, St Louis VA Med Ctr, Dept Surg, Olin Business Sch, St Louis, MO USA. [Hall, Bruce Lee] Washington Univ, St Louis VA Med Ctr, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce Lee] BJC Healthcare St Louis, St Louis, MO USA. RP Stey, AM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 10940 Wilshire Blvd,Suite 710, Los Angeles, CA 90024 USA. EM as013j@gmail.com FU Robert Wood Johnson Foundation; US Department of Veterans Affairs FX Dr Stey's time for this publication was supported by The Robert Wood Johnson Foundation Clinical Scholars program and the US Department of Veterans Affairs. NR 35 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD AUG PY 2014 VL 219 IS 2 BP 237 EP U207 DI 10.1016/j.jamcollsurg.2014.02.029 PG 9 WC Surgery SC Surgery GA AN3LM UT WOS:000340489600013 PM 24891210 ER PT J AU Maggiore, RJ Dale, W Gross, CP Feng, T Tew, WP Mohile, SG Owusu, C Klepin, HD Lichtman, SM Gajra, A Ramani, R Katheria, V Zavala, L Hurria, A AF Maggiore, Ronald J. Dale, William Gross, Cary P. Feng, Tao Tew, William P. Mohile, Supriya G. Owusu, Cynthia Klepin, Heidi D. Lichtman, Stuart M. Gajra, Ajeet Ramani, Rupal Katheria, Vani Zavala, Laura Hurria, Arti CA Canc Aging Res Grp TI Polypharmacy and Potentially Inappropriate Medication Use in Older Adults with Cancer Undergoing Chemotherapy: Effect on Chemotherapy-Related Toxicity and Hospitalization During Treatment SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE polypharmacy; cancer; elderly; chemotherapy; toxicity ID ADVERSE DRUG-REACTIONS; ELDERLY-PATIENTS; BEERS CRITERIA; PREVALENCE; QUALITY; PEOPLE; APPROPRIATENESS; METAANALYSIS; POPULATION; MANAGEMENT AB OBJECTIVES: To evaluate the prevalence of polypharmacy and potentially inappropriate medication (PIM) use and the association between these and chemotherapy-related adverse events in older adults with cancer undergoing chemotherapy. DESIGN: Secondary analysis of prospectively collected data. SETTING: Outpatient oncology clinics in seven academic medical centers. PARTICIPANTS: Adults aged 65 and older with cancer undergoing chemotherapy. MEASUREMENTS: Measures included number of daily medications (polypharmacy); PIM use based on three indices (Beers, Zhan, and Drugs to Avoid in the Elderly criteria), and use of six "high risk" medication classes for adverse drug events (anticoagulants, antiplatelet agents, opioids, insulin, oral hypoglycemics, antiarrhythmics). Using multivariate logistic regression, the relations were evaluated between these criteria and Grade 3 to 5 chemotherapy-related toxicity and between these criteria and hospitalization during chemotherapy. RESULTS: Participants (N = 500; mean age 73, 61% Stage IV disease) took a mean of 5 +/- 4 daily medications (range 0-23). PIM use was common (up to 29% according to Beers criteria). No association was found between number of daily medications (reference 0-3 medications) and toxicity (4-9 medications, odds ratio (OR) = 1.34, 95% confidence interval (CI) = 0.92-1.97; >= 10 medications, OR = 0.82, 95% CI = 0.45-1.49) or hospitalization (>= 4 medications, OR = 1.34, 95% CI = 0.82-2.18, P = .24). There was also no association between PIM use and toxicity (P = .93) or hospitalization (P = .98). No medication class was associated with either outcome. CONCLUSIONS: Polypharmacy and PIM use were common but were not associated with chemotherapy-related toxicity or hospitalization in older adults with cancer. C1 [Maggiore, Ronald J.] Portland VA Med Ctr, Portland, OR USA. [Maggiore, Ronald J.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Dale, William] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Gross, Cary P.] Yale Univ, Ctr Comprehens Canc, New Haven, CT USA. [Gross, Cary P.] Yale Univ, Sch Med, New Haven, CT USA. [Feng, Tao; Ramani, Rupal; Katheria, Vani; Zavala, Laura; Hurria, Arti] City Hope Natl Med Ctr, Ctr Comprehens Canc, Duarte, CA 91001 USA. [Tew, William P.; Lichtman, Stuart M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Mohile, Supriya G.] Univ Rochester, Rochester, NY USA. [Owusu, Cynthia] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Klepin, Heidi D.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Gajra, Ajeet] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Gajra, Ajeet] Syracuse Vet Affairs Med Ctr, Syracuse, NY USA. RP Hurria, A (reprint author), City Hope Natl Med Ctr, Canc & Aging Res Program, 1500 E Duarte Rd, Duarte, CA 91001 USA. EM ahurria@coh.org FU Paul Beeson Career Development Award in Aging Research [K23 AG026749-01, 1 K08 AG24842]; American Society of Clinical Oncology; Association of Specialty Professors; Junior Development Award in Geriatric Oncology; National Institute on Aging Geriatric Research Training Grant [T32 AG19134]; John A. Hartford Center of Excellence in Geriatrics FX This research was supported by Paul Beeson Career Development Award in Aging Research K23 AG026749-01, (PI: Dr. Hurria) and American Society of Clinical Oncology, Association of Specialty Professors, Junior Development Award in Geriatric Oncology (PI: Dr. Hurria). Dr. Maggiore's efforts are supported by National Institute on Aging Geriatric Research Training Grant T32 AG19134 under the guidance of Drs. Gross, Hurria, and Thomas Gill. Dr. Dale's efforts are supported by the John A. Hartford Center of Excellence in Geriatrics. Dr. Gross's efforts are supported by Paul Beeson Career Development Award in Aging Research 1 K08 AG24842. NR 38 TC 17 Z9 17 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2014 VL 62 IS 8 BP 1505 EP 1512 DI 10.1111/jgs.12942 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3JE UT WOS:000340482800011 PM 25041361 ER PT J AU Gillespie, SM Brandt, LE Chang, A Chao, SH Corcoran, AM Miller, R Harper, GM Levine, SA Medina-Walpole, A AF Gillespie, Suzanne M. Brandt, Lynsey E. Chang, Anna Chao, Serena H. Corcoran, Amy M. Miller, Rachel Harper, G. Michael Levine, Sharon A. Medina-Walpole, Annette TI Staying in the Game: The 10-Step Approach to Sustaining Geriatrics Education in Hospitalists and Subspecialty Providers SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE geriatrics education; Donald W. Reynolds Foundation; hospitalist and subspecialist education ID FACULTY-DEVELOPMENT PROGRAM; MEDICAL-STUDENTS; CURRICULUM; PATIENT; CARE AB Geriatrics as a field has been fortunate to have the support of several philanthropic organizations to advance geriatrics education and training in the past two decades. Awardees of such grants were presented with unparalleled opportunities to develop new and innovative educational initiatives affecting learners at multiple levels and in multiple disciplines and specialties. The lessons learned from the Donald W. Reynolds Foundation initiatives about effect and sustainability are invaluable to the ongoing strategic development of geriatrics nationally. This article highlights successful educational initiatives developed at four institutions with past and current Donald W. Reynolds Foundation funding. Following an ice hockey playbook, this article identifies 10 strategies and initiatives to "stay in the geriatrics game" by training hospitalists and subspecialty providers. The authors' collective experience suggests that geriatrics educational initiatives can not only influence provider education, but also improve the care of older adults in multiple settings. C1 [Gillespie, Suzanne M.; Medina-Walpole, Annette] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Brandt, Lynsey E.; Corcoran, Amy M.; Miller, Rachel] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Chang, Anna; Harper, G. Michael] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Chang, Anna; Harper, G. Michael] San Francisco VA Med Ctr, San Francisco, CA USA. [Chao, Serena H.; Levine, Sharon A.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Medina-Walpole, A (reprint author), Monroe Community Hosp, 435 East Henrietta Rd, Rochester, NY 14620 USA. EM annette_medinawalpole@urmc.rochester.edu FU Donald W. Reynold's Foundation FX Sponsor's Role: The educational initiatives described in this manuscript were developed through financial support from the Donald W. Reynold's Foundation. NR 20 TC 1 Z9 1 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2014 VL 62 IS 8 BP 1575 EP 1582 DI 10.1111/jgs.12934 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA AN3JE UT WOS:000340482800021 PM 25040491 ER PT J AU Haedersdal, M Sakamoto, FH Farinelli, WA Doukas, AG Tam, J Anderson, RR AF Haedersdal, Merete Sakamoto, Fernanda H. Farinelli, William A. Doukas, Apostolos G. Tam, Joshua Anderson, R. Rox TI Pretreatment With Ablative Fractional Laser Changes Kinetics and Biodistribution of Topical 5-Aminolevulinic Acid (ALA) and Methyl Aminolevulinate (MAL) SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE ablative fractional laser; drug delivery; fluorescence microscopy; fluorescence photography; protoporphyrin IX ID BASAL-CELL CARCINOMA; PROTOPORPHYRIN-IX FLUORESCENCE; MULTIPLE ACTINIC KERATOSES; NORMAL HUMAN SKIN; PHOTODYNAMIC THERAPY; STRATUM-CORNEUM; DRUG-DELIVERY; DERIVATIVES; PORPHYRINS; UPDATE AB Background and Objectives: 5-Aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) are porphyrin precursors used topically for photodynamic therapy (PDT). Previous studies have established that ablative fractional laser (AFXL) increases topical drug uptake. We evaluated kinetics and biodistribution of ALA-and MAL-induced porphyrins on intact and disrupted skin due to AFXL. Materials and Methods: Two Yorkshire swine were exposed to CO2 AFXL (10.6 mu m, 1,850 mu m ablation depth) and subsequent topical application of ALA and MAL cream formulations (20%, weight/weight). Porphyrin fluorescence was quantified by digital fluorescence photography (30, 90, and 180 minutes) and fluorescence microscopy at specific skin depths (180 minutes). Results: Porphyrins gradually formed over time, differently on intact and AFXL-disrupted skin. On intact skin (no AFXL), fluorescence photography showed that MAL initially induced higher fluorescence than ALA (t = 30 minutes MAL 21.1 vs. ALA 7.7 au, t = 90 minutes MAL 39.0 vs. ALA 26.6 (P< 0.009)) but reached similar intensities for long-term applications (t = 180 minutes MAL 56.6 vs. ALA 52 au, P = ns). AFXL considerably enhanced porphyrin fluorescence from both photosensitizers (P< 0.05). On AFXL-exposed skin, MAL expressed higher fluorescence than ALA for short-term application (t 30 minutes, AFXL-MAL 26.4 vs. AFXL-ALA 14.1 au, P< 0.001), whereas ALA over time overcame MAL and induced the highest fluorescence intensities obtained (t 180 minutes, AFXL-MAL 98.6 vs. AFXL-ALA 112.0 au, P< 0.001). In deep skin layers, fluorescence microscopy showed higher fluorescence in hair follicle epithelium for ALA than MAL (t = 180 minutes, 1.8 mm, AFXL-MAL 35.3 vs. AFXL-ALA 46.7 au, P< 0.05). Conclusions: AFXL changes kinetics and biodistribution of ALA and MAL. It appears that AFXL-ALA favors targeting deep structures. (C) 2014 Wiley Periodicals, Inc. C1 [Haedersdal, Merete; Sakamoto, Fernanda H.; Farinelli, William A.; Doukas, Apostolos G.; Tam, Joshua; Anderson, R. Rox] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Haedersdal, Merete] Univ Copenhagen, Bispebjerg Hosp, Dept Dermatol, DK-2400 Copenhagen NV, Denmark. RP Haedersdal, M (reprint author), Univ Copenhagen, Bispebjerg Hosp, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. EM mhaedersdal@dadlnet.dk FU Danish Council for Independent Research \ Medical Sciences (FSS); Aage Bang Foundation; A.P. Moller Foundation for the Advancement of Medical Science FX Study was supported by the Danish Council for Independent Research vertical bar Medical Sciences (FSS), the Aage Bang Foundation, and the A.P. Moller Foundation for the Advancement of Medical Science. Metvix-placebo cream was kindly supplied by Photocure ASA, Oslo, Norway. NR 35 TC 13 Z9 13 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2014 VL 46 IS 6 BP 462 EP 469 DI 10.1002/lsm.22259 PG 8 WC Dermatology; Surgery SC Dermatology; Surgery GA AN4AC UT WOS:000340529000004 PM 24842112 ER PT J AU Mitchell, CM AF Mitchell, Caroline M. TI Positive endometrial cultures: pathologic or incidental? SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID CAVITY; WOMEN C1 Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. RP Mitchell, CM (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD AUG PY 2014 VL 21 IS 8 BP 785 EP 785 DI 10.1097/gme.0000000000000283 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA AN4LP UT WOS:000340559600001 PM 24937031 ER PT J AU Kannan, TR Krishnan, M Ramasamy, K Becker, A Pakhomova, ON Hart, PJ Baseman, JB AF Kannan, Thirumalai R. Krishnan, Manickam Ramasamy, Kumaraguruparan Becker, Argentina Pakhomova, Olga N. Hart, P. John Baseman, Joel B. TI Functional mapping of community-acquired respiratory distress syndrome (CARDS) toxin of Mycoplasma pneumoniae defines regions with ADP-ribosyltransferase, vacuolating and receptor-binding activities SO MOLECULAR MICROBIOLOGY LA English DT Article ID TOXIGENIC ESCHERICHIA-COLI; PROTEIN HOMOLOGY DETECTION; SITE-DIRECTED MUTAGENESIS; HEAT-LABILE ENTEROTOXIN; CHOLERA-TOXIN; PERTUSSIS TOXIN; HELICOBACTER-PYLORI; RIBOSYLATING TOXINS; ASTHMA; INFECTIONS AB Community-acquired respiratory distress syndrome (CARDS) toxin from Mycoplasma pneumoniae is a 591-amino-acid virulence factor with ADP-ribosyltransferase (ADPRT) and vacuolating activities. It is expressed at low levels during in vitro growth and at high levels during colonization of the lung. Exposure of experimental animals to purified recombinant CARDS toxin alone is sufficient to recapitulate the cytopathology and inflammatory responses associated with M. pneumoniae infection in humans and animals. Here, by molecular modelling, serial truncations and site-directed mutagenesis, we show that the N-terminal region is essential for ADP-ribosylating activity. Also, by systematic truncation and limited proteolysis experiments we identified a portion of the C-terminal region that mediates toxin binding to mammalian cell surfaces and subsequent internalization. In addition, the C-terminal region alone induces vacuolization in a manner similar to full-length toxin. Together, these data suggest that CARDS toxin has a unique architecture with functionally separable N-terminal and C-terminal domains. C1 [Kannan, Thirumalai R.; Krishnan, Manickam; Ramasamy, Kumaraguruparan; Baseman, Joel B.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Airway Inflammat Res, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Becker, Argentina; Pakhomova, Olga N.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Hart, P. John] South Texas Vet Hlth Care Syst, Dept Vet Affairs, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Kannan, TR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Ctr Airway Inflammat Res, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. EM kannan@uthscsa.edu; baseman@uthscsa.edu FU National Institute of Allergy and Infectious Diseases [U19AI070412]; Kleberg Foundation; Robert A. Welch Foundation [AQ-1399]; National Center for Research Resources at the National Institute of Health [RR-15301]; US Department of Energy, Office of Basic Energy Sciences [W-31-109-ENG-38]; Cancer Therapy & Research Center (CTRC) Cancer Center Support Grant [NCI P30CA054174]; UTHSCSA Executive Research Committee FX We thank Tiffany McDonald Marsh, Pramod Gowda, Brandon Guin and Dr Sowmya Balasubramanian for their technical assistance. We would like to thank Rose Garza for assembling the manuscript. This work was supported by Award Number U19AI070412 from the National Institute of Allergy and Infectious Diseases, The Kleberg Foundation, and the Robert A. Welch Foundation Grant AQ-1399 (PJH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. This work is partially the result of research conducted at the Northeastern Collaborative Access Team (NE-CAT) beam lines of the Advanced Photon Source, supported by award RR-15301 from the National Center for Research Resources at the National Institute of Health. Use of the Advanced Photon Source is supported by the US Department of Energy, Office of Basic Energy Sciences, under contract No. W-31-109-ENG-38. This work was also supported in part by the Cancer Therapy & Research Center (CTRC) Cancer Center Support Grant, NCI P30CA054174 and support for the X-ray Crystallography Core Laboratory by the UTHSCSA Executive Research Committee is gratefully acknowledged. NR 52 TC 8 Z9 9 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0950-382X EI 1365-2958 J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2014 VL 93 IS 3 BP 568 EP 581 DI 10.1111/mmi.12680 PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA AN1VF UT WOS:000340371200014 PM 24948331 ER PT J AU Deer, TR Mekhail, N Petersen, E Krames, E Staats, P Pope, J Saweris, Y Lad, SP Diwan, S Falowski, S Feler, C Slavin, K Narouze, S Merabet, L Buvanendran, A Fregni, F Wellington, J Levy, RM AF Deer, Timothy R. Mekhail, Nagy Petersen, Erika Krames, Elliot Staats, Peter Pope, Jason Saweris, Youssef Lad, Shivanand P. Diwan, Sudhir Falowski, Steven Feler, Claudio Slavin, Konstantin Narouze, Samer Merabet, Lotfi Buvanendran, Asokumar Fregni, Felipe Wellington, Joshua Levy, Robert M. TI The Appropriate Use of Neurostimulation: Stimulation of the Intracranial and Extracranial Space and Head for Chronic Pain SO NEUROMODULATION LA English DT Article DE Cranial nerve stimulation; deep brain stimulation; migraine; motor cortex stimulation; neurostimulation; occipital nerve stimulation; peripheral nerve stimulation; trigeminal nerve stimulation; vagal nerve stimulation ID MOTOR-CORTEX-STIMULATION; OCCIPITAL NERVE-STIMULATION; DEEP BRAIN-STIMULATION; SPINAL-CORD STIMULATION; CHRONIC CLUSTER HEADACHE; TERM-FOLLOW-UP; SUBCUTANEOUS FIELD STIMULATION; DORSAL-ROOT GANGLION; LOW-BACK-PAIN; RETROSPECTIVE CASE SERIES AB Introduction: The International Neuromodulation Society (INS) has identified a need for evaluation and analysis of the practice of neurostimulation of the brain and extracranial nerves of the head to treat chronic pain. Methods: The INS board of directors chose an expert panel, the Neuromodulation Appropriateness Consensus Committee (NACC), to evaluate the peer-reviewed literature, current research, and clinical experience and to give guidance for the appropriate use of these methods. The literature searches involved key word searches in PubMed, EMBASE, and Google Scholar dated 1970-2013, which were graded and evaluated by the authors. Results: The NACC found that evidence supports extracranial stimulation for facial pain, migraine, and scalp pain but is limited for intracranial neuromodulation. High cervical spinal cord stimulation is an evolving option for facial pain. Intracranial neurostimulation may be an excellent option to treat diseases of the nervous system, such as tremor and Parkinson's disease, and in the future, potentially Alzheimer's disease and traumatic brain injury, but current use of intracranial stimulation for pain should be seen as investigational. Conclusions: The NACC concludes that extracranial nerve stimulation should be considered in the algorithmic treatment of migraine and other disorders of the head. We should strive to perfect targets outside the cranium when treating pain, if at all possible. C1 [Deer, Timothy R.; Pope, Jason] Ctr Pain Relief, Charleston, WV 25301 USA. [Mekhail, Nagy; Saweris, Youssef] Cleveland Clin, Evidence Based Pain Management Res & Educ, Cleveland, OH 44106 USA. [Petersen, Erika] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Krames, Elliot] Pacific Pain Treatment Ctr, San Francisco, CA USA. [Staats, Peter] Premier Pain Management Ctr, Shrewsbury, NJ USA. [Staats, Peter] Johns Hopkins Univ, Baltimore, MD USA. [Lad, Shivanand P.] Duke Univ, Med Ctr, Div Neurosurg, Durham, NC 27710 USA. [Diwan, Sudhir] Lenox Hill Hosp, Manhattan Spine & Pain Med, New York, NY 10021 USA. [Falowski, Steven] St Lukes Neurosurg Associates, Bethlehem, PA USA. [Feler, Claudio] Univ Tennessee, Memphis, TN USA. [Feler, Claudio] Valley View Hosp, Glenwood Springs, CO USA. [Slavin, Konstantin] Univ Illinois, Chicago, IL USA. [Narouze, Samer] Summa Western Reserve Hosp, Cuyahoga Falls, OH USA. [Merabet, Lotfi] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Merabet, Lotfi] Harvard Univ, Schepens Eye Res Inst, Sch Med, Boston, MA USA. [Buvanendran, Asokumar] Rush Univ, Dept Anesthesia, Med Ctr, Chicago, IL 60612 USA. [Fregni, Felipe] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA USA. [Wellington, Joshua] Indiana Univ, Pain Med Ctr, Indianapolis, IN 46204 USA. [Levy, Robert M.] Univ Florida, Coll Med, Jacksonville, FL USA. RP Deer, TR (reprint author), Ctr Pain Relief, 400 Court St,Ste 100, Charleston, WV 25301 USA. EM doctdeer@aol.com FU International Neuromodulation Society; Medtronic Inc.; St. Jude Medical Inc.; Boston Scientific Corp.; Nevro Corp.; Spinal Modulation Inc. FX This project was supported by the International Neuromodulation Society and was partially funded by a series of unrestricted educational grants from Medtronic Inc., St. Jude Medical Inc., Boston Scientific Corp., Nevro Corp., and Spinal Modulation Inc. No corporate entities had any direct input into the contents of this manuscript, or the conclusions of the collaborators. NR 185 TC 11 Z9 11 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1094-7159 EI 1525-1403 J9 NEUROMODULATION JI Neuromodulation PD AUG PY 2014 VL 17 IS 6 BP 551 EP 570 DI 10.1111/ner.12215 PG 20 WC Medicine, Research & Experimental; Clinical Neurology SC Research & Experimental Medicine; Neurosciences & Neurology GA AN3PK UT WOS:000340500200004 PM 25112890 ER PT J AU Chong, EW Guymer, RH Klein, R Klein, BE Cotch, MF Wang, JJ Shlipak, MG Wong, TY AF Chong, Elaine W. Guymer, Robyn H. Klein, Ronald Klein, Barbara E. Cotch, Mary Frances Wang, Jie Jin Shlipak, Michael G. Wong, Tien Y. TI Is Renal Function Associated with Early Age-Related Macular Degeneration? SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE age-related macular degeneration; kidney; renal function ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; COMPLEMENT-FACTOR-H; BLUE-MOUNTAINS-EYE; GLOMERULONEPHRITIS TYPE-II; SERUM CYSTATIN-C; BEAVER DAM EYE; FUNDUS CHANGES; RISK; PREVALENCE AB Purpose. Age-related macular degeneration (AMD) and chronic kidney disease both involve immune dysregulation and may share underlying pathophysiologic changes to systemic homeostasis. Hence, we aim to evaluate associations between impaired kidney function and early AMD, in a search for urinary biomarkers for AMD. Methods. A population-based, cross-sectional analysis of persons aged 45 to 84 years was conducted with renal function measured using serum creatinine and cystatin C levels and the estimated glomerular filtration rate (eGFR) calculated. Age-related macular degeneration status was ascertained from retinal photographs. Results. Of 5874 participants, 221 had early AMD. High serum cystatin C and low eGFR (<= 60 ml/min/1.73 m(2)) were not associated with early AMD in our multivariate analyses. Among normotensive persons, however, highest versus other deciles of cystatin C were associated with an increased prevalence of early AMD (odds ratio, 1.80; 95% confidence interval, 1.00 to 3.23). Conclusions. Results could not confirm an association between kidney function and early AMD. The borderline association between cystatin C and early AMD in normotensive persons require further verification. C1 [Chong, Elaine W.; Guymer, Robyn H.; Wang, Jie Jin; Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic 3002, Australia. [Klein, Ronald; Klein, Barbara E.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Wang, Jie Jin] Univ Sydney, Ctr Vis Res, Sydney, NSW 2006, Australia. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco VA Med Ctr, San Francisco, CA USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore Eye Res Inst, Singapore 117595, Singapore. RP Chong, EW (reprint author), Univ Melbourne, Ctr Eye Res Australia, 32 Gisborne St, East Melbourne, Vic 3002, Australia. EM elainechongwt@alumni.unimelb.edu.au RI Wang, Jie Jin/P-1499-2014; OI Wang, Jie Jin/0000-0001-9491-4898; Cotch, Mary Frances/0000-0002-2046-4350 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169] FX This study was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 40 TC 3 Z9 3 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD AUG PY 2014 VL 91 IS 8 BP 860 EP 864 PG 5 WC Ophthalmology SC Ophthalmology GA AN4KL UT WOS:000340556500008 PM 24879085 ER PT J AU Davies, L Randolph, G AF Davies, Louise Randolph, Gregory TI Evidence-Based Evaluation of the Thyroid Nodule SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Thyroid; Thyroid nodule; Thyroid cancer; Evaluation; Thyroid neoplasm risk ID FINE-NEEDLE-ASPIRATION; OCCULT PAPILLARY CARCINOMA; BRAF V600E MUTATION; CANCER-RISK; INCREASING INCIDENCE; SYSTEMATIC AUTOPSY; BETHESDA SYSTEM; UNITED-STATES; PATIENT AGE; PREVALENCE AB This article reviews the most current literature on thyroid nodule evaluation, with particular attention to the problem of the incidentally identified thyroid nodule. Although traditional risk factors for thyroid cancer, such as age, gender, and familial syndromes, are still important, the manner in which a thyroid nodule comes to attention is of great importance these days when considering how to proceed in a workup. Most thyroid nodules today are discovered through radiologic imaging tests performed for other reasons. This article covers the key considerations that are vital in balancing the risks and benefits of thyroid nodule workup and treatment. C1 [Davies, Louise] Dept Vet Affairs Med Ctr, VA Outcomes Grp, White River Jct, VT 05009 USA. [Davies, Louise] Geisel Sch Med Dartmouth, Otolaryngol Sect, Hanover, NH 03755 USA. [Davies, Louise] Dartmouth Inst Hlth Policy & Clin Practice, Lebanon, NH 03766 USA. [Randolph, Gregory] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol,Div Thyroid & Parathyroid Su, Boston, MA 02114 USA. [Randolph, Gregory] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. RP Davies, L (reprint author), VA Outcomes Grp, 111B,215 North Main St, White River Jct, VT 05009 USA. EM louise.davies@va.gov FU Department of Veterans Affairs FX The Department of Veterans Affairs. NR 57 TC 3 Z9 3 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0030-6665 EI 1557-8259 J9 OTOLARYNG CLIN N AM JI Otolaryngol. Clin. N. Am. PD AUG PY 2014 VL 47 IS 4 BP 461 EP + DI 10.1016/j.otc.2014.04.008 PG 15 WC Otorhinolaryngology SC Otorhinolaryngology GA AN2UH UT WOS:000340440800003 PM 25041951 ER PT J AU Coltrera, MD AF Coltrera, Marc D. TI Clinician-Performed Thyroid Ultrasound SO OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Ultrasound; Office-based; Thyroid cancer; Training; Validation; Competency ID FINE-NEEDLE-ASPIRATION; PREDICTIVE-VALUE; 3 SETS; NODULES; CARCINOMA; PAPILLARY; SONOGRAPHY; MANAGEMENT; BIOPSY; GUIDELINES AB This article is intended to demystify the process for those with a potential interest in acquiring ultrasound skills. It is not intended to be a comprehensive review of head and neck ultrasound but, rather, is focused on the bare minimum requirements and considerations involved in clinician-performed ultrasound. The article covers the initial diagnosis and the unparalleled usefulness of ultrasound for surgical planning just before incision. Further readings are listed at the end of the article to direct the reader to some excellent texts to help build confidence and experience. C1 [Coltrera, Marc D.] Univ Washington, Dept OTO HNS, Seattle, WA 98195 USA. [Coltrera, Marc D.] VA Puget Sound, OTO HNS Div, Seattle, WA 98108 USA. RP Coltrera, MD (reprint author), Univ Washington, Dept OTO HNS, 1959 Northeast Pacific,Box 356515, Seattle, WA 98195 USA. EM Coltrera@u.washington.edu NR 37 TC 4 Z9 4 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0030-6665 EI 1557-8259 J9 OTOLARYNG CLIN N AM JI Otolaryngol. Clin. N. Am. PD AUG PY 2014 VL 47 IS 4 BP 491 EP + DI 10.1016/j.otc.2014.04.001 PG 18 WC Otorhinolaryngology SC Otorhinolaryngology GA AN2UH UT WOS:000340440800005 PM 25041953 ER PT J AU Banks, CA Schlosser, RJ Wang, EW Casey, SE Mulligan, RM Mulligan, JK AF Banks, Caroline A. Schlosser, Rodney J. Wang, Eric W. Casey, Sarah E. Mulligan, Ryan M. Mulligan, Jennifer K. TI Macrophage Infiltrate Is Elevated in CRSwNP Sinonasal Tissue Regardless of Atopic Status SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE macrophage; chronic rhinosinusitis; nasal polyps; atopy ID RELATIVE CORTICOSTEROID INSENSITIVITY; CHRONIC RHINOSINUSITIS; DENDRITIC CELLS; NASAL POLYPS; ALLERGIC RHINITIS; ALTERNATIVE ACTIVATION; ALVEOLAR MACROPHAGES; CHRONIC SINUSITIS; SEVERE ASTHMA; DISEASE AB Objective. Macrophages are major producers of inflammatory cytokines; however, their role in chronic rhinosinusitis (CRS) has not been clearly defined. The aim of this study was to quantify macrophages in sinus tissue of patients with various subtypes of CRS and determine the impact of atopic status on macrophage infiltrate. Study Design. Prospective immunohistochemical study of human sinonasal tissue. Setting. Academic medical center. Subjects and Methods. Human sinonasal tissue was taken from patients with CRS with nasal polyposis (CRSwNP, n = 8), CRS without nasal polyposis (CRSsNP, n = 8), and controls (n = 8) undergoing surgery for CSF leak repair or endoscopic excision of non-secreting pituitary tumor. Samples were immunohistochemically stained for macrophage/monocyte markers Mac387 and CD68. Results. CRSwNP patients had significantly increased numbers of Mac387 and CD68 cells compared to control patients (P < .05) or CRSsNP patients (P < .01). CRSsNP had significantly increased number of cells staining for CD68 compared to controls (P < .05). The increased presence of macrophages measured by either marker in CRSwNP was independent of atopic status. Conclusion. Macrophages are increased in CSRwNP patients regardless of atopic status and may contribute to the immunopathology of CRS. C1 [Banks, Caroline A.; Schlosser, Rodney J.; Mulligan, Jennifer K.] Med Univ S Carolina, Dept Otolaryngol, Charleston, SC 29425 USA. [Schlosser, Rodney J.] Ralph H Johnson VA Med Ctr, Dept Surg, Charleston, SC USA. [Wang, Eric W.] Univ Pittsburgh, Dept Otolaryngol, Pittsburgh, PA 15260 USA. [Casey, Sarah E.; Mulligan, Ryan M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Mulligan, Jennifer K.] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC USA. [Mulligan, Jennifer K.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. RP Banks, CA (reprint author), Med Univ S Carolina, Dept Otolaryngol, 135 Rutledge Ave,MSC 550, Charleston, SC 29425 USA. EM Caroline_Banks@MEEI.HARVARD.EDU OI Wang, Eric/0000-0002-1180-5854 NR 39 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2014 VL 151 IS 2 BP 215 EP 220 DI 10.1177/0194599814528672 PG 6 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YZ UT WOS:000340453300005 PM 24705220 ER PT J AU Dwojak, SM Finkelstein, DM Emerick, KS Lee, JH Petereit, DG Deschler, DG AF Dwojak, Sunshine M. Finkelstein, Dianne M. Emerick, Kevin S. Lee, John H. Petereit, Daniel G. Deschler, Daniel G. TI Poor Survival for American Indians with Head and Neck Squamous Cell Carcinoma SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE American Indians; head and neck cancer; disparities; human papillomavirus ID HUMAN-PAPILLOMAVIRUS INFECTION; ALASKA NATIVES; NORTHERN-PLAINS; CANCER CARE; ORAL-CAVITY; HEALTH-CARE; DISPARITIES; WHITE; STAGE; WOMEN AB Objective. To examine patient characteristics, treatment modalities, and human papillomavirus (HPV) prevalence to identify potential mediators of disparities that may lead to differences in outcomes for American Indians with head and neck squamous cell carcinoma (HNSCC). Study Design. Historical cohort study. Setting. Community cancer centers. Patients and Methods. We reviewed all patients older than 18 years with a new diagnosis of HNSCC in South Dakota from 1999 to 2009. We assessed tissue samples from cases of oropharyngeal cancer for the presence of HPV DNA. Results. In total, 474 white patients were compared with 32 American Indians. American Indians experienced significantly worse survival compared with whites (hazard ratio [HR], 0.59; P = .05), even after controlling for other factors such as age, sex, distance, Charlson comorbidity index, alcohol abuse, smoking, insurance, and disease stage. American Indians had a greater risk of alcohol abuse (68% vs 42%; P = .008), current smoking (67% vs 49%; P = .03), living more than 1 hour from a cancer center (81% vs 30%; P < .001), lacking private insurance (24% vs 68%; P < .001), and late-stage disease presentation (stages III and IV) (74% vs 55%; P = .04). There were no detected differences in age, sex, medical comorbidities, tumor site, tumor grade, HPV status, time to treatment, or type of treatment received. Conclusion. American Indians in South Dakota with HNSCC have poorer survival compared with white patients. Once presented to a cancer center, American Indians received nearly identical treatment to white patients. Disparities in outcomes arise primarily due to sociodemographic factors and later stage at presentation. C1 [Dwojak, Sunshine M.; Emerick, Kevin S.; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Dwojak, Sunshine M.; Emerick, Kevin S.; Deschler, Daniel G.] Harvard Univ, Sch Med, Boston, MA USA. [Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Lee, John H.] Sanford Canc Res Ctr, Sioux Falls, SD USA. [Petereit, Daniel G.] Rapid City Reg Hosp, John T Vucurevich Canc Care Inst, Rapid City, SD USA. RP Dwojak, SM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM sunshine_dwojak@meei.harvard.edu FU National Institutes of Health [T32DC000020]; American Head and Neck Society; Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources); National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000170-05] FX This work was supported by a grant from the National Institutes of Health T32DC000020 and by a pilot grant from the American Head and Neck Society. This work was also conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources) and the National Center for Advancing Translational Sciences, National Institutes of Health Award 8UL1TR000170-05 and financial contributions from Harvard University and its affiliated academic health care centers. NR 31 TC 3 Z9 3 U1 2 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2014 VL 151 IS 2 BP 265 EP 271 DI 10.1177/0194599814533083 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YZ UT WOS:000340453300013 PM 24781656 ER PT J AU Davis, KS Byrd, JK Mehta, V Chiosea, SI Kim, S Ferris, RL Johnson, JT Duvvuri, U AF Davis, Kara S. Byrd, J. Kenneth Mehta, Vikas Chiosea, Simon I. Kim, Seungwon Ferris, Robert L. Johnson, Jonas T. Duvvuri, Umamaheswar TI Occult Primary Head and Neck Squamous Cell Carcinoma: Utility of Discovering Primary Lesions SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE unknown primary tumor; oropharyngeal; HPV; cervical metastases; squamous cell carcinoma; unknown primary; human papilloma virus; base of tongue; tonsil; oropharyngeal cancer ID HUMAN-PAPILLOMAVIRUS; UNKNOWN PRIMARY; OROPHARYNGEAL CANCER; POSITIVE HEAD; MANAGEMENT; SURVIVAL; HPV; DIAGNOSIS; STRATEGY; TUMORS AB Objective. Cancer of an unknown primary (CUP) squamous cell carcinoma metastatic to cervical lymph nodes is a challenging problem for the treating physician. Our aim is to determine if identification of the primary tumor is associated with improved oncologic outcomes and/or tumor characteristics including human papilloma virus (HPV) status. Study Design. Retrospective, matched-pairs analysis contrasting 2 cohorts based upon discovery of primary lesion. Setting. Tertiary teaching hospital. Subjects and Methods. Records of 136 patients initially diagnosed as carcinoma of unknown primary were retrospectively reviewed (1980-2010) and divided into 2 cohorts based on discovery of the primary lesion. Primary outcome measures were overall survival and time to recurrence according to Kaplan-Meier analysis. A nested subset of 22 patients in which the primary was discovered were matched to 22 patients remaining undiscovered according to nodal stage and age. Results. Discovered lesions were more likely to exhibit HPV positivity (P < .001). Matched-pairs analyses demonstrated that discovery of the primary was associated with better overall survival (HR = 0.125; 95% confidence interval [CI], 0.019-0.822; P = .030). Discovery of the primary was associated with improved cause-specific survival (HR = 0.142; 95% CI, 0.021-0.93; P = .0418) and disease-free survival (HR = 0.25; 95% CI, 0.069-0.91; P = .03). Conclusion. HPV positivity is associated with discovery of the primary tumor. Discovery of the primary lesion is associated with improved overall survival, cause-specific survival, and disease-free survival in patients initially presenting as CUP in matched-pair and cohort comparison analyses. C1 [Davis, Kara S.; Byrd, J. Kenneth; Kim, Seungwon; Ferris, Robert L.; Johnson, Jonas T.; Duvvuri, Umamaheswar] Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, Pittsburgh, PA 15213 USA. [Mehta, Vikas] Louisiana State Univ, Hlth Sci Ctr Shreveport, Dept Otolaryngol Head & Neck Surg, Shreveport, LA 71105 USA. [Chiosea, Simon I.] Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA. [Duvvuri, Umamaheswar] VA Pittsburgh Hlth Syst, Pittsburgh, PA USA. RP Davis, KS (reprint author), Univ Pittsburgh, Med Ctr, Dept Otolaryngol Head & Neck Surg, 200 Lothrop St Suite 500, Pittsburgh, PA 15213 USA. EM davisks@upmc.edu FU NIH [UL1 RR024153, UL1TR000005]; Department of Veterans Affairs, BLS RD; PNC Foundation FX NIH grants (UL1 RR024153 and UL1TR000005) funded statistical analysis. This was supported in part by funds from the Department of Veterans Affairs, BLS R&D and the PNC Foundation (U.D.). NR 20 TC 12 Z9 12 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD AUG PY 2014 VL 151 IS 2 BP 272 EP 278 DI 10.1177/0194599814533494 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA AN2YZ UT WOS:000340453300014 PM 24812081 ER PT J AU Maglione, MA Das, L Raaen, L Smith, A Chari, R Newberry, S Shanman, R Perry, T Goetz, MB Gidengil, C AF Maglione, Margaret A. Das, Lopamudra Raaen, Laura Smith, Alexandria Chari, Ramya Newberry, Sydne Shanman, Roberta Perry, Tanja Goetz, Matthew Bidwell Gidengil, Courtney TI Safety of Vaccines Used for Routine Immunization of US Children: A Systematic Review SO PEDIATRICS LA English DT Review DE evidence-based medicine; vaccine/immunization; infectious disease ID HUMAN ROTAVIRUS VACCINE; INACTIVATED INFLUENZA VACCINE; MUMPS-RUBELLA VACCINATION; CONJUGATE VACCINE; DOUBLE-BLIND; DATALINK PROJECT; HEALTHY INFANTS; UNITED-STATES; THROMBOCYTOPENIC PURPURA; POSTMARKETING EVALUATION AB BACKGROUND: Concerns about vaccine safety have led some parents to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical for population health. This study systematically reviewed the literature on the safety of routine vaccines recommended for children in the United States. METHODS: Data sources included PubMed, Advisory Committee on Immunization Practices statements, package inserts, existing reviews, manufacturer information packets, and the 2011 Institute of Medicine consensus report on vaccine safety. We augmented the Institute of Medicine report with more recent studies and increased the scope to include more vaccines. Only studies that used active surveillance and had a control mechanism were included. Formulations not used in the United States were excluded. Adverse events and patient and vaccine characteristics were abstracted. Adverse event collection and reporting was evaluated by using the McHarm scale. We were unable to pool results. Strength of evidence was rated as high, moderate, low, or insufficient. RESULTS: Of 20 478 titles identified, 67 were included. Strength of evidence was high for measles/mumps/rubella (MMR) vaccine and febrile seizures; the varicella vaccine was associated with complications in immunodeficient individuals. There is strong evidence that MMR vaccine is not associated with autism. There is moderate evidence that rotavirus vaccines are associated with intussusception. Limitations of the study include that the majority of studies did not investigate or identify risk factors for AEs; and the severity of AEs was inconsistently reported. CONCLUSIONS: We found evidence that some vaccines are associated with serious AEs; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide. C1 [Maglione, Margaret A.; Das, Lopamudra; Raaen, Laura; Smith, Alexandria; Chari, Ramya; Newberry, Sydne; Shanman, Roberta; Perry, Tanja; Gidengil, Courtney] RAND Corp, Santa Monica, CA 90407 USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Gidengil, Courtney] Boston Childrens Hosp, Boston, MA USA. RP Maglione, MA (reprint author), RAND Corp, 1776 Main St Mailstop 4W, Santa Monica, CA 90407 USA. EM maglione@rand.org OI Goetz, Matthew/0000-0003-4542-992X FU Agency for Healthcare Research and Quality [HHSA290200710062I]; US Department of Health and Human Services FX Supported under Contract No. HHSA290200710062I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services. NR 97 TC 34 Z9 35 U1 13 U2 230 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 AUG PY 2014 VL 134 IS 2 BP 325 EP 337 DI 10.1542/peds.2014-1079 PG 13 WC Pediatrics SC Pediatrics GA AN0HS UT WOS:000340266000059 PM 25086160 ER PT J AU Liberman, RF Getz, KD Lin, AE Higgins, CA Sekhavat, S Markenson, GR Anderka, M AF Liberman, Rebecca F. Getz, Kelly D. Lin, Angela E. Higgins, Cathleen A. Sekhavat, Sepehr Markenson, Glenn R. Anderka, Marlene TI Delayed Diagnosis of Critical Congenital Heart Defects: Trends and Associated Factors SO PEDIATRICS LA English DT Article DE critical congenital heart defects; delayed diagnosis; neonatal; prenatal diagnosis; infant; newborn; neonatal screening ID PULSE OXIMETRY; DISEASE; NEWBORNS; INFANTS; MORTALITY AB OBJECTIVE: We aimed to examine trends in timing of diagnosis of critical congenital heart defects (CCHDs) and factors associated with delayed diagnosis (diagnosis after discharge home following delivery). METHODS: We examined a population-based retrospective cohort of CCHD cases among live births identified through the Massachusetts Birth Defects Monitoring Program. Congenital heart defects were considered critical if the infant received corrective surgery, interventional catheterization, palliative care, or died as a result of the defect within 12 months of birth. Timing of initial diagnosis was classified as prenatal, postnatal before discharge home, or delayed. Demographic, perinatal, and mortality information was obtained from the Registry of Vital Records and Statistics. Prevalence ratios (PRs) were used to examine associations with delayed diagnosis. RESULTS: Among 460 467 live births to Massachusetts residents between 2004 and 2009, we identified 916 CCHD cases, of which 126 (13.8%) had delayed diagnosis. Rates of prenatal CCHD diagnosis increased from 44.9% in 2004 to 63.8% in 2009, whereas rates of delayed diagnosis decreased from 17.1% to 10.6% over the same time period. Among cases with delayed diagnosis, the most common defects were coarctation, pulmonary valve stenosis, and tetralogy of Fallot. Delayed diagnosis was associated with delivery outside a tertiary hospital (adjusted PR: 3.6 [95% confidence interval: 2.5-5.2]) and isolated CCHD (adjusted PR: 1.7 [95% confidence interval: 1.1-2.7]). CONCLUSIONS: Despite increasing prenatal diagnosis of CCHDs, delayed diagnosis still occurs in over 10% of cases. Understanding factors associated with delayed diagnosis could help to improve prenatal and postnatal screening efforts, including pulse oximetry testing. C1 [Liberman, Rebecca F.; Getz, Kelly D.; Higgins, Cathleen A.; Anderka, Marlene] Massachusetts Dept Publ Hlth, Boston, MA 02108 USA. [Lin, Angela E.] MassGen Hosp Children, Boston, MA USA. [Sekhavat, Sepehr] Boston Med Ctr, Boston, MA USA. [Markenson, Glenn R.] Baystate Med Ctr, Springfield, MA USA. RP Liberman, RF (reprint author), Massachusetts Dept Publ Hlth, Ctr Birth Defects Res & Prevent, 250 Washington St,5th Floor, Boston, MA 02108 USA. EM rebecca.liberman@state.ma.us FU NICHD NIH HHS [T32 HD052458] NR 21 TC 12 Z9 12 U1 0 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 AUG PY 2014 VL 134 IS 2 BP E373 EP E381 DI 10.1542/peds.2013-3949 PG 9 WC Pediatrics SC Pediatrics GA AN0HS UT WOS:000340266000007 PM 25070301 ER PT J AU Xu, S Shetterly, S Raebel, MA Ho, PM Tsai, TT Magid, D AF Xu, Stanley Shetterly, Susan Raebel, Marsha A. Ho, P. Michael Tsai, Thomas T. Magid, David TI Estimating the effects of time-varying exposures in observational studies using Cox models with stabilized weights adjustment SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE drug-eluting stent; clopidogrel; time-varying exposure; Cox model; stabilized weights; pharmacoepidemiology ID MARGINAL STRUCTURAL MODELS; PROPENSITY SCORE; COVARIANCE ANALYSIS; COUNTING-PROCESSES; REGRESSION-MODEL; SURVIVAL-DATA; CLOPIDOGREL; THERAPY; STENT; IMPLANTATION AB Purpose Assessing the safety and effectiveness of medical products with observational electronic medical record data is challenging when the treatment is time-varying. The objective of this paper is to develop a Cox model stratified by event times with stabilized weights (SWs) adjustment to examine the effect of time-varying treatment in observational studies. Methods Time-varying SWs are calculated at unique event times and are used in a Cox model stratified by event times to estimate the effect of time-varying treatment. We applied this method in examining the effect of an antiplatelet agent, clopidogrel, on events, including bleeding, myocardial infarction, and death after a drug-eluting stent was implanted in coronary artery. Clopidogrel use may change over time on the basis of patients' behavior (e. g., non-adherence) and physicians' recommendations (e. g., end of duration of therapy). We also compared the results with those from a Cox model for counting processes adjusting for all covariates used in creating SWs. Results We demonstrate that the (i) results from the stratified Cox model without SWs adjustment and the Cox model for counting processes without covariate adjustment are identical in analyzing the clopidogrel data; and (ii) the effects of clopidogrel on bleeding, myocardial infarction, and death are larger in the stratified Cox model with SWs adjustment compared with those from the Cox model for counting processes with covariate adjustment. Conclusions The Cox model stratified by event times with time-varying SWs adjustment is useful in estimating the effect of time-varying treatments in observational studies while balancing for known confounders. Copyright (C) 2014 John Wiley & Sons, Ltd. C1 [Xu, Stanley; Shetterly, Susan; Raebel, Marsha A.; Ho, P. Michael; Tsai, Thomas T.; Magid, David] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO 80237 USA. [Xu, Stanley; Raebel, Marsha A.; Ho, P. Michael; Tsai, Thomas T.; Magid, David] Univ Colorado, Denver, CO 80202 USA. [Ho, P. Michael; Tsai, Thomas T.] Denver VA Med Ctr, Denver, CO USA. RP Xu, S (reprint author), Kaiser Permanente Colorado, Inst Hlth Res, POB 378066, Denver, CO 80237 USA. EM stan.xu@kp.org FU Strategic Initiatives Funds of Kaiser Permanente Colorado; Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness 16 (DEcIDE) program [290-05-0033]; National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical and Translational Sciences Institute [UL1 TR001082] FX This project was supported by the Strategic Initiatives Funds of Kaiser Permanente Colorado and funded under Contract No. 290-05-0033 from the Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness 16 (DEcIDE) program. Xu was also supported by National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical and Translational Sciences Institute Grant Number UL1 TR001082. Contents are the authors' sole responsibility and do not necessarily represent official NIH views. NR 36 TC 2 Z9 2 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 EI 1099-1557 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2014 VL 23 IS 8 BP 812 EP 818 DI 10.1002/pds.3601 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA AN1PG UT WOS:000340355200005 PM 24596337 ER PT J AU Manchette, AM Drucker, AG Januzzi, JL AF Manchette, Anastasia M. Drucker, Adrienne G. Januzzi, James L., Jr. TI Acute Coronary Syndrome Antiplatelet Alternatives in Clopidogrel Allergy SO PHARMACOTHERAPY LA English DT Article DE acute coronary syndrome; clopidogrel; hypersensitivity; allergy; antiplatelet; cross-reactivity ID UNSTABLE ANGINA; MYOCARDIAL-INFARCTION; ISCHEMIC EVENTS; ASPIRIN; PRASUGREL; TRIAL; MANAGEMENT; HEPARIN; PATIENT; DEATH AB No published information exists to support the safe use of ticagrelor in patients with a clopidogrel allergy. This study involved an institutional review board-approved retrospective review of patients with a documented clopidogrel allergy who subsequently received ticagrelor between July 2011 and February 2014. We report the cases of two patients with a history of hypersensitivity to clopidogrel in whom ticagrelor was used successfully without documented incident. In addition, principles suggesting a lack of cross-sensitivity between ticagrelor and clopidogrel are reviewed. These cases combined with theoretical evidence support the use of ticagrelor in patients with hypersensitivity to clopidogrel. C1 [Manchette, Anastasia M.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Drucker, Adrienne G.] eCare, Partners Healthcare, Boston, MA USA. [Januzzi, James L., Jr.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Januzzi, James L., Jr.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Manchette, AM (reprint author), Massachusetts Gen Hosp, Dept Pharm, 55 Fruit St,GRB 005, Boston, MA 02114 USA. EM Amanchette@partners.org NR 19 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-0008 EI 1875-9114 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2014 VL 34 IS 8 BP E152 EP E156 DI 10.1002/phar.1446 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN2KL UT WOS:000340413900003 PM 24898185 ER PT J AU Lippa, SM Agbayani, KA Hawes, S Jokic, E Caroselli, JS AF Lippa, Sara M. Agbayani, Kristina A. Hawes, Samuel Jokic, Emily Caroselli, Jerome S. TI Effort in Acute Traumatic Brain Injury: Considering More Than Pass/Fail SO REHABILITATION PSYCHOLOGY LA English DT Article DE effort; head injury; performance validity; traumatic brain injury ID NEUROPSYCHOLOGICAL STATUS RBANS; SYMPTOM VALIDITY TESTS; STATUS EFFORT INDEX; REPEATABLE BATTERY; TEST-PERFORMANCE; HEAD-INJURY; GALVESTON ORIENTATION; COGNITIVE IMPAIRMENT; HUNTINGTON DISEASE; GERIATRIC SAMPLES AB Purpose/Objective: Performance validity is often conceptualized as a dichotomous process. Effort likely lies on a continuum, however, and psychologists' tendency to rely on pass/fail descriptors of one's effort may not be the only approach. The current study aims to show that when performance validity is considered on a continuum, it may provide clinical information related to cognitive functioning. Research Method/Design: Forty-four patients with moderate or severe traumatic brain injury were evaluated with the Repeatable Battery for the Assessment of Neuropsychological Status upon their emergence from posttraumatic amnesia. From this data, previously developed effort index scores and "other cognitive functions" index scores were calculated. Results: Performance on the effort index significantly accounted for the patients' performance on a cognitive composite score after considering education and severity of injury. Conclusions/Implications: Findings suggest that more in-depth analysis of validity test performance is beneficial to gauge a patient's level of effort and is important to consider when interpreting results and in treatment planning. C1 [Lippa, Sara M.; Agbayani, Kristina A.; Hawes, Samuel; Jokic, Emily; Caroselli, Jerome S.] TIRR Mem Hermann Hosp, Dept Psychol Neuropsychol, Houston, TX USA. [Lippa, Sara M.] VA Boston Healthcare Syst, Boston, MA USA. [Agbayani, Kristina A.] Univ Houston, Dept Psychol, Houston, TX 77004 USA. [Hawes, Samuel] Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15260 USA. [Caroselli, Jerome S.] Baylor Coll Med, Dept Phys Med & Rehabil, Houston, TX 77030 USA. RP Lippa, SM (reprint author), Boston VA Med Ctr, Translat Res Ctr TBI & Stress Disorders TRACTS, 150 S Huntington Ave 182-JP, Boston, MA 02130 USA. EM saralippa@gmail.com FU NIMH NIH HHS [T32 MH018951] NR 63 TC 1 Z9 1 U1 1 U2 1 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0090-5550 EI 1939-1544 J9 REHABIL PSYCHOL JI Rehabil. Psychol. PD AUG PY 2014 VL 59 IS 3 BP 306 EP 312 DI 10.1037/a0037217 PG 7 WC Psychology, Clinical; Rehabilitation SC Psychology; Rehabilitation GA AN2RH UT WOS:000340432500007 PM 25133905 ER PT J AU Riess, H Kraft-Todd, G AF Riess, Helen Kraft-Todd, Gordon TI EMPATHY: A Tool to Enhance Nonverbal Communication Between Clinicians and Their Patients SO ACADEMIC MEDICINE LA English DT Article ID NEURAL BASIS; MEDICAL-EDUCATION; DECISION-MAKING; HEALTH OUTCOMES; CENTERED CARE; EMOTION; MODEL; TOUCH; NEUROBIOLOGY; NEUROSCIENCE AB There is a gap in the medical education literature on teaching nonverbal detection and expression of empathy. Many articles do not address nonverbal interactions, instead focusing on "what to say" rather than "how to be." This focus on verbal communication overlooks the essential role nonverbal signals play in the communication of emotions, which has significant effects on patient satisfaction, health outcomes, and malpractice claims. This gap is addressed with a novel teaching tool for assessing nonverbal behavior using the acronym E.M.P.A.T.H.Y.-E: eye contact; M: muscles of facial expression; P: posture; A: affect; T: tone of voice; H: hearing the whole patient; Y: your response. This acronym was the cornerstone of a randomized controlled trial of empathy training at Massachusetts General Hospital, 2010-2012. Used as an easy-to-remember checklist, the acronym orients medical professionals to key aspects of perceiving and responding to nonverbal emotional cues. An urgent need exists to teach nonverbal aspects of communication as medical practices must be reoriented to the increasing cultural diversity represented by patients presenting for care. Where language proficiency may be limited, nonverbal communication becomes more crucial for understanding patients' communications. Furthermore, even in the absence of cultural differences, many patients are reluctant to disagree with their clinicians, and subtle nonverbal cues may be the critical entry point for discussions leading to shared medical decisions. A detailed description of the E.M.P.A.T.H.Y. acronym and a brief summary of the literature that supports each component of the teaching tool are provided. C1 [Riess, Helen] Harvard Univ, Sch Med, Boston, MA USA. [Riess, Helen; Kraft-Todd, Gordon] Massachusetts Gen Hosp, Empathy & Relat Sci Program, Boston, MA 02114 USA. [Kraft-Todd, Gordon] Yale Univ, Human Cooperat Lab, New Haven, CT USA. RP Riess, H (reprint author), Massachusetts Gen Hosp, Wang ACC Suite 812, Boston, MA 02114 USA. EM hriess@mgh.harvard.edu NR 72 TC 14 Z9 14 U1 6 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-2446 EI 1938-808X J9 ACAD MED JI Acad. Med. PD AUG PY 2014 VL 89 IS 8 BP 1108 EP 1112 DI 10.1097/ACM.0000000000000287 PG 5 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA AN0PQ UT WOS:000340286900012 PM 24826853 ER PT J AU Gordon, M Frumento, P Skoldenberg, O Greene, M Garellick, G Rolfson, O AF Gordon, Max Frumento, Paolo Skoldenberg, Olof Greene, Meridith Garellick, Goran Rolfson, Ola TI Women in Charnley class C fail to improve in mobility to a higher degree after total hip replacement SO ACTA ORTHOPAEDICA LA English DT Article ID HEALTH-STATUS; ARTHROPLASTY; OUTCOMES; QUESTIONNAIRE; AGE AB Background - The Charnley comorbidity classification organizes patients into 3 classes: (A) 1 hip involved, (B) 2 hips involved, and (C) other severe comorbidities. Although this simple classification is a known predictor of health-related quality of life (HRQoL) after total hip replacement (THR), interactions between Charnley class, sex, and age have not been investigated and there is uncertainty regarding whether A and B should be grouped together. Methods - We selected a nationwide cohort of patients from the Swedish Hip Arthroplasty Register operated with THR due to primary osteoarthritis between 2008 and 2010. For estimation of HRQoL, we used the generic health outcome questionnaire EQ-5D of the EuroQol group. This consists of 2 parts: the EQ-5D index and the EQ VAS estimates. We modeled the EQ-5D index and the EQ VAS against the self-administered Charnley classification. Confounding was controlled for using preoperative HRQoL values, pain, and previous contralateral hip surgery. Results - We found that women in class C had a poorer EQ-5D outcome than men. This effect was mostly due to the fact that women failed to improve in the mobility dimension; only 40% improved, while about 50% of men improved. Age did not interact with Charnley class. We also found that the classification performed best without splitting or aggregating classes. Interpretation - Our results suggests that the self-administered Charnley classification should be used in its full capacity and that it may be interesting to devote special attention to women in Charnley class C. C1 [Gordon, Max; Greene, Meridith; Garellick, Goran; Rolfson, Ola] Swedish Hip Arthroplasty Register, Gothenburg, Sweden. [Gordon, Max; Skoldenberg, Olof] Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden. [Frumento, Paolo] Karolinska Inst, IMM, Stockholm, Sweden. [Greene, Meridith] Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. [Greene, Meridith; Garellick, Goran; Rolfson, Ola] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Orthopaed, Gothenburg, Sweden. RP Gordon, M (reprint author), Swedish Hip Arthroplasty Register, Gothenburg, Sweden. EM max@gforge.se RI Gordon, Max/M-4330-2014; OI Gordon, Max/0000-0002-8080-5815; Rolfson, Ola/0000-0001-6534-1242 NR 28 TC 7 Z9 7 U1 2 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1745-3674 EI 1745-3682 J9 ACTA ORTHOP JI Acta Orthop. PD AUG PY 2014 VL 85 IS 4 BP 335 EP 341 DI 10.3109/17453674.2014.931199 PG 7 WC Orthopedics SC Orthopedics GA AM8FS UT WOS:000340108300001 PM 24954483 ER PT J AU Ulku, CH Cheng, JT Guignard, J Rosowski, JJ AF Ulku, Cagatay Han Cheng, Jeffrey Tao Guignard, Jeremie Rosowski, John J. TI Comparisons of the mechanics of partial and total ossicular replacement prostheses with cartilage in a cadaveric temporal bone preparation SO ACTA OTO-LARYNGOLOGICA LA English DT Article DE Ossiculopasty; tympanoplasty; temporal bone study ID TYMPANIC MEMBRANE; STROBOSCOPIC HOLOGRAPHY; MIDDLE-EAR; TYMPANOPLASTY; RECONSTRUCTION; MOTION; SURFACE AB Conclusions: Reconstruction of the ossicular chain differentially affects the motion of the tympanic membrane (TM) and the stapes. Objectives: To determine the effect of different ossicular replacement procedures on the sound-induced motion of the TM and stapes. Methods: A combination of digital stroboscopic holography and laser Doppler vibrometry was used to determine the sound-induced motion of the TM and stapes in cadaveric temporal bones in which the ossicular chain was reconstructed using 12 varied standard techniques. The variations included the use of total or partial ossicular prosthesis, size of cartilage interposed between the TM and the prosthesis, and the length or fit of the prosthesis between the TM and stapes. The measurements were carried out in repeated measures format, so that each manipulation was performed in each temporal bone. Results: The volume displacement of the TM was in general reduced by reconstruction, with the largest reductions occurring with high-frequency stimulation in the reconstructions with a 'large' cartilage oval interposed between the TM and the prosthesis. Larger stapes motions in response to low-frequency sound were observed with either 'loose' or 'best' fit TORP with a 'small' cartilage plate between the TM and the prosthesis. C1 [Ulku, Cagatay Han; Cheng, Jeffrey Tao; Guignard, Jeremie; Rosowski, John J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02115 USA. [Ulku, Cagatay Han; Cheng, Jeffrey Tao; Guignard, Jeremie; Rosowski, John J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Ulku, Cagatay Han] Necmettin Erbakan Univ, Meram Med Fac, Dept Otolaryngol, Konya, Turkey. RP Rosowski, JJ (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02115 USA. EM john_rosowski@meei.harvard.edu FU US National Institute of Deafness and other Communicative Disorders [R01DC004798]; TUBITAK, the Scientific and Research Council of Turkey (TUBITAK) [2011 - 1059B191100156] FX This study was originally conceived with the aid of our deceased colleague, Saumil N. Merchant MD. We would like to thank Mike Ravicz at the Massachusetts Eye and Ear Infirmary, and Professor Cosme Furlong and his students at the Worcester Polytechnic Institute for aid in the design and implementation of the different measurement systems. This work was supported by a grant from the US National Institute of Deafness and other Communicative Disorders (R01DC004798, PI JJR), and a grant from TUBITAK, the Scientific and Research Council of Turkey (TUBITAK (2011 - 1059B191100156, to C. H. U.). NR 15 TC 2 Z9 2 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0001-6489 EI 1651-2251 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD AUG PY 2014 VL 134 IS 8 BP 776 EP 784 DI 10.3109/00016489.2014.898187 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA AM8OY UT WOS:000340137200002 PM 24847945 ER PT J AU Greene, SJ Shah, AN Butler, J Ambrosy, AP Anker, SD Chioncel, O Collins, SP Dinh, W Dunnmon, PM Fonarow, GC Lam, CSP Mentz, RJ Pieske, B Roessig, L Rosano, GMC Sato, N Vaduganathan, M Gheorghiade, M AF Greene, Stephen J. Shah, Ami N. Butler, Javed Ambrosy, Andrew P. Anker, Stefan D. Chioncel, Ovidiu Collins, Sean P. Dinh, Wilfried Dunnmon, Preston M. Fonarow, Gregg C. Lam, Carolyn S. P. Mentz, Robert J. Pieske, Burkert Roessig, Lothar Rosano, Giuseppe M. C. Sato, Naoki Vaduganathan, Muthiah Gheorghiade, Mihai TI Designing effective drug and device development programs for hospitalized heart failure: A proposal for pretrial registries SO AMERICAN HEART JOURNAL LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; EUROBSERVATIONAL RESEARCH-PROGRAM; VENTRICULAR EJECTION FRACTION; ESC-HF PILOT; MYOCARDIAL-INFARCTION; CLINICAL-TRIALS; PATIENT CHARACTERISTICS; THROMBUS ASPIRATION; UNITED-STATES; RISK-FACTORS AB Recent international phase III clinical trials of novel therapies for hospitalized heart failure (HHF) have failed to improve the unacceptably high postdischarge event rate. These large studies have demonstrated notable geographic and site-specific variation in patient profiles and enrollment. Possible contributors to the lack of success in HHF outcome trials include challenges in selecting clinical sites capable of (1) providing adequate numbers of appropriately selected patients and (2) properly executing the study protocol. We propose a "pretrial registry" as a novel tool for improving the efficiency and quality of international HHF trials by focusing on the selection and cultivation of high-quality sites. A pretrial registry may help assess a site's ability to achieve adequate enrollment of the target patient population, integrate protocol requirements into clinical workflow, and accomplish appropriate follow-up. Although such a process would be associated with additional upfront resource investment, this appropriation may be modest in comparison with the downstream costs associated with maintenance of poorly performing sites, failed clinical trials, and the global health and economic burden of HHF. This review is based on discussions between scientists, clinical trialists, and regulatory representatives regarding methods for improving international HHF trials that took place at the United States Food and Drug Administration on January 12th, 2012. C1 [Greene, Stephen J.; Shah, Ami N.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Butler, Javed] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Ambrosy, Andrew P.] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Anker, Stefan D.] Univ Med Ctr Gottingen, Dept Innovat Clin Trials, Gottingen, Germany. [Chioncel, Ovidiu] Univ Med & Pharm Carol Davila, Inst Emergency Cardiovasc Dis Prof CC Iliescu, Bucharest, Romania. [Collins, Sean P.] Vanderbilt Univ, Dept Emergency Med, Nashville, TN 37235 USA. [Dinh, Wilfried] Witten Univ, Dept Cardiol, Witten, Germany. [Dinh, Wilfried] Bayer Pharma AG, Clin Sci, Global Drug Discovery, Berlin, Germany. [Dunnmon, Preston M.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. [Lam, Carolyn S. P.] Natl Univ Hlth Syst, Singapore, Singapore. [Mentz, Robert J.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Pieske, Burkert] Dept Cardiol, Graz, Austria. [Roessig, Lothar] Bayer Pharma AG, Global Clin Dev, Berlin, Germany. [Rosano, Giuseppe M. C.] IRCC San Raffaele, Div Cardiol, Rome, Italy. [Sato, Naoki] Nippon Med Sch, Musashi Kosugi Hosp, Tokyo, Kanagawa, Japan. [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, 201 E Huron St,Galter 3-150, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI chioncel, ovidiu/0000-0002-3197-3628 FU Vifor Pharma; Bayer; Novartis; Abbott; Servier; Vifor; NIH/NHLBI; Medtronic; Radiometer; Cardiorentis; NHLBI; AHRQ; Gambro FX S.D.A. has received honoraria from Vifor Pharma, Bayer, CardioMems, ThermoFisher, St Jude Medical, Novartis, and Cardiorentis and received research support from Vifor Pharma, Bayer, and Novartis; O.C. has received research support from Abbott, Servier, and Vifor and served as a consultant for Philips, Novartis, and Janssen; S.P.C. has received research support from NIH/NHLBI, Medtronic, Radiometer, Cardiorentis, and Novartis and served as a consultant for Medtronic, Trevena, Novartis, Janssen, and Radiometer; W.D. and L.R. are employees of Bayer Pharma AG; G.C.F. has received research support from NHLBI, AHRQ, and Gambro and has served as a consultant for Novartis, Medtronic, Bayer, Johnson & Johnson, and Medicines Company; N.S. has received honoraria from Otsuka Pharmacueticals, Daiichi-Sankyo, Novartis Pharma, Eisai, Bayer, Boehringer-Ingelheim, Bristol-Myers, Philips Respironics, Ono Pharma, Kyowa-Hakko- Kirin, and Astellas and served as a consultant for Novartis and Bayer; B.P. has received modest speaker honoraria or served as a steering committee member for Bayer Healthcare, Novartis, Stealth Peptides, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichio Sankyo Medtronic, and Biotronik; M.G. has served as a consultant or received honoraria from Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals North America, Inc, and Trevena Therapeutics. All other authors have no relevant conflicts to declare. NR 55 TC 15 Z9 15 U1 3 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2014 VL 168 IS 2 BP 142 EP 149 DI 10.1016/j.ahj.2014.05.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9NG UT WOS:000340207700007 PM 25066552 ER PT J AU Blazing, MA Giugliano, RP Cannon, CP Musliner, TA Tershakovec, AM White, JA Reist, C McCagg, A Braunwald, E Califf, RM AF Blazing, Michael A. Giugliano, Robert P. Cannon, Christopher P. Musliner, Thomas A. Tershakovec, Andrew M. White, Jennifer A. Reist, Craig McCagg, Amy Braunwald, Eugene Califf, Robert M. TI Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population SO AMERICAN HEART JOURNAL LA English DT Article ID INTENSIVE STATIN THERAPY; PLACEBO-CONTROLLED TRIAL; LOW-DENSITY-LIPOPROTEIN; LDL CHOLESTEROL; AORTIC-STENOSIS; CLINICAL-TRIALS; PLUS EZETIMIBE; EFFICACY; DISEASE; SAFETY AB Background The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is evaluating the potential benefit for reduction in major cardiovascular (CV) events from the addition of ezetimibe versus placebo to 40 mg/d of simvastatin therapy in patients who present with acute coronary syndromes and have low-density lipoprotein cholesterol (LDL-C) <= 125 mg/dL. Methods The primary composite end point is CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization (>= 30 days postrandomization). The simvastatin monotherapy arm's LDL-C target is <70 mg/dL. Ezetimibe was assumed to further lower LDL-C by 15 mg/dL and produce an estimated similar to 8% to 9% treatment effect. The targeted number of events is 5,250. Results We enrolled 18,144 patients with either ST-segment elevation MI (STEMI, n = 5,192) or UA/non-ST-segment elevation MI (UA/NSTEMI, n = 12,952) from October 2005 to July 2010. Western Europe (40%) and North America (38%) were the leading enrolling regions. The STEMI cohort was younger and had a higher percentage of patients naive to lipid-lowering treatment compared with the UA/NSTEMI cohort. The UA/NSTEMI group had a higher prevalence of diabetes, hypertension, and prior MI. Median LDL-C at entry was 100 mg/dL for STEMI and 93 mg/dL for UA/NSTEMI patients. Conclusions This trial is evaluating LDL-C lowering beyond previously targeted LDL-C levels. The results depend on achieving the desired separation of LDL-C with ezetimibe and on the assumption that ezetimibe's lowering of LDL-C will have similar event reduction efficacy as the LDL-C lowering from a statin. The results could affect future therapies and guidelines. C1 [Blazing, Michael A.; White, Jennifer A.; Reist, Craig; Califf, Robert M.] Duke Clin Res Inst, Durham, NC USA. [Giugliano, Robert P.; Cannon, Christopher P.; McCagg, Amy; Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, Thrombolysis Myocardial Infarct TIMI Study Grp, Boston, MA 02115 USA. [Musliner, Thomas A.; Tershakovec, Andrew M.] Merck & Co Inc, Rahway, NJ 07065 USA. RP Blazing, MA (reprint author), Duke Univ, Med Ctr, Box 3126, Durham, NC 27710 USA. EM michael.blazing@dm.duke.edu FU Merck; Amgen; Daiichi-Sankyo; Accumetrics; Arisaph; AstraZeneca; Boehringer-Ingelheim; CSL Behring; Essentialis; GlaxoSmithKline; Janssen; Regeneron; Sanofi; Takeda; Johnson Johnson; Beckman-Coulter; Roche Diagnostics; Sanofi-Aventis; Bristol-Myers Squibb FX Dr Blazing has served as an advisory board member for Merck, has consulted for AstraZeneca and Novartis, and has received grant support from Merck (to the Duke Clinical Research Institute). Dr Giugliano has received grant support from Amgen, Daiichi-Sankyo, and Merck (to the Thrombolysis in Myocardial Infarction [TIMI] Study Group) and honoraria from Amgen, Beckman-Coulter, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen, Lexicon, Merck, Regeneron, and Sanofi. Dr Cannon has received research grants and support from Accumetrics, Arisaph, AstraZeneca, Boehringer-Ingelheim, CSL Behring, Essentialis, GlaxoSmithKline, Janssen, Merck, Regeneron, Sanofi, and Takeda and has served on an advisory board for Bristol-Myers Squibb, Lipimedix, and Pfizer. Drs Musliner and Tershakovec are employees and stockholders of Merck. Dr Braunwald has received grant support from AstraZeneca, Johnson & Johnson, Beckman-Coulter, Daiichi-Sankyo, Merck, Roche Diagnostics, Sanofi-Aventis, GlaxoSmithKline, and Bristol-Myers Squibb (to the TIMI Study Group) and honoraria from Amorcyte, The Medicines Company, Medscape, Bayer, Daiichi-Sankyo, Menarini International, and Sanofi-Aventis. Dr Califf's disclosures are available at https://www.dcri.org/about-us/conflict-of-interest. The other authors have no disclosures. NR 28 TC 49 Z9 51 U1 2 U2 16 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 EI 1097-5330 J9 AM HEART J JI Am. Heart J. PD AUG PY 2014 VL 168 IS 2 BP 205 EP + DI 10.1016/j.ahj.2014.05.004 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM9NG UT WOS:000340207700015 PM 25066560 ER PT J AU Elshaikh, MA Yashar, CM Wolfson, AH Cardenes, HR Erickson, B Jhingran, A Jolly, S Kidd, E Lee, LJ Mayr, NA Moore, D Rao, GG Small, W Varia, MA Wahl, AO Yuh, W Gaffney, DK AF Elshaikh, Mohamed A. Yashar, Catheryn M. Wolfson, Aaron H. Cardenes, Higinia Rosa Erickson, Beth Jhingran, Anuja Jolly, Shruti Kidd, Elizabeth Lee, Larissa J. Mayr, Nina A. Moore, David Rao, Gautam G. Small, William, Jr. Varia, Mahesh A. Wahl, Andrew O. Yuh, William Gaffney, David K. CA Expert Panel Radiation Oncology-Gy TI ACR Appropriateness Criteria (R) Advanced Stage Endometrial Cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE endometrial cancer; advanced stage; appropriateness criteria; multimodality; chemotherapy; radiation treatment ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-III TRIAL; PAPILLARY-SEROUS-CARCINOMA; PELVIC RADIATION-THERAPY; WHOLE ABDOMINAL RADIATION; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; MULTICENTER EVALUATION; CORPUS CANCER; I TRIAL AB Objectives: Patients with advanced stage endometrial carcinoma constitute a heterogeneous group of patients with different stages, tumor histologic types, and involved sites. Hysterectomy, bilateral salpingo-ophorectomy, and surgical staging are the cornerstone of surgical management in these patients. The optimal adjuvant therapy is yet to be established. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Results: Four clinical variants were developed to address common scenarios in the management of women with advanced-stage endometrial carcinoma. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. Conclusions: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with advanced-stage endometrial carcinoma. C1 [Elshaikh, Mohamed A.] Henry Ford Hlth Syst, Dept Radiat Oncol, Detroit, MI 48202 USA. [Jolly, Shruti] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [Yashar, Catheryn M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Kidd, Elizabeth] Stanford Canc Ctr, Stanford, CA USA. [Wolfson, Aaron H.] Univ Miami, Miami, FL USA. [Cardenes, Higinia Rosa] Indiana Univ, Med Ctr, Indianapolis, IN USA. [Moore, David] Indiana Univ Sch Med, Indianapolis, IN 46202 USA. [Erickson, Beth] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lee, Larissa J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mayr, Nina A.] Univ Washington, UW Med, Seattle, WA 98195 USA. [Yuh, William] Univ Washington, Fred Hutchinson Canc Ctr, Seattle, WA 98195 USA. [Rao, Gautam G.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Rao, Gautam G.] Amer Soc Clin Oncol, Alexandria, VA USA. [Small, William, Jr.] Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. [Varia, Mahesh A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Wahl, Andrew O.] Univ Nebraska Med Ctr, Omaha, NE USA. [Gaffney, David K.] Univ Utah, Med Ctr, Salt Lake City, UT USA. RP Elshaikh, MA (reprint author), Henry Ford Hlth Syst, Dept Radiat Oncol, 2799W Grand Blvd M2, Detroit, MI 48202 USA. EM melshai1@hfhs.org FU NCI NIH HHS [P30 CA016672] NR 51 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2014 VL 37 IS 4 BP 391 EP 396 DI 10.1097/COC.0000000000000098 PG 6 WC Oncology SC Oncology GA AM9PJ UT WOS:000340213200014 PM 24977691 ER PT J AU Larkin, J Fishman, M Wood, L Negrier, S Olivier, K Pyle, L Gorbunovn, V Jonasch, E Andrews, L Staehler, M AF Larkin, James Fishman, Mayer Wood, Laura Negrier, Sylvie Olivier, Kara Pyle, Linda Gorbunovn, Vera Jonasch, Eric Andrews, Lori Staehler, Michael TI Axitinib for the Treatment of Metastatic Renal Cell Carcinoma Recommendations for Therapy Management to Optimize Outcomes SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Review DE axitinib; toxicity; side effect management; treatment optimization; renal cell carcinoma; tyrosine kinase inhibitor ID CANCER-RELATED FATIGUE; BLOOD-PRESSURE; TARGETED THERAPIES; SOLID TUMORS; CHEMOTHERAPY; INHIBITION; REGRESSION; DYSPHONIA; SUNITINIB; EFFICACY AB Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with-a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment. C1 [Larkin, James; Negrier, Sylvie; Pyle, Linda] Royal Marsden, Dept Med, Renal Canc Unit, London, England. [Fishman, Mayer] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Wood, Laura] Cleveland Clin, Inst Canc, Cleveland, OH 44106 USA. [Olivier, Kara] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gorbunovn, Vera] NN Blokhin Russian Canc Res Ctr, Moscow, Russia. [Jonasch, Eric] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Andrews, Lori] Texas Oncol PA Sammons Canc Ctr Baylor, Dallas, TX USA. [Staehler, Michael] Univ Munich, Dept Urol, Munich, Germany. RP Larkin, J (reprint author), Royal Marsden Hosp, Renal Canc Unit, Dept Med, London SW3 6JJ, England. EM james.larkin@rmh.nhs.uk FU Pfizer Inc. FX The authors thank C. Choi, L. Cisar, S. Hariharan, G. Maurin, J. Ryan and C. Taylor of Pfizer Inc. for their support during the meeting held on July 29, 2011 in London UK Editorial support was provided by Minal Kotecha at ACUMED (Tytherington, UK) and was funded by Pfizer Inc. NR 38 TC 6 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2014 VL 37 IS 4 BP 397 EP 403 DI 10.1097/COC.0b013e31827b45f9 PG 7 WC Oncology SC Oncology GA AM9PJ UT WOS:000340213200015 PM 23357974 ER PT J AU Van Hyfte, GJ Kozak, LE Lepore, M AF Van Hyfte, Gregory J. Kozak, Leila E. Lepore, Michael TI A Survey of the Use of Complementary and Alternative Medicine in Illinois Hospice and Palliative Care Organizations SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE complementary and alternative medicine; integrative palliative care; complementary therapies; hospice care; hospice administration; end-of-life care; family caregivers; service delivery ID THERAPY; CANCER AB This research assesses complementary and alternative medicine (CAM) use and administration for patients and family caregivers in Illinois hospice and palliative care organizations. An online survey was administered to a sample of 108 contacts of Illinois organizations listed in the National Hospice and Palliative Care Organization website, and 90.3% of the responding organizations offered some type of CAM. The top 5 most frequently offered CAM modalities to patients were pet therapy (64.5%), music therapy (61.3%), massage therapy (54.8%), art therapy (29.0%), and energy therapies (25.8%); these were the same top 5 offered to families but with different frequencies. Findings regarding utilization, administration, financing, and spiritual/ cultural competency are discussed with policy recommendations for data collection, administrative improvements, and integration of CAM providers into service delivery. C1 [Van Hyfte, Gregory J.] Dept Hlth Educ, Chicago, IL 60622 USA. [Kozak, Leila E.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Kozak, Leila E.] Univ Washington, Sch Publ Hlth, Dept Hlth Serv, Seattle, WA 98195 USA. [Lepore, Michael] Planetree, Dept Qual Res & Evaluat, Derby, CT USA. [Lepore, Michael] Brown Univ, Dept Hlth Serv Policy & Practice, Providence, RI 02912 USA. RP Van Hyfte, GJ (reprint author), Dept Hlth Educ, 2611W Chicago Ave, Chicago, IL 60622 USA. EM gregory@uchicago.edu FU Arthur Quern Fellowship at the University of Chicago; Graduate Program in Health Administration; Policy in the School of Social Service Administration; VA Puget Sound Health Care System, Seattle, Washington through Health Services Research and Development Service as part of Dr Kozak's fellowship [TPP 61-61-023] FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Arthur Quern Fellowship at the University of Chicago, Graduate Program in Health Administration and Policy in the School of Social Service Administration. Dr Kozak's work was supported in part by resources from the VA Puget Sound Health Care System, Seattle, Washington through Health Services Research and Development Service as part of Dr Kozak's fellowship, grant # TPP 61-61-023. NR 19 TC 0 Z9 0 U1 2 U2 14 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 EI 1938-2715 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD AUG PY 2014 VL 31 IS 5 BP 553 EP 561 DI 10.1177/1049909113500378 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA AM8BV UT WOS:000340095200013 PM 23943631 ER PT J AU Jacobsen, HB Reme, SE Sembajwe, G Hopcia, K Stiles, TC Sorensen, G Porter, JH Marino, M Buxton, OM AF Jacobsen, Henrik B. Reme, Silje E. Sembajwe, Grace Hopcia, Karen Stiles, Tore C. Sorensen, Glorian Porter, James H. Marino, Miguel Buxton, Orfeu M. TI Work Stress, Sleep Deficiency, and Predicted 10-Year Cardiometabolic Risk in a Female Patient Care Worker Population SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE cardiometabolic risk; nurses; sleep maintenance; physical activity; follow-up; work-family conflict ID CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; OLDER-ADULTS; SHIFT WORK; FAMILY CONFLICT; DURATION; WOMEN; OBESITY AB Objectives The aim of this study was to investigate the longitudinal effect of work-related stress, sleep deficiency, and physical activity on 10-year cardiometabolic risk among an all-female worker population. Methods Data on patient care workers (n = 99) was collected 2 years apart. Baseline measures included: job stress, physical activity, night work, and sleep deficiency. Biomarkers and objective measurements were used to estimate 10-year cardiometabolic risk at follow-up. Significant associations (P < 0.05) from baseline analyses were used to build a multivariable linear regression model. Results The participants were mostly white nurses with a mean age of 41 years. Adjusted linear regression showed that having sleep maintenance problems, a different occupation than nurse, and/or not exercising at recommended levels at baseline increased the 10-year cardiometabolic risk at follow-up. Conclusions In female workers prone to work-related stress and sleep deficiency, maintaining sleep and exercise patterns had a strong impact on modifiable 10-year cardiometabolic risk. (C) 2014 Wiley Periodicals, Inc. C1 [Jacobsen, Henrik B.; Reme, Silje E.; Hopcia, Karen; Sorensen, Glorian; Buxton, Orfeu M.] Harvard Univ, Sch Publ Hlth, Ctr Work Hlth & Wellbeing, Boston, MA 02115 USA. [Jacobsen, Henrik B.; Stiles, Tore C.] Norwegian Univ Sci & Technol, N-7034 Trondheim, Norway. [Reme, Silje E.] Uni Res, Uni Hlth, Bergen, Norway. [Sembajwe, Grace] CUNY, Sch Publ Hlth, Hunter Coll, New York, NY 10021 USA. [Sembajwe, Grace; Hopcia, Karen] Partners Hlth Care Syst, Partners Occupat Hlth Serv, Boston, MA USA. [Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Hlth & Human Dev, Boston, MA 02115 USA. [Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Porter, James H.; Buxton, Orfeu M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Marino, Miguel] Oregon Hlth & Sci Univ, Div Biostat, Dept Family Med Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Buxton, Orfeu M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. RP Jacobsen, HB (reprint author), NTNU, Fac Med, Dept Circulat & Med Imaging, POB 8905 MTFS, N-7491 Trondheim, Norway. EM henrik.b.jacobsen@ntnu.no FU National Institute for Occupational Safety and Health [U19OH008861]; National Center for Research Resources [UL1RR025758-04]; Work, Family, and Health Network [U01AG5186989]; National Heart, Lung, and Blood Institute [R01HL107240]; Dean Hashimoto and Partners Occupational Health Service FX Contract grant sponsor: National Institute for Occupational Safety and Health; Contract grant number: U19OH008861; Contract grant sponsor: National Center for Research Resources. Grant number; Contract grant number: UL1RR025758-04; Contract grant sponsor: Work, Family, and Health Network; Contract grant number: U01AG5186989; Contract grant sponsor: National Heart, Lung, and Blood Institute; Contract grant number: R01HL107240; Contract grant sponsor: Dean Hashimoto and Partners Occupational Health Service. NR 65 TC 7 Z9 7 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0271-3586 EI 1097-0274 J9 AM J IND MED JI Am. J. Ind. Med. PD AUG PY 2014 VL 57 IS 8 BP 940 EP 949 DI 10.1002/ajim.22340 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AM9EH UT WOS:000340182800009 PM 24809311 ER PT J AU Pejo, E Santer, P Jeffrey, S Gallin, H Husain, SS Raines, DE AF Pejo, Ervin Santer, Peter Jeffrey, Spencer Gallin, Hilary Husain, S. Shaukat Raines, Douglas E. TI Analogues of Etomidate Modifications around Etomidate's Chiral Carbon and the Impact on In Vitro and In Vivo Pharmacology SO ANESTHESIOLOGY LA English DT Article ID MULTIPLE TRAUMA PATIENTS; LOW-DOSE ETOMIDATE; ADRENOCORTICAL-FUNCTION; GABA(A) RECEPTOR; METHOXYCARBONYL-ETOMIDATE; ANESTHETIC ETOMIDATE; CUSHINGS-SYNDROME; INDUCTION AGENT; BINDING-SITE; MORTALITY AB Background: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure-activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate's chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). Methods: The gamma-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed alpha(1)(L264T)beta(3)gamma(2L) and alpha(1)(L264T)beta(1)gamma(2L) gamma-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). Results: All four drugs activated both gamma-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest gamma-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing beta(3) subunits than beta(1) subunits; however, dihydrogen etomidate's subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. Conclusion: The linkage between the structure of etomidate's chiral center and its pharmacology suggests that altering etomidate's chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities. C1 [Pejo, Ervin; Santer, Peter; Jeffrey, Spencer; Gallin, Hilary; Husain, S. Shaukat; Raines, Douglas E.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Raines, DE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St,GRB444, Boston, MA 02114 USA. EM draines@partners.org OI Santer, Peter/0000-0002-1735-0774 FU National Institutes of Health, Bethesda, Maryland [R01-GM087316]; Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts FX This study was supported by grant R01-GM087316 from the National Institutes of Health, Bethesda, Maryland, and the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts. NR 44 TC 8 Z9 8 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2014 VL 121 IS 2 BP 290 EP 301 DI 10.1097/ALN.0000000000000268 PG 12 WC Anesthesiology SC Anesthesiology GA AM7EW UT WOS:000340028500012 PM 24777068 ER PT J AU Solt, K Van Dort, CJ Chemali, JJ Taylor, NE Kenny, JD Brown, EN AF Solt, Ken Van Dort, Christa J. Chemali, Jessica J. Taylor, Norman E. Kenny, Jonathan D. Brown, Emery N. TI Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia SO ANESTHESIOLOGY LA English DT Article ID PROPOFOL-INDUCED UNCONSCIOUSNESS; DOPAMINERGIC-NEURONS; EMERGENCE DELIRIUM; SLEEP; CONSCIOUSNESS; RECEPTORS; CHILDREN; WAKING; BRAIN; METHYLPHENIDATE AB Background: Methylphenidate or a D1 dopamine receptor agonist induces reanimation (active emergence) from general anesthesia. The authors tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. Methods: In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120 mu A. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. Results: To maintain loss of righting, the dose of isoflurane was 0.9% +/- 0.1 vol%, and the target plasma dose of propofol was 4.4 +/- 1.1 g/ml (mean +/- SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from delta (< 4 Hz) to theta (4-8 Hz). In all rats with substantia nigra electrodes, stimulation did not elicit an arousal response or significant electroencephalogram changes. Conclusions: Electrical stimulation of the VTA, but not the substantia nigra, induces reanimation during general anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA neurons, but not substantia nigra neurons, induces reanimation from general anesthesia. C1 [Solt, Ken; Van Dort, Christa J.; Taylor, Norman E.; Brown, Emery N.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Solt, Ken; Van Dort, Christa J.; Chemali, Jessica J.; Taylor, Norman E.; Kenny, Jonathan D.; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Solt, K (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,GRB 444, Boston, MA 02114 USA. EM ksolt@mgh.harvard.edu OI Kenny, Jonathan/0000-0003-3745-3217; Solt, Ken/0000-0001-5328-2062 FU National Institutes of Health, Bethesda, Maryland [TR01-GM104948, DP1-OD003646, K08-GM094394] FX Supported by grants TR01-GM104948, DP1-OD003646, and K08-GM094394 from the National Institutes of Health, Bethesda, Maryland. NR 40 TC 17 Z9 18 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2014 VL 121 IS 2 BP 311 EP 319 DI 10.1097/ALN.0000000000000117 PG 9 WC Anesthesiology SC Anesthesiology GA AM7EW UT WOS:000340028500014 PM 24398816 ER PT J AU Kamdar, NV de Gialluly, PS AF Kamdar, Nirav Vikram de Gialluly, Pascal Scemama TI Academic Anesthesia: Innovate to Avoid Extinction SO ANESTHESIOLOGY LA English DT Letter C1 [Kamdar, Nirav Vikram; de Gialluly, Pascal Scemama] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kamdar, NV (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM nkamdar@partners.org NR 3 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2014 VL 121 IS 2 BP 427 EP 428 DI 10.1097/ALN.0000000000000317 PG 2 WC Anesthesiology SC Anesthesiology GA AM7EW UT WOS:000340028500033 PM 25050502 ER PT J AU Rathmell, JP Lien, CA Harman, A AF Rathmell, James P. Lien, Cynthia A. Harman, Ann TI Corporate Interests Necessitate Conflict of Interest Declarations by All Authors Reply SO ANESTHESIOLOGY LA English DT Letter C1 [Rathmell, James P.; Lien, Cynthia A.; Harman, Ann] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rathmell, JP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rathmell.james@mgh.harvard.edu NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2014 VL 121 IS 2 BP 432 EP 432 DI 10.1097/ALN.0000000000000327 PG 1 WC Anesthesiology SC Anesthesiology GA AM7EW UT WOS:000340028500038 PM 25050507 ER PT J AU Tung, ES Tung, MG Altenburger, EM Pauls, DL Keuthen, NJ AF Tung, Esther S. Tung, Matthew G. Altenburger, Erin M. Pauls, David L. Keuthen, Nancy J. TI The relationship between hair pulling style and quality of life SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article DE hair pulling; trichotillomania; quality of life; depression ID TRICHOTILLOMANIA; INVENTORY; DEPRESSION; IMPACT; SCALE AB BACKGROUND: Past research has found different associations between hair pulling (HP) variables and quality of life (QOL), especially after controlling for depression. This study examined HP styles (automatic vs focused) for their associations with QOL and whether depression accounted for these relationships. METHODS: Our sample consisted of 187 adults who met DSM-IV diagnostic criteria for trichotillomania (TTM) or chronic HP (TTM criteria except B and/or C). Clinician-administered interviews were used to diagnose TTM/HP. Participants completed self-report scales for HP style and severity, QOL, and severity of depression. RESULTS: Significant correlations were reported between QOL and the focused style of HP, as well as with interference and distress from HP. Exploratory analyses also revealed a correlation between number of HP sites and QOL. None of the correlations remained significant after controlling for severity of depression. CONCLUSIONS: These results indicate that future research on HP style also should consider the impact of co-occurring depressive symptoms. Interventions addressing both depression and HP should be considered in treatment planning to optimize outcomes. C1 [Tung, Esther S.; Pauls, David L.; Keuthen, Nancy J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Tung, Matthew G.] Harvard Univ, Sch Med, Boston, MA USA. [Altenburger, Erin M.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. RP Keuthen, NJ (reprint author), Massachusetts Gen Hosp, OCD & Related Disorders Program, 185 Cambridge St,Suite 2200, Boston, MA 02114 USA. EM nkeuthen@partners.org FU Greater Kansas City Community Foundation; Trichotillomania Learning Center FX This research was financially supported by grants from the Greater Kansas City Community Foundation and the Trichotillomania Learning Center. The funding sponsors had no role in study design, data collection, data analysis or interpretation, manuscript preparation, or the decision to submit the manuscript for publication. NR 17 TC 0 Z9 0 U1 0 U2 3 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 1040-1237 EI 1547-3325 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD AUG PY 2014 VL 26 IS 3 BP 193 EP 198 PG 6 WC Psychiatry SC Psychiatry GA AM9OX UT WOS:000340212000006 PM 25166481 ER PT J AU Thoma, B Rolston, D Lin, M AF Thoma, Brent Rolston, Daniel Lin, Michelle TI Global Emergency Medicine Journal Club: Social Media Responses to the March 2014 Annals of Emergency Medicine Journal Club on Targeted Temperature Management SO ANNALS OF EMERGENCY MEDICINE LA English DT Editorial Material ID CARDIAC-ARREST; HYPOTHERMIA AB In March 2014, Annals of Emergency Medicine continued a successful collaboration with an academic Web site, Academic Life in Emergency Medicine (ALiEM), to host another Global Emergency Medicine Journal Club session featuring the 2013 New England Journal of Medicine article "Targeted Temperature Management at 33 degrees C (91.4 degrees F) Versus 36 degrees C (96.8 degrees F) After Cardiac Arrest" by Nielsen et al. This online journal club used Twitter conversations, a live videocast with the authors, and detailed discussions on the ALiEM Web site's comment section. This summary article details the community discussion, shared insights, and analytic data generated using this novel, multiplatform approach. C1 [Thoma, Brent] Massachusetts Gen Hosp, Learning Lab, Dept Emergency Med, Boston, MA 02114 USA. [Thoma, Brent] Massachusetts Gen Hosp, Div Med Simulat, Dept Emergency Med, Boston, MA 02114 USA. [Thoma, Brent] Univ Saskatchewan, Saskatoon, SK, Canada. [Rolston, Daniel] Univ Calif Los Angeles, Dept Anesthesiol, Los Angeles, CA 90024 USA. [Lin, Michelle] Univ Calif San Francisco, Dept Emergency Med, San Francisco, CA 94143 USA. RP Thoma, B (reprint author), Massachusetts Gen Hosp, Learning Lab, Dept Emergency Med, Boston, MA 02114 USA. EM brent.thoma@usask.ca OI Rolston, Daniel/0000-0001-7595-2418; Thoma, Brent/0000-0003-1124-5786 NR 15 TC 14 Z9 14 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD AUG PY 2014 VL 64 IS 2 BP 207 EP 212 DI 10.1016/j.annemergmed.2014.06.003 PG 6 WC Emergency Medicine SC Emergency Medicine GA AM9PV UT WOS:000340214400022 PM 25059776 ER PT J AU Fitzpatrick, AM Gao, LL Smith, BL Cetrulo, CL Colwell, AS Winograd, JM Yaremchuk, MJ Austen, WG Liao, EC AF Fitzpatrick, Aisling M. Gao, Lin Lin Smith, Barbara L. Cetrulo, Curtis L., Jr. Colwell, Amy S. Winograd, Jonathan M. Yaremchuk, Michael J. Austen, William G., Jr. Liao, Eric C. TI Cost and Outcome Analysis of Breast Reconstruction Paradigm Shift SO ANNALS OF PLASTIC SURGERY LA English DT Article DE breast cancer reconstruction; prophylactic mastectomy; single-stage acellular dermal matrix; deep inferior epigastric perforator (DIEP) flap ID SKIN-SPARING MASTECTOMY; CONTRALATERAL PROPHYLACTIC MASTECTOMY; NIPPLE-AREOLA COMPLEX; FREE TRAM; AUTOLOGOUS RECONSTRUCTION; NEOPLASTIC INVOLVEMENT; PERFORATOR FLAP; CANCER PATIENTS; TISSUE MATRIX; DIEP FLAP AB Increased bilateral mastectomy for breast cancer treatment has generated an increased demand for bilateral breast reconstruction. This study examines changing patterns of reconstruction over the last decade to accommodate increased case volume and decreased morbidity associated with reconstruction. A single institution series of 3171 consecutive breast reconstruction cases of more than 10 years was divided into 2 periods, that is, 1999 to 2004 and 2005 to 2010. Bilateral breast reconstruction case volume increased 260% from 1999 to 2004 (n = 237) to 2005 to 2010 (n = 634). Mean patient age at diagnosis decreased by 7 years (P < 0.001). In 2005 to 2010, autologous reconstruction decreased from 60% to 26%, implant-based reconstruction increased from 40% to 74%. There was a noted increase in single-stage implant reconstruction and selective application of perforator flaps for bilateral autologous reconstruction (P < 0.001). Two-staged tissue expander reconstruction accounted for the greatest share of total cost (45%) in the later period. A younger patient demographic and increased case volume were accommodated through increased single-staged and prosthesis-based procedures. C1 [Fitzpatrick, Aisling M.; Gao, Lin Lin; Cetrulo, Curtis L., Jr.; Colwell, Amy S.; Winograd, Jonathan M.; Yaremchuk, Michael J.; Austen, William G., Jr.; Liao, Eric C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Smith, Barbara L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Surg Oncol,Breast Canc Program, Boston, MA 02114 USA. [Liao, Eric C.] Harvard Stem Cell Inst, Ctr Regenerat Med, Boston, MA USA. RP Liao, EC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, WACC 435,15 Parkman St, Boston, MA 02114 USA. EM cliao@partners.org FU American Surgical Association Research Fellowship; Plastic Surgery Education Foundation; Harvard Stem Cell Institute; March of Dimes Basil O'Connor Starter Scholar Award; Shriners Hospitals for Children FX Supported by the American Surgical Association Research Fellowship, Plastic Surgery Education Foundation, Harvard Stem Cell Institute, the March of Dimes Basil O'Connor Starter Scholar Award, and the Shriners Hospitals for Children (E.C.L.). NR 56 TC 9 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD AUG PY 2014 VL 73 IS 2 BP 141 EP 149 DI 10.1097/SAP.0b013e318276d979 PG 9 WC Surgery SC Surgery GA AM8RH UT WOS:000340144200007 PM 23407253 ER PT J AU Lindsay, RW Bhama, P Weinberg, J Hadlock, TA AF Lindsay, Robin W. Bhama, Prabhat Weinberg, Julie Hadlock, Tessa A. TI The Success of Free Gracilis Muscle Transfer to Restore Smile in Patients With Nonflaccid Facial Paralysis SO ANNALS OF PLASTIC SURGERY LA English DT Article DE facial paralysis; facial reanimation; gracilis free muscle transfer ID QUALITY-OF-LIFE; BELLS-PALSY; THERAPEUTIC STRATEGIES; NERVE PARALYSIS; MOTOR-NERVE; SYNKINESIS; VALIDATION; EXCURSION; FACE; PREDNISOLONE AB Background: Development of synkinesis, hypertonicity, and poor smile excursion after facial nerve insult and recovery contribute to disfigurement, psychological difficulties, and an inability to convey emotion via facial expression. Despite treatment with physical therapy and chemodenervation, some patients who recover from transient flaccid facial paralysis never spontaneously regain the ability to perform a meaningful smile. Methods: Prospective evaluation was performed on 20 patients with nonflaccid facial paralysis who underwent free gracilis muscle transfer. Patients were evaluated using the quality-of-life (QOL) FaCE survey, Facial Nerve Grading Scale, and Facegram to quantify QOL improvement, smile excursion, and symmetry after muscle transfer. Results: A statistically significant increase in the FaCE score was seen after muscle transfer (paired 2-tailed t test, P < 0.039). In addition, there was a statistically significant improvement in the smile score on the Facial Nerve Grading Scale (P < 0.002), in the lower lip length at rest (P = 0.01) and with smile (P = 0.0001), and with smile symmetry (P = 0.0077) after surgery. Conclusions: Free gracilis muscle transfer has become a mainstay in the management armamentarium for patients who develop severe reduction in oral commissure movement after facial nerve insult and recovery. The operation achieves a high overall success rate, and innovations involving transplanting thinner segments of muscle avoid a cosmetic deformity secondary to excess bulk. This study demonstrates a quantitative improvement in QOL and facial function after free gracilis muscle transfer in patients who failed to achieve a meaningful smile after physical therapy. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Lindsay, RW (reprint author), Massachusetts Eye & Ear Infirm, Div Facial Plast & Reconstruct Surg, 243 Charles St, Boston, MA 02114 USA. EM robin_lindsay@meei.harvard.edu FU Academy of Facial Plastics and Reconstructive Surgery FX This work was supported in part by the Leslie Bernstein Grant from the Academy of Facial Plastics and Reconstructive Surgery. NR 27 TC 11 Z9 11 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD AUG PY 2014 VL 73 IS 2 BP 177 EP 182 DI 10.1097/SAP.0b013e3182a0df04 PG 6 WC Surgery SC Surgery GA AM8RH UT WOS:000340144200014 PM 24051452 ER PT J AU Rosenfeld, MR Ye, XB Supko, JG Desideri, S Grossman, SA Brem, S Mikkelson, T Wang, D Chang, YYC Hu, J McAfee, Q Fisher, J Troxel, A Piao, SF Heitjan, DF Tan, KS Pontiggia, L O'Dwyer, PJ Davis, LE Amaravadi, RK AF Rosenfeld, Myrna R. Ye, Xiaobu Supko, Jeffrey G. Desideri, Serena Grossman, Stuart A. Brem, Steven Mikkelson, Tom Wang, Daniel Chang, Yunyoung C. Hu, Janice McAfee, Quentin Fisher, Joy Troxel, Andrea Piao, Shengfu Heitjan, Daniel F. Tan, Kay See Pontiggia, Laura O'Dwyer, Peter J. Davis, Lisa E. Amaravadi, Ravi K. TI A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme SO AUTOPHAGY LA English DT Article DE autophagy; hydroxychloroquine; glioblastoma ID MALIGNANT GLIOMA-CELLS; INDUCED AUTOPHAGY; CHLOROQUINE; SURVIVAL; PHARMACOKINETICS; APOPTOSIS; NECROSIS; DISEASES AB Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ. C1 [Rosenfeld, Myrna R.; Ye, Xiaobu; Supko, Jeffrey G.; Desideri, Serena; Grossman, Stuart A.; Brem, Steven; Mikkelson, Tom; Fisher, Joy] Univ Penn, Adult Brain Tumor Consortium, Philadelphia, PA 19104 USA. [Rosenfeld, Myrna R.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Ye, Xiaobu; Desideri, Serena; Grossman, Stuart A.; Fisher, Joy] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Supko, Jeffrey G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Brem, Steven] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Neurosurg, Tampa, FL 33682 USA. [Mikkelson, Tom] Henry Ford Hosp, Hermelin Brain Tumor Ctr Neurol, Detroit, MI 48202 USA. [Wang, Daniel; Chang, Yunyoung C.; Hu, Janice; McAfee, Quentin; Piao, Shengfu; O'Dwyer, Peter J.; Davis, Lisa E.; Amaravadi, Ravi K.] Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Troxel, Andrea; Heitjan, Daniel F.; Tan, Kay See] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Pontiggia, Laura] Univ Sci, Dept Math Phys & Stat, Philadelphia, PA USA. [O'Dwyer, Peter J.; Amaravadi, Ravi K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Davis, Lisa E.] Univ Sci, Philadelphia Coll Pharm, Philadelphia, PA USA. RP Amaravadi, RK (reprint author), Perelman Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. EM ravi.amaravadi@uphs.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075; Rosenfeld, Myrna/0000-0001-5095-2534 FU NCI, CTEP grant [1R21CA133898, 3R21CA133898, 1K23CA120862] FX This work was supported by NCI 1R21CA133898 (RA), NCI 3R21CA133898 (RA), 1K23CA120862(RA), CTEP grant. We thank the ABTC Central Office for data collection and integration. We thank Ray Meade and biomedical imaging core for EM processing and technical advice. NR 27 TC 76 Z9 79 U1 3 U2 10 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD AUG PY 2014 VL 10 IS 8 BP 1359 EP 1368 DI 10.4161/auto.28984 PG 10 WC Cell Biology SC Cell Biology GA AN0HU UT WOS:000340266200002 PM 24991840 ER PT J AU Vogl, DT Stadtmauer, EA Tan, KS Heitjan, DF Davis, LE Pontiggia, L Rangwala, R Piao, SF Chang, YYC Scott, EC Paul, TM Nichols, CW Porter, DL Kaplan, J Mallon, G Bradner, JE Amaravadi, RK AF Vogl, Dan T. Stadtmauer, Edward A. Tan, Kay See Heitjan, Daniel F. Davis, Lisa E. Pontiggia, Laura Rangwala, Reshma Piao, Shengfu Chang, Yunyoung C. Scott, Emma C. Paul, Thomas M. Nichols, Charles W. Porter, David L. Kaplan, Janeen Mallon, Gayle Bradner, James E. Amaravadi, Ravi K. TI Combined autophagy and proteasome inhibition A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma SO AUTOPHAGY LA English DT Article DE myeloma; autophagy; proteasome ID MANTLE CELL LYMPHOMA; ENDOPLASMIC-RETICULUM STRESS; NON-HODGKINS-LYMPHOMA; MULTIPLE-MYELOMA; CANCER CELLS; ANTITUMOR-ACTIVITY; INDUCED APOPTOSIS; COMBINATION; PROLIFERATION; DEXAMETHASONE AB The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy. C1 [Vogl, Dan T.; Stadtmauer, Edward A.; Rangwala, Reshma; Piao, Shengfu; Chang, Yunyoung C.; Scott, Emma C.; Paul, Thomas M.; Nichols, Charles W.; Porter, David L.; Kaplan, Janeen; Mallon, Gayle; Amaravadi, Ravi K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Tan, Kay See; Heitjan, Daniel F.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Davis, Lisa E.] Univ Sci Philadelphia, Dept Pharm Practice & Pharm Adm, Philadelphia, PA USA. [Pontiggia, Laura] Univ Sci Philadelphia, Dept Math Phys & Stat, Philadelphia, PA USA. [Bradner, James E.] Dana Farber Canc Inst, Div Hematol Neoplasia, Boston, MA 02115 USA. RP Vogl, DT (reprint author), Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. EM dan.vogl@uphs.upenn.edu FU Millennium Pharmaceuticals; University of Pennsylvania Abramson Cancer Center; National Cancer Institute [K23CA120862, K23CA130074, P30CA016520]; National Center for Research Resources [UL1-RR-024134] FX The authors thank Cezary R Swider, Joy Cannon, and Martin Carroll at the University of Pennsylvania Stem Cell and Xenograft Core, for processing samples. One of the authors (RR) is now an employee of Merck. This research was supported by a Special Fellow in Clinical Research award from the Leukemia & Lymphoma Society (DTV), a research grant from Millennium Pharmaceuticals, a pilot project grant from the University of Pennsylvania Abramson Cancer Center, National Cancer Institute grants K23CA120862 (RKA), K23CA130074 (DTV), and P30CA016520 (DFH, KST), and National Center for Research Resources grant UL1-RR-024134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Center for Research Resources, or the National Institutes of Health. NR 44 TC 78 Z9 79 U1 2 U2 24 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD AUG PY 2014 VL 10 IS 8 BP 1380 EP 1390 DI 10.4161/auto.29264 PG 11 WC Cell Biology SC Cell Biology GA AN0HU UT WOS:000340266200004 PM 24991834 ER PT J AU Lucena-Araujo, AR Kim, HT Jacomo, RH Melo, RA Bittencourt, R Pasquini, R Pagnano, K Fagundes, EM Chauffaille, MD Chiattone, CS Lima, AS Kwaan, HC Gallagher, R Niemeyer, CM Schrier, SL Tallman, MS Grimwade, D Ganser, A Berliner, N Ribeiro, RC Lo-Coco, F Lowenberg, B Sanz, MA Rego, EM AF Lucena-Araujo, Antonio R. Kim, Haesook T. Jacomo, Rafael H. Melo, Raul A. Bittencourt, Rosane Pasquini, Ricardo Pagnano, Katia Fagundes, Evandro M. Chauffaille, Maria de Lourdes Chiattone, Carlos S. Lima, Ana S. Kwaan, Hau C. Gallagher, Robert Niemeyer, Charlotte M. Schrier, Stanley L. Tallman, Martin S. Grimwade, David Ganser, Arnold Berliner, Nancy Ribeiro, Raul C. Lo-Coco, Francesco Lowenberg, Bob Sanz, Miguel A. Rego, Eduardo M. TI Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE acute promyelocytic leukaemia; International Consortium on Acute Promyelocytic Leukaemia; KMT2E (MLL5); developing countries; all-trans retinoic acid ID RISK-ADAPTED TREATMENT; HISTONE METHYLTRANSFERASE; MYELOID-LEUKEMIA; CD56 EXPRESSION; PML; GENE; MLL5; MONOCHEMOTHERAPY; CONSOLIDATION; MUTATIONS AB The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0.006), 2-year overall survival (OS) (P = 0.005) and 2-year disease-free survival (DFS) rates (P = 0.037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0.04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7.18, 95% confidence interval [CI]: 1.71-30.1; P = 0.007) and shorter OS (hazard ratio [HR]: 0.27, 95% CI: 0.08-0.87; P = 0.029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10.3, 95% CI: 2.49-43.2; P = 0.001) and shorter survival (HR: 0.17, 95% IC: 0.05-0.53; P = 0.002), while the association with DFS was of marginal significance (HR: 1.01; 95% CI: 0.99-1.02; P = 0.06). In summary, low KMT2E expression may predict poor outcome in APL patients. C1 [Lucena-Araujo, Antonio R.; Jacomo, Rafael H.; Lima, Ana S.; Rego, Eduardo M.] Univ Sao Paulo, Med Sch Ribeirao Preto, BR-14048900 Ribeirao Preto, SP, Brazil. [Lucena-Araujo, Antonio R.; Jacomo, Rafael H.; Lima, Ana S.; Rego, Eduardo M.] Univ Sao Paulo, Ctr Cell Based Therapy, BR-14048900 Ribeirao Preto, SP, Brazil. [Kim, Haesook T.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Melo, Raul A.] Fundacao HEMOPE, Recife, PE, Brazil. [Bittencourt, Rosane] Univ Fed Rio Grande do Sul, Porto Alegre, RS, Brazil. [Pasquini, Ricardo] Univ Fed Parana, BR-80060000 Curitiba, Parana, Brazil. [Pagnano, Katia] Univ Estadual Campinas, Campinas, SP, Brazil. [Fagundes, Evandro M.] Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. [Chauffaille, Maria de Lourdes] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Chiattone, Carlos S.] Santa Casa Med Sch, Sao Paulo, Brazil. [Kwaan, Hau C.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Gallagher, Robert] Albert Einstein Canc Ctr, New York, NY USA. [Niemeyer, Charlotte M.] Univ Med Ctr, Freiburg, Germany. [Schrier, Stanley L.] Stanford Univ, Stanford, CA 94305 USA. [Tallman, Martin S.] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, New York, NY 10021 USA. [Grimwade, David] Kings Coll London, Sch Med, London WC2R 2LS, England. [Ganser, Arnold] Hannover Med Sch, Hannover, Germany. [Berliner, Nancy] Harvard Univ, Sch Med, Boston, MA USA. [Ribeiro, Raul C.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Lowenberg, Bob] Univ Roma Tor Vergata, Dept Biomedicine & Prevent, Rome, Italy. [Lo-Coco, Francesco] Santa Lucia Fdn, Rome, Italy. [Lowenberg, Bob] Erasmus MC, Rotterdam, Netherlands. [Sanz, Miguel A.] Valencia Univ Med Sch, Valencia, Spain. RP Rego, EM (reprint author), Univ Sao Paulo, Med Sch Ribeirao Preto, Av Bandeirantes 3900, BR-14048900 Ribeirao Preto, SP, Brazil. EM emrego@hcrp.fmrp.usp.br RI Rego, Eduardo/A-1058-2012 OI Rego, Eduardo/0000-0003-1567-4086 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/08135-2]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNpQ) [573754/2008-0]; FAPESP [2007/55067-1] FX We gratefully acknowledge all members of the International Consortium on Acute Promyelocytic Leukaemia of the American Society of Hematology. This investigation was supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Grant #2013/08135-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNpQ, Grant #573754/2008-0). A.R.L.A. received fellowship from FAPESP (#2007/55067-1). NR 41 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 EI 1365-2141 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD AUG PY 2014 VL 166 IS 4 BP 540 EP 549 DI 10.1111/bjh.12921 PG 10 WC Hematology SC Hematology GA AM9YR UT WOS:000340237900009 PM 24796963 ER PT J AU Moschetta, M Reale, A Marasco, C Vacca, A Carratu, MR AF Moschetta, M. Reale, A. Marasco, C. Vacca, A. Carratu, M. R. TI Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review ID DUAL PI3K/MTOR INHIBITOR; PROTEIN-KINASE B; MAMMALIAN TARGET; CELL-GROWTH; BINDING PARTNER; BIOLOGICAL-PROPERTIES; PI3K/AKT ACTIVATION; INSULIN-RESISTANCE; COLORECTAL-CANCER; COWDEN-DISEASE AB The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy-dependent signals. It activates PKC- and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway. C1 [Moschetta, M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Moschetta, M.; Reale, A.; Vacca, A.] Univ Bari Med Sch Aldo Moro, Dept Biomed Sci & Human Oncol, Sect Internal Med, Bari, Italy. [Marasco, C.; Carratu, M. R.] Univ Bari Med Sch Aldo Moro, Dept Biomed Sci & Human Oncol, Sect Pharmacol, Bari, Italy. RP Moschetta, M (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02115 USA. EM michele_moschetta@dfci.harvard.edu OI Carrato, Maria/0000-0002-9709-6533 FU Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) [10099, 9965]; European Commission Seventh Framework Programme (EU FP7 OVER-MyR, Grant, Brussels, Belgium [278206]; Ministry of Health, Rome, Italy [PRIN 2012] FX This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) - Investigator Grant (Grant No. 10099) and 5 per thousand Molecular Clinical Oncology Special Program (Grant No. 9965); by the European Commission Seventh Framework Programme (EU FP7 OVER-MyR, Grant No. 278206), Brussels, Belgium; and by the Ministry of Health (Project No. PRIN 2012), Rome, Italy. The sponsors of this study are public or non-profit organizations that support science in general. They had no role in gathering, analysing or interpreting the data. The authors are fully responsible for the content and editorial decisions for this manuscript. NR 132 TC 19 Z9 21 U1 0 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2014 VL 171 IS 16 BP 3801 EP 3813 DI 10.1111/bph.12749 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA AN0IT UT WOS:000340268700003 PM 24780124 ER PT J AU Sanford, SD Zhao, FM Salsman, JM Chang, VT Wagner, LI Fisch, MJ AF Sanford, Stacy D. Zhao, Fengmin Salsman, John M. Chang, Victor T. Wagner, Lynne I. Fisch, Michael J. TI Symptom Burden Among Young Adults With Breast or Colorectal Cancer SO CANCER LA English DT Article DE prospective study; young adults; breast cancer; colorectal cancer ID AGE; COLON AB BACKGROUND: Cancer incidence has increased among young adults (YAs) and survival rates have not improved compared with other age groups. Patient-reported outcomes may enhance our understanding of this vulnerable population. METHODS: In a multisite prospective study, patients completed a cancer symptom inventory at the time of enrollment (T1) and 4 weeks to 5 weeks later (T2). YAs (those aged <= 39 years) with breast or colorectal cancer were compared with older adults (those aged >= 40 years) with breast or colorectal cancer with regard to symptom severity, symptom interference, changes over time, and medical care. RESULTS: Participants included 1544 patients with breast cancer (96 of whom were YAs) and 718 patients with colorectal cancer (37 of whom were YAs). Compared with older adults, YAs with breast cancer were more likely to report moderate/severe drowsiness, hair loss, and symptom interference with relationships at T1. YAs with colorectal cancer were more likely to report moderate/severe pain, fatigue, nausea, distress, drowsiness, shortness of breath, and rash plus interference in general activity, mood, work, relationships, and life enjoyment compared with older adults. Compared with older adults, shortness of breath, appetite, and sore mouth were more likely to improve in YAs with breast cancer; vomiting was less likely to improve in YAs with colorectal cancer. Referrals for supportive care were few, especially among patients with colorectal cancer. YAs with breast cancer were somewhat more likely to be referred to nutrition and psychiatry services than older patients. CONCLUSIONS: YAs reported symptom severity, symptom interference, and variations over time that were distinct from older patients. Distinctions were found to differ by diagnostic group. These findings enhance the understanding of symptom burden in YAs and inform the development of targeted interventions and future research. (C) 2014 American Cancer Society. C1 [Sanford, Stacy D.; Salsman, John M.; Wagner, Lynne I.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Chicago, IL 60611 USA. [Zhao, Fengmin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Chang, Victor T.] Univ Med & Dent New Jersey, Dept Med, Vet Affairs New Jersey Hlth Care Syst, Newark, NJ 07103 USA. [Fisch, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Palliat Care & Rehabil Med, Houston, TX 77030 USA. RP Sanford, SD (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Dept Med Social Sci, 675 N St Clair St,Suite 21-100, Chicago, IL 60611 USA. EM ssanford@nmff.org FU National Cancer Institute, National Institutes of Health [CA34604, CA27525]; Department of Health and Human Services FX The current study was conducted by the Eastern Cooperative Oncology Group (Robert Comis, MD) and supported in part by Public Health Service grants CA34604 and CA27525, and grants from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. NR 16 TC 2 Z9 2 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2014 VL 120 IS 15 BP 2255 EP 2263 DI 10.1002/cncr.28297 PG 9 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500007 PM 24890659 ER PT J AU Rosenberg, SM Tamimi, RM Gelber, S Ruddy, KJ Bober, SL Kereakoglow, S Borges, VF Come, SE Schapira, L Partridge, AH AF Rosenberg, Shoshana M. Tamimi, Rulla M. Gelber, Shari Ruddy, Kathryn J. Bober, Sharon L. Kereakoglow, Sandra Borges, Virginia F. Come, Steven E. Schapira, Lidia Partridge, Ann H. TI Treatment-Related Amenorrhea and Sexual Functioning in Young Breast Cancer Survivors SO CANCER LA English DT Article DE sexual dysfunction; breast cancer; amenorrhea; chemotherapy; premenopausal ID QUALITY-OF-LIFE; BODY-IMAGE; WOMEN; HEALTH; CARCINOMA; SYMPTOMS; AGE; TAMOXIFEN; FERTILITY; DIAGNOSIS AB BACKGROUND: Sexual dysfunction is a known complication of adjuvant therapy for breast cancer and an important determinant of quality of life. However, few studies have explored how treatment and other factors affect sexual functioning in young breast cancer survivors. METHODS: Four hundred sixty-one premenopausal women with stage 0 through III breast cancer were surveyed an average of 1 year after diagnosis as part of a prospective cohort study of women who were aged <= 40 years at diagnosis. Sexual interest and dysfunction were assessed using the Cancer Rehabilitation Evaluation System (CARES). Mean CARES scores were compared and multiple regression models were fit to assess treatment and a range of menopausal and somatic symptoms in relation to sexual functioning. RESULTS: Mean CARES sexual interest and dysfunction scores were both highest (indicating poorer functioning) among women who received chemotherapy and were amenorrheic from treatment. After accounting for menopausal and somatic symptoms, treatment-associated amenorrhea remained associated with decreased interest but was no longer an independent predictor of dysfunction. In the multivariable analysis, independent predictors of dysfunction included vaginal pain symptoms, poorer body image, and fatigue. Sexual interest was associated with vaginal pain symptoms, body image, and weight problems. CONCLUSIONS: Factors associated with decreased sexual functioning in young breast cancer survivors can often be ameliorated. The current findings have implications for premenopausal women with other types of cancer who might be experiencing amenorrhea because of chemotherapy or surgery. Increased awareness and early intervention is essential to help improve sexual functioning and associated quality of life for all young cancer survivors. (C) 2014 American Cancer Society. C1 [Rosenberg, Shoshana M.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Rosenberg, Shoshana M.; Gelber, Shari; Ruddy, Kathryn J.; Bober, Sharon L.; Kereakoglow, Sandra; Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Tamimi, Rulla M.; Ruddy, Kathryn J.; Bober, Sharon L.; Come, Steven E.; Schapira, Lidia; Partridge, Ann H.] Harvard Univ, Sch Med, Boston, MA USA. [Borges, Virginia F.] Univ Colorado, Div Med Oncol, Denver, CO 80202 USA. [Come, Steven E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Schapira, Lidia] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM ahpartridge@partners.org FU National Cancer Institute [NIH 5 R25 CA 057711, R25 CA92203]; Susan G. Komen for the Cure FX The Young Women's Breast Cancer Study is supported by Susan G. Komen for the Cure. Dr. Rosenberg was supported by the National Cancer Institute (NIH 5 R25 CA 057711; R25 CA92203). NR 28 TC 19 Z9 21 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2014 VL 120 IS 15 BP 2264 EP 2271 DI 10.1002/cncr.28738 PG 8 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500008 PM 24891236 ER PT J AU Dizon, DS Mackay, HJ Thomas, GM Werner, TL Kohn, EC Hess, D Rose, PG Covens, AL AF Dizon, Don S. Mackay, Helen J. Thomas, Gillian M. Werner, Theresa L. Kohn, Elise C. Hess, Dina Rose, Peter G. Covens, Allan L. TI State of the Science in Cervical Cancer: Where We Are Today and Where We Need to Go SO CANCER LA English DT Review DE cervical cancer; clinical trials; human papillomavirus; immunotherapy; anti-angiogenesis; screening; prevention ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-III TRIAL; PELVIC RADIATION-THERAPY; PLUS CISPLATIN; RIBONUCLEOTIDE REDUCTASE; CONCURRENT CHEMOTHERAPY; ADJUVANT GEMCITABINE; IMMUNE-RESPONSES; IVA CARCINOMA; STAGE IIB AB Invasive cervical cancer remains an important global cause of death, despite the declining prevalence within the United States. Definitive therapies, including surgical resection of early-stage disease and chemoradiation for locally advanced disease, can be curative. For women who experience local or distant recurrences, the prognosis remains poor and better treatments are required. On July 18, 2013, The Gynecologic Oncology Group sponsored a State of the Science in Cervical Cancer Symposium with experts, researchers, clinicians, and interested stakeholders. This article summarize the progress that has been made, questions that require further investigation, and contemporary genomic findings and innovative treatments that may help inform the next generation of clinical trials for patients with cervical cancer. (C) 2014 American Cancer Society. C1 [Dizon, Don S.] Massachusetts Gen Hosp, Ctr Canc, Gillette Ctr Gynecol Oncol, Boston, MA 02114 USA. [Dizon, Don S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Mackay, Helen J.] Princess Margaret Hosp, Div Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. [Mackay, Helen J.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Thomas, Gillian M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Radiat Oncol, Toronto, ON, Canada. [Thomas, Gillian M.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Dept Obstet & Gynecol, Toronto, ON, Canada. [Werner, Theresa L.] Univ Utah, Sch Med, Dept Med, Div Oncol, Salt Lake City, UT USA. [Kohn, Elise C.] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Hess, Dina] NCI, Gynecol Oncol Steering Comm, EMMES Corp, Rockville, MD USA. [Rose, Peter G.] Cleveland Clin Fdn, Dept Obstet & Gynecol, Div Gynecol Oncol, Cleveland, OH 44195 USA. [Covens, Allan L.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Div Gynecol Oncol, Dept Obstet & Gynecol, Toronto, ON, Canada. RP Dizon, DS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Gillette Ctr Gynecol Oncol, 55 Fruit St, Boston, MA 02114 USA. EM ddizon@mgh.harvard.edu NR 37 TC 12 Z9 14 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2014 VL 120 IS 15 BP 2282 EP 2288 DI 10.1002/cncr.28722 PG 7 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500010 PM 24737608 ER PT J AU Sacher, AG Janne, PA Oxnard, GR AF Sacher, Adrian G. Jaenne, Pasi A. Oxnard, Geoffrey R. TI Management of Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors in Patients With Advanced Non-Small Cell Lung Cancer SO CANCER LA English DT Review DE non-small cell lung cancer; targeted therapy; epidermal growth factor receptor (EGFR); acquired resistance ID BRAIN RADIATION-THERAPY; EGFR MUTATIONS; GEFITINIB THERAPY; MET AMPLIFICATION; GENE-MUTATIONS; NONINVASIVE DETECTION; ACTIVATING MUTATIONS; 1ST-LINE GEFITINIB; PHASE-3 TRIAL; ERLOTINIB AB The widespread adoption of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the first-line treatment of patients with advanced EGFR-mutated non-small cell lung cancer has resulted in acquired tyrosine kinase inhibitor resistance becoming a ubiquitous clinical problem. The identification of specific mechanisms of acquired resistance has allowed a better understanding of the biology and natural history of resistant disease, but is only now starting to impact treatment decisions. Strategies for managing acquired resistance in patients with advanced non-small cell lung cancer are complex and must be adapted to the individual characteristics of each patient's cancer. Although combination chemotherapy is the presumed standard of care for most patients, prospective trial data are lacking, highlighting the importance of offering patients participation in clinical trials in this setting. Emerging data from trials of third-generation mutant-specific EGFR kinase inhibitors suggests particular promise with this class of agents. (C) 2014 American Cancer Society. C1 [Sacher, Adrian G.; Jaenne, Pasi A.; Oxnard, Geoffrey R.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02215 USA. [Sacher, Adrian G.] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Jaenne, Pasi A.; Oxnard, Geoffrey R.] Brigham & Womens Hosp, Dept Thorac Oncol, Boston, MA 02115 USA. [Jaenne, Pasi A.; Oxnard, Geoffrey R.] Harvard Univ, Sch Med, Boston, MA USA. RP Oxnard, GR (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,Dana 1234, Boston, MA 02215 USA. EM Geoffrey_oxnard@dfci.harvard.edu RI Sacher, Adrian/I-8080-2016 OI Sacher, Adrian/0000-0001-7865-2701 FU National Cancer Institute of the National Institutes of Health [R01CA114465, P50CA090578]; Conquer Cancer Foundation of the American Society of Clinical Oncology FX Supported in part by the National Cancer Institute of the National Institutes of Health (grants R01CA114465 and P50CA090578) and by the Conquer Cancer Foundation of the American Society of Clinical Oncology. NR 71 TC 8 Z9 10 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 1 PY 2014 VL 120 IS 15 BP 2289 EP 2298 DI 10.1002/cncr.28723 PG 10 WC Oncology SC Oncology GA AM9ZV UT WOS:000340241500011 PM 24752335 ER PT J AU Harshman, LC Drake, CG Wargo, JA Sharma, P Bhardwaj, N AF Harshman, Lauren C. Drake, Charles G. Wargo, Jennifer A. Sharma, Padmanee Bhardwaj, Nina TI Cancer Immunotherapy Highlights from the 2014 ASCO Meeting SO CANCER IMMUNOLOGY RESEARCH LA English DT Article AB The promise of cancer immunotherapy was validated officially in March 2011 when the FDA approved Yervoy (ipilimumab; Bristol-Myers Squibb) for the treatment of unresectable or metastatic melanoma. The approval was based on results of a randomized, double-blind clinical trial establishing that ipilimumab (a humanized antiCTLA-4 monoclonal antibody) treatment extended the overall survival of patients with advanced melanoma. CTLA-4 is a member of the so-called family of checkpoint regulators, which are expressed on immune cells that activate or inhibit an immune response. An increasing number of immune checkpoint regulators are now being identified and targeted for immunotherapy. At the 2014 meeting of the American Society of Clinical Oncology (ASCO), it was reported that checkpoint blockade as a monotherapy or combination therapy was used successfully to treat advanced melanoma and non-small cell lung cancer. Checkpoint blockade immunotherapy was also used successfully for the treatment of other cancers, most notably genitourinary cancers such as urothelial bladder cancer and metastatic renal cell carcinoma. This report is a compiled summary of cancer immunotherapy highlights presented at the 2014 ASCO meeting by various investigators. (C) 2014 AACR. C1 [Harshman, Lauren C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Drake, Charles G.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Wargo, Jennifer A.; Sharma, Padmanee] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Bhardwaj, Nina] Icahn Sch Med Mt Sinai, New York, NY 10029 USA. RP Sharma, P (reprint author), Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol 1515 Holcombe Blvd, Houston, TX 77030 USA. EM PadSharma@mdanderson.org; Nina.Bhardwaj@mssm.edu FU Janssen; Bristol-Myers Squibb FX L. C. Harshman has served as a consultant/advisory board member for Aveo, Pfizer, Bristol-Myers Squibb, and Dendreon. C. G. Drake has received research support from Janssen and Bristol-Myers Squibb. He is a coinventor on a patent related to LAG-3, which is currently unlicensed. He also serves as a consultant/advisory board member for Bristol-Myers Squibb, Compugen, Dendreon, ImmunExcite, Merck, Pfizer, and Roche/Genentech. J.A. Wargo serves on the speakers' bureau for Dava Oncology. P. Sharma has an ownership interest (including patents) in Jounce and is a consultant/advisory board member for GlaxoSmithKline, Bristol-Myers Squibb, and MedImmune. N. Bhardwaj serves as a consultant/advisory board member for Dendreon and Merck. NR 23 TC 15 Z9 16 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD AUG PY 2014 VL 2 IS 8 BP 714 EP 719 DI 10.1158/2326-6066.CIR-14-0119 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA AM7HI UT WOS:000340036000003 PM 25092813 ER PT J AU Vasan, N Boyer, JL Herbst, RS AF Vasan, Neil Boyer, Julie L. Herbst, Roy S. TI A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Review ID INDUCED MYELOPROLIFERATIVE DISEASE; SYNTHETIC LETHAL INTERACTIONS; K-RAS; FARNESYLTRANSFERASE INHIBITORS; PROTEIN TRANSFERASE; PHASE-II; MEDIATED ACTIVATION; PANCREATIC-CANCER; MUTATIONS; FARNESYL AB Of the numerous oncogenes implicated inhuman cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e. g., Rce1, Icmt, Pded), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a "Ras renaissance," signified by new Ras and Ras pathway-targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non-small cell lung cancer as a case example. (C) 2014 AACR. C1 [Vasan, Neil] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Boyer, Julie L.] Weill Cornell Med Coll, Sandra & Edward Meyer Canc Ctr, New York, NY USA. [Herbst, Roy S.] Yale Canc Ctr, New Haven, CT USA. [Herbst, Roy S.] Smilow Canc Hosp Yale New Haven, New Haven, CT USA. RP Herbst, RS (reprint author), Yale Univ, 333 Cedar St,WWW 221, New Haven, CT 06520 USA. EM roy.herbst@yale.edu FU NIH [MSTP TG 2T32GM07205, 5R01CA155196-04] FX This study was supported by the NIH under award number MSTP TG 2T32GM07205 (to N. Vasan) and 5R01CA155196-04, Personalizing NSCLC Therapy: Exploiting KRAS activated pathways (to R. Herbst). NR 78 TC 25 Z9 26 U1 3 U2 27 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 3921 EP 3930 DI 10.1158/1078-0432.CCR-13-1762 PG 10 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500005 PM 24893629 ER PT J AU Patel, CG Yee, AJ Scullen, TA Nemani, N Santo, L Richardson, PG Laubach, JP Ghobrial, IM Schlossman, RL Munshi, NC Anderson, KC Raje, NS AF Patel, Chirayu G. Yee, Andrew J. Scullen, Tyler A. Nemani, Neeharika Santo, Loredana Richardson, Paul G. Laubach, Jacob P. Ghobrial, Irene M. Schlossman, Robert L. Munshi, Nikhil C. Anderson, Kenneth C. Raje, Noopur S. TI Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID MESENCHYMAL STEM-CELLS; ZOLEDRONIC ACID; CANCER-PATIENTS; BIOCHEMICAL MARKERS; WORKING GROUP; METASTASES; OSTEONECROSIS; RESORPTION; JAW; DEXAMETHASONE AB Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling. Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA. Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients. Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. (C) 2014 AACR. C1 [Patel, Chirayu G.; Yee, Andrew J.; Scullen, Tyler A.; Nemani, Neeharika; Santo, Loredana; Raje, Noopur S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Richardson, Paul G.; Laubach, Jacob P.; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Anderson, Kenneth C.] Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Richardson, Paul G.; Laubach, Jacob P.; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma Res, Boston, MA 02115 USA. [Yee, Andrew J.; Nemani, Neeharika; Santo, Loredana; Richardson, Paul G.; Laubach, Jacob P.; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Anderson, Kenneth C.; Raje, Noopur S.] Harvard Univ, Sch Med, Boston, MA USA. RP Raje, NS (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM nraje@partners.org FU ASCO Career Development Award; ASH Research Trainee Award FX N.S. Raje was funded by the ASCO Career Development Award. C. G. Patel was funded by an ASH Research Trainee Award. NR 32 TC 5 Z9 5 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 3955 EP 3961 DI 10.1158/1078-0432.CCR-14-0434 PG 7 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500008 PM 24958808 ER PT J AU Patani, N Dunbier, AK Anderson, H Ghazoui, Z Ribas, R Anderson, E Gao, Q A'hern, R Mackay, A Lindemann, J Wellings, R Walker, J Kuter, I Martin, LA Dowsett, M AF Patani, Neill Dunbier, Anita K. Anderson, Helen Ghazoui, Zara Ribas, Ricardo Anderson, Elizabeth Gao, Qiong A'hern, Roger Mackay, Alan Lindemann, Justin Wellings, Robert Walker, Jill Kuter, Irene Martin, Lesley-Ann Dowsett, Mitch TI Differences in the Transcriptional Response to Fulvestrant and Estrogen Deprivation in ER-Positive Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID AROMATASE INHIBITOR THERAPY; PLACEBO-CONTROLLED TRIAL; POSTMENOPAUSAL WOMEN; ANDROGEN RECEPTOR; ENDOCRINE THERAPY; GENE-EXPRESSION; DOUBLE-BLIND; PHASE-II; PURE ANTIESTROGEN; RANDOMIZED-TRIAL AB Purpose: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high-over low-dose fulvestrant, reflect distinct transcriptional responses. Experimental Design: Global gene expression profiles from ER alpha-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. Results: The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ER alpha, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29). Conclusions: The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ER alpha activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens. (C) 2014 AACR. C1 [Patani, Neill; Dunbier, Anita K.; Ghazoui, Zara; Dowsett, Mitch] Royal Marsden Fdn Trust, London, England. [Patani, Neill; Anderson, Helen; Ribas, Ricardo; Gao, Qiong; Mackay, Alan; Martin, Lesley-Ann; Dowsett, Mitch] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London, England. [Anderson, Elizabeth; Lindemann, Justin; Wellings, Robert; Walker, Jill] AstraZeneca, Macclesfield, Cheshire, England. [A'hern, Roger] Inst Canc Res, Clin Trials & Stat Unit, Sutton, Surrey, England. [Dunbier, Anita K.] Univ Otago, Dept Biochem, Dunedin, New Zealand. [Anderson, Elizabeth] Boehringer Ingelheim GmbH & Co KG, Vienna, Austria. [Kuter, Irene] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dowsett, M (reprint author), Royal Marsden Hosp, Acad Dept Biochem, Fulham Rd, London SW3 6JJ, England. EM Mitch.Dowsett@icr.ac.uk FU Mary-Jean Mitchell Green Foundation; AstraZeneca; Breakthrough Breast Cancer; NHS; Medical Research Council Clinical Research Training Fellowship [G1100450] FX This work was funded by the Mary-Jean Mitchell Green Foundation and AstraZeneca. Prof. Mitch Dowsett and Dr. Lesley-Ann Martin are supported by Breakthrough Breast Cancer and NHS funding to the Royal Marsden NIHR Biomedical Research Centre. Neill Patani is funded by a Medical Research Council Clinical Research Training Fellowship (G1100450). NR 47 TC 5 Z9 5 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 3962 EP 3973 DI 10.1158/1078-0432.CCR-13-1378 PG 12 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500009 PM 24916694 ER PT J AU Yoon, C Park, DJ Schmidt, B Thomas, NJ Lee, HJ Kim, TS Janjigian, YY Cohen, DJ Yoon, SS AF Yoon, Changhwan Park, Do Joong Schmidt, Benjamin Thomas, Nicholas J. Lee, Hae-June Kim, Teresa S. Janjigian, Yelena Y. Cohen, Deirdre J. Yoon, Sam S. TI CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED ESOPHAGOGASTRIC CANCER; LABEL PHASE-3 TRIAL; STEM-CELLS; SELF-RENEWAL; CAPECITABINE; PATHWAY; GROWTH; TUMORIGENICITY; MAINTENANCE; OXALIPLATIN AB Purpose: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. Experimental Design: Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. Results: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. Conclusions: HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+ ) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels. (C) 2014 AACR. C1 [Yoon, Changhwan; Park, Do Joong; Thomas, Nicholas J.; Lee, Hae-June; Kim, Teresa S.; Yoon, Sam S.] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Janjigian, Yelena Y.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Cohen, Deirdre J.] NYU, Med Ctr, Dept Med, New York, NY 10016 USA. [Schmidt, Benjamin] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lee, Hae-June] Korea Inst Radiol & Med Sci, Div Radiat Effects, Seoul, South Korea. RP Yoon, SS (reprint author), Mem Sloan Kettering Canc Ctr, H-1209,1275 York Ave, New York, NY 10065 USA. EM yoons@mskcc.org OI Cohen, Deirdre/0000-0002-6178-9266 FU NIH [1R01 CA158301-01, N01 CM62204]; Society for Surgical Oncology Clinical Investigator Award FX This study was supported by NIH grants 1R01 CA158301-01 (to S.S. Yoon) and N01 CM62204 (to D.J. Cohen), and the Society for Surgical Oncology Clinical Investigator Award (to S.S. Yoon). NR 37 TC 26 Z9 28 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 3974 EP 3988 DI 10.1158/1078-0432.CCR-14-0011 PG 15 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500010 PM 24947926 ER PT J AU Shao, CL Sullivan, JP Girard, L Augustyn, A Yenerall, P Rodriguez-Canales, J Liu, H Behrens, C Shay, JW Wistuba, II Minna, JD AF Shao, Chunli Sullivan, James P. Girard, Luc Augustyn, Alexander Yenerall, Paul Rodriguez-Canales, Jaime Liu, Hui Behrens, Carmen Shay, Jerry W. Wistuba, Ignacio I. Minna, John D. TI Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non-Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway SO CLINICAL CANCER RESEARCH LA English DT Article ID TRANS-RETINOIC ACID; BREAST-CANCER; INITIATING CELLS; GENE-EXPRESSION; PROSTATE-CANCER; RESISTANCE; LINES; ALDH1A1; MARKER; 4-HYDROPEROXYCYCLOPHOSPHAMIDE AB Purpose: Lung cancer stem cells (CSC) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic, and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. Experimental Design: A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH(+) versus ALDH(-) cells. RT-PCR, Western blot analysis, and Aldefluor assay were used to validate identified genes. To explore the function in CSCs, we manipulated their expression followed by colony and tumor formation assays. Results: We identified a subset of genes that were differentially expressed in common in ALDH(+) cells, among which ALDH1A3 was the most upregulated gene in ALDH(+) versus ALDH(-) cells. shRNA-mediated knockdown of ALDH1A3 in non-small cell lung cancer (NSCLC) resulted in a dramatic reduction in ALDH activity, clonogenicity, and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. In contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH(+) cells also expressed more activated STAT3 than ALDH(-) cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH(+) cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well-differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival. Conclusions: Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH(+) subpopulation in NSCLCs. (C) 2014 AACR. C1 [Shao, Chunli; Girard, Luc; Augustyn, Alexander; Yenerall, Paul; Minna, John D.] Hamon Ctr Therapeut Oncol Res, Boston, MA USA. [Shao, Chunli; Girard, Luc; Augustyn, Alexander; Yenerall, Paul; Minna, John D.] Simmons Comprehens Canc Ctr, Boston, MA USA. [Sullivan, James P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sullivan, James P.] Harvard Univ, Sch Med, Boston, MA USA. [Rodriguez-Canales, Jaime; Liu, Hui; Behrens, Carmen; Wistuba, Ignacio I.] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA. [Shay, Jerry W.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Girard, Luc; Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. RP Minna, JD (reprint author), Univ Texas SW Med Ctr Dallas, 6000 Harry Hines Blvd, Dallas, TX 75390 USA. EM john.minna@utsouthwestern.edu FU CPRIT; NCI SPORE [P50CA70907]; UTSW Cancer Center Support Grant [5P30-CA142543]; Gillson-Longenbaugh Foundation; NSCOR [NNX11AC54G] FX This project was supported by CPRIT to J.D. Minna, C. Shao, L. Girard, CB, IIW, NCI SPORE P50CA70907 to JDM, CS, LG, CB, JWS, IIW, UTSW Cancer Center Support Grant 5P30-CA142543, the Gillson-Longenbaugh Foundation, to JDM and NSCOR NNX11AC54G to JDM and JWS. NR 46 TC 29 Z9 31 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2014 VL 20 IS 15 BP 4154 EP 4166 DI 10.1158/1078-0432.CCR-13-3292 PG 13 WC Oncology SC Oncology GA AM9DF UT WOS:000340179500025 PM 24907115 ER PT J AU Cheney, MD Chen, MH Zhang, DJ Phillips, JG Loffredo, MJ D'Amico, AV AF Cheney, Matthew D. Chen, Ming-Hui Zhang, Danjie Phillips, John G. Loffredo, Marian J. D'Amico, Anthony V. TI Greatest Percentage of Involved Core Length and the Risk of Death From Prostate Cancer in Men With Highest Gleason Score >= 7 SO CLINICAL GENITOURINARY CANCER LA English DT Article DE Androgen deprivation therapy; Biopsy; Needle; Prognosis; Prostatic neoplasms; Radiation therapy ID EXTERNAL-BEAM RADIATION; ANDROGEN DEPRIVATION THERAPY; NEEDLE-BIOPSY TISSUE; RADICAL PROSTATECTOMY; PATHOLOGICAL STAGE; MORPHOMETRIC MEASUREMENTS; PROGNOSTIC-SIGNIFICANCE; CONSENSUS CONFERENCE; BIOCHEMICAL FAILURE; COMPETING RISK AB No deaths from prostate cancer (PC) were observed in men with Gleason score (GS) 7 and a differing, lower GS core (ComboGS), greatest percentage of involved core length < 50%, and favorable intermediate-risk disease despite radiation therapy (RT) alone in 83%. Whether de-escalated therapy with high-dose RT alone is appropriate for these men is being tested prospectively in the Radiation Therapy Oncology Group (RTOG) 0815 clinical trial. Introduction/Background: Men with highest GS >= 7 and a differing, lower GS core (ComboGS) have decreased PC-specific mortality (PCSM) risk after RT or RT and androgen deprivation therapy (ADT). Whether the greatest percentage of involved core length (GPC) modulates this risk is unknown. Patients and Methods: Men with GS >= 7 PC (n = 333) consecutively treated between December 1989 and July 2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%) comprised the study cohort. The GPC was calculated using biopsy core and tumor lengths. We used competing risks regression to assess whether increasing GPC was associated with increased PCSM risk in men with or without ComboGS adjusting for risk group, age, and treatment. Results: After a median follow-up of 5.36 years (interquartile range, 3.22-7.61 years), 92 (28%) men died, 28 (30%) of PC. Increasing GPC was significantly associated with increased risk of PCSM (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P = .005). Men with GPC >= 50% versus < 50% had significantly greater PCSM estimates when ComboGS was present (P < .001) versus absent (P = .55). Of the 127 men with ConnboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; neither in men with GS 7 and favorable intermediate-risk PC. Conclusion: Men treated with RT for ComboGS, GPC < 50%, GS 7, and favorable intermediate-risk PC have a very low risk of early PCSM. The RTOG 0815 trial will establish whether ADT is necessary to optimize curability in these men. (C) 2014 Elsevier Inc. All rights reserved. C1 [Cheney, Matthew D.; Phillips, John G.] Harvard Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui; Zhang, Danjie] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Loffredo, Marian J.; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Cheney, MD (reprint author), Brigham & Womens Hosp, Harvard Radiat Oncol Program, ASBI LL2,75 Francis Sc, Boston, MA 02115 USA. EM mcheney@lroc.harvard.edu NR 44 TC 3 Z9 3 U1 2 U2 4 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2014 VL 12 IS 4 BP 234 EP 240 DI 10.1016/j.clgc.2014.01.006 PG 7 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AM7WJ UT WOS:000340079100003 PM 24594503 ER PT J AU Bellmunt, J Pons, F Foreshew, A Fay, AP Powles, T Porta, C Bracarda, S Lampron, ME Cerbone, L Sternberg, CN Hutson, TE Choueiri, TK AF Bellmunt, Joaquim Pons, Francesc Foreshew, Abigail Fay, Andre P. Powles, Thomas Porta, Camillo Bracarda, Sergio Lampron, Megan E. Cerbone, Linda Sternberg, Cora N. Hutson, Thomas E. Choueiri, Toni K. TI Sequential Targeted Therapy After Pazopanib Therapy in Patients With Metastatic Renal Cell Cancer: Efficacy and Toxicity SO CLINICAL GENITOURINARY CANCER LA English DT Article DE mTOR inhibitor; Pazopanib; Renal cell carcinoma; Sequential therapy; VEGF-targeted therapy ID KIDNEY CANCER; CARCINOMA; SORAFENIB; SUNITINIB; AGENTS; TRIAL AB Sequential therapy benefits patients with metastatic RCC. However, the best sequence of drugs has not been established. We evaluated the efficacy and toxicity of subsequent therapies in 35 patients after pazopanib progression. On second-line, targeting VEGF was an effective strategy, although OS was not significantly different among patients treated with VEGF targeted therapies or mTOR inhibitors. Introduction/Background: Patients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy. Patients and Methods: Patients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented. Results: Subsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti-VEGF- and everolimus-treated patients, respectively (P = .021). Conclusion: In this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi. (C) 2014 Elsevier Inc. All rights reserved. C1 [Bellmunt, Joaquim; Fay, Andre P.; Lampron, Megan E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Bellmunt, Joaquim; Pons, Francesc] Hosp del Mar, Barcelona, Spain. [Foreshew, Abigail; Powles, Thomas] St Bartholomews Hosp, London, England. [Porta, Camillo] IRCCS San Matteo Univ Hosp Fundant, Pavia, Italy. [Bracarda, Sergio] Ist Toscano Tumori, Arezzo, Italy. [Cerbone, Linda; Sternberg, Cora N.] San Camilo & Forlanini Hosp, Rome, Italy. [Hutson, Thomas E.; Choueiri, Toni K.] GU Ctr Excellence Texas Oncol, Dallas, TX USA. RP Bellmunt, J (reprint author), Dana Farber Canc Inst, 450 Brookline Ave DANA 1230, Boston, MA 02215 USA. EM joaquim_bellmunt@dfci.harvard.edu OI Porta, Camillo/0000-0003-2412-1563 FU Pfizer; GlaxoSmithKline; Novartis; GSK; AVEO Oncology; Bayer-Schering; Sanofi; Bayer FX Thomas Powles: consultant, speaker, and research funding from Pfizer, GlaxoSmithKline, and Novartis; Sergio Bracarda: advisory board for Pfizer, Aveo-Astellas, Bayer, Novartis, GlaxoSmithKline and Boheringer-Ingelheim, honoraria from GSK, Pfizer, and Novartis; Cora N. Sternberg: honoraria from GlaxoSmithKline, Pfizer, and AVEO Oncology; Camillo Ports: consultant and/or speaker for GlaxoSmithKline, Pfizer, Bayer-Schering, Novartis, Astellas, Aveo, and Boehringer-Ingelheim, research grants from Bayer-Schering and Novartis; Toni K. Choueiri: consultancy from Pfizer and Novartis, advisory board from Pfizer, Novartis, Aveo, GlaxoSmithKline, and Exelixis, research funding from Pfizer; Joaquim Bellmunt: consultancy from Pfizer and Novartis, advisory board from Pfizer, Novartis, Aveo, and GlaxoSmithKline, research funding from Sanofi; Thomas E. Hutson: consulatnt, speaker, and research funding from Pfizer, GlaxoSmithKline, Novartis, Aveo, and Bayer. The remaining authors have stated that they have no conflicts of interest. NR 31 TC 6 Z9 6 U1 0 U2 6 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1558-7673 EI 1938-0682 J9 CLIN GENITOURIN CANC JI Clin. Genitourin. Cancer PD AUG PY 2014 VL 12 IS 4 BP 262 EP 269 DI 10.1016/j.clgc.2014.03.002 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA AM7WJ UT WOS:000340079100007 PM 24795159 ER PT J AU Rabideau, DJ Nierenberg, AA Sylvia, LG Friedman, ES Bowden, CL Thase, ME Ketter, TA Ostacher, MJ Reilly-Harrington, N Iosifescu, DV Calabrese, JR Leon, AC Schoenfeld, DA AF Rabideau, Dustin J. Nierenberg, Andrew A. Sylvia, Louisa G. Friedman, Edward S. Bowden, Charles L. Thase, Michael E. Ketter, Terence A. Ostacher, Michael J. Reilly-Harrington, Noreen Iosifescu, Dan V. Calabrese, Joseph R. Leon, Andrew C. Schoenfeld, David A. TI A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania 6th Annual Conference on Statistical Issues in Clinical Trials - Dynamic Treatment Regimes CY 2013 CL Univ Pennsylvania, Philadelphia, PA HO Univ Pennsylvania ID MODERATE-DOSE-USE; MARGINAL STRUCTURAL MODELS; BIPOLAR DISORDER; LITHIUM-TREATMENT; RATING-SCALE; ATTRITION; DROPOUT; LITMUS; PREDICTORS AB Background Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis. Purpose The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. Methods We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. Results Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. Limitations LITMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified. Conclusions In LITMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial. C1 [Rabideau, Dustin J.; Schoenfeld, David A.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Nierenberg, Andrew A.; Sylvia, Louisa G.; Reilly-Harrington, Noreen] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Nierenberg, Andrew A.; Sylvia, Louisa G.; Reilly-Harrington, Noreen] Harvard Univ, Sch Med, Boston, MA USA. [Friedman, Edward S.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Bowden, Charles L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Thase, Michael E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Ketter, Terence A.; Ostacher, Michael J.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Iosifescu, Dan V.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Sch Med, Dept Psychiat, Cleveland, OH 44106 USA. [Leon, Andrew C.] Weill Cornell Med Coll, New York, NY USA. RP Rabideau, DJ (reprint author), Massachusetts Gen Hosp, Ctr Biostat, 50 Staniford St,Suite 560, Boston, MA 02114 USA. EM drabideau@partners.org OI Ostacher, Michael/0000-0003-0353-7535 FU NIMH NIH HHS [N01MH80001] NR 26 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD AUG PY 2014 VL 11 IS 4 BP 494 EP 502 DI 10.1177/1740774514531096 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AN0WX UT WOS:000340305800014 PM 24872362 ER PT J AU Borson, S Chodosh, J AF Borson, Soo Chodosh, Joshua TI Developing Dementia-Capable Health Care Systems: A 12-Step Program SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Dementia; Alzheimer disease; Primary care; Comprehensive management; Care coordination; Partnership; Quality measurement; Annual wellness visit ID AMERICAN GERIATRICS SOCIETY; RANDOMIZED CONTROLLED-TRIAL; PATIENT-CENTERED CARE; SERVICES-TASK-FORCE; OLDER-ADULTS; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; MANAGEMENT INTERVENTION; MEDICAL HOME; DIABETES-MELLITUS AB Improving the quality, comprehensiveness, and coordination of health care for people with dementia is a primary goal of the National Alzheimer's Plan. In this article, the key principles of high-quality dementia care for nonspecialist clinicians and health care leaders are synthesized, a framework for operationalizing its components is presented, and simple steps for developing dementia-capable health care systems are offered. C1 [Borson, Soo] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Borson, Soo] Univ Washington, Sch Nursing, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Chodosh, Joshua] Univ Calif Los Angeles, David Geffen Sch Med, V CAMP, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Borson, S (reprint author), 2375 South Toledo Ave, Palm Springs, CA 92264 USA. EM soob@uw.edu OI Chodosh, Joshua/0000-0001-7784-4306 NR 92 TC 4 Z9 4 U1 6 U2 23 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2014 VL 30 IS 3 BP 395 EP + DI 10.1016/j.cger.2014.05.001 PG 27 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AM7UH UT WOS:000340073700002 PM 25037288 ER PT J AU Wang, LY Borisovskaya, A Maxwell, AL Pascualy, M AF Wang, Lucy Y. Borisovskaya, Anna Maxwell, Andrea L. Pascualy, Marcella TI Common Psychiatric Problems in Cognitively Impaired Older Patients Causes and Management SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Dementia; Behavioral and psychological symptoms; Agitation; Depression; Psychosis; Anxiety ID RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED-TRIAL; NURSING-HOME RESIDENTS; SEVERE ALZHEIMERS-DISEASE; PSYCHOLOGICAL SYMPTOMS; DOUBLE-BLIND; NEUROPSYCHIATRIC SYMPTOMS; BEHAVIORAL SYMPTOMS; ATYPICAL ANTIPSYCHOTICS; GENERALIZED ANXIETY AB Although dementias are defined by their cognitive and functional deficits, psychiatric problems are common, contribute to patient distress and burden, and precipitate institutionalization. Successful treatment involves understanding that physiologic, psychological, and environmental factors can contribute to the development of these symptoms. By carefully assessing each of these factors, clinicians can individualize treatment and flexibly use nonpharmacologic and pharmacologic approaches tailored to patients and the context of care. Although there exist limitations to many treatment options, clinicians can still adapt current knowledge to develop a multifaceted treatment approach that improves the quality of life for patients and their caregivers. C1 [Wang, Lucy Y.; Borisovskaya, Anna; Maxwell, Andrea L.; Pascualy, Marcella] VA Puget Sound Healthcare Syst, Mental Hlth Serv, Seattle, WA 98108 USA. [Wang, Lucy Y.; Borisovskaya, Anna; Maxwell, Andrea L.; Pascualy, Marcella] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98108 USA. RP Wang, LY (reprint author), VA Puget Sound Healthcare Syst, Mental Hlth Serv, 1660 South Columbian Way,S-116, Seattle, WA 98108 USA. EM lucy.wang@va.gov FU VA Clinical Science Research and Development (CSR&D) Career Development Award Program [3125]; VA Puget Sound Health Care System, Seattle, Washington FX This work is supported by resources from the VA Puget Sound Health Care System, Seattle, Washington. Dr. Wang is supported by the VA Clinical Science Research and Development (CSR&D) Career Development Award Program (Project ID: 3125). NR 105 TC 3 Z9 3 U1 2 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2014 VL 30 IS 3 BP 443 EP + DI 10.1016/j.cger.2014.04.002 PG 26 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AM7UH UT WOS:000340073700004 PM 25037290 ER PT J AU Merel, S DeMers, S Vig, E AF Merel, Susan DeMers, Shaune Vig, Elizabeth TI Palliative Care in Advanced Dementia SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Dementia; Palliative care; End-of-life care; Cognitive impairment; Skilled nursing facilities; Advance directives ID NURSING-HOME RESIDENTS; OF-LIFE CARE; PERCUTANEOUS ENDOSCOPIC GASTROSTOMY; SURROGATE DECISION-MAKERS; PLACEBO-CONTROLLED TRIAL; FEEDING-TUBE INSERTION; NEUROPSYCHIATRIC SYMPTOMS; ALZHEIMER-DISEASE; HOSPICE CARE; MEDICATION USE AB Because neurodegenerative dementias are progressive and ultimately fatal, a palliative approach focusing on comfort, quality of life, and family support can have benefits for patients, families, and the health system. Elements of a palliative approach include discussion of prognosis and goals of care, completion of advance directives, and a thoughtful approach to common complications of advanced dementia. Physicians caring for patients with dementia should formulate a plan for end-of-life care in partnership with patients, families, and caregivers, and be prepared to manage common symptoms at the end of life in dementia, including pain and delirium. C1 [Merel, Susan] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA 98195 USA. [DeMers, Shaune] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Vig, Elizabeth] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Vig, Elizabeth] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA. RP Merel, S (reprint author), Univ Washington, Dept Med, Div Gen Internal Med, 1959 NE Pacific St,Box 356429, Seattle, WA 98195 USA. EM smerel@uw.edu NR 114 TC 2 Z9 2 U1 7 U2 32 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2014 VL 30 IS 3 BP 469 EP + DI 10.1016/j.cger.2014.04.004 PG 25 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AM7UH UT WOS:000340073700005 PM 25037291 ER PT J AU Moye, J Rouse, SJ AF Moye, Jennifer Rouse, Susan J. TI Posttraumatic Stress in Older Adults When Medical Diagnoses or Treatments Cause Traumatic Stress SO CLINICS IN GERIATRIC MEDICINE LA English DT Article DE Posttraumatic stress disorder (PTSD); Geriatric; Cardiac; Cancer ID MYOCARDIAL-INFARCTION; CARDIAC-ARREST; DISORDER; PTSD; VETERANS; SURVIVORS; CANCER; CARE; CONSEQUENCES; COMORBIDITY AB Most older patients adapt after catastrophic medical diagnoses and treatments, but a significant number may develop posttraumatic stress disorder (PTSD) symptoms. PTSD symptoms create added burden for the individual, family, and health care system for the patient's recovery. Medical-related PTSD may be underdiagnosed by providers who may be unaware that these health problems can lead to PTSD symptoms. Treatment research is lacking, but pharmacologic and nonpharmacologic approaches to treatment may be extrapolated and adjusted from the literature focusing on younger adults. Additional study is needed. C1 [Moye, Jennifer; Rouse, Susan J.] VA Boston Healthcare Syst, Brockton, MA 02301 USA. [Moye, Jennifer] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Brockton Div, 940 Belmont St, Brockton, MA 02301 USA. EM jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU Department of Veterans Affairs Rehabilitation Research and Development Service [5101RX000104-02] FX This material is the result of work supported with resources and the use of facilities at the Boston VA Medical Center. Dr J. Moye received funding for research from the Department of Veterans Affairs Rehabilitation Research and Development Service #5101RX000104-02. NR 48 TC 5 Z9 5 U1 1 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 EI 1879-8853 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD AUG PY 2014 VL 30 IS 3 BP 577 EP + DI 10.1016/j.cger.2014.04.006 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA AM7UH UT WOS:000340073700010 PM 25037296 ER PT J AU Hayano, K Yoshida, H Zhu, AX Sahani, DV AF Hayano, Koichi Yoshida, Hiroyuki Zhu, Andrew X. Sahani, Dushyant V. TI Fractal Analysis of Contrast-Enhanced CT Images to Predict Survival of Patients with Hepatocellular Carcinoma Treated with Sunitinib SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Contrast-enhanced CT; Hepatocellular carcinoma; Heterogeneity; Sunitinib; Fractal analysis ID SQUAMOUS-CELL CARCINOMA; COMPUTED-TOMOGRAPHY; TEXTURE ANALYSIS; SPATIAL HETEROGENEITY; IMAGING TECHNIQUES; TUMOR VASCULATURE; DYNAMIC CT; BLOOD-FLOW; CHEMOTHERAPY; THERAPY AB Intratumoral heterogeneity is a well-recognized feature of malignancy. To assess the heterogeneity of tumor using fractal analysis of contrast-enhanced computed tomography (CE-CT) images for predicting survival of hepatocellular carcinoma (HCC) patients treated with sunitinib. The patient cohort comprised 23 patients (19 men, 4 women; mean age 61.5 years) with HCC who underwent CE-CT at baseline and after one cycle of sunitinib. Arterial-phase (AP) and portal-phase (PP) CE-CT images were analyzed using a plugin software for ImageJ (NIH, Bethesda, MD). A differential box-counting method was employed to calculate the fractal dimension (FD) of the tumor. Tumor FD, density, and size were compared with survival. Median progression-free survival (PFS) was 4.43 months. Patients were grouped into a favorable PFS (PFS > 4.43 months; 9 patients) and an unfavorable PFS group (PFS a parts per thousand currency sign4.43; 13 patients). The baseline FD on both the AP and PP images was lower in the favorable PFS group than in the unfavorable PFS group (both P = 0.03). There was a significant difference in the change of the FD on the AP image between the favorable and unfavorable PFS groups (P = 0.02). Tumor density and size showed no significant correlations with PFS. In the Kaplan-Meier analysis, patients with tumors showing lower FD on the AP image at baseline showed longer PFS (P = 0.002). Patients with tumors showing a greater reduction in the FD on the PP image after one cycle of the therapy showed longer overall survival (P = 0.002). The FD of the tumor on CE-CT images may be a useful biomarker for HCC patients treated with sunitinib. C1 [Hayano, Koichi; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Yoshida, Hiroyuki] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zhu, Andrew X.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Hayano, K (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM khayano@partners.org; yoshida.hiro@mgh.harvard.edu; AZHU@partners.org; dsahani@partners.org NR 37 TC 5 Z9 5 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 EI 1573-2568 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD AUG PY 2014 VL 59 IS 8 BP 1996 EP 2003 DI 10.1007/s10620-014-3064-z PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA AM7MJ UT WOS:000340051200112 PM 24563237 ER PT J AU Nolte, JEH Neumann, T Manne, JM Lo, J Neumann, A Mostardt, S Abbara, S Hoffmann, U Brady, TJ Wasem, J Grinspoon, SK Gazelle, GS Goehler, A AF Nolte, Julia E. H. Neumann, Till Manne, Jennifer M. Lo, Janet Neumann, Anja Mostardt, Sarah Abbara, Suhny Hoffmann, Udo Brady, Thomas J. Wasem, Juergen Grinspoon, Steven K. Gazelle, G. Scott Goehler, Alexander TI Cost-effectiveness analysis of coronary artery disease screening in HIV-infected men SO EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY LA English DT Article DE Coronary heart disease; cost-effectiveness; HIV; Markov model; prevention ID COMPUTED-TOMOGRAPHY ANGIOGRAPHY; MYOCARDIAL-INFARCTION RATES; CARDIOVASCULAR RISK-FACTORS; HEART-DISEASE; ANTIRETROVIRAL THERAPY; SMOKING-CESSATION; PREVALENCE; FAILURE; INDIVIDUALS; PREDICTION AB Background: HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screening for HIV-positive men at intermediate or greater CAD risk. Design: We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men. Methods: Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the stress testing + medication and CCTA + medication strategies, patients with 1-2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the stress testing + intervention and CCTA + intervention strategies, patients with these results underwent ICA and received percutaneous coronary intervention. Results: Compared to no screening, the stress testing + medication, stress testing + intervention, CCTA + medication, and CCTA + intervention strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost-effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 Euros per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening, but only stress testing + medication every 5 years remained cost-effective. At a willingness-to-pay threshold of 83,000 (sic)/QALY (similar to 100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%. Conclusions: Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care. C1 [Nolte, Julia E. H.; Gazelle, G. Scott; Goehler, Alexander] Massachusetts Gen Hosp, Inst Technol Assessment, Dept Radiol, Boston, MA 02114 USA. [Nolte, Julia E. H.; Lo, Janet; Abbara, Suhny; Hoffmann, Udo; Brady, Thomas J.; Grinspoon, Steven K.; Gazelle, G. Scott; Goehler, Alexander] Harvard Univ, Sch Med, Boston, MA USA. [Nolte, Julia E. H.; Neumann, Anja; Mostardt, Sarah; Wasem, Juergen; Goehler, Alexander] Univ Duisburg Essen, Alfried Krupp von Bohlen & Halbach Fdn, Inst Hlth Syst Management, Essen, Germany. [Neumann, Till] Univ Duisburg Essen, West German Heart Inst, Essen, Germany. [Manne, Jennifer M.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Lo, Janet; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Abbara, Suhny; Hoffmann, Udo; Brady, Thomas J.; Goehler, Alexander] Massachusetts Gen Hosp, Cardiac MR, PET, CT Program,Dept Radiol, Boston, MA 02114 USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Goehler, Alexander] UMIT Univ Hlth Sci Med Informat & Technol, Deptartment Publ Hlth Med Decis Making & Hlth Tec, Hall In Tirol, Austria. RP Goehler, A (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM alex@mgh-ita.org OI Wasem, Juergen/0000-0001-9653-168X FU German Competence Network Heart Failure; National Institute of Health [NIH R01 HL095123, K24 DK 064545, K23 HL 092792] FX This work was supported by the German Competence Network Heart Failure (stipend to JEHN) and the National Institute of Health (Ruth Kirschstein National Research Award T32 to AG, NIH R01 HL095123 and K24 DK 064545 to SKG, K23 HL 092792 to JL). NR 30 TC 3 Z9 3 U1 3 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 2047-4873 EI 2047-4881 J9 EUR J PREV CARDIOL JI Eur. J. Prev. Cardiol. PD AUG PY 2014 VL 21 IS 8 BP 972 EP 979 DI 10.1177/2047487313483607 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AM8YH UT WOS:000340164800006 PM 23539717 ER PT J AU DuBrock, HM Channick, RN AF DuBrock, Hilary M. Channick, Richard N. TI Macitentan for the treatment of pulmonary arterial hypertension SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Article DE endothelin receptor antagonist; macitentan; pulmonary arterial hypertension ID ENDOTHELIN RECEPTOR ANTAGONIST; HEALTHY-SUBJECTS; ETB-RECEPTOR; DOUBLE-BLIND; PHARMACOKINETICS; BOSENTAN; PHARMACODYNAMICS; PHARMACOLOGY; EFFICACY; HUMANS AB Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of symptomatic pulmonary arterial hypertension (PAH). Compared to other endothelin receptor antagonists, in vitro and in vivo studies have demonstrated that macitentan has improved tissue targeting, a longer duration of action and an improved safety profile. Macitentan is available as a once daily oral medication and has been well tolerated in clinical trials. The recently published Study with an Endothelin Receptor Antagonist in PAH to Improve cliNical Outcomes (SERAPHIN), which was the first event-driven trial ever done in PAH, also demonstrated the benefit of macitentan on reducing the likelihood of a composite endpoint of morbidity and mortality events without a significant difference in mortality. C1 [DuBrock, Hilary M.; Channick, Richard N.] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA. RP DuBrock, HM (reprint author), Massachusetts Gen Hosp, Div Pulm & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM hwomble@partners.org FU Actelion pharmaceuticals FX R Channick has received research grants from Actelion pharmaceuticals and has served as a consultant for Actelion. H DuBrock has no conflicts of interest to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. NR 36 TC 0 Z9 0 U1 0 U2 6 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD AUG PY 2014 VL 8 IS 4 BP 393 EP 399 DI 10.1586/17476348.2014.937708 PG 7 WC Respiratory System SC Respiratory System GA AM8OQ UT WOS:000340135800004 PM 24998329 ER PT J AU Shah, MM Dobbin, ZC Nowsheen, S Wielgos, M Katre, AA Alvarez, RD Konstantinopoulos, PA Yang, ES Landen, CN AF Shah, Monjri M. Dobbin, Zachary C. Nowsheen, Somaira Wielgos, Monica Katre, Ashwini A. Alvarez, Ronald D. Konstantinopoulos, Panagiotis A. Yang, Eddy S. Landen, Charles N. TI An ex vivo assay of XRT-induced Rad51 foci formation predicts response to PARP-inhibition in ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; PARP inhibitor; Homologous recombination deficiency; Rad51 ID IONIZING-RADIATION; SOMATIC MUTATIONS; DNA-DAMAGE; IN-VIVO; BRCA1; CELLS; TUMOR; REPAIR; CHEMOTHERAPY; SENSITIVITY AB Objective. BRCA-positive ovarian cancer patients derive benefit PARP inhibitors. Approximately 50% of ovarian cancer tumors have homologous recombination (HR) deficiencies and are therefore "BRCA-like," possibly rendering them sensitive to PARP inhibition. However, no predictive assay exists to identify these patients. We sought to determine if irradiation-induced Rad51 foci formation, a known marker of HR, correlated to PARP inhibitor response in an ovarian cancer model. Methods. Ovarian cancer cell lines were exposed to PARP-inhibitor ABT-888 to determine effect on growth. Rad51 protein expression prior to irradiation was determined via Western blot. Cultured cells and patient-derived xenograft tumors (PDX) were irradiated and probed for Rad51 foci. In vivo PDX tumors were treated with ABT-888 and carboplatin; these results were correlated with the ex vivo ionizing radiation assay. Results. Three of seven cell lines were sensitive to ABT-888. Sensitive lines had the lowest Rad51 foci formation rate after irradiation, indicating functional HR deficiency. Approximately 50% of the PDX samples had decreased Rad51 foci formation. Total Rad51 protein levels were consistently low, suggesting that DNA damage induction is required to characterize HR status. The ex vivo IR assay accurately predicted which PDX models were sensitive to PARP inhibition in vitro and in vivo. ABT-888 alone reduced orthotopic tumor growth by 51% in A2780ip2 cell line, predicted to respond by the ex vivo assay. Three PDX models' response also correlated with the assay. Conclusions. The ex vivo IR assay correlates with response to PARP inhibition. Analysis of total Rad51 protein is not a reliable substitute. (C) 2014 Elsevier Inc. All rights reserved. C1 [Shah, Monjri M.; Dobbin, Zachary C.; Katre, Ashwini A.; Alvarez, Ronald D.; Landen, Charles N.] Univ Alabama Birmingham, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Nowsheen, Somaira; Wielgos, Monica; Yang, Eddy S.] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL 35294 USA. [Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP Landen, CN (reprint author), Univ Alabama Birmingham, Dept Obstet & Gynecol, 176F RM 10250,619 19th St S, Birmingham, AL 35294 USA. EM clanden@uabmc.edu FU Southeast Cancer Foundation; University of Alabama at Birmingham Center for Clinical and Translational Science [5UL1RR025777] FX Funding support was provided in part by the Lewis-Moseley Award from the Southeast Cancer Foundation (to ESY and CNL) and the University of Alabama at Birmingham Center for Clinical and Translational Science (5UL1RR025777) to CNL. NR 32 TC 12 Z9 12 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 331 EP 337 DI 10.1016/j.ygyno.2014.05.009 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900022 PM 24844596 ER PT J AU Eskander, RN Osann, K Dickson, E Holman, LL Rauh-Hain, JA Spoozak, L Wu, EJ Krill, L Fader, AN Tewari, KS AF Eskander, Ramez N. Osann, Kathryn Dickson, Elizabeth Holman, Laura L. Rauh-Hain, J. Alejandro Spoozak, Lori Wu, Eijean Krill, Lauren Fader, Amanda Nickles Tewari, Krishnansu S. TI Assessment of palliative care training in gynecologic oncology: A gynecologic oncology fellow research network study SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Palliative care; Education; End of life care; Gynecologic cancer; Hospice; Fellowship training ID OF-LIFE CARE; END; CANCER; OUTCOMES AB Objective. Palliative care is recognized as an important component of oncologic care. We sought to assess the quality/quantity of palliative care education in gynecologic oncology fellowship. Methods. A self-administered on-line questionnaire was distributed to current gynecologic oncology fellow and candidate members during the 2013 academic year. Descriptive statistics, bivariate and multivariate analyses were performed. Results. Of 201 fellow and candidate members, 74.1% (n = 149) responded. Respondents were primarily women (75%) and white (76%). Only 11% of respondents participated in a palliative care rotation. Respondents rated the overall quality of teaching received on management of ovarian cancer significantly higher than management of patients at end of life (EOL), independent of level of training (8.25 vs. 6.23; p < 0.0005). Forty-six percent reported never being observed discussing transition of care from curative to palliative with a patient, and 56% never received feedback about technique regarding discussions on EOL care. When asked to recall their most recent patient who had died, 83% reported enrollment in hospice within 4 weeks of death. Fellows reporting higher quality EOL education were significantly more likely to feel prepared to care for patients at EOL (p < 0.0005). Mean ranking of preparedness increased with the number of times a fellow reported discussing changing goals from curative to palliative and the number of times he/she received feedback from an attending (p < 0.0005). Conclusions. Gynecologic oncology fellow/candidate members reported insufficient palliative care education. Those respondents reporting 'higher quality EOL training felt more prepared to care for dying patients and to address complications commonly encountered in this setting. (C) 2014 Elsevier Inc. All rights reserved. C1 [Eskander, Ramez N.; Krill, Lauren; Tewari, Krishnansu S.] Univ Calif Irvine, Dept Obstet & Gynecol, Div Gynecol Oncol, Orange, CA 92668 USA. [Osann, Kathryn] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Dickson, Elizabeth] Univ Minnesota, Dept Obstet & Gynecol, Div Gynecol Oncol, Minneapolis, MN 55455 USA. [Holman, Laura L.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, DC USA. [Rauh-Hain, J. Alejandro] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Gynecol Oncol, Boston, MA 02114 USA. [Spoozak, Lori] Albert Einstein Coll Med, Dept Obstet & Gynecol, Div Gynecol Oncol, Bronx, NY 10467 USA. [Wu, Eijean] Univ So Calif, Dept Obstet & Gynecol, Med Ctr, Div Gynecol Oncol, Los Angeles, CA 90089 USA. [Fader, Amanda Nickles] Johns Hopkins Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Baltimore, MD USA. RP Eskander, RN (reprint author), Dept Obstet & Gynecol, Div Gynecol Oncol, 101 City Dr South,Bldg 56,Suite 264, Orange, CA 92868 USA. EM Eskander@uci.edu FU NCI NIH HHS [T32 CA101642, P30 CA062203, T32 CA060396] NR 20 TC 7 Z9 7 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 379 EP 384 DI 10.1016/j.ygyno.2014.05.021 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900028 PM 24887355 ER PT J AU Burke, WM Orr, J Leitao, M Salom, E Gehrig, P Olawaiye, AB Brewer, M Boruta, D Villella, J Herzog, T Abu Shahin, F AF Burke, William M. Orr, James Leitao, Mario Salom, Emery Gehrig, Paola Olawaiye, Alexander B. Brewer, Molly Boruta, Dave Villella, Jeanine Herzog, Tom Abu Shahin, Fadi CA SGO Clinical Practice Endometrial Soc Gynecologic Oncology Clinical TI Endometrial cancer: A review and current management strategies: Part I SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Endometrial cancer; Review; Surgery; Diagnosis; Risk factors; Evaluation ID GYNECOLOGIC-ONCOLOGY-GROUP; PORT-SITE METASTASES; UTERINE-CANCER; ABDOMINAL HYSTERECTOMY; PREOPERATIVE EVALUATION; SURGICAL CYTOREDUCTION; PELVIC LYMPHADENECTOMY; VAGINAL HYSTERECTOMY; COMPUTED-TOMOGRAPHY; RADIATION-THERAPY AB Endometrial carcinoma is the most common gynecologic malignancy. A thorough understanding of the epidemiology, pathophysiology, and management strategies for this cancer allows the obstetrician-gynecologist to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. The Society of Gynecologic Oncology's Clinical Practice Committee has reviewed the literature and created evidence-based practice recommendations for diagnosis and treatment. This article examines: Risk factors, including genetic predisposition Diagnostic and metastatic evaluation Surgical management of early and advanced cancer, including lymphadenectomy in early cancer. (C) 2014 Elsevier Inc. All rights reserved. C1 [Burke, William M.] Valley Hosp, Div Gynecol Oncol, Paramus, NJ USA. [Burke, William M.] Columbia Univ, Med Ctr, New York, NY USA. [Orr, James] Florida Gynecol Oncol, Ft Myers, FL USA. [Leitao, Mario] Mem Sloan Kettering Canc Ctr, Gynecol Serv, New York, NY 10021 USA. [Salom, Emery] Florida Int Univ, Div Gynecol Oncol, Miami, FL 33199 USA. [Gehrig, Paola] Univ N Carolina, Div Gynecol Oncol, Chapel Hill, NC USA. [Olawaiye, Alexander B.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Brewer, Molly] Univ Connecticut, Ctr Hlth, Carole & Ray Neag Comprehens Canc Ctr, Div Gynecol Oncol, Farmington, CT USA. [Boruta, Dave] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Villella, Jeanine] Winthrop Univ Hosp, Div Gynecol Oncol, Long Isl City, NY USA. [Villella, Jeanine] SUNY Stony Brook, Sch Med, Div Gynecol Oncol, Long Isl City, NY USA. [Herzog, Tom] Columbia Univ, Med Ctr, Div Gynecol Oncol, New York, NY USA. [Abu Shahin, Fadi] Florida Gynecol Oncol, Ft Myers, FL USA. RP Burke, WM (reprint author), One Valley Hlth Plaza, Paramus, NJ 07652 USA. EM wmb7@columbia.edu FU Society of Gynecologic Oncology (SGO) FX Manuscript editing was funded by the Society of Gynecologic Oncology (SGO). NR 73 TC 56 Z9 58 U1 9 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 385 EP 392 DI 10.1016/j.ygyno.2014.05.018 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900029 ER PT J AU Burke, WM Orr, J Leitao, M Salom, E Gehrig, P Olawaiye, AB Brewer, M Boruta, D Herzog, TJ Abu Shahin, F AF Burke, William M. Orr, James Leitao, Mario Salom, Emery Gehrig, Paola Olawaiye, Alexander B. Brewer, Molly Boruta, Dave Herzog, Thomas J. Abu Shahin, Fadi CA SGO Clinical Practice Endometrial Soc Gynecologic Oncology Clinical TI Endometrial cancer: A review and current management strategies: Part II SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Endometrial cancer; Radiation; Chemotherapy; Hormones; Fertility; Surveillance ID GYNECOLOGIC-ONCOLOGY-GROUP; PAPILLARY SEROUS CARCINOMA; MULTIMODALITY ADJUVANT CHEMOTHERAPY; FERTILITY-SPARING TREATMENT; PLATINUM-BASED CHEMOTHERAPY; EXTERNAL-BEAM RADIOTHERAPY; RADIATION-THERAPY; LYNCH-SYNDROME; YOUNG-WOMEN; INTERMEDIATE-RISK AB Endometrial carcinoma is the most common gynecologic malignancy. A thorough understanding of the epidemiology, pathophysiology, and management strategies for this cancer allows the obstetrician gynecologist to identify women at increased risk, contribute toward risk reduction, and facilitate early diagnosis. The Society of Gynecologic Oncology's Clinical Practice Committee has reviewed the literature through March of 2014 and created evidence-based practice recommendations for diagnosis and treatment. The level of recommendations used is based on the method used by the U.S. Preventive Services Task Force (A: There is good evidence to support the recommendation, B: There is fair evidence to support the recommendation, C: There is insufficient evidence to support the recommendation; however, the recommendation may be made on other grounds, D: There is fair evidence against the recommendation, E: There is good evidence against the recommendation.). It is not the purpose of this document to provide a complete review of the literature on all aspects of endometrial cancer. This article examines: Adjuvant therapy, including radiation, vaginal brachytherapy, and chemotherapy Therapy for advanced disease, including chemotherapy and radiation therapy alone and in combination as well as hormone therapy Treatment for synchronous endometrial and ovarian cancer Fertility-sparing treatment Post-treatment patient surveillance The role of hormone replacement therapy in the development of endometrial carcinoma Novel targeted therapies. (C) 2014 Elsevier Inc. All rights reserved. C1 [Burke, William M.] Valley Hosp, Div Gynecol Oncol, Paramus, NJ USA. [Burke, William M.] Columbia Univ, Med Ctr, New York, NY USA. [Orr, James; Abu Shahin, Fadi] Florida Gynecol Oncol, Ft Myers, FL USA. [Leitao, Mario] Mem Sloan Kettering Canc Ctr, Gynecol Serv, New York, NY 10021 USA. [Salom, Emery] Florida Int Univ, Div Gynecol Oncol, Miami, FL 33199 USA. [Gehrig, Paola] Univ N Carolina, Div Gynecol Oncol, Chapel Hill, NC USA. [Olawaiye, Alexander B.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [Brewer, Molly] Univ Connecticut, Ctr Hlth, Carole & Ray Neag Comprehens Canc Ctr, Div Gynecol Oncol, Farmington, CT USA. [Boruta, Dave] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Herzog, Thomas J.] Columbia Univ, Med Ctr, Div Gynecol Oncol, New York, NY USA. RP Burke, WM (reprint author), One Valley Hlth Plaza, Paramus, NJ 07652 USA. EM wmb7@columbia.edu RI Burke, William/C-1203-2012 FU Society of Gynecologic Oncology (SGO) FX Manuscript editing was funded by the Society of Gynecologic Oncology (SGO). NR 71 TC 29 Z9 30 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 393 EP 402 DI 10.1016/j.ygyno.2014.06.003 PG 10 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900030 ER PT J AU Mirabeau-Beale, KL Viswanathan, AN AF Mirabeau-Beale, Kristina L. Viswanathan, Akila N. TI Quality of life (QOL) in women treated for gynecologic malignancies with radiation therapy: A literature review of patient - reported outcomes SO GYNECOLOGIC ONCOLOGY LA English DT Review DE Quality of life; Sexual dysfunction; Endometrial cancer; Cervical cancer; Vulvar cancer ID LONG-TERM SURVIVORS; ADVANCED CERVICAL-CARCINOMA; CANCER SURVIVORS; ENDOMETRIAL CARCINOMA; SEXUAL FUNCTION; EUROPEAN-ORGANIZATION; VAGINAL BRACHYTHERAPY; TREATMENT-MODALITIES; RANDOMIZED-TRIAL; ONCOLOGY-GROUP AB Objective. To summarize the literature on quality of life for patients treated with definitive radiation for gynecologic cancers, with a specific focus on patient reported outcomes. Methods. A literature review was performed to summarize studies about patient-reported outcomes and quality of life in women with gynecologic malignancies who were treated with definitive radiation therapy. Summaries are by disease site, including endometrial, cervical and vulvar cancers. Results. Over 20 different survey instruments have been used to describe patient-reported outcomes for women treated with radiation for gynecologic cancer. Regardless of disease site, all patients describe a degree of compromise in physical and social functioning, as well as sexual dysfunction. Specific symptoms which are most bothersome for patients vary by disease site, such as bowel concerns predominating for endometrial cancer patients, while body image is more concerning for cervical cancer patients. Conclusions. Several quality of life concerns exist for women treated with radiation therapy for gynecologic malignancies. Significant overlap exists in the QOL issues affecting these patients. Whether to combine or separate surveys by diagnosis, treatment type, age, or time point should be explored further. Assessing patients' psychological, emotional, and physical concerns helps to understand long-term adjustment, enabling incorporation of these domains into future trials that will ultimately improve patient well-being. (C) 2014 Elsevier Inc All rights reserved. C1 [Mirabeau-Beale, Kristina L.] Harvard Radiat Oncol Program, Boston, MA USA. [Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mirabeau-Beale, KL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM kmirabeau-beale@partners.org FU NIH [R21 167800] FX Thank you to Barbara Silver for review of this manuscript. Dr Viswanathan receives funding through NIH R21 167800. NR 57 TC 12 Z9 12 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 403 EP 409 DI 10.1016/j.ygyno.2014.05.008 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900031 PM 24844593 ER PT J AU Myers, A Barry, WT Hirsch, MS Matulonis, U Lee, L AF Myers, Andrea Barry, William T. Hirsch, Michelle S. Matulonis, Ursula Lee, Larissa TI beta-Catenin mutations in recurrent FIGO IA grade I endometrioid endometrial cancers SO GYNECOLOGIC ONCOLOGY LA English DT Letter C1 [Myers, Andrea; Matulonis, Ursula] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Barry, William T.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Hirsch, Michelle S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lee, Larissa] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. RP Lee, L (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM llee@lroc.harvard.edu NR 5 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 BP 426 EP 427 DI 10.1016/j.ygyno.2014.06.010 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900034 PM 24952365 ER PT J AU Esselen, K Wright, A Kim, J Horowitz, N AF Esselen, K. Wright, A. Kim, J. Horowitz, N. TI Multiple lines of chemotherapy in recurrent epithelial ovarian cancer, are more lines better? A decision analytic model SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Esselen, K.; Horowitz, N.] Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Esselen, K.; Wright, A.; Horowitz, N.] Harvard Univ, Sch Med, Boston, MA USA. [Wright, A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, J.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Hlth Decis Sci, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 EI 1095-6859 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD AUG PY 2014 VL 134 IS 2 MA 6 BP 431 EP 432 DI 10.1016/j.ygyno.2014.04.024 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA AN0YM UT WOS:000340309900045 ER EF